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Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.
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Ácidos Nucleicos Livres , Pré-Eclâmpsia , RNA , Ácidos Nucleicos Livres/sangue , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Valor Preditivo dos Testes , Gravidez , RNA/sangue , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) not only caused the COVID-19 pandemic but also had a major impact on farmed mink production in several European countries. In Denmark, the entire population of farmed mink (over 15 million animals) was culled in late 2020. During the period of June to November 2020, mink on 290 farms (out of about 1100 in the country) were shown to be infected with SARS-CoV-2. Genome sequencing identified changes in the virus within the mink and it is estimated that about 4000 people in Denmark became infected with these mink virus variants. However, the routes of transmission of the virus to, and from, the mink have been unclear. Phylogenetic analysis revealed the generation of multiple clusters of the virus within the mink. Detailed analysis of changes in the virus during replication in mink and, in parallel, in the human population in Denmark, during the same time period, has been performed here. The majority of cases in mink involved variants with the Y453F substitution and the H69/V70 deletion within the Spike (S) protein; these changes emerged early in the outbreak. However, further introductions of the virus, by variants lacking these changes, from the human population into mink also occurred. Based on phylogenetic analysis of viral genome data, we estimate, using a conservative approach, that about 17 separate examples of mink to human transmission occurred in Denmark but up to 59 such events (90% credible interval: (39-77)) were identified using parsimony to count cross-species jumps on transmission trees inferred using Bayesian methods. Using the latter approach, 136 jumps (90% credible interval: (117-164)) from humans to mink were found, which may underlie the farm-to-farm spread. Thus, transmission of SARS-CoV-2 from humans to mink, mink to mink, from mink to humans and between humans were all observed.
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COVID-19 , Vison , Filogenia , SARS-CoV-2 , Vison/virologia , COVID-19/transmissão , COVID-19/virologia , COVID-19/epidemiologia , COVID-19/veterinária , SARS-CoV-2/genética , Animais , Dinamarca/epidemiologia , Humanos , Pandemias , Fazendas , Betacoronavirus/genética , Betacoronavirus/classificação , Genoma Viral , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Infecções por Coronavirus/transmissão , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.
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BACKGROUND: Analysis of time-resolved postprandial metabolomics data can improve the understanding of metabolic mechanisms, potentially revealing biomarkers for early diagnosis of metabolic diseases and advancing precision nutrition and medicine. Postprandial metabolomics measurements at several time points from multiple subjects can be arranged as a subjects by metabolites by time points array. Traditional analysis methods are limited in terms of revealing subject groups, related metabolites, and temporal patterns simultaneously from such three-way data. RESULTS: We introduce an unsupervised multiway analysis approach based on the CANDECOMP/PARAFAC (CP) model for improved analysis of postprandial metabolomics data guided by a simulation study. Because of the lack of ground truth in real data, we generate simulated data using a comprehensive human metabolic model. This allows us to assess the performance of CP models in terms of revealing subject groups and underlying metabolic processes. We study three analysis approaches: analysis of fasting-state data using principal component analysis, T0-corrected data (i.e., data corrected by subtracting fasting-state data) using a CP model and full-dynamic (i.e., full postprandial) data using CP. Through extensive simulations, we demonstrate that CP models capture meaningful and stable patterns from simulated meal challenge data, revealing underlying mechanisms and differences between diseased versus healthy groups. CONCLUSIONS: Our experiments show that it is crucial to analyze both fasting-state and T0-corrected data for understanding metabolic differences among subject groups. Depending on the nature of the subject group structure, the best group separation may be achieved by CP models of T0-corrected or full-dynamic data. This study introduces an improved analysis approach for postprandial metabolomics data while also shedding light on the debate about correcting baseline values in longitudinal data analysis.
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Medicina , Metabolômica , Humanos , Simulação por Computador , Análise de Dados , Nível de SaúdeRESUMO
INTRODUCTION: Longitudinal metabolomics data from a meal challenge test contains both fasting and dynamic signals, that may be related to metabolic health and diseases. Recent work has explored the multiway structure of time-resolved metabolomics data by arranging it as a three-way array with modes: subjects, metabolites, and time. The analysis of such dynamic data (where the fasting data is subtracted from postprandial states) reveals dynamic markers of various phenotypes, and differences between fasting and dynamic states. However, there is still limited success in terms of extracting static and dynamic biomarkers for the same subject stratifications. OBJECTIVES: Through joint analysis of fasting and dynamic metabolomics data, our goal is to capture static and dynamic biomarkers of a phenotype for the same subject stratifications providing a complete picture, that will be more effective for precision health. METHODS: We jointly analyze fasting and dynamic metabolomics data collected during a meal challenge test from the COPSAC 2000 cohort using coupled matrix and tensor factorizations (CMTF), where the dynamic data (subjects by metabolites by time) is coupled with the fasting data (subjects by metabolites) in the subjects mode. RESULTS: The proposed data fusion approach extracts shared subject stratifications in terms of BMI (body mass index) from fasting and dynamic signals as well as the static and dynamic metabolic biomarker patterns corresponding to those stratifications. Specifically, we observe a subject stratification showing the positive association with all fasting VLDLs and higher BMI. For the same subject stratification, a subset of dynamic VLDLs (mainly the smaller sizes) correlates negatively with higher BMI. Higher correlations of the subject quantifications with the phenotype of interest are observed using such a data fusion approach compared to individual analyses of the fasting and postprandial state. CONCLUSION: The CMTF-based approach provides a complete picture of static and dynamic biomarkers for the same subject stratifications-when markers are present in both fasting and dynamic states.
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Biomarcadores , Jejum , Metabolômica , Período Pós-Prandial , Humanos , Biomarcadores/sangue , Biomarcadores/metabolismo , Metabolômica/métodos , Jejum/metabolismo , Masculino , Feminino , Adulto , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Analysis of time-resolved postprandial metabolomics data can improve our understanding of the human metabolism by revealing similarities and differences in postprandial responses of individuals. Traditional data analysis methods often rely on data summaries or univariate approaches focusing on one metabolite at a time. OBJECTIVES: Our goal is to provide a comprehensive picture in terms of the changes in the human metabolism in response to a meal challenge test, by revealing static and dynamic markers of phenotypes, i.e., subject stratifications, related clusters of metabolites, and their temporal profiles. METHODS: We analyze Nuclear Magnetic Resonance (NMR) spectroscopy measurements of plasma samples collected during a meal challenge test from 299 individuals from the COPSAC2000 cohort using a Nightingale NMR panel at the fasting and postprandial states (15, 30, 60, 90, 120, 150, 240 min). We investigate the postprandial dynamics of the metabolism as reflected in the dynamic behaviour of the measured metabolites. The data is arranged as a three-way array: subjects by metabolites by time. We analyze the fasting state data to reveal static patterns of subject group differences using principal component analysis (PCA), and fasting state-corrected postprandial data using the CANDECOMP/PARAFAC (CP) tensor factorization to reveal dynamic markers of group differences. RESULTS: Our analysis reveals dynamic markers consisting of certain metabolite groups and their temporal profiles showing differences among males according to their body mass index (BMI) in response to the meal challenge. We also show that certain lipoproteins relate to the group difference differently in the fasting vs. dynamic state. Furthermore, while similar dynamic patterns are observed in males and females, the BMI-related group difference is observed only in males in the dynamic state. CONCLUSION: The CP model is an effective approach to analyze time-resolved postprandial metabolomics data, and provides a compact but a comprehensive summary of the postprandial data revealing replicable and interpretable dynamic markers crucial to advance our understanding of changes in the metabolism in response to a meal challenge.
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Metabolômica , Período Pós-Prandial , Humanos , Período Pós-Prandial/fisiologia , Masculino , Feminino , Metabolômica/métodos , Adulto , Jejum/metabolismo , Análise de Componente Principal , Espectroscopia de Ressonância Magnética/métodos , Pessoa de Meia-Idade , Análise de Dados , Metaboloma/fisiologiaRESUMO
BACKGROUND: Infantile colic is a common condition with limited knowledge about later clinical manifestations. We evaluated the role of the early life gut microbiome in infantile colic and later development of atopic and gastrointestinal disorders. METHODS: Copenhagen Prospective Studies on Asthma in Childhood2010 cohort was followed with 6 years of extensive clinical phenotyping. The 1-month gut microbiome was analyzed by 16S rRNA sequencing. Infantile colic was evaluated at age 3 months by interviews. Clinical endpoints included constipation to age 3 years and prospectively diagnosed asthma and atopic dermatitis in the first 6 years of life, and allergic sensitization from skin prick tests, specific Immunoglobulin E, and component analyses. RESULTS: Of 695 children, 55 children (7.9%) had infantile colic. Several factors were associated with colic including race, breastfeeding, and pets. The 1-month gut microbiome composition and taxa abundances were not associated with colic, however a sparse Partial Least Squares model including combined abundances of nine species was moderately predictive of colic: median, cross-validated AUC = 0.627, p = .003. Children with infantile colic had an increased risk of developing constipation (aOR, 2.88 [1.51-5.35], p = .001) later in life, but also asthma (aHR, 1.69 [1.02-2.79], p = .040), atopic dermatitis (aHR, 1.84 [1.20-2.81], p = .005) and had a higher number of positive allergic components (adjusted difference, 116% [14%-280%], p = .012) in the first 6 years. These associations were not mediated by gut microbiome differences. CONCLUSIONS: We link infantile colic with risk of developing constipation and atopic disorders in the first 6 years of life, which was not mediated through an altered gut microbiome at age 1-month. These results suggest infantile colic to involve gastrointestinal and/or atopic mechanisms.
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BACKGROUND AND AIMS: Implementation of screening modalities have reduced the burden of colorectal cancer (CRC), but high false positive rates pose a major problem for colonoscopy capacity. We aimed to create a tailored screening algorithm that expands the fecal immunochemical test (FIT) with a blood specimen and current age to improve selection of individuals for diagnostic colonoscopy. METHODS: In this prospective multi-center study, eight blood-based biomarkers (CEA, Ferritin, hsCRP, HE4, Cyfra21-1, Hepsin, IL-8 and OPG) were investigated in 1,977 FIT positive individuals from the Danish national CRC screening program undergoing follow-up colonoscopy. Specimens were analyzed on ARCHITECT i2000®, ARCHITECT c8000® or Luminex xMAP® machines. FIT analyses and blood-based biomarker data were combined with clinical data (i.e., age and colonoscopy findings) in a cross-validated logistic regression model (algorithm) benchmarked against a model solely using the FIT result (FIT model) applying different cutoffs for FIT positivity. RESULTS: The cohort included individuals with CRC (n = 240), adenomas (n = 938) or no neoplastic lesions (n = 799). The cross-validated algorithm combining the eight biomarkers, quantitative FIT result and age performed superior to the FIT model in discriminating CRC versus non-CRC individuals (AUC 0.77 versus 0.67, p < 0.001). When discriminating individuals with either CRC or high- or medium-risk adenomas versus low-risk adenomas or clean colorectum, the AUCs were 0.68 versus 0.64 for the algorithm and FIT model, respectively. CONCLUSIONS: The algorithm presented here can improve patient allocation to colonoscopy, reducing colonoscopy burden without compromising cancer and adenomas detection rates or vice versa.
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BACKGROUND: Adenoma surveillance guidelines are based on non-fecal immunochemical test (FIT)-based screening settings. However, colorectal cancer (CRC) risk may be different in FIT-positive screening populations. We evaluated the CRC and advanced adenoma risk within the recommended surveillance periods in the Danish FIT-based CRC screening program for participants with intermediate or high risk adenomas according to 2010 European guidelines. Furthermore, we estimated CRC risk for those who were not recommended surveillance according to European Society of Gastrointestinal Endoscopy (ESGE) 2020 guidelines. METHODS: Using nationwide health registries, we identified 17 936 FIT-screening participants from 2014-2017 with adenomas undergoing surveillance (high risk 1 year, intermediate risk 3 years). Participants with a follow-up examination were included (N = 10 068). Relative risk (RR) of CRC and advance adenoma was compared between intermediate and high risk groups and between intermediates who were recommended surveillance (S) or no surveillance (NS) according to 2020 ESGE guidelines. RESULTS: During surveillance, CRC occurred in 0.59% of the high risk group and 1.11% of the intermediate risk group (RR 0.53 [95%CI 0.34-0.84]). The high risk group had a 24% increased risk of advanced adenoma. CRC occurred in 1.69% of the intermediateNS group and 0.87% of the intermediateS group (RR 1.94 [95%CI 1.18-3.21]), and RR for advanced adenoma was 1.19 (95%CI 1.03-1.37). CONCLUSION: CRC detection was lower among participants rated at higher risk at initial CRC screening. Findings at first screen-derived colonoscopy might not be as good a predictor of CRC risk in a FIT-positive screening population.
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Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis ß-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-ß (transforming growth factor-ß) (highest in the Veillonella cluster) and Wnt/ß-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.
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Asma , Hipersensibilidade , Microbiota , Feminino , Masculino , Humanos , Transcriptoma , Sons Respiratórios/genética , Asma/genética , Microbiota/genéticaRESUMO
BACKGROUND: Exposure to ambient air pollution has been linked to asthma, allergic rhinitis, and other inflammatory disorders, but little is known about the underlying mechanisms. OBJECTIVE: We studied the potential mechanisms leading from prenatal ambient air pollution exposure to asthma and allergy in childhood. METHODS: Long-term exposure to nitrogen dioxide (NO2) as well as to particulate matter with a diameter of ≤2.5 and ≤10 µm (PM2.5 and PM10) were modeled at the residence level from conception to 6 years of age in 700 Danish children followed clinically for development of asthma and allergy. Nasal mucosal immune mediators were assessed at age 4 weeks and 6 years, inflammatory markers in blood at 6 months, and nasal epithelial DNA methylation and gene expression at age 6 years. RESULTS: Higher prenatal air pollution exposure with NO2, PM2.5, and PM10 was associated with an altered nasal mucosal immune profile at 4 weeks, conferring an increased odds ratio [95% confidence interval] of 2.68 [1.58, 4.62] for allergic sensitization and 2.63 [1.18, 5.81] for allergic rhinitis at age 6 years, and with an altered immune profile in blood at age 6 months conferring increased risk of asthma at age 6 years (1.80 [1.18, 2.76]). Prenatal exposure to ambient air pollution was not robustly associated with immune mediator, epithelial DNA methylation, or gene expression changes in nasal cells at age 6 years. CONCLUSION: Prenatal exposure to ambient air pollution was associated with early life immune perturbations conferring risk of allergic rhinitis and asthma. These findings suggest potential mechanisms of prenatal exposure to ambient air pollution on the developing immune system.
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Poluentes Atmosféricos , Asma , Efeitos Tardios da Exposição Pré-Natal , Rinite Alérgica , Criança , Gravidez , Feminino , Humanos , Lactente , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Dióxido de Nitrogênio/efeitos adversos , Asma/etiologia , Asma/induzido quimicamente , Material Particulado/efeitos adversos , Rinite Alérgica/induzido quimicamente , Exposição Ambiental/efeitos adversosRESUMO
OBJECTIVES: The traditional view on psychiatric disorders as categorical and distinct is being challenged by perspectives emphasizing the relevance of dimensional and transdiagnostic assessment. However, most diagnostic instruments are based on a categorical view with a threshold-approach to disease classification. METHODS: We here describe algorithms for dimensionalizing the psychopathological ratings of the widely used diagnostic interview for children and adolescents, the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL). We further evaluate the criterion-related construct validity of the dimensionalized attention-deficit/hyperactivity disorder (ADHD) scales using Rasch models in a sample of 590 children (mean age 10.29 (.36), 49% girls). RESULTS: The algorithms generate scores of current symptom load, i.e., the sum of clinician-rated symptoms within each disorder assessed with the interview. We found support for counting symptoms of inattention and hyperactivity/impulsivity, respectively, but not for a single combined ADHD scale. CONCLUSIONS: The algorithms constitute an initial step in creating a framework for clinician-rated dimensional analyses of symptoms derived from the K-SADS-PL, but future studies are needed to further evaluate the construct validity of the remaining scales and the reliability and clinical utility of the method. We believe that our proposed algorithms offer a novel method of dimensional psychopathological assessment, which can be applied in multiple branches of child and adolescent psychiatry.
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Transtorno do Deficit de Atenção com Hiperatividade , Criança , Feminino , Humanos , Adolescente , Masculino , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Reprodutibilidade dos Testes , Psicopatologia , Escalas de Graduação Psiquiátrica , Psiquiatria do AdolescenteRESUMO
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 (Pâ =â .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (Pâ =â .037). A reduction in the number of gastroenteritis episodes (Pâ =â .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66-.97]; Pâ =â .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.
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Ácidos Graxos Ômega-3 , Gastroenterite , Gravidez , Feminino , Pré-Escolar , Humanos , Óleos de Peixe/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Gastroenterite/prevenção & controleRESUMO
We analyzed wastewater samples from 14 aircraft arriving in Denmark directly from China during January 9-February 12, 2023. Wastewater from 11 aircraft was SARS-CoV-2-positive by PCR; 6 predominantly contained BQ.1 and XBB.1 subvariants. Wastewater-based surveillance can contribute to public health monitoring of SARS-CoV-2 and other emerging infectious agents.
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COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2/genética , Águas Residuárias , China/epidemiologia , Aeronaves , Dinamarca/epidemiologiaRESUMO
BACKGROUND: We recently conducted a double-blinded randomised controlled trial showing that fish-oil supplementation during pregnancy reduced the risk of persistent wheeze or asthma in the child by 30%. Here, we explore the mechanisms of the intervention. METHODS: 736 pregnant women were given either placebo or n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in the third trimester in a randomised controlled trial. Deep clinical follow-up of the 695 children in the trial was done at 12 visits until age 6 years, including assessment of genotype at the fatty acid desaturase (FADS) locus, plasma fatty acids, airway DNA methylation, gene expression, microbiome and metabolomics. RESULTS: Supplementation with n-3 LCPUFA reduced the overall risk of non-atopic asthma by 73% at age 6 (relative risk (RR) 0.27 (95% CI 0.06 to 0.85), p=0.042). In contrast, there was no overall effect on asthma with atopic traits (RR 1.42 (95% CI 0.63 to 3.38), p=0.40), but this was significantly modified by maternal FADS genotype and LCPUFA blood levels (interaction p<0.05), and supplementation did reduce the risk of atopic asthma in the subgroup of mothers with FADS risk variants and/or low blood levels of n-3 LCPUFA before the intervention (RR 0.31 (95% CI 0.11 to 0.75), p=0.016). Furthermore, n-3 LCPUFA significantly reduced the number of infections (croup, gastroenteritis, tonsillitis, otitis media and pneumonia) by 16% (incidence rate ratio 0.84 (95% CI 0.74 to 0.96), p=0.009). CONCLUSIONS: n-3 LCPUFA supplementation in pregnancy showed protective effects on non-atopic asthma and infections. Protective effects on atopic asthma depended on maternal FADS genotype and n-3 LCPUFA levels. This indicates that the fatty acid pathway is involved in multiple mechanisms affecting the risk of asthma subtypes and infections. TRIAL REGISTRATION NUMBER: NCT00798226.
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Asma , Ácidos Graxos Ômega-3 , Criança , Feminino , Humanos , Gravidez , Óleos de Peixe/uso terapêutico , Suplementos Nutricionais , Asma/prevenção & controle , Ácidos GraxosRESUMO
BACKGROUND: Colorectal cancer (CRC) screening reduces all-cause and CRC-related mortality. New research demonstrates that the faecal haemoglobin concentration (f-Hb) may indicate the presence of other serious diseases not related to CRC. We investigated the association between f-Hb, measured by a faecal immunochemical test (FIT), and both all-cause mortality and cause of death in a population-wide cohort of screening participants. METHODS: Between 2014 and 2018, 1,262,165 participants submitted a FIT for the Danish CRC screening programme. We followed these participants, using the Danish CRC Screening Database and several other national registers on health and population, until December 31, 2018. We stratified participants by f-Hb and compared them using a Cox proportional hazards regression on all-cause mortality and cause of death reported as adjusted hazard ratios (aHRs). We adjusted for several covariates, including comorbidity, socioeconomic factors, demography and prescription medication. RESULTS: We observed 21,847 deaths in the study period. Our multivariate analyses indicated an association relationship between increasing f-Hb and the risk of dying in the study period. This risk increased steadily from aHR 1.38 (95% CI: 1.32, 1.44) in those with a f-Hb of 7.1-11.9 µg Hb/g faeces to 2.20 (95% CI: 2.10, 2.30) in those with a f-Hb ≥60.0 µg Hb/g faeces, when compared to those with a f-Hb ≤7.0 µg Hb/g faeces. The pattern remained when excluding CRC from the analysis. Similar patterns were observed between incrementally increasing f-Hb and the risk of dying from respiratory disease, cardiovascular disease and cancers other than CRC. Furthermore, we observed an increased risk of dying from CRC with increasing f-Hb. CONCLUSIONS: Our findings support the hypothesis that f-Hb may indicate an elevated risk of having chronic conditions if causes for the bleeding have not been identified. The mechanisms still need to be established, but f-Hb may be a potential biomarker for several non-CRC diseases.
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Neoplasias Colorretais , Detecção Precoce de Câncer , Humanos , Causas de Morte , Neoplasias Colorretais/diagnóstico , Fezes/química , Hemoglobinas/análise , Sangue Oculto , Colonoscopia , Programas de RastreamentoRESUMO
Mink, on a farm with about 15,000 animals, became infected with SARS-CoV-2. Over 75% of tested animals were positive for SARS-CoV-2 RNA in throat swabs and 100% of tested animals were seropositive. The virus responsible had a deletion of nucleotides encoding residues H69 and V70 within the spike protein gene as well as the A22920T mutation, resulting in the Y453F substitution within this protein, seen previously in mink. The infected mink recovered and after free-testing of 300 mink (a level giving 93% confidence of detecting a 1% prevalence), the animals remained seropositive. During further follow-up studies, after a period of more than 2 months without any virus detection, over 75% of tested animals again scored positive for SARS-CoV-2 RNA. Whole genome sequencing showed that the viruses circulating during this re-infection were most closely related to those identified in the first outbreak on this farm but additional sequence changes had occurred. Animals had much higher levels of anti-SARS-CoV-2 antibodies in serum samples after the second round of infection than at free-testing or during recovery from initial infection, consistent with a boosted immune response. Thus, it was concluded that following recovery from an initial infection, seropositive mink were readily re-infected by SARS-CoV-2.
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COVID-19/veterinária , COVID-19/virologia , Vison/imunologia , Vison/virologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Teste de Ácido Nucleico para COVID-19 , Teste Sorológico para COVID-19 , Fazendas , Seguimentos , Humanos , Mutação , Faringe/virologia , Filogenia , RNA Viral , Reinfecção/virologia , Sequenciamento Completo do GenomaRESUMO
INTRODUCTION: Rural children have a lower risk of asthma and atopic diseases than urban children. However, whether indoor microbiota in non-farming rural homes provides protection is unclear. METHODS: Here, we examine if microbes in the beds of rural and urban infants are associated with later development of atopic diseases. We studied fungi and bacteria in the beds of 6-month-old infants (n = 514) in association with the risk of asthma, allergic rhinitis, eczema and aeroallergen sensitization at 6 years of age in the prospective COPSAC2010 cohort. RESULTS: Both fungal and bacterial diversity were lower in the beds of children, who later developed allergic rhinitis (-0.22 [-0.43,-0.01], padj = .04 and -.24 [-0.42,-0.05], padj = .01 respectively) and lower bacterial richness was discovered in beds of children later developing asthma (-41.34 [-76.95,-5.73], padj = .02) or allergic rhinitis (-45.65 [-81.19,-10.10], padj = .01). Interestingly, higher fungal diversity and richness were discovered in the beds of children developing eczema (0.23 [0.02,0.43], padj = .03 and 29.21 [1.59,56.83], padj = .04 respectively). We defined a limited set of fungal and bacterial genera that predicted rural/urban environment. Some rural-associated bacterial genera such as Romboutsia and Bacillus and fungal genera Spegazzinia and Physcia were also associated with reduced risk of diseases, including eczema. These fungal and bacterial fingerprints predicting the living environment were associated with asthma and allergic rhinitis, but not eczema, with rural compositions being protective. The bed dust bacteria mediated 27% of the protective association of a rural living environment for allergic rhinitis (p = .04). CONCLUSIONS: Bed dust microbes can be differentially associated with airway- and skin-related diseases. The differing bed dust microbiota between rural and urban infants may influence their later risk of asthma and allergic rhinitis.
Assuntos
Asma , Eczema , Rinite Alérgica , Lactente , Criança , Humanos , Estudos Prospectivos , Asma/epidemiologia , Asma/etiologia , Poeira , Bactérias , Rinite Alérgica/epidemiologia , Rinite Alérgica/etiologia , FungosRESUMO
BACKGROUND: Intake of fish-oil and fatty fish during pregnancy has been shown to reduce the risk of childhood asthma but biomarkers of such intake are lacking. OBJECTIVE: To establish biomarkers of prenatal fish-oil exposure from newborn dry blood spot metabolomics profiles and assess their relevance for childhood asthma risk stratification. METHODS: The Danish COPSAC2010 mother-child cohort was utilized to investigate the effect of a double-blinded randomized controlled trial of fish-oil supplementation during pregnancy on dry blood spot liquid-chromatography mass spectrometry-based metabolomics profiles of 677 newborns. We thereafter investigated the association between fish-oil associated biomarkers in the newborn and development of asthma-related outcomes. Replication was sought in the independent observational COPSAC2000 cohort with 387 newborn metabolomics profiles. RESULTS: The newborn metabolomics profiles differed between children in the fish-oil vs. placebo group in COPSAC2010 (area under the receiver operator curve = 0.94 ± 0.03, p < .001). The fish-oil metabolomics profile and the top biomarker, 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) were both associated with a decreased risk of asthma by age 6 years (HR = 0.89, p = .002 and HR = 0.67, p = .005, respectively). In COPSAC2000 , newborn CMPF level was also inversely associated with asthma risk by age 6 years (HR = 0.69, p = .01). Troublesome lung symptoms and common infections in the first 3 years were also inversely associated with newborn CMPF levels in both cohorts. CONCLUSIONS: Newborn children's blood levels of the furan fatty acid metabolite CMPF reflect fish-oil and fatty fish intake during pregnancy and are associated with a lower risk of asthma across two cohorts, which could aid newborn screening for childhood asthma.
Assuntos
Asma , Ácidos Graxos , Gravidez , Feminino , Animais , Óleos de Peixe , Asma/diagnóstico , Asma/epidemiologia , Asma/tratamento farmacológico , Furanos , Biomarcadores , Suplementos NutricionaisRESUMO
BACKGROUND: Evidence suggests maternal pregnancy dietary intake and nutrition in the early postnatal period to be of importance for the newborn child's health. However, studies investigating diet-related metabolites transferred from mother to child on disease risk in childhood are lacking. We sought to investigate the influence of vertically transferred metabolites on risk of atopic diseases and infections during preschool age. METHODS: In the Danish population-based COPSAC2010 mother-child cohort, information on 10 diet-related vertically transferred metabolites from metabolomics profiles of dried blood spots (DBS) at age 2-3 days was analyzed in relation to the risk of childhood asthma, allergy, eczema, and infections using principal component and single metabolite analyses. RESULTS: In 678 children with DBS measurements, a coffee-related metabolite profile reflected by principal component 1 was inversely associated with risk of asthma (odds ratio (95% CI) 0.78 (0.64; 0.95), p = .014) and eczema at age 6 years (0.79 (0.65; 0.97), p = .022). Furthermore, increasing stachydrine (fruit-related), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (fish-related), and ergothioneine (fruit-, green vegetables-, and fish-related) levels were all significantly associated with reduced risks of infections at age 0-3 years (p < .05). CONCLUSION: This study demonstrates associations between pregnancy diet-related vertically transferred metabolites measured in children in early life and risk of atopic diseases and infections in childhood. The specific metabolites associated with a reduced disease risk in children may contribute to the characterization of a healthy nutritional profile in pregnancy using a metabolomics-based unbiased tool for predicting childhood health.