Enteroaggregative Escherichia coli in mid-Norway: A prospective, case control study.

BACKGROUND: The use of molecular methods has led to increased detection of Enteroaggregative Escherichia coli (EAEC) in faecal samples. Studies have yielded conflicting results regarding the clinical relevance of this finding. The objective of this study was to investigate the prevalence of EAEC in faecal samples from patients with diarrhoea and healthy controls and describe characteristics of EAEC positive persons. METHODS: From March 1st, 2017 to February 28th, 2019, we investigated all consecutive faecal samples from patients with diarrhoea received at the laboratory and collected faecal samples from randomly invited healthy controls from mid-Norway. Real-time multiplex PCR was used for detection of bacterial, viral, and parasitic pathogens. We registered sex, age, urban versus non-urban residency, and travel history for all participants. Statistical analyses were performed with Pearson chi-squared test, Kruskal-Wallis test, and Mann-Whitney U test. RESULTS: We identified EAEC in 440 of 9487 (4.6%) patients with diarrhoea and 8 of 375 (2.2%) healthy controls. The EAEC prevalence was 19.1% among those with diarrhoea and recent foreign travel and 2.2% in those without travel history independent of diarrhoea. Concomitant pathogens were detected in 64.3% of EAEC-positive patients with diarrhoea. The median age was 28.5 in those with EAEC-positive diarrhoea and 38 in those with EAEC-negative diarrhoea (p <0.01). In patients with diarrhoea, travel was reported in 72% of those with EAEC and concomitant pathogens, and 54% and 12% in those with only EAEC and no EAEC, respectively (p <0.01). CONCLUSIONS: EAEC was a common detection, particularly in patients with diarrhoea and recent international travel, and was found together with other intestinal pathogens in the majority of cases. Our results suggest that domestically acquired EAEC is not associated with diarrhoea. Patients with EAEC-positive diarrhoea and concomitant pathogens were young and often reported recent travel history compared to other patients with diarrhoea.

Filaggrin Mutation Status and Prevention of Atopic Dermatitis with Maternal Probiotic Supplementation.

The World Allergy Organization recommends probiotics in the prevention of atopic dermatitis in high-risk populations. Mutations in the filaggrin gene (FLG) result in an increased risk of atopic dermatitis through disruption of the skin keratin layer. This exploratory study investigated whether the preventive effect of maternal probiotics was evident in children with and without FLG mutations. DNA was collected from children (n = 228) from the Probiotic in the Prevention of Allergy among Children in Trondheim (ProPACT) study. Samples were analysed for 3 common FLG mutations (R501X, R2447X, and 2282del4). Overall, 7% of children had heterozygous FLG mutations; each child had only one of the 3 mutations. Mutation status had no association with atopic dermatitis (RR = 1.1; 95% CI 0.5 to 2.3). The risk ratio (RR) for having atopic dermatitis following maternal probiotics was 0.6 (95% CI 0.4 to 0.9) and RR was similar if the child expressed an FLG mutation (RR = 0.6; 95% CI 0.1 to 4.1) or wildtype FLG (RR = 0.6; 95% CI 0.4 to 0.9). The preventive  effect of probiotics for atopic dermatitis was also evident in children without FLG mutation. Larger confirmatory studies are needed.

Childbirth experiences in women with polycystic ovary syndrome: A cohort study.

INTRODUCTION: Women with polycystic ovary syndrome (PCOS) have more pregnancy complications like gestational diabetes, hypertension, and preterm labor than other women. Metformin has been used in an attempt to improve pregnancy outcomes. Our study aims to explore childbirth experiences in women with PCOS compared with a reference population. It also explores the potential influence of metformin, obesity, pregnancy complications, and the duration and mode of birth on childbirth experiences. MATERIAL AND METHODS: This study is a cohort study combining data from two randomized trials conducted in Norway, Sweden and Iceland. The PregMet2 study (ClinicalTrials.gov, NCT01587378) investigated the use of metformin vs. placebo in pregnant women with PCOS. The Labour Progression Study (ClinicalTrials.gov, NCT02221427) compared the WHO partograph to Zhang's guidelines for progression of labor and were used as the reference population. A total of 365 women with PCOS and 3604 reference women were included. Both studies used the Childbirth Experience Questionnaire (CEQ). Main outcome measures were total CEQ score and four domain scores. The CEQ scores were compared using Mann-Whitney U test for women in Robson group 1 with PCOS (n = 131) and reference women (n = 3604). CEQ scores were also compared between metformin-treated (n = 180) and placebo-treated (n = 185) women with PCOS, and for different subgroups of women with PCOS. RESULTS: There was no difference in total CEQ score between women with PCOS and reference women-Wilcoxon-Mann-Whitney (WMW)-odds 0.96 (95% confidence interval [CI] 0.78-1.17). We detected no difference in CEQ scores between the metformin- and placebo-treated women with PCOS (WMW-odds 1.13, 95% CI 0.89-1.43). Complications in pregnancy did not affect CEQ (WMW-odds 1, 95% CI 0.76-1.31). Higher body mass index (WMW-odds 0.75, 95% CI 0.58-0.96), longer duration of labor (WMW-odds 0.69, 95% CI 0.49-0.96), and cesarean section (WMW-odds 0.29, 95% CI 0.2-0.42) were associated with lower CEQ scores in women with PCOS. CONCLUSIONS: Women with PCOS experience childbirth similarly to the reference women. Metformin did not influence childbirth experience in women with PCOS, neither did pregnancy complications. Obesity, long duration of labor or cesarean section had a negative impact on childbirth experience.

Anthropometrics of neonates born to mothers with PCOS with metformin or placebo exposure in utero.

INTRODUCTION: Fetal growth may be affected by both maternal polycystic ovary syndrome (PCOS) and metformin therapy. Here, we explore the effect of intrauterine metformin exposure on birth anthropometrics of infants born to women with PCOS. We also investigated whether the effect of metformin on birth anthropometrics is modified by maternal pre-pregnancy body mass index, PCOS hyperandrogenic phenotype, serum androgen levels, preconception use of metformin and offspring sex. Additionally, we assessed newborn anthropometrics in relation to a national reference population. MATERIAL AND METHODS: Individual data from three randomized controlled triasl were pooled. The randomized controlled trials investigated the effects of metformin in pregnant women with PCOS. In all, 397 and 403 were randomized to the metformin and placebo groups, respectively. A Scandinavian growth reference was used to calculate sex and gestational age adjusted z-scores. Linear regression models were used to estimate the effect of metformin on offspring z-scores of head circumference, birth length, birthweight, placental weight, body mass index, ponderal index and birthweight:placental weight ratio. S-testosterone, s-androstenedione, and s-sex-hormone binding globulin from four timepoints in pregnancy were analyzed. RESULTS: Compared with the PCOS-placebo group, newborns in the PCOS-metformin group had larger head circumference (head circumference z-score: mean difference = 0.25, 95% CI = 0.11- 0.40). This effect of metformin on head circumference z-score was particularly observed among offspring of overweight/obese mothers and mothers with hyperandrogenic PCOS-phenotype. We observed no difference in other anthropometric measures between the metformin and placebo groups or any clear interaction between maternal androgen levels and metformin. Newborns in the PCOS-placebo group were shorter than in the reference population (birth length z-score: mean = -0.04, 95% CI = -0.05 to -0.03), but head circumference and birthweight were similar. CONCLUSIONS: Larger head circumference was observed at birth in metformin-exposed offspring of mothers with PCOS. PCOS-offspring were also shorter, with a similar birthweight to the reference population, indirectly indicating higher weight-to-height ratio at birth.

App-Delivered Cognitive-Behavioral Therapy for Insomnia Among Patients with Comorbid Musculoskeletal Complaints and Insomnia Referred to 4-Week Inpatient Multimodal Rehabilitation: Protocol for a Randomized Clinical Trial.

Background: Insomnia is prevalent among patients receiving treatment for long-term musculoskeletal complaints in inpatient rehabilitation settings. Cognitive-behavioral therapy for insomnia (CBT-I) is effective for improving sleep quality in patients with pain, but a lack of therapists often limits the capacity to use this therapy in rehabilitation programs. The aim of this randomized clinical trial (RCT) is to evaluate the effectiveness of app-delivered CBT-I adjunct to inpatient multimodal rehabilitation for individuals with comorbid musculoskeletal complaints and insomnia, compared with rehabilitation (usual care) only. Methods: This RCT has two parallel arms: 1) inpatient multimodal rehabilitation and 2) app-delivered CBT-I adjunct to inpatient multimodal rehabilitation. Patients referred to Unicare Helsefort (Norway) with long-term chronic musculoskeletal complaints are invited to the study. Eligible and consenting participants will be randomized to the intervention and usual care at a ratio of 2:1. Assessments will be carried out at baseline (prior to randomization), 6 weeks (at the end of rehabilitation), 3 months (primary outcome), as well as 6 and 12 months after the rehabilitation. The primary outcome is insomnia severity measured at 3 months. Secondary outcomes include pain intensity, health-related quality of life, fatigue, physical function, work ability, expectations about sick leave length, sick leave, and prescribed medication. Exploratory analyses are planned to identify moderators and mediators of the effect of the app-delivered intervention. Discussion: This RCT will provide novel knowledge about the effectiveness of app-delivered CBT-I as an adjunct to usual care among patients participating in inpatient multimodal pain rehabilitation. Regardless of the results from this trial, the results will improve our understanding of the utility of dCBT-I in the field of rehabilitation and the importance of adding sleep therapy to this patient group. Trial Registration: This trial was prospectively registered in ClinicalTrials.gov October 10, 2022 (ClinicalTrials.gov identifier: NCT05572697).

Randomised controlled trial of exercise training during lactation on breast milk composition in breastfeeding people with overweight/obesity: a study protocol for the MILKSHAKE trial.

Breast milk from people with overweight/obesity may differ in composition compared with that from normal-weight people. Exercise training can modify breast milk composition in rodent models, with a beneficial impact demonstrated on the offspring's metabolism, but whether these findings translate to humans is unclear. This trial aims to determine the effect of an exercise intervention on breast milk composition and whether an exercise-induced modification of breast milk impacts the infants' growth and body composition. Effect of Exercise Training on Breastmilk Composition is a randomised, controlled trial with two parallel groups, one exercise group and one control group, with a 1:1 allocation. We will include a minimum of 62 exclusively breastfeeding participants, 6 weeks postpartum. The exercise intervention lasts 8 weeks and comprises 25 supervised endurance exercise sessions with moderate or high intensity. The primary outcome measure is the change in the relative concentration of the human milk oligosaccharide 3'sialyllactose in breast milk from baseline at 6 weeks postpartum to the end of the intervention period. Secondary outcomes include breast milk concentrations of other metabolites, cytokines, hormones and microRNA, maternal health outcomes, infant growth, infant gut microbiome and infant circulating microRNA. Maternal and infant outcomes will be measured before, during and after the intervention period, with a follow-up of the infants until they are 24 months old. Trial registration number NCT05488964.

Intranasal analgesia for acute moderate to severe pain in children - a systematic review and meta-analysis.

BACKGROUND: Children in acute pain often receive inadequate pain relief, partly from difficulties administering injectable analgesics. A rapid-acting, intranasal (IN) analgesic may be an alternative to other parenteral routes of administration. Our review compares the efficacy, safety, and acceptability of intranasal analgesia to intravenous (IV) and intramuscular (IM) administration; and to compare different intranasal agents. METHODS: We searched Cochrane Library, MEDLINE/PubMed, Embase, Web of Knowledge, Clinicaltrials.gov, Controlled-trials.com/mrcr, Clinicaltrialsregister.eu, Apps.who.int/trialsearch. We also screened reference lists of included trials and relevant systematic reviews. Studies in English from any year were included. Two authors independently assessed all studies. We included randomised trials (RCTs) of children 0-16, with moderate to severe pain; comparing intranasal analgesia to intravenous or intramuscular analgesia, or to other intranasal agents. We excluded studies of procedural sedation or analgesia. We extracted study characteristics and outcome data and assessed risk of bias with the ROB 2.0-tool. We conducted meta-analysis and narrative review, evaluating the certainty of evidence using GRADE. Outcomes included pain reduction, adverse events, acceptability, rescue medication, ease of and time to administration. RESULTS: We included 12 RCTs with a total of 1163 children aged 3 to 20, most below 10 years old, with a variety of conditions. Our review shows that: - There may be little or no difference in pain relief (single dose IN vs IV fentanyl MD 4 mm, 95% CI -8 to 16 at 30 min by 100 mm VAS; multiple doses IN vs IV fentanyl MD 0, 95%CI -0.35 to 0.35 at 15 min by Hannallah score; single dose IN vs IV ketorolac MD 0.8, 95% CI -0.4 to 1.9 by Faces Pain Scale-Revised), adverse events (single dose IN vs IV fentanyl RR 3.09, 95% CI 0.34 to 28.28; multiple doses IN vs IV fentanyl RR 1.50, 95%CI 0.29 to 7.81); single dose IN vs IV ketorolac RR 0.716, 95% CI 0.23 to 2.26), or acceptability (single dose IN vs IV ketorolac RR 0.83, 95% CI 0.66 to 1.04) between intranasal and intravenous analgesia (low certainty evidence). - Intranasal diamorphine or fentanyl probably give similar pain relief to intramuscular morphine (narrative review), and are probably more acceptable (RR 1.60, 95% CI 1.42 to 1.81) and tolerated better (RR 0.061, 95% CI 0.03 to 0.13 for uncooperative/negative reaction) (moderate certainty); adverse events may be similar (narrative review) (low certainty). - Intranasal ketamine gives similar pain relief to intranasal fentanyl (SMD 0.05, 95% CI -0.20 to 0.29 at 30 min), while having a higher risk of light sedation (RR 1.74, 95% CI 1.30 to 2.35) and mild side effects (RR 2.16, 95% CI 1.72 to 2.71) (high certainty). Need for rescue analgesia is probably similar (RR 0.85, 95% CI 0.62 to 1.17) (moderate certainty), and acceptability may be similar (RR 1.15, 95% CI 0.89 to 1.48) (low certainty). CONCLUSIONS: Our review suggests that intranasal analgesics are probably a good alternative to intramuscular analgesics in children with acute moderate to severe pain; and may be an alternative to intravenous administration. Intranasal ketamine gives similar pain relief to fentanyl, but causes more sedation, which should inform the choice of intranasal agent.

Systemic inflammatory proteins in offspring following maternal probiotic supplementation for atopic dermatitis prevention.

BACKGROUND: Maternal probiotic supplementation has a promising effect on atopic dermatitis (AD) prevention in infancy. In the randomised controlled study, Probiotics in the Prevention of Allergy among Children in Trondheim (ProPACT), maternal probiotics reduced the cumulative incidence of AD in their offspring by 40% at 2 years of age. However, our understanding on how probiotics prevented AD is still limited, and the role of inflammatory proteins in infants following maternal probiotic supplementation is unclear. We hypothesised that maternal probiotics lowered pro-inflammatory proteins and increased anti-inflammatory proteins in their 2-year-old children as a mechanism of AD prevention. We aimed to explore this hypothesis and the association between these proteins and the presence of AD, severity of AD, and the degree of preventive effect of probiotics. METHODS: Plasma samples were collected from 2-year-old children (n = 202) during the ProPACT study, a randomised placebo-controlled trial of maternal probiotic supplementation. These samples were analysed for 92 inflammatory proteins using a multiplex proximity extension assay. Associations between inflammatory proteins and the presence and severity of AD, and the degree of preventive effect, was estimated individually using regression analysis and then collectively using unsupervised cluster analysis. RESULTS: Several proteins were observed to differ between the groups. The probiotic group had lower CCL11 and IL-17C, while children with AD had higher IL-17C, MCP-4, uPA, and CD6. Cytokine CCL20 and IL-18 had moderate correlation (r = 0.35 and r = 0.46) with the severity of AD. The cluster analysis revealed that children in the cluster of samples with the highest value of immune checkpoint receptors and inflammatory suppressor enzymes showed the greatest AD preventive effect from probiotics. CONCLUSIONS: The proteins associated with both maternal probiotic supplementation and the presence and severity of AD warrant attention because of their potential biological relevance. Cluster analysis may provide a new insight when considering which subgroups benefit from probiotic supplementation. Larger studies are needed to confirm the results. TRIAL REGISTRATION NUMBER: The study was retrospectively registered at ClinicalTrials.gov (NCT00159523) on 12nd September 2005.

Breast milk microRNAs: Potential players in oral tolerance development.

Breast milk is an essential source of nutrition and hydration for the infant. In addition, this highly complex biological fluid contains numerous immunologically active factors such as microorganisms, immunoglobulins, cytokines and microRNAs (miRNAs). Here, we set out to predict the function of the top 10 expressed miRNAs in human breast milk, focusing on their relevance in oral tolerance development and allergy prevention in the infant. The top expressed miRNAs in human breast milk were identified on basis of previous peer-reviewed studies gathered from a recent systematic review and an updated literature search. The miRNAs with the highest expression levels in each study were used to identify the 10 most common miRNAs or miRNA families across studies and these were selected for subsequent target prediction. The predictions were performed using TargetScan in combination with the Database for Annotation, Visualization and Integrated Discovery. The ten top expressed miRNAs were: let-7-5p family, miR-148a-3p, miR-30-5p family, miR-200a-3p + miR-141-3p, miR-22-3p, miR-181-5p family, miR-146b-5p, miR-378a-3p, miR-29-3p family, miR-200b/c-3p and miR-429-3p. The target prediction identified 3,588 potential target genes and 127 Kyoto Encyclopedia of Genes and Genomes pathways; several connected to the immune system, including TGF-b and T cell receptor signaling and T-helper cell differentiation. This review highlights the role of breast milk miRNAs and their potential contribution to infant immune maturation. Indeed, breast milk miRNAs seem to be involved in several pathways that influence oral tolerance development.

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.

Modified prolonged exposure therapy as Early Intervention after Rape (The EIR-study): study protocol for a multicenter randomized add-on superiority trial.

BACKGROUND: Sexual assault and rape are the traumatic life events with the highest probability for posttraumatic stress disorder (PTSD), which can have devastating consequences for those afflicted by the condition. Studies indicate that modified prolonged exposure (mPE) therapy may be effective in preventing the development of PTSD in recently traumatized individuals, and especially for people who have experienced sexual assault. If a brief, manualized early intervention can prevent or reduce post-traumatic symptoms in women who have recently experienced rape, healthcare services targeted for these populations (i.e., sexual assault centers, SACs) should consider implementing such interventions as part of routine care. METHODS/DESIGN: This is a multicenter randomized controlled add-on superiority trial that enrolls patients attending sexual assault centers within 72 h after rape or attempted rape. The objective is to assess whether mPE shortly after rape can prevent the development of post-traumatic stress symptoms. Patients will be randomized to either mPE plus treatment as usual (TAU) or TAU alone. The primary outcome is the development of post-traumatic stress symptoms 3 months after trauma. Secondary outcomes will be symptoms of depression, sleep difficulties, pelvic floor hyperactivity, and sexual dysfunction. The first 22 subjects will constitute an internal pilot trial to test acceptance of the intervention and feasibility of the assessment battery. DISCUSSION: This study will guide further research and clinical initiatives for implementing strategies for preventing post-traumatic stress symptoms after rape and provide new knowledge about which women may benefit the most from such initiatives and for revising existing treatment guidelines within this area. TRIAL REGISTRATION: ClinicalTrials.gov NCT05489133. Registered on 3 August 2022.

Differences in gastrointestinal hormones and appetite ratings between individuals with and without obesity-A systematic review and meta-analysis.

Determining if gastrointestinal (GI) hormone response to food intake differs between individuals with, and without, obesity may improve our understanding of obesity pathophysiology. A systematic review and meta-analysis of studies assessing the concentrations of GI hormones, as well as appetite ratings, following a test meal, in individuals with and without obesity was undertaken. Systematic searches were conducted in the databases MEDLINE, Embase, Cochrane Library, PsycINFO, Web of Science, and ClinicalTrials.gov. A total of 7514 unique articles were retrieved, 115 included in the systematic review, and 70 in the meta-analysis. The meta-analysis compared estimated standardized mean difference in GI hormones' concentration, as well as appetite ratings, between individuals with and without obesity. Basal and postprandial total ghrelin concentrations were lower in individuals with obesity compared with controls, and this was reflected by lower postprandial hunger ratings in the former. Individuals with obesity had a lower postprandial concentration of total peptide YY compared with controls, but no significant differences were found for glucagon-like peptide 1, cholecystokinin, or other appetite ratings. A large methodological and statistical heterogeneity among studies was found. More comprehensive studies are needed to understand if the differences observed are a cause or a consequence of obesity.

Insights into the quantification and reporting of model-related uncertainty across different disciplines.

Quantifying uncertainty associated with our models is the only way we can express how much we know about any phenomenon. Incomplete consideration of model-based uncertainties can lead to overstated conclusions with real-world impacts in diverse spheres, including conservation, epidemiology, climate science, and policy. Despite these potentially damaging consequences, we still know little about how different fields quantify and report uncertainty. We introduce the "sources of uncertainty" framework, using it to conduct a systematic audit of model-related uncertainty quantification from seven scientific fields, spanning the biological, physical, and political sciences. Our interdisciplinary audit shows no field fully considers all possible sources of uncertainty, but each has its own best practices alongside shared outstanding challenges. We make ten easy-to-implement recommendations to improve the consistency, completeness, and clarity of reporting on model-related uncertainty. These recommendations serve as a guide to best practices across scientific fields and expand our toolbox for high-quality research.

Trends in use of specialized formula for managing cow's milk allergy in young children.

BACKGROUND: Excessive use of specialized formula for cow's milk allergy was reported in England, but complete analysis has not been undertaken and trends in other countries are unknown. Some specialized formula products, especially amino-acid formula (AAF), have high free sugars content. We evaluated specialized formula trends in countries with public databases documenting national prescription rates. METHODS: Cross-sectional analysis of national prescription databases in the United Kingdom, Norway and Australia. Outcomes were volume and cost of specialized formula, and proportion of infants prescribed specialized formula. Expected volumes assumed 1% cow's milk allergy incidence and similar formula feeding rates between infants with and without milk allergy. RESULTS: Prescribed volumes of specialized formula for infants rose 2.8-fold in England from 2007 to 2018, with similar trends in other regions of the United Kingdom. Volumes rose 2.2-fold in Norway from 2009 to 2020 and 3.2-fold in Australia from 2001 to 2012. In 2020, total volumes were 9.7- to 12.6-fold greater than expected in England, 8.3- to 15.6-fold greater than expected in Norway and 3.3- to 4.5-fold greater than expected in Australia, where prescribing restrictions were introduced in 2012. In Norway, the proportion of infants prescribed specialized formula increased from 2.2% in 2009 to 6.9% in 2020, or 11.2- to 13.3-fold greater than expected. In 2020, specialized formula for infants cost US$117 (103 euro) per birth in England, US$93 (82 euro) in Norway and US$27 (23 euro) in Australia. Soya formula prescriptions exceeded expected volumes 5.5- to 6.4-fold in England in 1994 and subsequently declined, co-incident with public health concerns regarding soya formula safety. In 2020, 30%-50% of prescribed specialized formula across the three countries was AAF. CONCLUSIONS: In England, Norway and Australia, specialized formula prescriptions increased in the early 21st century and exceeded expected levels. Unnecessary specialized formula use may make a significant contribution to free sugars consumption in young children.

Non-Coding RNAs in Human Breast Milk: A Systematic Review.

Breast milk is the primary source of nutrition and hydration for the newborn infant but also plays an important role in the child's first immune defense. Additionally, several breast milk factors have been implicated in immune-related health outcomes later in life, including immunoglobulins, cytokines, chemokines, growth factors and, more recently, non-coding RNA (ncRNA) species. In this systematic review, we provide a comprehensive summary of the current literature on endogenous ncRNAs found in human breast milk. Thirty (30) relevant studies were identified and, whilst the majority studies focused on microRNAs (miRNAs), there is evidence that breast milk contains high quantities of RNA which also include long-coding RNAs, circular RNAs, as well as other short RNAs and fragmented tRNA and rRNAs. Among studies investigating miRNAs, miR-148a-3p, miR-30a/d-5p, miR-22-3p, miR-146b-5p, miR-200a/c-3p, and the 5p end of the let-7 miRNAs were commonly reported among the top 10 miRNAs in the cell, lipid, and skim milk fractions of breast milk. Methodological difference and small sample sizes limit the possibility of conclusively identifying which maternal and infant characteristics affect the miRNA profile. The highly expressed miRNAs were generally reported to be similar across lactational stage, milk fraction, maternal and infant characteristics, or infant growth and health. All the same, individual studies identify potential differences in miRNA expression levels which should be confirmed by future studies. Stability, uptake, and physiological functions of miRNAs were also considered in several studies. Breast milk miRNAs are relatively resistant to a range of harsh conditions and uptake experiments suggest that extracellular vesicles containing miRNAs and circular RNAs can be taken up by intestinal epithelial cells. Although the evidence regarding the functional effect of breast milk miRNAs is limited, the predicted functions range from metabolic and biosynthetic processes to signaling pathways, cellular adhesion, communication, growth, and differentiation. Finally, this systematic review highlights some of the methodological challenges and knowledge gaps which can help direct future research in this field. In particular, it is important to further investigate the bioavailability of miRNAs in different milk fractions, and to characterize other ncRNAs which are largely unstudied. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=138989, identifier CRD42020138989.

Allergy-related diseases and early gut fungal and bacterial microbiota abundances in children.

BACKGROUND: The early gut microbiota has been proposed as an important link between environmental exposures and development of allergy-related diseases. Beyond the widely investigated associations between the gut bacterial microbiota, we investigated the involvement of early gut mycobiota and gut permeability in the pathogenesis of asthma, allergic rhinoconjunctivitis (AR) and eczema. METHODS: In the Probiotics in the Prevention of Allergy among Children in Trondheim trial with maternal probiotic supplementation, we collected faecal samples at four timepoints between 0 and 2 years from a cohort of 278 children. Clinical information on allergy-related diseases was collected in a paediatric examination at 2 years and questionnaires at 6 weeks and 1, 2 and 6 years. By quantitative PCR and 16S/ITS1 MiSeq rRNA gene sequencing, we analysed the gut bacterial and fungal microbiota abundance and bacterial diversity and explored associations with allergy-related diseases. We also measured gut permeability markers (lipopolysaccharide-binding protein [LBP] and fatty acid-binding protein 2 [FABP2]). RESULTS: Children with higher fungal abundance at 2 years were more likely to develop asthma and AR by 6 years, odds ratios 1.70 (95% CI: 1.06-2.75) and 1.41 (1.03-1.93), respectively. We explored causal connections, and children with eczema at 1-2 years appeared to have more mature bacterial microbiota, as well as being depleted of Enterococcus genus. Although LBP and FABP2 did not correlate with eczema, increased bacterial abundance was associated with increased serum FABP2. CONCLUSIONS: We observed positive associations between gut fungal abundance and allergy-related disease, but increased gut permeability does not appear to be involved in the underlying mechanisms for this association. Our findings should be confirmed in future microbiota studies.

Duration of breastfeeding, age at introduction of complementary foods and allergy-related diseases: a prospective cohort study.

BACKGROUND: The influences of breastfeeding and infant diet in the prevention of allergy-related diseases are uncertain and many of the studies conducted on the topic are limited by methodological challenges. Our aim was to assess whether the duration of breastfeeding and age at complementary food introduction affected the prevalence of asthma, wheeze, allergic rhinoconjunctivitis (ARC) and eczema at two and six years of age. METHODS: We used information gathered between 2000 and 2014 through questionnaires in the Prevention of Allergy among Children in Trondheim (PACT) study, a prospective cohort study in Trondheim, Norway. The current study includes 6802 children who submitted questionnaires detailing breastfeeding duration and or age at introduction to complementary foods, as well as at least one of the child health questionnaires completed at two and six years of age. Adjusted odds ratios (aORs) were calculated for each combination of exposure and outcomes and sensitivity analyses were performed to assess the possible influence of recall bias and reverse causality. RESULTS: The mean duration of breastfeeding was 11 months (SD 5.6) in this study population and 5695 of 6796 (84%) infants had been breastfed for at least 6 months. We did not find any conclusive preventative effect of longer breastfeeding on parental reported doctor-diagnosed asthma, aOR 0.79 (95% CI 0.51, 1.21). However, at 6 years of age we observed a reduction in the less strictly defined outcome wheeze, aOR 0.71 (95% CI 0.53, 0.95). Longer breastfeeding was associated with a reduced risk of ARC at 2 years, aOR 0.65 (95% CI 0.49, 0.86), with a continued protective trend at 6 years, aOR 0.77 (95% CI 0.58, 1.04). CONCLUSIONS: Longer breastfeeding resulted in a reduced risk of wheeze and a trend towards a protective effect on ARC up until school age. No conclusive associations were seen between the duration of breastfeeding or age at introduction to complementary foods and prevention of asthma, wheeze, ARC and eczema. TRIAL REGISTRATION: The trial is registered in Current Controlled Trials as ISRCTN28090297 .