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How people wake up and regain alertness in the hours after sleep is related to how they are sleeping, eating, and exercising. Here, in a prospective longitudinal study of 833 twins and genetically unrelated adults, we demonstrate that how effectively an individual awakens in the hours following sleep is not associated with their genetics, but instead, four independent factors: sleep quantity/quality the night before, physical activity the day prior, a breakfast rich in carbohydrate, and a lower blood glucose response following breakfast. Furthermore, an individual's set-point of daily alertness is related to the quality of their sleep, their positive emotional state, and their age. Together, these findings reveal a set of non-genetic (i.e., not fixed) factors associated with daily alertness that are modifiable.

ObjectiveChronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH-driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment.MethodsPotential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N-[1-(1-oxopropy)-4-piperidinyl]-N'-(trifluoromethoxy)phenyl]-urea (TPPU) on weight-bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs.ResultsIn human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration.ConclusionOur novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.

Background/Objective: Although low-methoxy (LM) pectin (polysaccharides extracted from citrus peels) can reduce inflammation by binding to and inhibiting the TLR-2 pathway in animal models and in vitro studies, the anti-inflammatory effects of LM pectin in humans and mood have not been explored to date. The purpose of this study is to assess the role of dietary supplementation with LM pectin in healthy volunteers on inflammatory markers and on mood, specifically anxiety and depression. Methods: We carried out a 4-week dietary intervention with LM citrus pectin on healthy volunteers (N = 14, age 40 ± 16 y, BMI 24.7 ± 3.0 kg/m2, sex F 57%) comparing the effects of daily supplementation with 20 g of LM citrus pectin versus 10 g of maltodextrin as the control (N = 15 age 43.2 ± 11 y, BMI 25.18 ± 2.0 kg/m2, sex F 66%). The effects on mood and inflammation were also tested with LM pectin at 5 g, 10 g and 15 g (2 weeks each) in an independent cohort of n = 15 healthy volunteers (age 36 ± 21 y, BMI 23.5 ± 2.4 kg/m2, sex F 80%). We assessed serum levels of TNF-alpha (downstream from TLR-2 activation), IL-1 beta, IL-6, IL-10, INF-gamma, CRP, zonulin and TLR-2 concentration which were measured using ELISA in blood samples collected at both the baseline and follow-up visits. Validated measures of anxiety and depression were collected at baseline and follow-up. Results: Supplementation with 20 g of LM pectin resulted in decreases in the pro-inflammatory markers TNF-alpha, IL-1 beta, IL-6 and INF-gamma (all p < 0.05) and an increase in anti-inflammatory marker IL-10 (p = 0.01) at the end of the 4 weeks. No such effects were observed in the control group. In addition, a significant drop in anxiety scores (from 8.38 to 4.46, p < 0.006) was found with the 20 g/day intervention but not in the control arm. In the dose–response study, anti-inflammatory effects were seen only at 15 g for TNFα (p < 0.003) and a suggestive increase in IL-10 (p = 0.08), alongside a drop in TLR-2 (p < 0.027). No significant anti-inflammatory effects were observed at 5 g and 10 g doses of LM pectin supplementation. Significant dose-dependent drops in both anxiety and depression scores were found with 10 g (p < 0.001) and 15 g per day (p < 0.0002). Conclusions: The current study identifies anxiety-reducing and anti-inflammatory effects of supplementation with 15 g/day LM pectin in healthy humans. Further research is needed to elucidate the precise mechanism and to validate the efficient dose and minimum duration of supplementation. [ABSTRACT FROM AUTHOR]

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Background: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols). Methods: We included 1053 individuals from the TwinsUK cohort with vitamin A-related metabolites measured in serum and faeces, diet history, and gut microbiome composition assessed by shotgun metagenome sequencing. Results were replicated in 327 women from the ZOE PREDICT-1 study. Results: Five vitamin A-related serum metabolites were positively correlated with microbiome alpha diversity (r = 0.15 to r = 0.20, p < 4 × 10−6). Carotenoid compounds were positively correlated with the short-chain fatty-acid-producing bacteria Faecalibacterium prausnitzii and Coprococcus eutactus. Retinol was not associated with any microbial species. We found that gut microbiome composition could predict circulating levels of carotenoids and oxoretinoic acid with AUCs ranging from 0.66 to 0.74 using random forest models, but not retinol (AUC = 0.52). The healthy eating index (HEI) was strongly associated with gut microbiome diversity and with all carotenoid compounds, but not retinoids. We investigated the mediating role of carotenoid compounds on the effect of a healthy diet (HEI) on gut microbiome diversity, finding that carotenoids significantly mediated between 18 and 25% of the effect of HEI on gut microbiome alpha diversity. Conclusions: Our results show strong links between circulating carotene compounds and gut microbiome composition and potential links to a healthy diet pattern. [ABSTRACT FROM AUTHOR]

Background: Hip fractures in frail patients result in excess mortality not accounted for by age or comorbidities. The mechanisms behind the high risk of mortality remain undetermined but are hypothesized to be related to the inflammatory status of frail patients. Methods: In a prospective observational exploratory cohort study of hospitalized frail hip fracture patients, 92 inflammatory markers were tested in pre-operative serum samples and markers were tested against 6-month survival post-hip fracture surgery and incidence of acute kidney injury (AKI). After correcting for multiple testing, adjustments for comorbidities and demographics were performed on the statistically significant markers. Results: Of the 92 markers tested, circulating levels of fibroblast growth factor 23 (FGF-23) and interleukin-15 receptor alpha (IL15RA), both involved in renal disease, were significantly correlated with 6-month mortality (27.5% overall) after correcting for multiple testing. The incidence of postoperative AKI (25.4%) was strongly associated with 6-month mortality, odds ratio = 10.57; 95% CI [2.76-40.51], and with both markers plus estimated glomerular filtration rate (eGFR)- cystatin C (CYSC) but not eGFR-CRE. The effect of these markers on mortality was significantly mediated by their effect on postoperative AKI. Conclusion: High postoperative mortality in frail hip fracture patients is highly correlated with preoperative biomarkers of renal function in this pilot study. The effect of preoperative circulating levels of FGF-23, IL15RA, and eGFR-CYSC on 6-month mortality is in part mediated by their effect on postoperative AKI. Creatinine-derived preoperative renal function measures were very poorly correlated with postoperative outcomes in this group. [ABSTRACT FROM AUTHOR]

The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease. Analyses from the gut microbiome of over 1,000 individuals from the PREDICT 1 study, for which detailed long-term diet information as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements are available, unveil new associations between specific gut microbes, dietary habits and cardiometabolic health., Author(s): Francesco Asnicar [sup.1] , Sarah E. Berry [sup.2] , Ana M. Valdes [sup.3] [sup.4] , Long H. Nguyen [sup.5] , Gianmarco Piccinno [sup.1] , David A. Drew [sup.5] , [...]

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

A total of 2,618,862 participants reported their potential symptoms of COVID-19 on a smartphone-based app. Among the 18,401 who had undergone a SARS-CoV-2 test, the proportion of participants who reported loss of smell and taste was higher in those with a positive test result (4,668 of 7,178 individuals; 65.03%) than in those with a negative test result (2,436 of 11,223 participants; 21.71%) (odds ratio = 6.74; 95% confidence interval = 6.31-7.21). A model combining symptoms to predict probable infection was applied to the data from all app users who reported symptoms (805,753) and predicted that 140,312 (17.42%) participants are likely to have COVID-19. Analysis of data from a smartphone-based app designed for large-scale tracking of potential COVID-19 symptoms, used by over 2.5 million participants in the United Kingdom and United States, shows that loss of taste and smell sensations is predictive of potential SARS-CoV-2 infection., Author(s): Cristina Menni [sup.1] , Ana M. Valdes [sup.1] [sup.2] , Maxim B. Freidin [sup.1] , Carole H. Sudre [sup.3] , Long H. Nguyen [sup.4] , David A. Drew [sup.4] [...]

Metabolic responses to food influence risk of cardiometabolic disease, but large-scale high-resolution studies are lacking. We recruited n = 1,002 twins and unrelated healthy adults in the United Kingdom to the PREDICT 1 study and assessed postprandial metabolic responses in a clinical setting and at home. We observed large inter-individual variability (as measured by the population coefficient of variation (s.d./mean, %)) in postprandial responses of blood triglyceride (103%), glucose (68%) and insulin (59%) following identical meals. Person-specific factors, such as gut microbiome, had a greater influence (7.1% of variance) than did meal macronutrients (3.6%) for postprandial lipemia, but not for postprandial glycemia (6.0% and 15.4%, respectively); genetic variants had a modest impact on predictions (9.5% for glucose, 0.8% for triglyceride, 0.2% for C-peptide). Findings were independently validated in a US cohort (n = 100 people). We developed a machine-learning model that predicted both triglyceride (r = 0.47) and glycemic (r = 0.77) responses to food intake. These findings may be informative for developing personalized diet strategies. The ClinicalTrials.gov registration identifier is (https://clinicaltrials.gov/ct2/show/NCT03479866). The PREDICT 1 trial shows large inter-individual variations in postprandial metabolic responses to standardized meals in over 1,000 participants, demonstrating potential for development of personalized nutrition strategies., Author(s): Sarah E. Berry [sup.1] , Ana M. Valdes [sup.2] [sup.3] , David A. Drew [sup.4] , Francesco Asnicar [sup.5] , Mohsen Mazidi [sup.6] , Jonathan Wolf [sup.7] , Joan [...]

ObjectivesTo identify genetic associations with hip osteoarthritis (HOA), we performed a meta-analysis of genome-wide association studies (GWAS) of HOA.MethodsThe GWAS meta-analysis included approximately 2.5 million imputed HapMap single nucleotide polymorphisms (SNPs). HOA cases and controls defined radiographically and by total hip replacement were selected from the Osteoporotic Fractures in Men (MrOS) Study and the Study of Osteoporotic Fractures (SOF) (654 cases and 4697 controls, combined). Replication of genome-wide significant SNP associations (p ≤5×10(-8)) was examined in five studies (3243 cases and 6891 controls, combined). Functional studies were performed using in vitro models of chondrogenesis and osteogenesis.ResultsThe A allele of rs788748, located 65 kb upstream of the IGFBP3 gene, was associated with lower HOA odds at the genome-wide significance level in the discovery stage (OR 0.71, p=2×10(-8)). The association replicated in five studies (OR 0.92, p=0.020), but the joint analysis of discovery and replication results was not genome-wide significant (p=1×10(-6)). In separate study populations, the rs788748 A allele was also associated with lower circulating IGFBP3 protein levels (p=4×10(-13)), suggesting that this SNP or a variant in linkage disequilibrium could be an IGFBP3 regulatory variant. Results from functional studies were consistent with association results. Chondrocyte hypertrophy, a deleterious event in OA pathogenesis, was largely prevented upon IGFBP3 knockdown in chondrocytes. Furthermore, IGFBP3 overexpression induced cartilage catabolism and osteogenic differentiation.ConclusionsResults from GWAS and functional studies provided suggestive links between IGFBP3 and HOA.

ObjectivesOsteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.MethodsWe performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used.ResultsWe accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis).ConclusionsNovel genetic loci for hip OA were found in this meta-analysis of GWAS.

Background: Despite an acute knee injury being a major risk factor for osteoarthritis, the factors that initiate and maintain this risk of longer-term knee symptoms are poorly understood. Bioactive lipids derived from omega-3 and -6 polyunsaturated fatty acids have key roles in the regulation of the inflammatory response and have been linked to joint damage and osteoarthritis pain in translational models. Hypothesis: There would be associations between systemic levels of bioactive lipids and knee symptoms longitudinally after an acute knee injury and related knee surgery. Study Design: Controlled laboratory study. Methods: This study analyzed a subset of young, active adults who had sustained an acute knee injury (recruited via a surgical care pathway) and healthy age- and sex-matched controls. Surgery, if performed, was conducted after the baseline serum sample was taken and before the 3-month and 2-year visits. Liquid chromatography–tandem mass spectrometry of 41 bioactive lipids was carried out in sera of (1) 47 injured participants (median age, 28 years) collected at baseline (median, 24 days after injury), 3 months, and 2 years, along with the Knee injury and Osteoarthritis Outcome Score, and (2) age- and sex-matched controls. Results: Levels of the omega-3 polyunsaturated fatty acids eicosapentaenoic acid (P ≤.0001) and docosahexaenoic acid (P ≤.0001) and the pro-resolving lipid mediators 17– and 14–hydroxydocosahexaenoic acid, and 18-hydroxyeicosapentaenoic acid were all significantly greater at baseline in injured participants compared with the later time points and also higher than in healthy controls (P =.0019 and P ≤.0001, respectively). Levels of pro-inflammatory prostaglandins E2 and D2, leukotriene B4, and thromboxane B2 were significantly lower at baseline compared with the later time points. Higher levels of 8,9–, 11,12–, and 14,15–dihydroxyeicosatrienoic acid (DHET) were cross-sectionally associated with more severe knee pain/symptoms according to the Knee injury and Osteoarthritis Outcome Score at 2 years (P =.0004, R 2 = 0.251; P =.0002, R 2 = 0.278; and P =.0012, R 2 = 0.214, respectively). Conclusion: The profile of pro-resolving versus pro-inflammatory lipids at baseline suggests an initial activation of pro-resolution pathways, followed by the later activation of pro-inflammatory pathways. Clinical Relevance: In this largely surgically managed cohort, the association of soluble epoxide hydrolase metabolites, the DHETs, with more severe knee symptoms at 2 years provides a rationale for further investigation into the role of this pathway in persisting knee symptoms in this population, including potential therapeutic strategies. [ABSTRACT FROM AUTHOR]