Safety and Effectiveness of Bypassing Oral Immunotherapy Buildup With an Initial Phase of Sublingual Immunotherapy for Higher-Risk Food Allergy.

BACKGROUND: Because of its favorable safety, sublingual immunotherapy (SLIT) for food allergy has been proposed as an alternative treatment for those in whom oral immunotherapy (OIT) is of higher risk-older children, adolescents, adults, and those with a history of severe reactions. Although safe, SLIT has been shown to be less effective than OIT. OBJECTIVE: To describe the safety of multifood SLIT in pediatric patients aged 4 to 18 years and the effectiveness of bypassing OIT buildup with an initial phase of SLIT. METHODS: Patients aged 4 to 18 years were offered (multi)food SLIT. Patients built up to 2 mg protein SLIT maintenance over the course of 3 to 5 visits under nurse supervision. After 1 to 2 years of daily SLIT maintenance, patients were offered a low-dose oral food challenge (OFC) (cumulative dose, 300 mg protein) with the goal of bypassing OIT buildup. RESULTS: Between summer 2020 and winter 2023, 188 patients were enrolled in SLIT (median age, 11 years). Four patients (2.10%) received epinephrine during buildup and went to the emergency department, but none experienced grade 4 (severe) reaction. A subset of 20 patients had 50 low-dose OFCs to 300 mg protein and 35 (70%) OFCs were successful, thereby bypassing OIT buildup. CONCLUSIONS: In combination with very favorable safety of SLIT, with no life-threatening reactions and few reactions requiring epinephrine, we propose that an initial phase of SLIT to bypass supervised OIT buildup be considered for children in whom OIT is considered to be of higher risk.

Safety and effectiveness of the Canadian food ladders for children with IgE-mediated food allergies to cow's milk and/or egg.

BACKGROUND: Food ladders are tools designed to facilitate home-based dietary advancement in children with food allergies through stepwise exposures to increasingly allergenic forms of milk and egg. Several studies have now documented safety and efficacy of food ladders. In 2021, we published a Canadian adaptation of the previously existing milk and egg ladders originating in Europe using foods more readily available/consumed in Canada. Our study adds to the growing body of evidence supporting food ladder use and provides safety and effectiveness data for our Canadian adaptation of the milk and egg ladders. METHODS: Surveys were distributed to families of children using the Canadian Milk Ladder and/or the Canadian Egg Ladder at baseline, with follow up surveys at 3 months, 6 months, and 12 months. Data were analyzed using REDCap and descriptive and inferential statistics are presented. RESULTS: One hundred and nine participants were started on milk/egg ladders between September 2020 and June 2022. 53 participants responded to follow up surveys. Only 2 of 53 (3.8%) participants reported receiving epinephrine during the study. Severe grade 4 reactions (defined according to the modified World Allergy Organization grading system) were not reported by any participants. Minor cutaneous adverse reactions were common, with about 71% (n = 10/14) of respondents reporting cutaneous adverse reactions by 1 year of food ladder use. An increasing proportion of participants could tolerate most foods from steps 2-4 foods after 3, 6, and 12 months of the food ladder compared to baseline. CONCLUSION: The Canadian food ladders are safe tools for children with cow's milk and/or egg allergies, and participants tolerated a larger range of foods with food ladder use compared to baseline.

Optimizing vitamin D status in polycystic ovary syndrome: a systematic review and dose-response meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder in women of reproductive age. Vitamin D supplementation is a promising complementary therapy for PCOS, yet there is no consensus on an optimal dose, leading to a lack of evidence-based supplementation guidelines. OBJECTIVE: The objective of this study was to conduct a vitamin D dose-response meta-analysis among women with PCOS. DATA SOURCES: MEDLINE, CINAHL, and EMBASE databases from inception to November 2022 were searched for relevant articles. DATA EXTRACTION: Study screening and bias assessment were conducted by 2 independent reviewers. Eight relevant studies were identified; data for serum 25(OH)D (nmol/L) at baseline and at 12 weeks in each intervention group (mean ± SD) and vitamin D dose were extracted. DATA ANALYSIS: Estimates across studies were used to create a pooled curve, using restricted cubic splines with knots at the 10th, 50th, and 90th percentiles of the distribution of doses, to estimate the mean difference in effect for serum 25(OH)D at each dose compared with 0 IU/day. Sensitivity analyses were conducted fixing knots at 4000 IU/day and 7000 IU/day, which were a priori identified as potentially important thresholds, and to assess model fit and estimate heterogeneity. The pooled analysis demonstrated strong evidence of a dose-response relationship (P < .001), suggesting an increasing effect with increasing dose. An initial increase in serum 25(OH)D was evident until doses of approximately 3000 IU/day; this was followed by a plateau in effect between approximately 3000 IU/day and 5000 IU/day. The effect of supplementation with >5000 IU/day was unclear, given the minimal data at higher doses. The curve produced robust results for moderate doses (3000 IU/day to 4000 IU/day), which were not sensitive to model specification. CONCLUSION: Women with PCOS are responsive to vitamin D supplementation, but the benefit of providing doses of >3000 IU/day appears minimal. Further data is required to determine dose-response at doses of >5000 IU/day, and whether higher intakes provide a clinically meaningful advantage in this population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42021259396.

Cow's milk alternatives for children with cow's milk allergy and beyond.

Cow's milk allergy (CMA) is one of the most common food allergies in the first years of life, with worldwide prevalence estimated to range from 2% to 5%. While the majority of children with CMA will eventually develop tolerance to cow's milk proteins (it is estimated that >75% of children with CMA develop tolerance to cow's milk proteins by the age of 3 years, and >90% develop tolerance by the age of 6 years), the selection of an appropriate cow's milk (CM) alternative for those with CMA is vital to ensure adequate growth and development during childhood. The increasing number of CM alternative products on the commercial market with markedly different nutritional content and micronutrient fortification adds a layer of complexity that can be challenging for both families and clinicians to navigate. This article aims to provide guidance and clarity to Canadian paediatricians and primary care clinicians on recommending the most appropriate, safe, and nutritionally optimal CM alternatives for individuals with CMA, and beyond.

Patient selection for milk and egg ladders using a food ladder safety checklist.

A food ladder is a form of home-based dietary advancement therapy that gradually increases exposure to an allergenic food through the gradual introduction of egg or milk containing food with increasing quantity and allergenicity from extensively heated forms, such as baked goods, to less processed products. While widely considered safe, the food ladder is not risk-free and most of the egg and milk ladder studies only included preschoolers with mild egg and milk allergies, and with no or well-controlled asthma. We propose a Food Ladder Safety Checklist to assist with patient selection using "4 A's" based on available evidence for food ladders, including Age, active or poorly controlled Asthma, history of Anaphylaxis, and Adherence.

Pregnancy-induced alterations of 1-carbon metabolism and significance for maternal nutrition requirements.

OBJECTIVES: The pregnancy-induced alterations in 1-carbon (1C) metabolism, effects of advancing gestation on maternal plasma concentrations of methyl nutrients, and potential implications for maternal dietary intake and infant clinical outcomes are summarized in this narrative review. BACKGROUND: 1C metabolism encompasses a series of pathways where 1C units are transferred among nutrients such as B vitamins, choline, and amino acids (the methyl nutrients). Use of isotopic tracers and measuring methyl nutrients in maternal plasma and infant cord blood has advanced the understanding of 1C flux in pregnancy and kinetics of maternal-placental-fetal transfer. Methyl nutrients are supplied from maternal plasma to the placenta and fetus to support growth and 1C metabolism in these compartments. METHODS: A literature review was completed in MEDLINE and Google Scholar using search terms related to 1C metabolism, methyl nutrients, and nutrition requirements in pregnancy. English-language articles were reviewed in which 1C metabolism in pregnancy, maternal-placental-fetal transfer of methyl nutrients, and determinants of maternal plasma concentrations of methyl nutrients among healthy pregnant women were assessed. DISCUSSION: Adaptations in 1C metabolism occur throughout a healthy pregnancy to support this unique period of accelerated growth. Studies report similar temporal changes in plasma concentrations of many methyl nutrients, including B vitamins, choline, betaine, methionine, and cysteine, among healthy pregnant women from diverse geographic regions. Other key findings discussed in this review include an apparent high degree of B vitamin transfer to the placenta and fetus, influence of choline supplementation on 1C flux and possible benefit of supplementation for infant cognitive development, and that glycine may be conditionally essential in pregnancy. CONCLUSION: Understanding the flux of 1C metabolism in pregnancy and methyl nutrient transfer from maternal plasma is needed to establish appropriate plasma references ranges and, ultimately, dietary recommendations that aim to prevent deficiency and associated adverse health outcomes for mother and baby.

Canadian food ladders for dietary advancement in children with IgE-mediated allergy to milk and/or egg.

Food ladders are clinical tools already widely used in Europe for food reintroduction in milk- and egg-allergic children. Previously developed milk and egg ladders have limited applicability to Canadian children due to dietary differences and product availability. Herein we propose a Canadian version of cow's milk and egg food ladders and discuss the potential role that food ladders may have in the care of children with IgE-mediated allergies to cow's milk and/or egg, as either a method of accelerating the acquisition of tolerance in those who would outgrow on their own, or as a form of modified oral immunotherapy in those with otherwise persistent allergy.

Determinants of fatty acid content and composition of human milk fed to infants born weighing <1250 g.

BACKGROUND: Infants born at very low birth weight (VLBW) are vulnerable to deficits in fatty acids (FAs) but little is known of factors that influence the intakes or composition of their human milk feeds. OBJECTIVES: We aimed to identify sources of variability in the fat composition of human milk fed to VLBW infants and examine the impact of milk source (mother's own or donor) on fat and FA intakes. METHODS: Serial samples of mother's milk (n = 476) and donor milk (n = 53) fed to infants born weighing <1250 g (n = 114 infants from 100 mothers) were collected [Optimizing Mothers' Milk for Preterm Infants (OptiMoM) randomized clinical trial]. Fat and FA were analyzed using a mid-infrared human milk analyzer and GC with flame ionization detection. RESULTS: At full enteral feeding, donor milk is estimated to provide 1.3 g · kg-1 · d-1 less total fat than mature mother's milk (recommended intake: 4.8 g · kg-1 · d-1), and 5-9 mg · kg-1 · d-1 less DHA (22:6n-3) and arachidonic acid (20:4n-6) (estimated average requirement: 55-60 and 35-45 mg · kg-1 · d-1, respectively) than colostrum or transitional milk. Similar deficits were observed in measured intakes of a subset of OptiMoM infants. In multivariable-adjusted models, maternal ethnicity had medium to large [≥0.5 SD score (SDS)] effects on DHA, SFAs, and MUFAs. Mothers with prepregnancy BMI in overweight and obese categories had higher milk total fat (ß: 0.35; 95% CI: 0.10, 0.61 and ß: 0.46; 95% CI: 0.16, 0.77 SDS, respectively). Those with BMI ≥30 in addition had higher proportions of SFAs (ß: 0.61; 95% CI: 0.33, 0.89 SDS) and lower DHA (ß: -0.54; 95% CI: -0.89, -0.20 SDS). Other factors, such as gestational age and income, were also associated with FA composition. CONCLUSIONS: The fat and FA content of human milk fed to VLBW infants is variable. Care must be taken to ensure fat and FA intakes meet recommendations, particularly when feeding a high proportion of donor milk.This trial was registered at clinicaltrials.gov as NCT02137473.

Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children With Sickle Cell Disease.

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a variant (rs344) in the HBB gene encoding the ß-globin subunit of hemoglobin. Chronic hemolytic anemia and increased erythropoiesis and RBC turnover in individuals with SCD can result in increased needs for folate and other B-vitamins. We assessed B-vitamin status, and the distribution of folate forms, including unmetabolized folic acid (UMFA), in Canadian children with SCD supplemented with 1 mg/d folic acid (current routine practice). Non-fasted serum and plasma samples were analyzed for concentrations of folate, and vitamins B-2, B-6, and B-12. Eleven individuals (45% male; SCD type: HbSS n = 8, HbSC n = 2, HbSß0-Thal n = 1), with a median (IQR) age of 14 (7, 18) years, were included. Total folate concentrations were 3-27 times above the deficiency cut-off (10 nmol/L), and 64% of children had elevated folate levels (>45.3 nmol/L). UMFA (>0.23 nmol/L) was detected in all children, and 36% of participants had elevated levels of UMFA (>5.4 nmol/L). All children were vitamin B-12 sufficient (>150 pmol/L), and the majority (55%) had sufficient B-6 status (>30 nmol/L). Among this sample of Canadian children with SCD, there was limited evidence of B-vitamin deficiencies, but UMFA was detectable in all children.

Can Automated Hematology Analyzers Predict the Presence of a Genetic Hemoglobinopathy? An Analysis of Hematological Biomarkers in Cambodian Women.

Genetic hemoglobinopathies are the most common single-gene disorder worldwide. Some automated hematology analyzers have the capability of flagging individuals who may have hematological disorders based on complete blood count (CBC) biomarkers. We aimed to evaluate the accuracy of a hematology analyzer in identifying genetic hemoglobinopathies in Cambodian women and to determine which hematological biomarkers are the best predictors. A CBC was completed using a Sysmex XN-1000 analyzer and hemoglobinopathies were determined with capillary hemoglobin electrophoresis for 808 nonpregnant Cambodian women. Sysmex XN-1000 Interpretive Program (IP) messages, which flag potential hematological disorders, were produced from CBC results. Then, 2 × 2 tables were used to determine sensitivity and specificity of the IP message "Hemoglobin defect" to detect a genetic hemoglobinopathy. Receiver operating characteristic (ROC) analyses assessed the diagnostic ability of six CBC biomarkers to predict a genetic hemoglobinopathy. In total, 74% of women had a hemoglobinopathy (predominantly Hb E and α-thalassemia). "Hb defect" IP message sensitivity and specificity for genetic hemoglobinopathy detection were 10.4% and 98.6%, respectively. Variable selection strategies yielded a two-variable model including mean corpuscular volume (MCV) and red blood cell (RBC) count (AIC = 99.83, AUCROC = 0.98 (95% CI: 0.97, 0.99)) for the prediction of a homozygous EE disorder. Sensitivity and specificity values do not justify the use of Sysmex XN-1000 IP flag messages for identification of genetic hemoglobinopathies in Cambodian women. Development of an algorithm based on MCV and RBC biomarkers may optimize the screening ability of automated hematology analyzers.

Regression to the Mean: A Statistical Phenomenon of Worthy Consideration in Anemia Research.

BACKGROUND: Regression to the mean (RTM) is a statistical phenomenon where second measurements are more likely to be closer to the mean. This is particularly observed in those with baseline values further from the mean. Anemic individuals (hemoglobin <120 g/L) are often recruited when evaluating iron supplementation programs, as they are more likely to elicit a greater hemoglobin response; however, they are also at greater risk for RTM as their baseline values are lower than the overall population mean. OBJECTIVE: The aim was to calculate and apply RTM to a previously conducted iron supplementation trial of women in Cambodia at increasingly severe baseline anemia cutoffs (hemoglobin <120 g/L, <115 g/L, and <110 g/L). METHODS: Women received either 60 mg/d iron (n = 191) or placebo (n = 185) for 12 wk. Hemoglobin was measured at baseline and at 12 wk (endline), and change in hemoglobin was calculated in each group for each cutoff. RTM was calculated in the placebo group at each cutoff and applied to the change observed at each cutoff in the iron group to obtain the RTM-free effect. RESULTS: In the placebo group, mean change in hemoglobin increased as cutoffs became more extreme (0.9 g/L to 1.9 g/L in those with baseline hemoglobin <120 g/L and <110 g/L, respectively). RTM estimates similarly increased: 1.0 g/L (<120 g/L), 1.3 g/L (<115 g/L), and 1.8 g/L (<110g/L). When applying RTM to the iron group, we found that ∼10% of the "treatment effect" could be attributable to RTM at each cutoff. However, iron supplementation was still effective in increasing hemoglobin, with an increased effect in those with lower baseline values, as proven by the RTM-free effect at each cutoff: 8.7 g/L (<120 g/L), 10.9 g/L (<115 g/L), and 13.6g/L (<110 g/L). CONCLUSIONS: RTM may have accounted for ∼10% of the observed change in hemoglobin following iron supplementation; however, appropriate use of a placebo group in the statistical analyses of the trial controls for this potential RTM effect.

Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial.

BACKGROUND: Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B vitamin, due to increased RBC production and turnover in the disease. High-dose supplementation with 1-5 mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d) have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥ 0.2 mg/d, are not fully understood. The objective of this study is to determine efficacy of, and alterations in folate metabolism from high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation. METHODS: In this double-blind randomized controlled cross-over trial, children with SCD (n = 36, aged 2-19 years) will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12 weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period. DISCUSSION: As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04011345 . Registered on July 8, 2019.

The Homozygous Hemoglobin EE Variant Is Associated with Poorer Riboflavin Status in Cambodian Women of Reproductive Age.

BACKGROUND: Riboflavin is required for erythropoiesis, which is increased in people with hemoglobinopathies due to increased hemolysis and erythrocyte turnover. Dietary intake and status of riboflavin is poor in Cambodia, where hemoglobinopathies are common. OBJECTIVE: We assessed the association between genetic hemoglobin disorders and riboflavin status in women of reproductive age in Cambodia. METHODS: Venous blood samples from 515 Cambodian women of reproductive age, 18-45 y, were analyzed for biomarker status of riboflavin [erythrocyte glutathione reductase activation coefficient (EGRac)], genetic hemoglobin (Hb) disorders, and hematological indices. Linear regression analysis was used to estimate the association between EGRac with Hb, ferritin, and Hb genotypes. EGRac was log transformed in the analyses, and the regression coefficients represent the geometric mean differences. RESULTS: Genetic Hb disorders were present in 57% of the population, with the homozygous hemoglobin E variant (Hb EE) occurring in ∼10% of women (n = 53). Deficient (EGRac ≥1.40) or marginal riboflavin status (EGRac ≥1.30 and <1.40) was observed in 92% (n = 475) of women. The variant Hb EE genotype was associated with 18% (95% CI: 9%, 28%) higher geometric mean EGRac values than the normal Hb AA genotype (P < 0.001). CONCLUSIONS: Although riboflavin biomarker deficiency or marginal status is widely prevalent in Cambodian women, lower riboflavin status was observed more frequently in women with the Hb EE genotype than in women with normal Hb AA. The relation between genetic Hb disorders and riboflavin warrants further investigation. This trial was registered at clinicaltrials.gov as NCT01593423 and NCT02481375.

Knowledge, perceptions, and consumption of whole grains among university students.

PURPOSE: Differences in knowledge, perceptions, and consumption of whole grains were compared between students who had taken an introductory university nutrition course and those who had not. METHODS: The sample consisted of two groups: 109 students who had completed a nutrition course and 61 who had not. The two samples were drawn from second-year nursing students and students in second-year psychology courses, respectively. All students completed a 25-item questionnaire. Chi-square tests were used to identify associations between completion of a nutrition course and responses. RESULTS: Nutrition education students had more knowledge of whole grain recommendations, of whole grains available in stores, and of whole grains as a factor in disease risk reduction (p<0.05). In contrast, non-nutrition education students had more knowledge of whole grain health claims, reported a greater preference for the taste of whole grains, and had a greater than mean intake of whole grain cereals (p<0.05). CONCLUSIONS: This prelimary study indicates that completion of an introductory nutrition course has a greater influence on positive perceptions of whole grains than on students' consumption frequency or knowledge of whole grains. Further study may provide more information on nutrition education and whole grains.