Iron Fortification and Inulin Supplementation in Early Infancy: Evaluating the Impact on Iron Metabolism and Trace Mineral Status in a Piglet Model.

Background: Infant formula in the United States contains abundant iron, raising health concerns about excess iron intake in early infancy. Objectives: Using a piglet model, we explored the impact of high iron fortification and prebiotic or synbiotic supplementation on iron homeostasis and trace mineral bioavailability. Methods: Twenty-four piglets were stratified and randomly assigned to treatments on postnatal day 2. Piglets were individually housed and received an iron-adequate milk diet (AI), a high-iron milk diet (HI), HI supplemented with 5% inulin (HI with a prebiotic [HIP]), or HIP with an oral gavage of Ligilactobacillus agilis YZ050, an inulin-fermenting strain, every third day (HI with synbiotic [HIS]). Milk was provided in 14 meals daily, mimicking formula feeding in infants. Fecal consistency score and body weight were recorded daily or every other day. Blood and feces were sampled weekly, and tissues collected on postnatal day 29. Data were analyzed using mixed model analysis of variance with repeated measures whenever necessary. Results: Diet did not affect growth. HI increased hemoglobin, hematocrit, and serum iron compared to AI. Despite marginal adequacy, AI upregulated iron transporter genes and maintained satisfactory iron status in most pigs. HI upregulated hepcidin gene expression in liver, caused pronounced tissue iron deposition, and markedly increased colonic and fecal iron. Inulin supplementation, regardless of L. agilis YZ050, not only attenuated hepatic iron overload but also decreased colonic and fecal iron without altering pH or the expression of iron regulatory genes. HI lowered zinc (Zn) and copper (Cu) in the duodenum and liver compared to AI, whereas HIP and HIS further decreased Zn and Cu in the liver and diminished colonic and fecal trace minerals. Conclusions: Early-infancy excessive iron fortification causes iron overload and compromises Zn and Cu absorption. Inulin decreases trace mineral absorption likely by enhancing gut peristalsis and stool frequency.

Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors.

BACKGROUND: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. METHODS: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together. RESULTS: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. CONCLUSION: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.

Asthma medication and risk of dental diseases in children - A prospective cohort study.

BACKGROUND: Dental caries and enamel defects are the main causes of poor dental health in children, with a substantial impact on their well-being. Use of inhaled asthma medication is a suspected risk factor, but there is a lack of prospective studies investigating this and other prenatal and early life risk factors. METHODS: Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort (COPSAC2010 ) consists of 700 women who were recruited at 24 weeks of pregnancy. 588 of their children participated in a dental examination at 6 years of age (84%) at the COPSAC2010 research unit. Caries was defined as decayed, missing, or filled surfaces. Enamel defect was defined as demarcated opacity, post-eruptive enamel breakdown, and/or atypical restoration on at least one molar. Caries and enamel defects were assessed in both deciduous and permanent dentitions. RESULTS: We found no associations between inhaled corticosteroids or ß2 -agonists or asthma symptoms in early childhood and the risk of caries or enamel defects by 6 years of age. Furthermore, we found no strong pre-, peri-, or postnatal risk factors for dental diseases at 6 years, except from nominally significant associations between antibiotic use in pregnancy (OR = 1.25, [1.01-1.54]), maternal education level (OR = 1.57, [1.01-2.45]), having a dog at home (OR = 0.50, [0.27-0.93]), and risk of enamel defects. CONCLUSIONS: Use of inhaled corticosteroids, ß2 -agonists, or asthma symptoms in the first 6 years of life were not associated with the development of caries or enamel defects. This finding is reassuring for parents and physicians prescribing asthma medication for young children.

Monocyte phenotype and extracellular vesicles in HIV-1, HIV-2, and HIV-1/2 dual infection.

OBJECTIVE: AIDS-defining illness develops at higher CD4 + T-cell counts in individuals infected with HIV-2 compared with HIV-1-infected, which suggests that the two types of HIV may have different effects on other compartments of the immune system. We here investigate monocyte phenotype, activation and macrophage-derived extracellular vesicles in individuals with different HIV types. DESIGN: Cross-sectional. METHODS: ART-naive HIV-1 ( n  = 83), HIV-2 ( n  = 63), and HIV-1/2 dually positive ( n  = 27) participants were recruited in Bissau, Guinea-Bissau, together with HIV-negative controls ( n  = 26). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for monocyte phenotype and activation, and plasma was analyzed for extracellular vesicle forms of CD163 and CD206. RESULTS: Compared with HIV-negative controls, all groups of HIV-positive participants had a skewed monocyte phenotype with a higher proportion of intermediate monocytes, increased CD163 expression and elevated serum levels of the inflammatory biomarkers soluble (s)CD163 and sCD206. HIV-2-positive participants had lower CD163 monocyte expression than HIV-1-positive participants, regardless of HIV RNA or CD4 + cell count. Levels of sCD206 extracellular vesicles were increased in all HIV groups, and higher in HIV-1 compared with HIV-2-positive participants. CONCLUSION: The monocyte phenotype of HIV-2-positive participants deviated less from healthy controls than did HIV-1 participants. HIV-2-positive participants also had a lower concentration of extracellular CD206 vesicles compared with HIV-1-positive participants. This does not explain the difference in AIDS development.

Elevated third trimester corticosteroid levels are associated with fewer offspring infections.

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquid-chromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10-7 to 0.002) and improved lung function metrics (P = 0.020-0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life.Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226.

The Impact of Baseline 25-Hydroxyvitamin D Level and Gestational Age on Prenatal Vitamin D Supplementation to Prevent Offspring Asthma or Recurrent Wheezing.

BACKGROUND: Prenatal vitamin D deficiency is associated with asthma or recurrent wheezing in offspring. However, evidence from randomized trials on the efficacy of vitamin D supplementation is inconclusive. OBJECTIVES: We aimed to examine the differential efficacy of prenatal vitamin D supplementation based on the maternal baseline vitamin D status and the starting time of supplementation to prevent early life asthma or recurrent wheezing. METHODS: We conducted a secondary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized double-blind trial of prenatal vitamin D supplementation initiated at 10-18 weeks (wks) of gestation (4400 IU of intervention/day compared with 400 IU of placebo/day) to prevent offspring asthma or recurrent wheezing by the age of 6 years. We assessed the effect of modification of supplementation by maternal baseline vitamin D status at enrollment and the timing of initiation of supplementation. RESULTS: An inverse relationship was observed between maternal 25-hydroxyvitamin D (25(OH)D) levels at trial entry and 25(OH)D levels during late pregnancy (32-38 wks of gestation) in both supplementation arms (P < 0.001). Overall, supplementation efficacy was not dependent on the maternal baseline 25(OH)D status. However, a trend toward the reduction of asthma or recurrent wheezing was observed across the baseline groups in the intervention arm (P = 0.01), with the greatest reduction observed in the most severely vitamin D-deficient women (25(OH)D < 12 ng/mL; adjusted odds ratio [aOR] = 0.48; confidence interval [CI]: 0.17, 1.34). Gestational age at trial enrollment modified supplementation efficacy, showing a greater reduction of offspring asthma or recurrent wheezing with earlier intervention during pregnancy (aOR = 0.85; CI = 0.76, 0.95), particularly in women who were 9-12 wk pregnant (aOR = 0.45; CI = 0.24, 0.82). CONCLUSIONS: Pregnant women with severe vitamin D deficiency show the greatest 25(OH)D improvement because of supplementation. In these women, a vitamin D dose of 4400 IU might have a preventive role in the development of early life offspring asthma or recurrent wheezing. Gestational age is suggested to modify the efficacy of prenatal vitamin D supplementation, showing the highest beneficial effect if supplementation is started during the first trimester of pregnancy. This study is an ancillary analysis from the VDAART, which is registered in ClinicalTrials.gov as NCT00902621.

Outcomes reported in randomized controlled trials for mixed and non-IgE-mediated food allergy: Systematic review.

BACKGROUND: Mixed and non-IgE-mediated food allergy is a subset of immune-mediated adverse food reactions that can impose a major burden on the quality of life of affected patients and their families. Clinical trials to study these diseases are reliant upon consistent and valid outcome measures that are relevant to both patients and clinicians, but the degree to which such stringent outcome reporting takes place is poorly studied. OBJECTIVE: As part of the Core Outcome Measures for Food Allergy (COMFA) project, we identified outcomes reported in randomized clinical trials (RCT) of treatments for mixed or non-IgE-mediated food allergy. DESIGN: In this systematic review, we searched the Ovid, MEDLINE and Embase databases for RCTs in children or adults investigating treatments for food protein-induced enterocolitis syndrome, food protein-induced allergic proctocolitis, food protein-induced enteropathy and eosinophilic gastrointestinal disorders including eosinophilic esophagitis [EoE], eosinophilic gastritis and eosinophilic colitis published until 14 October 2022. RESULTS: Twenty-six eligible studies were identified, with 23 focused on EoE (88%). Most interventions were corticosteroids or monoclonal antibodies. All EoE studies assessed patient-reported dysphagia, usually using a non-validated questionnaire. Twenty-two of 23 EoE studies used peak tissue eosinophil count as the primary outcome, usually using a non-validated assessment method, and other immunological markers were only exploratory. Thirteen (57%) EoE studies reported endoscopic outcomes of which six used a validated scoring tool recently recommended as a core outcome for EoE trials. Funding source was not obviously associated with likelihood of an RCT reporting mechanistic versus patient-reported outcomes. Only 3 (12%) RCTs concerned forms of food allergy other than EoE, and they reported on fecal immunological markers and patient-reported outcomes. CONCLUSIONS: Outcomes measured in clinical trials of EoE and non-IgE-mediated food allergy are heterogeneous and largely non-validated. Core outcomes for EoE have been developed and need to be used in future trials. For other forms of mixed or non-IgE-mediated food allergies, core outcome development is needed to support the development of effective treatments. SYSTEMATIC REVIEW REGISTRATION: OSF public registry DOI:10.17605/OSF.IO/AZX8S.

Supplementation With Fish Oil in Pregnancy Reduces Gastroenteritis in Early Childhood.

BACKGROUND: We hypothesized that insufficient intake of fish oil-derived omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy is a contributing factor to gastroenteritis in early childhood. We examined the effect of n-3 LCPUFA supplementation on gastroenteritis symptoms in the offspring's first 3 years of life. METHODS: This was a double-blinded, randomized controlled trial whereby 736 mothers were administered n-3 LCPUFA or control from pregnancy week 24 until 1 week after birth. We measured the number of days with gastroenteritis, number of episodes with gastroenteritis, and the risk of having a gastroenteritis episode in the first 3 years of life. RESULTS: A median reduction of 2.5 days with gastroenteritis (P = .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (P = .037). A reduction in the number of gastroenteritis episodes (P = .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66-.97]; P = .023) were also shown. CONCLUSIONS: Fish oil supplementation from the 24th week of pregnancy led to a reduction in the number of days and episodes with gastroenteritis symptoms in the first 3 years of life. The findings suggest n-3 LCPUFA supplementation as a preventive measure against gastrointestinal infections in early childhood. CLINICAL TRIALS REGISTRATION: NCT00798226.

Fish Oil and Vitamin D Supplementations in Pregnancy Protect Against Childhood Croup.

BACKGROUND: Croup is a prevalent respiratory disorder in early childhood most often caused by parainfluenza virus infections. There are no preventive strategies; therefore, we investigated the potential effects of prenatal micronutrient supplementations. OBJECTIVE: To investigate the supplementation effects of (1) 2.4-g n-3 long-chained polyunsaturated fatty acid (n-3 LCPUFA) (fish oil) versus olive oil and (2) high-dose (2800 IU/d) versus standard-dose (400 IU/d) of vitamin D from pregnancy week 24 until 1 week after birth on the risk for offspring croup during the double-blinded first 3 years of life in a secondary analysis of a 2 × 2 factorial designed randomized controlled trial. METHODS: The study was completed in the Danish population-based single-center Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, which included 736 pregnant women. Croup was diagnosed by physicians' clinical examinations and medical record checks. Potential mediating mechanisms were investigated using blood metabolomics, airway cytokines, and airway microbiome. RESULTS: Of 695 children, 97 had croup before age 3 years (14%). The risk of croup was reduced in the n-3 LCPUFA (ncases / ntotal = 38/346; 11%) versus olive oil group (59 of 349 children; 17%) (hazard ratio = 0.62; 95% CI, 0.41-0.93; P = .02) and in the high-dose vitamin D group (32 of 295 children; 11%) versus the standard-dose group (51 of 286 children; 18%) (hazard ratio = 0.60; 95% CI, 0.38-0.93; P = .02). There was no evidence of interaction or additive effects between the supplements (Pinteraction = .56). Furthermore, the results did not change when they were adjusted for each other, persistent wheeze, and lower respiratory tract infection. CONCLUSIONS: This analysis of the double-blinded period of the Copenhagen Prospective Studies on Asthma in Childhood 2010 randomized controlled trial of n-3 LCPUFA and high-dose vitamin D supplementation during pregnancy demonstrated a reduced risk of croup in early childhood.

Childhood asthma is associated with development of type 1 diabetes and inflammatory bowel diseases: a Danish nationwide registry study.

Asthma and autoimmune disorders might be affected by opposing immune mechanisms, T helper cells type 2 (Th2) and T helper cells type 1 (Th1) immunity, respectively. Knowledge on comorbidity can increase understanding of the underlying etiologies. We aim to examine the association between childhood asthma and subsequent risk of type 1 diabetes (T1D) and inflammatory bowel diseases (IBD) in Danish children. Children of Danish origin born during 1991-1996 were included and childhood asthma, defined as a minimum of two collected prescriptions of inhalation corticosteroids age 5-7 years, was linked to hospitalisations with either T1D or IBD after age 8. Associations between childhood asthma and incidence of T1D and IBD were analysed using sex- and year stratified Cox regression. A total of 366,200 children were included in the study, 4.9% had asthma, which increased the risk of both T1D and IBD, hazard ratios of 1.32 (1.08-1.61) and 1.27 (1.09-1.48). In this large nationwide Danish study, we found that children with asthma have increased risk of developing immune diseases T1D and IBD. This contradicts the Th1 vs Th2 paradigm and points towards shared disease mechanisms and risk factors.

Reduced Steroid Metabolites Identify Infection-Prone Children in Two Independent Pre-Birth Cohorts.

Recurrent respiratory infections are a leading cause of morbidity and mortality in early life, but there is no broadly accepted means to identify infection-prone children during this highly vulnerable period. In this study, we investigated associations between steroid metabolites and incident respiratory infections in two pre-birth cohorts to identify novel metabolomic signatures of early infection proneness. Children from the Vitamin D Antenatal Asthma Reduction Trial and the Copenhagen Prospective Studies on Asthma in Childhood were included, and profiling was performed on plasma samples collected at ages 1 and 6 years. Both cohorts recorded incidence of lower respiratory infections, upper respiratory infections, ear infections, and colds. Poisson regression analysis assessed the associations between 18 steroid metabolites and the total number of respiratory infections that occurred in offspring during follow-up. We found that steroid metabolites across androgenic, corticosteroid, pregnenolone, and progestin classes were reduced in children that suffered more infections, and these patterns persisted at age 6 years, generally reflecting consistency in direction of effect and significance. Our analysis suggested steroid metabolite measurement may be useful in screening for infection proneness during this critical developmental period. Future studies should clinically evaluate their potential utility as a clinical screening tool.

[Analyze of obesity indicators and effect of fertility preservation treatment in patients with endometrial atypical hyperplasia and early endometrial cancer].

Objective: To investigate the clinical features of obesity indicators in patients with endometrial atypical hyperplasia (EAH) and early endometrial cancer (EC) and analyze the relationship between these indexes and effect of fertility preservation therapy. Methods: The clinical data of patients with EAH, EC and endometrial benign lesions treated in Peking University People's Hospital from January 1, 2018 to June 30, 2021 who required fertility-sparing treatment were collected, and obesity indicators were calculated and analyzed retrospectively. Results: (1) Obesity indicators: the obesity [body mass index (BMI) ≥28 kg/m2] rate of patients with fertility preservation treatment was 40% (32/80), and abdominal obesity [waist circumference (WC) ≥80 cm] rate was 79% (63/80), and obesity indicators [BMI, WC, waist-hip ratio (WHR), weight height ratio (WHTR), body roundness index (BRI), lipid accumulation index (LAP), visceral adiposity index (VAI)] were higher than those with endometrial benign lesions (all P<0.001). (2) Related factors affecting the efficacy of fertility preservation treatment and their predictive value: EC, higher BMI, WC, WHR, WHTR and BRI were risk factors for lower complete remission rate after nine months' treatment (all P<0.05). The predictive values of BRI and WHTR combined with pathological type were superior to other indicators [area under the curve (AUC)=0.716; AUC=0.714]. (3) Relation of obesity indicators and glucolipid indicators:BMI, WC, WHR, WHTR, BRI, LAP and VAI were positively correlated with homeostasis model assessment-insulin resistance index, glycosylated hemoglobin, and triacylglycerol (all P<0.05); while VAI was negatively correlated with high density lipoprotein cholesterol (P<0.001). Conclusions: For patients with EAH and EC treated with fertility preservation therapy, abnormal obesity indexes affect the treatment effect. BRI and WHTR combined pathology have good predictive value for effect of fertility preservation treatment. In clinical practice, appropriate indicators could be selected to evaluate body shape, glucolipid metabolism and predict efficacy.

Mixed methods research in complementary and alternative medicine: a scoping review.

OBJECTIVE: To update the current characteristics about the scope and quality of mixed methods research (MMR) in complementary and alternative medicine (CAM) after nearly 10 years. METHODS: A 5-stage approach for conducting a scoping review was adopted. Articles published on the top 10 journals in CAM with the highest impact factor in 2020 were screened for MMR. Information of included articles were extracted, and then synthesized to illustrate the current state. Methodological quality was evaluated according to the Mixed Method Appraisal Tool (MMAT) 2018 version. RESULTS: A total of 55 (55/2991, 2%) articles using mixed methods were retrieved, including 17 medical studies and 38 ethnobotanical studies. We performed an in-depth analysis on the 17 medical studies, which studied cancer, stress, pain, fatigue, exercises, mindfulness intervention, herbal medicine use, art and acupuncture. Thirteen pilot studies applied MMR to evaluate the feasibility of interventions or programs (13/17, 76%); phenomenology was inferred as the most common philosophical assumptions (13/17, 76%); the most applied type of MMR was convergent design (16/17, 94%); integration often took place at integration (12/17, 71%). Among the 16 eligible studies for quality appraisal, majority were rated as good (14/16, 88%), whereas two studies were rated as poorly described. Primarily, a poor rating was due to incomplete reporting of data analysis and citations in qualitative components; lack of confounder controlling and the sampling strategy in quantitative components; poor description of integration and justification for mixed methods. Comparing with the previous review, fewer MMR were published in 2020 in CAM, but the proportion of studies that clearly reported MMR has increased by 4 times (4%→15%). CONCLUSION: CAM researchers need to realize the benefits that MMR can have on conducting further health care research. Our findings highlight that applying MMR will be helpful to understand the complex dynamics and interdisciplinary nature of complex intervention. In addition, addressing a standardized reporting criteria for MMR is recommended.

The developing airway and gut microbiota in early life is influenced by age of older siblings.

BACKGROUND: Growing up with siblings has been linked to numerous health outcomes and is also an important determinant for the developing microbiota. Nonetheless, research into the role of having siblings on the developing microbiota has mainly been incidental. RESULTS: Here, we investigate the specific effects of having siblings on the developing airway and gut microbiota using a total of 4497 hypopharyngeal and fecal samples taken from 686 children in the COPSAC2010 cohort, starting at 1 week of age and continuing until 6 years of age. Sibship was evaluated longitudinally and used for stratification. Microbiota composition was assessed using 16S rRNA gene amplicon sequencing of the variable V4 region. We found siblings in the home to be one of the most important determinants of the developing microbiota in both the airway and gut, with significant differences in alpha diversity, beta diversity, and relative abundances of the most abundant taxa, with the specific associations being particularly apparent during the first year of life. The age gap to the closest older sibling was more important than the number of older siblings. The signature of having siblings in the gut microbiota at 1 year was associated with protection against asthma at 6 years of age, while no associations were found for allergy. CONCLUSIONS: Having siblings is one of the most important factors influencing a child's developing microbiota, and the specific effects may explain previously established associations between siblings and asthma and infectious diseases. As such, siblings should be considered in all studies involving the developing microbiota, with emphasis on the age gap to the closest older sibling rather than the number of siblings. Video abstract.

Beam steering at the nanosecond time scale with an atomically thin reflector.

Techniques to mold the flow of light on subwavelength scales enable fundamentally new optical systems and device applications. The realization of programmable, active optical systems with fast, tunable components is among the outstanding challenges in the field. Here, we experimentally demonstrate a few-pixel beam steering device based on electrostatic gate control of excitons in an atomically thin semiconductor with strong light-matter interactions. By combining the high reflectivity of a MoSe2 monolayer with a graphene split-gate geometry, we shape the wavefront phase profile to achieve continuously tunable beam deflection with a range of 10°, two-dimensional beam steering, and switching times down to 1.6 nanoseconds. Our approach opens the door for a new class of atomically thin optical systems, such as rapidly switchable beam arrays and quantum metasurfaces operating at their fundamental thickness limit.

Genome-wide study of early and severe childhood asthma identifies interaction between CDHR3 and GSDMB.

BACKGROUND: Asthma with severe exacerbation is one of the most common causes of hospitalization among young children. Exacerbations are typically triggered by respiratory infections, but the host factors causing recurrent infections and exacerbations in some children are poorly understood. As a result, current treatment options and preventive measures are inadequate. OBJECTIVE: We sought to identify genetic interaction associated with the development of childhood asthma. METHODS: We performed an exhaustive search for pairwise interaction between genetic single nucleotide polymorphisms using 1204 cases of a specific phenotype of early childhood asthma with severe exacerbations in patients aged 2 to 6 years combined with 5328 nonasthmatic controls. Replication was attempted in 3 independent populations, and potential underlying immune mechanisms were investigated in the COPSAC2010 and COPSAC2000 birth cohorts. RESULTS: We found evidence of interaction, including replication in independent populations, between the known childhood asthma loci CDHR3 and GSDMB. The effect of CDHR3 was dependent on the GSDMB genotype, and this interaction was more pronounced for severe and early onset of disease. Blood immune analyses suggested a mechanism related to increased IL-17A production after viral stimulation. CONCLUSIONS: We found evidence of interaction between CDHR3 and GSDMB in development of early childhood asthma, possibly related to increased IL-17A response to viral infections. This study demonstrates the importance of focusing on specific disease subtypes for understanding the genetic mechanisms of asthma.

Association between Altered Cortisol Profiles and Neurobehavioral Impairment after Mild Traumatic Brain Injury in College Students.

Mild traumatic brain injury (mTBI) is the most common form of TBI, with more than 2.5 million TBI cases in the United States annually. Identification of easily obtainable biomarkers that track strongly with mTBI symptoms may improve our understanding of biological factors that contribute to mTBI symptom profiles and long-term outcomes. Notably, some individuals with mTBI exhibit circadian disruptions and elevated stress sensitivity, which in other clinical groups often correlate with disrupted secretion of cortisol, a glucocorticoid hormone that coordinates circadian and stress physiology. Here, we examined whether cortisol profiles could serve as a biomarker to complement the assessment of neurobehavioral sequelae after mTBI. We partnered with our on-campus health clinic to recruit college students seeking medical care after mTBI (n = 46) and compared this population to a well-matched non-injured student control group (n = 44). We collected data at an initial visit (shortly after injury in mTBI subjects) and one week later. At each visit, we evaluated neurobehavioral function using the Automated Neuropsychological Assessment Metric (ANAM). The subjects also provided cortisol samples through at-home saliva collection. We observed strong coherence between ANAM subjective and objective measures, indicating significant multi-dimensional impairment in subjects with mTBI. Further, female mTBI subjects exhibited diminished neurobehavioral function compared with males. Regardless of sex, decreased amplitude of diurnal cortisol and a blunted cortisol awakening response were associated with mTBI symptom severity and neurobehavioral impairment. Taken together, these findings suggest that salivary cortisol profiles may be a sensitive biomarker for studying underlying biological factors that impact mTBI symptoms and outcomes.

Height and bone mineral content after inhaled corticosteroid use in the first 6 years of life.

BACKGROUND: Infants and young children might be particularly susceptible to the potential side effects from inhaled corticosteroid (ICS) on height and bone mineral content (BMC), but this has rarely been studied in long-term prospective studies. METHODS: Children from two Copenhagen Prospective Studies on Asthma in Childhood cohorts were included. ICS use was registered prospectively from birth to age 6 and the cumulative dose was calculated. Primary outcomes were height and BMC from dual-energy X-ray absorptiometry (DXA) scans at age 6. RESULTS: At age 6, a total of 930 children (84%) from the cohorts had a valid height measurement and 792 (71%) had a DXA scan. 291 children (31%) received a cumulated ICS dose equivalent to or above 10 weeks of standard treatment before age 6. We found an inverse association between ICS use and height, -0.26 cm (95% CI: -0.45 to -0.07) per 1 year standard treatment from 0 to 6 years of age, p=0.006. This effect was mainly driven by children with ongoing treatment between age 5 and 6 years (-0.31 cm (95% CI: -0.52 to -0.1), p=0.004), while there was no significant association in children who stopped treatment at least 1 year before age 6 (-0.09 cm (95% CI: -0.46 to 0.28), p=0.64). There was no association between ICS use and BMC at age 6. CONCLUSIONS: ICS use in early childhood was associated with reduced height at age 6 years but only in children with continued treatment in the sixth year of life.

High-dose vitamin D supplementation in pregnancy and 25(OH)D sufficiency in childhood reduce the risk of fractures and improve bone mineralization in childhood: Follow-up of a randomized clinical trial.

BACKGROUND: Exposure to vitamin D in early life has been associated with improved bone mineralization, but no studies have investigated the combined effect of pregnancy supplementation and childhood 25(OH)D concentrations on bone health. METHODS: We analyzed the effect of serum 25(OH)D concentrations at age 6 months and 6 years and the combined effect with prenatal high-dose vitamin D (2800 vs. 400 IU/day) on bone mineral density (BMD) and content (BMC) assessed by dual-energy X-ray absorptiometry (DXA) scans at age 3 and 6 years and longitudinal risk of fractures in a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother-child cohort with enrollment from March 4, 2009, to November 17, 2010, and clinical follow-up until January 31, 2019 (NCT00856947). All participants randomized to intervention and with complete data were included in the analyses. FINDINGS: At age 6 months, serum 25(OH)D concentration was measured in 93% (n = 541) of 584 children. Children with sufficient (≥ 75 nmol/l) vs. insufficient (< 75 nmol/l) concentrations did not have lower risk of fractures: incidence rate ratio (95% CI); 0.64 (0.37;1.11), p = 0.11. However, vitamin D sufficient children from mothers receiving high-dose supplementation during pregnancy had a 60% reduced incidence of fractures compared with vitamin D insufficient children from mothers receiving standard-dose: 0.40 (0.19;0.84), p = 0.02.At age 6 years, serum 25(OH)D concentration was measured in 83% (n = 318) of 383 children with available DXA data. Whole-body bone mineralization was higher in vitamin D sufficient children at age 6 years; BMD, adjusted mean difference (aMD) (95% CI): 0.011 g/cm2 (0.001;0.021), p = 0.03, and BMC, aMD: 12.3 g (-0.8;25.4), p = 0.07, with the largest effect in vitamin D sufficient children from mothers receiving high-dose vitamin D supplementation; BMD, aMD: 0.016 g/cm2 (0.002;0.030), p = 0.03, and BMC, aMD: 23.5 g (5.5;41.5), p = 0.01. INTERPRETATION: Childhood vitamin D sufficiency improved bone mineralization and in combination with prenatal high-dose vitamin D supplementation reduced the risk of fractures. FUNDING: The study was supported by The Lundbeck Foundation R16-A1694, The Danish Ministry of Health 903,516, The Danish Council for Strategic Research 0603-00280B and The European Research Council 946,228.