Cross-Sectional Blood Metabolite Markers of Hypertension: A Multicohort Analysis of 44,306 Individuals from the COnsortium of METabolomics Studies

Hypertension is the main modifiable risk factor for cardiovascular morbidity and mortality but discovering molecular mechanisms for targeted treatment has been challenging. Here we investigate associations of blood metabolite markers with hypertension by integrating data from nine interconti- nental cohorts from the COnsortium of METabolomics Studies. We included 44,306 individuals with circulating metabolites (up to 813). Metabolites were aligned and inverse normalised to allow intra- platform comparison. Logistic models adjusting for covariates were performed in each cohort and results were combined using random-effect inverse-variance meta-analyses adjusting for multiple testing. We further conducted canonical pathway analysis to investigate the pathways underlying the hypertension-associated metabolites. In 12,479 hypertensive cases and 31,827 controls without renal impairment, we identified 38 metabolites, associated with hypertension after adjusting for age, sex, body mass index, ethnicity, and multiple testing. Of these, 32 metabolite associations, predominantly lipid (steroids and fatty acyls) and organic acids (amino-, hydroxy-, and keto-acids) remained after further adjusting for comorbidities and dietary intake. Among the identified metabolites, 5 were novel, including 2 bile acids, 2 glycerophospholipids, and ketoleucine. Pathway analysis further implicates the role of the amino-acids, serine/glycine, and bile acids in hypertension regulation. In the largest cross-sectional hypertension-metabolomics study to date, we identify 32 circulating metabolites (of which 5 novel and 27 confirmed) that are potentially actionable targets for intervention. Further in-vivo studies are needed to identify their specific role in the aetiology or progression of hypertension

Maternal dietary patterns, breastfeeding duration, and their association with child cognitive function and head circumference growth:A prospective mother-child cohort study

Background Early life is a critical period for neurodevelopment, where factors such as maternal nutrition and breastfeeding duration significantly impact the growth of head circumference and cognitive development in children. Our study aimed to explore the associations between maternal dietary patterns during pregnancy, duration of breastfeeding, and their impacts on child head circumference and cognitive outcomes. Methods and findings Our study utilised data from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort, which enrolled 700 mother–child pairs between 2008 and 2010 with 86% clinical follow-up at age 10. Pregnancy dietary patterns, described as ‘Varied’ and ‘Western,’ were derived from food frequency questionnaires and used to model quantitative metabolite scores via sparse partial least squares modelling of blood metabolome data. Cognitive development was assessed using the Bayley Scales of Infant Development at 2.5 years and the Wechsler Intelligence Scale for Children at age 10. Head circumference was measured from 20 weeks gestation to 10 years, and calibrated using related anthropometric measures. Growth trajectories were evaluated using linear mixed models and latent class trajectory models. Parental and child genetic influences for cognition and head circumference were controlled by including polygenic risk scores derived from genomic data. We found that a Western dietary pattern during pregnancy was associated with lower cognitive scores at age 2.5 (β −1.24 [−2.16, −0.32], p=0.008) and reduced head circumference growth (p-interaction &lt;0.0001). We found that a Varied dietary pattern during pregnancy was associated with higher estimated intelligence quotient (IQ) at age 10 (β 1.29 [0.27, 2.3], p=0.014). Additionally, head circumference growth was associated with higher cognitive scores at age 10 (β 3.40 [1.21, 5.60], p=0.002), and it partly mediates the association between the Varied dietary pattern and estimated IQ (proportion mediated 13.5% [0.01, 0.71], p=0.034). Extended breastfeeding duration was also independently associated with increased head circumference growth (p-interaction &lt;0.0001). These patterns and correlations were consistent even after adjusting for potential confounders and accounting for genetic influences. Conclusions Our findings reveal that a Western dietary pattern during pregnancy is associated with lower cognitive scores at age 2.5 and decreased head circumference growth, suggesting potential adverse impacts on early neurodevelopment. Conversely, a Varied dietary pattern is linked with a higher estimated IQ at age 10, with head circumference growth contributing to this positive outcome. These findings highlight the critical role of maternal nutrition during pregnancy, and duration of breastfeeding, in promoting optimal neurodevelopmental outcomes. Effective public health strategies should therefore focus on enhancing maternal dietary practices to support better cognitive and physical development in children.</p

COVID-19 lockdown, genetic ADHD susceptibility, and mental health in 10- year-old children

Previous studies report that the COVID-19 lockdown had an impact on the mental health of the pediatric population. In this study, we harness the deep neuropsychiatric phenotyping of the population-based COPSAC2010 (n = 700) cohort at age 10 to study the impact of the COVID-19 lockdown on mental health outcomes with focus on the role of the genetic vulnerability to attention-deficit/hyperactivity disorder (ADHD), in the form of polygenic risk scores (PRS). A total of 593 children were examined between 2019 and 2021, resulting in two groups of different children, those evaluated before the lockdown (n = 230) and those evaluated after (n = 363). Children assessed after the lockdown presented higher odds of being diagnosed with ADHD and had significantly higher scores in most neuropsychiatric scales, particularly in subscales pertaining to behavior and attention problems. We observed a significant interaction between the lockdown and ADHD PRS on several neuropsychiatric dimensions, with a large post-lockdown increase in children with a high PRS, while there was little to no pre-post difference in children with low PRS. These results indicate mental health consequences of the lockdown in children and suggest that genetically susceptible individuals are more affected by such stressors in childhood.</p

Exhaled nitric oxide and urinary EPX levels in infants: a pilot study

<p>Abstract</p> <p>Background</p> <p>Objective markers of early airway inflammation in infants are not established but are of great interest in a scientific setting. Exhaled nitric oxide (FeNO) and urinary eosinophilic protein X (uEPX) are a two such interesting markers.</p> <p>Objective</p> <p>To investigate the feasibility of measuring FeNO and uEPX in infants and their mothers and to determine if any relations between these two variables and environmental factors can be seen in a small sample size. This was conducted as a pilot study for the ongoing Swedish Environmental Longitudinal Mother and child Asthma and allergy study (SELMA).</p> <p>Methods</p> <p>Consecutive infants between two and six months old and their mothers at children's health care centres were invited, and 110 mother-infant pairs participated. FeNO and uEPX were analysed in both mothers and infants. FeNO was analyzed in the mothers online by the use of the handheld Niox Mino device and in the infants offline from exhaled air sampled during tidal breathing. A 33-question multiple-choice questionnaire that dealt with symptoms of allergic disease, heredity, and housing characteristics was used.</p> <p>Results</p> <p>FeNO levels were reduced in infants with a history of upper respiratory symptoms during the previous two weeks (p < 0.002). There was a trend towards higher FeNO levels in infants with windowpane condensation in the home (p < 0.05). There was no association between uEPX in the infants and the other studied variables.</p> <p>Conclusion</p> <p>The use of uEPX as a marker of early inflammation was not supported. FeNO levels in infants were associated to windowpane condensation. Measuring FeNO by the present method may be an interesting way of evaluating early airway inflammation. In a major population study, however, the method is difficult to use, for practical reasons.</p

Inhaler technique : facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT)

Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group

Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation

Rationale Asthma phenotyping requires novel biomarker discovery. Objectives To identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs). Methods An antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED. Results In U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation. Conclusions The plasma proteomic panel revealed previously unexplored yet potentially useful Type-2independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course