TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica.

Our gastrointestinal tract is a portal of entry for a number of bacteria and viruses. Thus, this tissue must develop ways to induce antigen-specific T cell and antibody responses quickly. Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue. Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica. Further, both neutralization of CCL20 using polyclonal antibody treatment and deletion of TLR1 resulted in a defect in CCR6+ dendritic cells (DCs), which produce innate cytokines that help to induce anti-Yersinia-specific T helper 17 (TH17) cells and IgA production. These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of TH17 immunity through the activation and recruitment of DCs

Oral human papillomavirus (HPV) infection in men who have sex with men: prevalence and lack of anogenital concordance.

To estimate the prevalence of oral detectable human papillomavirus (HPV) DNA in HIV-negative men who have sex with men (MSM) attending a sexual health clinic in London and concordance with anogenital HPV infection. Such data are important to improve our understanding of the epidemiology of oral HPV and the potential use of vaccines to prevent oropharyngeal cancers

Genetic Architecture of Quantitative Cardiovascular Traits: Blood Pressure, ECG and Imaging Phenotypes

Background: We provide an overview of the genetic architecture of quantitative cardiovascular phenotypes such as blood pressure (BP), electrocardiogram (ECG) and cardiac imaging measurements which play a critical and prognostic role in the management of numerous diseases. Methods: The genetics of BP, ECG and cardiac imaging traits have been studied in large-scale genome-wide association studies (GWASs). Results: To-date more than 1,400 BP loci have been discovered. These genetic loci harbouring known and novel BP-regulating genes, several of which are linked to existing drugs, that can be repurposed for BP treatment. Regarding the ECG indices, 437 independent signals have been reported for resting heart rate (n 400,000), mainly modulating the autonomic nervous system, as well as 202 loci for PR interval, 29 loci for QRS duration and 35 loci for QT interval. The LV GWASs (n 17,000) identified 14 loci harbouring genes regulating the cardiac developmental pathways. Conclusion: Large-scale genetic analyses of quantitative cardiovascular traits have yielded hundreds of susceptibility loci, candidate genes and key biological pathways, which significantly advance our understanding of their genetic architecture and shed lights on potential novel therapeutic targets

Evaluating the Impact of Physiological Variability in Genome-Wide Association Studies of Resting Heart Rate

Genome-wide association studies (GWAS) have discovered hundreds of genetic loci for resting heart rate (RHR). However, the impact of intra-individual variation in RHR on GWAS results is unclear. We evaluated this impact by analyzing two RHR recordings from N 61,000 subjects from UK Biobank. In addition, we modelled variations in RHR as independent white zero-mean Gaussian noise with a standard deviation of 0.5x, 1x, and 2x the standard deviation of the difference between the original RHR values (4,8, and 16 bpm, respectively). The two original RHR recordings were highly correlated (? =0.77), but results from the genetic analyses were s lightly different: the number of genome-wide significant (p < 5x10-8) variants at the locus with the strongest reported association (MYH6): n=39 vs. n=34; the p-value of the corresponding lead-variant, 3.6x10-24 vs. 2.1x10-19; and the estimated heritability 20.0% vs. 16.7%. Simulated data showed an inverse relationship between RHR variation and genetic association strength and heritability. Results formally demonstrate the impact of intra-individual RHR variability on the discovery of genetic variants in single-measurement studies

Interaction between ECG and Genetic Markers of Coronary Artery Disease

Coronary artery disease (CAD) is the main contributor to cardiovascular mortality in developed countries, making accurate diagnosis of utmost importance. We developed risk scores to assess CAD risk in a population without known cardiovascular disease by combining ECG and a genetic risk score (GRS) for CAD. We analysed data in 52,260 individuals in the UK Biobank study. ECG indices included heart rate, PR, QRS, QT and T-peak-to-T-end intervals, while we built the GRS from publicly available genome-wide association results for CAD that were derived in an independent population. In a training set (N = 39,195), the indices with the strongest CAD prognostic impact were the PR and QT intervals, and the GRS. When combined together into a Multivariate model, both the ECG markers and the GRS were independently associated with CAD. In an independent test set (N = 13,065), we then built three risk scores based on (1) ECG markers, (2) genetic data, and (3) a combination of ECG and genetic data, respectively. The hazard ratio (95% confidence interval) for CAD comparing high versus low-risk individuals was 6.5 (5.1 - 8.3),8.4 (6.4 - 10.8) and 8.4 (6.5 - 10.8) for the three risk scores, respectively. In conclusion, the inclusion of genetic markers into risk scores with ECG markers independently contributes to CAD risk prediction in a large population of individuals without known cardiovascular disease

Analysing electrocardiographic traits and predicting cardiac risk in UK biobank.

The electrocardiogram (ECG) is a commonly used clinical tool that reflects cardiac excitability and disease. Many parameters are can be measured and with the improvement of methodology can now be quantified in an automated fashion, with accuracy and at scale. Furthermore, these measurements can be heritable and thus genome wide association studies inform the underpinning biological mechanisms. In this review we describe how we have used the resources in UK Biobank to undertake such work. In particular, we focus on a substudy uniquely describing the response to exercise performed at scale with accompanying genetic information

Premature atrial and ventricular contractions detected on wearable-format electrocardiograms and prediction of cardiovascular events.

AIMS: Wearable devices are transforming the electrocardiogram (ECG) into a ubiquitous medical test. This study assesses the association between premature ventricular and atrial contractions (PVCs and PACs) detected on wearable-format ECGs (15 s single lead) and cardiovascular outcomes in individuals without cardiovascular disease (CVD). METHODS AND RESULTS: Premature atrial contractions and PVCs were identified in 15 s single-lead ECGs from N = 54 016 UK Biobank participants (median age, interquartile range, age 58, 50-63 years, 54% female). Cox regression models adjusted for traditional risk factors were used to determine associations with atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), stroke, life-threatening ventricular arrhythmias (LTVAs), and mortality over a period of 11.5 (11.4-11.7) years. The strongest associations were found between PVCs (prevalence 2.2%) and HF (hazard ratio, HR, 95% confidence interval = 2.09, 1.58-2.78) and between PACs (prevalence 1.9%) and AF (HR = 2.52, 2.11-3.01), with shorter prematurity further increasing risk. Premature ventricular contractions and PACs were also associated with LTVA (P < 0.05). Associations with MI, stroke, and mortality were significant only in unadjusted models. In a separate UK Biobank sub-study sample [UKB-2, N = 29,324, age 64, 58-60 years, 54% female, follow-up 3.5 (2.6-4.8) years] used for independent validation, after adjusting for risk factors, PACs were associated with AF (HR = 1.80, 1.12-2.89) and PVCs with HF (HR = 2.32, 1.28-4.22). CONCLUSION: In middle-aged individuals without CVD, premature contractions identified in 15 s single-lead ECGs are strongly associated with an increased risk of AF and HF. These data warrant further investigation to assess the role of wearable ECGs for early cardiovascular risk stratification

A Method to Minimise the Impact of ECG Marker Inaccuracies on the Spatial QRS-T angle: Evaluation on 1,512 Manually Annotated ECGs

© 2020 The Author(s) The spatial QRS-T angle (QRS-Ta) derived from the vectorcardiogram (VCG) is a strong risk predictor for ventricular arrhythmia and sudden cardiac death with potential use for mass screening. Accurate QRS-Ta estimation in the presence of ECG delineation errors is crucial for its deployment as a prognostic test. Our study assessed the effect of inaccurate QRS and T-wave marker placement on QRS-Ta estimation and proposes a robust method for its calculation. Reference QRS-Ta measurements were derived from 1,512 VCGs manually annotated by three expert reviewers. We systematically changed onset and offset timings of QRS and T-wave markers to simulate inaccurate placement. The QRS-Ta was recalculated using a standard approach and our proposed algorithm, which limits the impact of VCG marker inaccuracies by defining the vector origin as an interval preceding QRS-onset and redefines the beginning and end of QRS and T-wave loops. Using the standard approach, mean absolute errors (MAE) in peak QRS-Ta were >40% and sensitivity and precision in the detection of abnormality (>105°) were 15 ms. Using our proposed algorithm, MAE for peak QRS-Ta were reduced to 94% for inaccuracies up to ±15 ms. Similar results were obtained for mean QRS-Ta. In conclusion, inaccuracies of QRS and T-wave markers can significantly influence the QRS-Ta. Our proposed algorithm provides robust QRS-Ta measurements in the presence of inaccurate VCG annotation, enabling its use in large datasets

A Ru-catalyzed one-pot synthesis of homopropargylic amines from alkyl azides under photolytic conditions

A new synthetic method for homopropargylic amines from alkyl azides is presented. A salient feature of this reaction is the involvement of N-unsubstituted imines as the key intermediates, which are generated from alkyl azides by Ru catalysis under photolytic conditions. Notably, this method avoids the use of a protective group strategy in the homopropargylic amine synthesis.X111312sciescopu