BACKGROUND:A Western dietary pattern (WDP) is linked to socioeconomic status (SES) and has been proposed as a risk factor for childhood asthma. However, how SES influences the relationship between dietary patterns and asthma risk remains poorly understood. OBJECTIVE:We aimed to investigate the interplay between SES and WDP during pregnancy and early childhood on risk of childhood asthma. METHODS:We analyzed 594 mother-child pairs from the COPSAC2010 cohort. Maternal food frequency questionnaires (FFQs) were completed during pregnancy, and children were followed for asthma/wheeze until age 10 years. Untargeted plasma metabolomics profiles were obtained at pregnancy week 24 and child ages 6 and 18 months. A WDP score derived from FFQs was used to compute WDP metabolite scores using sparse partial least squares (sPLS). Associations between WDP and asthma/wheeze and their interactions with SES were evaluated by regression models. Replication was performed in 772 mother-child pairs from VDAART with comparable metabolomics data and in 388 children from COPSAC2000 with neonatal dried blood spot metabolomics. SES was defined using principal component analysis of household income, maternal education, and maternal age. RESULTS:In COPSAC2010, SES was inversely correlated with WDP (r = -0.40 to -0.14; p < .01). Significant WDP-SES interactions were observed for multiple asthma/wheeze outcomes (p < .05). Among children with low SES, higher maternal WDP FFQ-scores were associated with an increased risk of recurrent wheeze until 3 years (aHR = 1.29 [1.03-1.60], p = .023) and asthma until 10 years (aHR = 1.32 [1.06-1.65], p = .015) and higher child WDP metabolite-score were associated with asthma until 10 years (aHR = 1.87 [1.21-2.90], p = .005). No significant WDP-SES interactions were observed in the replication cohorts; however, low SES was independently associated with asthma/wheeze in VDAART, and higher WDP-scores were associated with increased risk in COPSAC2000 among low-SES children. CONCLUSIONS:WDP during pregnancy and early childhood is associated with increased risk of childhood asthma/wheeze, with evidence supporting a directional association with SES rather than effect modification.

BACKGROUND:Lipid species are emerging as biomarkers for cardiometabolic risk in both adults and children. The genetic regulation of lipid species and their impact on cardiometabolic risk during early life remain unexplored. METHODS:Using mass spectrometry-based lipidomics, we measured 227 plasma lipid species in 1149 children and adolescents (44.8% boys) with a median age of 11.2 years. We performed genome-wide association analyses to identify genetic variants influencing lipid species. Colocalisation and Mendelian randomisation (MR) analyses were performed to infer causality between lipid species and cardiometabolic outcomes. FINDINGS:We identified 37 genome-wide significant loci for 52 lipid species, nine of which are previously unreported. Colocalisation analyses revealed that seven lipid loci shared genetic variants associated with adult cardiometabolic outcomes. One-sample MR analysis identified positive causal associations between ceramides and liver enzymes, sphingomyelins and hemoglobin A1c (HbA1c), and phosphatidylethanolamines and high-sensitivity C-reactive protein in children and adolescents. Two-sample MR using adult-based summary statistics showed consistent direction of associations and indicated additional causal links, specifically between ceramides and elevated HbA1c levels, and phosphatidylinositols with elevated liver enzymes. INTERPRETATION:These findings highlight the potential long-term implications of plasma lipid genetic determinants on cardiometabolic risk. FUNDING:Novo Nordisk Foundation, The Innovation Fund Denmark, The Danish Heart Foundation, EU Horizon, and LundbeckFonden.

BACKGROUND:Studies have described sex differences in childhood asthma, allergy, and atopic dermatitis, but the development and clinical phenotype of these differences remain poorly understood. OBJECTIVE:To characterize sex differences in atopic disease throughout childhood and study the potential role of sex-steroid metabolites. METHODS:We examined sex differences in asthma, allergy, and atopic dermatitis using longitudinal generalized estimating equation models in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC)2000 (n = 411) and COPSAC2010 (n = 700) birth cohorts. We further examined possible mechanisms through early life sex-steroid metabolites. RESULTS:In combined analyses of COPSAC2000 and COPSAC2010 until age 6 years, males had a higher prevalence of asthma compared with females (25% vs 20%, odds ratio = 1.48; 95% CI, 1.09-2.02) and experienced more asthma exacerbations (incidence rate ratio = 1.87; 95% CI, 1.37-2.55). Males had a higher prevalence of allergic sensitization (37% vs 31%; odds ratio = 1.54; 95% CI, 1.20-1.98) and higher blood eosinophil count (geometric mean ratio = 1.16; 95% CI, 1.07-1.27), which may indicate type 2 inflammation. These sex differences persisted until age 18 years in COPSAC2000, except for asthma prevalence, whereas males had a higher prevalence of allergic rhinitis and a higher FeNO. During preschool age, five of the measured sex-steroid metabolites significantly mediated parts of the sex differences in allergic sensitization (range of proportion mediated, 0.16-0.18) and/or blood eosinophils (range of proportion mediated, 0.22-0.25). CONCLUSIONS:Males had a higher prevalence of asthma, more frequent asthma exacerbations, higher prevalence of allergic sensitization, and higher blood eosinophil count compared with females during early childhood across two birth cohorts. These sex differences, which may indicate type 2 inflammation, persisted into adolescence and were partly explained by sex-steroid metabolites.

Background/Objectives: Randomized clinical trials (RCTs) suggest that n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and high-dose vitamin D supplementation during pregnancy may protect against childhood asthma. However, the underlying mechanisms remain unclear. Methods: To explore the transcriptional effects of various concentrations of n-3 LCPUFA and vitamin D supplementation on in utero lung development, we cultured human lung organoids derived from BILX and SEHP human-induced pluripotent stem cell lines at the Sanger Institute (Cambridge, UK). The organoids were treated with either no supplementation, or low (0.01 µL/mL) or high (0.1 µL/mL) concentrations of n-3 LCPUFA, as well as no supplementation, or low (5 pM) or high (50 pM) concentrations of vitamin D. Organoids were matured for 50 days, with foregut spheroids embedded in Matrigel and later re-embedded individually to ensure robust growth. We then assessed the impact of these supplementations using RNA sequencing. Results: RNA sequencing of four replicates per condition (36 total samples) revealed that n-3 LCPUFA supplementation had a more substantial impact on gene regulation than vitamin D (differentially expressed genes, n = 907 vs. n = 23). CPT1A and ANGPTL4 genes were highly expressed in media cultured with a high concentration of n-3 LCPUFA, while CYP24A1 was among the highly expressed genes in media cultured with a high concentration of vitamin D. Enrichment analysis showed activation of PPAR pathways, suggesting that n-3 LCPUFA supplementation may protect against asthma by regulating lipid metabolism and inflammation. Conclusions: We identified several genes and pathways that may provide insights into the biological effects of n-3 LCPUFA and vitamin D supplementation on asthma pathophysiology.

Airspace or aerenchyma is crucial for plant development and acclimation to stresses such as hypoxia, drought, and nutritional deficiency. Although ethylene-mediated signaling cascades are known to regulate aerenchyma formation in stems and roots under hypoxic conditions, the precise mechanisms remain unclear. Moreover, the cellular dynamics underlying airspace formation in shoots are poorly understood. We investigated the stage-dependent structural dynamics of shoot aerenchyma in greater duckweed (Spirodela polyrhiza), a fast-growing aquatic herb with well-developed aerenchyma in its floating fronds. Using X-ray micro-computed tomography and histological analysis, we showed that the spatial framework of aerenchyma is established before frond volume increases, driven by cell division and expansion. The substomatal cavity connecting aerenchyma to stomata formed via programmed cell death (PCD) and was closely associated with guard cell development. Additionally, transcriptome analysis and pharmacological studies revealed that the organization of aerenchyma in greater duckweed is determined by the interplay between PCD and proliferation. This balance is governed by spatiotemporal regulation of phytohormone signaling involving ethylene, abscisic acid, and salicylic acid. Overall, our study reveals the structural dynamics and phytohormonal regulation underlying aerenchyma development in duckweed, improving our understanding of how plants establish distinct architectural arrangements. These insights hold the potential for wide-ranging application, not only in comprehending aerenchyma formation across various plant species but also in understanding how airspaces are formed within the leaves of terrestrial plants.

We previously demonstrated a beneficial effect of high-dose vitamin D in pregnancy on offspring bone and dental health. Here, we investigated the effect of maternal dietary patterns during pregnancy on the risk of bone fractures, bone mineralization and enamel defects until age 6 years in the offspring. Further, the influence of diet on the effect of high-dose vitamin D was analyzed in the COPSAC2010 mother–child cohort including 623 mother–child pairs. A weighted network analysis on FFQs revealed three specific maternal dietary patterns that associated (Bonferroni p < 0.05) with both offspring bone and dental health. The effect of prenatal high-dose (2800 IU/day) vs. standard-dose (400 IU/day) vitamin D on offspring bone mineral content (adjusted mean difference (aMD): 33.29 g, 95% CI: 14.48–52.09, p < 0.001), bone mineral density (aMD: 0.02 g/cm2 (0.01–0.04), p < 0.001), fracture risk (adjusted incidence rate ratio: 0.36 (0.16–0.84), p = 0.02), and enamel defects in primary (adjusted odds ratio (aOR): 0.13 (0.03–0.58), p < 0.01) and permanent molars (aOR: 0.25; (0.10–0.63), p < 0.01) was most pronounced when mothers had lower intake of fruit, vegetables, meat, eggs, sweets, whole grain, offal and fish. This study suggests that prenatal dietary patterns influence offspring bone and dental development, and should be considered in order to obtain the full benefits of vitamin D to enhance personalized supplementation strategy.

BackgroundExercise is considered as a cost-efficient option for individuals with mild cognitive impairment (MCI). Although the potential benefits of exercise for improving cognitive function are recognized, its impact on neuropsychiatric symptoms (NPS) and the quality of life (QoL) in individuals with MCI remains unclear.ObjectiveThis study aims to investigate the effects of exercise interventions on NPS, including depression, anxiety, sleep disorders, and the quality of life in individuals with MCI.ResultsThere were 17 randomized controlled trials (RCTs) involving 1,575 participants were included. The findings indicate a small but significant positive effect of exercise on depression (standardized mean difference [SMD] = −0.47, 95% confidence interval [CI]: −0.73 to −0.21), but the quality of the evidence is low. Mind–body exercises were relatively more effective in alleviating depression. No significant improvements were observed in sleep disorders (SMD = −1.27, 95% CI: −2.80 to 0.26). Exercise improved anxiety in one study but had no effect in the other. It also improved quality of life in seven studies, with two showing no effect.ConclusionThe findings suggest that exercise, particularly mind–body exercises, can improve depression in individuals with MCI. However, the effect of exercise on anxiety, sleep disorders, and quality of life is still uncertain, necessitating additional research. These findings underscore the significance of integrating customized exercise programs in managing MCI to boost quality of life and mitigate NPS.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/. ID: CRD42023445369.

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 COPS AC 2010 (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 2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P P < FDR5%) and type-2 inflammation (P P < .05). In VDAART, lower PGE2 2 and PGI2 2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P P < FDR5%). For wheeze/asthma, analyses in COPSAC201 201 0 showed that lower isoprostanes and PGF2 2 eicosanoids and higher PGD2 2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P P < .05), whereas analyses in VDAART showed that lower PGE2 2 and higher TXA2 2 eicosanoids at age 3 years associated with an increased risk at 6 years (P 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.

Pediatric obesity is a progressive, chronic disease that can lead to serious cardiometabolic complications. Here we investigated the peripheral lipidome in 958 children and adolescents with overweight or obesity and 373 with normal weight, in a cross-sectional study. We also implemented a family-based, personalized program to assess the effects of obesity management on 186 children and adolescents in a clinical setting. Using mass spectrometry-based lipidomics, we report an increase in ceramides, alongside a decrease in lysophospholipids and omega-3 fatty acids with obesity metabolism. Ceramides, phosphatidylethanolamines and phosphatidylinositols were associated with insulin resistance and cardiometabolic risk, whereas sphingomyelins showed inverse associations. Additionally, a panel of three lipids predicted hepatic steatosis as effectively as liver enzymes. Lipids partially mediated the association between obesity and cardiometabolic traits. The nonpharmacological management reduced levels of ceramides, phospholipids and triglycerides, indicating that lowering the degree of obesity could partially restore a healthy lipid profile in children and adolescents. A combination of cross-sectional study and lifestyle intervention program uncovered altered lipid profiles in children and adolescents with obesity and demonstrated that a personalized obesity management program can restore a healthy lipid profile.

Background We previously showed an association between neonatal bacterial airway colonisation and increased risk of persistent wheeze/asthma until age 5 years. Here, we study the association with persistent wheeze/asthma and allergy-related traits until age 18 years. Methods We investigated the association between airway colonisation with Streptococcus pneumoniae , Moraxella catarrhalis and/or Haemophilus influenzae in 1-month-old neonates from the COPSAC 2000 mother–child cohort and the development of persistent wheeze/asthma and allergy-related traits longitudinally until age 18 years using generalised estimating equations. Replication was sought in the similarly designed COPSAC 2010 cohort of 700 children. Results Neonatal airway colonisation was present in 66 (21%) out of 319 children and was associated with a 4-fold increased risk of persistent wheeze/asthma (adjusted OR 4.01 (95% CI 1.76–9.12); p<0.001) until age 7 years, but not from age 7 to 18 years. Replication in the COPSAC 2010 cohort showed similar results using 16S data. Colonisation was associated with an increased number of exacerbations (adjusted incidence rate ratio 3.20 (95% CI 1.38–7.44); p<0.01) until age 7 years, but not from age 7 to 18 years. Colonisation was associated with increased levels of blood eosinophils (adjusted geometric mean ratio 1.24 (95% CI 1.06–1.44); p<0.01) and tumour necrosis factor (TNF)-α (adjusted geometric mean ratio 1.09 (95% CI 1.02–1.16); p=0.01) until age 12 years. There were no associations with lung function, bronchial reactivity, fractional exhaled nitric oxide, allergic sensitisation, total IgE or atopic dermatitis up to age 18 years. Conclusions Neonatal airway colonisation was associated with early-onset persistent wheeze/asthma, exacerbations, elevated blood eosinophils and elevated TNF-α in blood, most prominent in early childhood, thereafter diminishing and no longer evident by age 18 years.

Background: Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts. Methods: Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC(2010) (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms. Findings: Increasing bilirubin (Z,Z) at ages 1.5-3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20-2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR =1.31 [0.97-1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5-3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81-0.91, p < 0.049) but without a significant interaction with the UGT1A genotype (p interactions > 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections. Conclusions: Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes. Funding: The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), Danish Council for Strategic Research (Grant no 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was supported by R01HL091528 from the NHLBI, UG3OD023268 from Office of The Director, National Institute of Health, and P01HL132825 from the NHLBI.

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 extent to which increased liver fat content influences differences in circulating metabolites and/or lipids between low-birth-weight (LBW) individuals, at increased risk of type 2 diabetes (T2D), and normal-birth-weight (NBW) controls is unknown. The objective of the study was to perform untargeted serum metabolomics and lipidomics analyses in 26 healthy, non-obese early-middle-aged LBW men, including five men with screen-detected and previously unrecognized non-alcoholic fatty liver disease (NAFLD), compared with 22 age- and BMI-matched NBW men (controls). While four metabolites (out of 65) and fifteen lipids (out of 279) differentiated the 26 LBW men from the 22 NBW controls (p ≤ 0.05), subgroup analyses of the LBW men with and without NAFLD revealed more pronounced differences, with 11 metabolites and 56 lipids differentiating (p ≤ 0.05) the groups. The differences in the LBW men with NAFLD included increased levels of ornithine and tyrosine (PFDR ≤ 0.1), as well as of triglycerides and phosphatidylcholines with shorter carbon-chain lengths and fewer double bonds. Pathway and network analyses demonstrated downregulation of transfer RNA (tRNA) charging, altered urea cycling, insulin resistance, and an increased risk of T2D in the LBW men with NAFLD. Our findings highlight the importance of increased liver fat in the pathogenesis of T2D in LBW individuals.

BACKGROUND:Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. OBJECTIVE:We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. METHODS:Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC2010, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. RESULTS:In COPSAC2010, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmic sphingolipid level (P < .01). CONCLUSIONS:This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.

BACKGROUND:There is evidence that both omega-3 long-chain polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and cocoa flavanols can improve cognitive performance in both healthy individuals and in those with memory complaints. However, their combined effect is unknown. OBJECTIVES:To investigate the combined effect of EPA/DHA and cocoa flavanols (OM3FLAV) on cognitive performance and brain structures in older adults with memory complaints. METHODS:A randomized placebo-controlled trial of DHA-rich fish oil (providing 1.1 g/d DHA and 0.4 g/d EPA) and a flavanol-rich dark chocolate (providing 500 mg/d flavan-3-ols) was conducted in 259 older adults with either subjective cognitive impairment or mild cognitive impairment. Participants underwent assessment at baseline, 3 mo, and 12 mo. The primary outcome was the number of false-positives on a picture recognition task from the Cognitive Drug Research computerized assessment battery. Secondary outcomes included other cognition and mood outcomes, plasma lipids, brain-derived neurotrophic factor (BDNF), and glucose levels. A subset of 110 participants underwent structural neuroimaging at baseline and at 12 mo. RESULTS:197 participants completed the study. The combined intervention had no significant effect on any cognitive outcomes, with the exception of reaction time variability (P = 0.007), alertness (P < 0.001), and executive function (P < 0.001), with a decline in function observed in the OM3FLAV group (118.6 [SD 25.3] at baseline versus 113.3 [SD 25.4] at 12 mo for executive function) relative to the control, and an associated decrease in cortical volume (P = 0.039). Compared with the control group, OM3FLAV increased plasma HDL, total cholesterol ratio (P < 0.001), and glucose (P = 0.008) and reduced TG concentrations (P < 0.001) by 3 mo, which were sustained to 12 mo, with no effect on BDNF. Changes in plasma EPA and DHA and urinary flavonoid metabolite concentrations confirmed compliance to the intervention. CONCLUSIONS:These results suggest that cosupplementation with ω-3 PUFAs and cocoa flavanols for 12 mo does not improve cognitive outcomes in those with cognitive impairment. This trial was registered at clinicaltrials.gov as NCT02525198.

BACKGROUND Diabetes is a major risk factor for the development of dementia, which has been proven to be associated with systemic inflammation. Acute pancreatitis, also a local and systemic inflammatory disease, is the most common gastrointestinal disease requiring acute hospitalization. OBJECTIVE The effect of acute pancreatitis on dementia was investigated in type 2 diabetic patients. METHODS Data was collected from the Korean National Health Insurance Service. The study sample included type 2 diabetes patients who received general health examination from 2009 to 2012. Cox proportional hazard regression analysis was used to evaluate the association between acute pancreatitis and dementia with adjustment of confounders. Stratified subgroup analysis by age, sex, smoking, alcohol consumption, hypertension, dyslipidemia, and body mass index was conducted. RESULTS Among the 2,328,671 participants in total, 4,463 patients had a history of acute pancreatitis before the health examination. During a median follow-up of 8.1 (IQR, 6.7-9.0) years, 194,023 participants (8.3%) developed all-cause dementia. Previous history of acute pancreatitis was a significant risk factor for dementia after adjustment of confounding variables (HR 1.39 [95% CI 1.26-1.53]). In the subgroup analysis, patient characteristics such as age under 65 years, male, current smoker, and alcohol consumption were significant risk factors for dementia in patients with a history of acute pancreatitis. CONCLUSION The history of acute pancreatitis was associated with the development of dementia in patients with diabetes. Because the risk of dementia increases with alcohol consumption and smoking in diabetic patients with history of acute pancreatitis, abstinence from alcohol and smoking should be recommended.

BACKGROUND & AIMS:Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD.METHODS:We performed mass spectrometry-based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization.RESULTS:We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co-down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of "pure ALD," as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels.CONCLUSIONS:Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.

We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.