Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions

Recent advances in understanding hypertension development in sub-Saharan Africa

Consistent reports indicate that hypertension is a particularly common finding in black populations. Hypertension occurs at younger ages and is often more severe in terms of blood pressure levels and organ damage than in whites, resulting in a higher incidence of cardiovascular disease and mortality. This review provides an outline of recent advances in the pathophysiological understanding of blood pressure elevation and the consequences thereof in black populations in Africa. This is set against the backdrop of populations undergoing demanding and rapid demographic transition, where infection with the Human Immunodeficiency Virus predominates, and where under and over-nutrition coexist. Collectively, recent findings from Africa illustrate an increased lifetime risk to hypertension from foetal life onwards. From young ages black populations display early endothelial dysfunction, increased vascular tone and reactivity, microvascular structural adaptions, as well as increased aortic stiffness resulting in elevated central and brachial blood pressures during the day and night, when compared to whites. Together with knowledge on the contributions of sympathetic activation and abnormal renal sodium handling, these pathophysiological adaptations result in subclinical and clinical organ damage at younger ages. This overall enhanced understanding on the determinants of blood pressure elevation in blacks encourages (a) novel approaches to assess and manage hypertension in Africa better, (b) further scientific discovery to develop more effective prevention and treatment strategies, and (c) policymakers and health advocates to collectively contribute in creating health-promoting environments in Africa

COPD Exacerbations, Air Pollutant Fluctuations, and Individual-Level Factors in the Pandemic Era

Sahar Mikaeeli,1– 3 Dany Doiron,1 Jean Bourbeau,1,4,5 Pei Zhi Li,1 Shawn D Aaron,6 Kenneth R Chapman,7 Paul Hernandez,8 François Maltais,9 Darcy D Marciniuk,10 Denis E O’Donnell,11 Don D Sin,12 Brandie L Walker,13 Wan C Tan,12 Simon Rousseau,3 Bryan A Ross1,4,5 On behalf of the CanCOLD Collaborative Research Group and the Canadian Respiratory Research Network1Respiratory Epidemiology and Clinical Research Unit, Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre (RI-MUHC), Montreal, Quebec, Canada; 2Division of Experimental Medicine, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada; 3Meakins-Christie Laboratories, Research Institute at McGill University Health Centre, Montreal, Canada; 4Division of Respiratory Medicine, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada; 5Montreal Chest Institute, McGill University Health Centre, Montreal, QC, Canada; 6The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; 7Toronto General Hospital Research Institute, University of Toronto, Toronto, Ontario, Canada; 8Department of Medicine, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; 9Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Québec, Canada; 10Respiratory Research Centre and Division of Respirology, Critical Care and Sleep Medicine; University of Saskatchewan, Saskatoon, Saskatchewan, Canada; 11Department of Medicine, Queen’s University, Kingston, Ontario, Canada; 12Centre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada; 13Department of Medicine, University of Calgary, Calgary, Alberta, CanadaCorrespondence: Bryan A Ross, Respiratory Epidemiology and Clinical Research Unit (RECRU), Research Institute of the McGill University Health Centre (RI-MUHC), 5252 De Maisonneuve, Room 3D.57, Montreal, QC, H4A 3S5, Canada, Tel +1-514-843-1465, Email [email protected]: Pandemic-era associations between air pollutant exposures and exacerbations of chronic obstructive pulmonary disease (COPD) are under-explored. Given the considerable observed pandemic-era pollutant fluctuations, these associations were investigated along with possible individual-level risk factors.Patients and Methods: Participants with spirometry-confirmed COPD from Canadian Cohort Obstructive Lung Disease (CanCOLD) were included, with data collected before (“pre-pandemic”) and during (“pandemic”) the COVID-19 pandemic. Nitrogen dioxide (NO2), fine particulate matter (PM2.5), ground-level ozone (O3), total oxidant (Ox) and weather data were obtained from national databases. Associations between each air pollutant and “symptom-based” exacerbations (increased dyspnea or sputum volume/purulence ≥ 48hrs) and “event-based” exacerbations (“symptom-based” plus requiring antibiotics, corticosteroids, or unscheduled healthcare use) were estimated in separate models. Generalized estimating equations (GEE) models were reported as rate ratios (RRs) per interquartile range (IQR) increment in pollutant concentration with 95% confidence intervals (95% CIs).Results: NO2, PM2.5, and Ox (NO2+O3) concentrations (but not O3) fell significantly during the pandemic. In the 673 participants with COPD included, both symptom-based and event-based exacerbation rates were likewise significantly higher during the pre-pandemic period. During the pre-pandemic period, Ox was positively associated with symptom-based exacerbations (RR: 1.21 [1.08,1.36]). During the pandemic period, Ox was positively associated with symptom-based (1.46 [1.13,1.89]) and event-based (1.43 [1.00,2.05]) exacerbations. Fewer self-reported pandemic protective behaviors, and higher viral infectious symptoms, were also associated with exacerbations. In stepwise multivariable risk-factor analyses, female gender (1.23 [1.04,1.45] and 1.41 [1.13,1.76]) and co-morbid asthma (1.65 [1.34,2.03] and 1.54 [1.19,2.00]) were associated with symptom-based and event-based exacerbations, respectively, blood eosinophils (1.42 [1.10,1.84]) were associated with event-based exacerbations, and each IQR increment in Ox was associated with symptom-based exacerbations (1.31 [1.06,1.61]).Conclusion: Ox exposure was consistently associated with symptom-based COPD exacerbations, and female gender, co-morbid asthma, and blood eosinophilia were found to be relevant risk factors.Plain language summary: Previous research has identified air pollution as a relevant non-infectious trigger for episodic ‘lung attacks’, referred to as exacerbations, in patients living with chronic obstructive pulmonary disease (COPD). Very few studies, however, have studied this relationship during the COVID-19 pandemic. During that time, there were large fluctuations in key forms of air pollution (air pollutants). The few studies available used population-level approaches and relied on hospital administrative coding of visits to classify the disease and to identify exacerbation events. This approach may lead to potentially missing clinically important non-severe events and may limit individual-level risk factor assessment around this period.This study was conducted in participants with COPD as confirmed by the gold-standard test, spirometry, who were living in 9 Canadian cities across 6 provinces. The results showed that while the air pollutants nitrogen dioxide (NO2), fine particulate matter (PM2.5), and total oxidant (Ox) concentrations were all notably higher before the pandemic (pre-pandemic), only ambient Ox concentration was consistently associated with exacerbations. This relationship was seen across both pre-pandemic and pandemic periods. Female gender, co-morbid asthma, and eosinophilia were identified as notable risk factors for exacerbations and were effect modifiers for the association between Ox exposure and exacerbations. This study adds to a very limited existing literature on the relationship between air pollutant fluctuations and exacerbations of COPD around the pandemic era and highlights important risk factors to guide targeted public health and exposure response interventions.Keywords: Chronic obstructive pulmonary disease, acute exacerbations of chronic obstructive pulmonary disease, ambient air pollution, COVID-19 pandemic, total oxidant concentratio

Respiratory Syncytial Virus (RSV) RNA loads in peripheral blood correlates with disease severity in mice

<p>Abstract</p> <p>Background</p> <p>Respiratory Syncytial Virus (RSV) infection is usually restricted to the respiratory epithelium. Few studies have documented the presence of RSV in the systemic circulation, however there is no consistent information whether virus detection in the blood correlates with disease severity.</p> <p>Methods</p> <p>Balb/c mice were inoculated with live RSV, heat-inactivated RSV or medium. A subset of RSV-infected mice was treated with anti-RSV antibody 72 h post-inoculation. RSV RNA loads were measured by PCR in peripheral blood from day 1-21 post-inoculation and were correlated with upper and lower respiratory tract viral loads, the systemic cytokine response, lung inflammation and pulmonary function. Immunohistochemical staining was used to define the localization of RSV antigens in the respiratory tract and peripheral blood.</p> <p>Results</p> <p>RSV RNA loads were detected in peripheral blood from day 1 to 14 post-inoculation, peaked on day 5 and significantly correlated with nasal and lung RSV loads, airway obstruction, and blood CCL2 and CXCL1 expression. Treatment with anti-RSV antibody reduced blood RSV RNA loads and improved airway obstruction. Immunostaining identified RSV antigens in alveolar macrophages and peripheral blood monocytes.</p> <p>Conclusions</p> <p>RSV RNA was detected in peripheral blood upon infection with live RSV, followed a time-course parallel to viral loads assessed in the respiratory tract and was significantly correlated with RSV-induced airway disease.</p

An Open Access Database of Genome-wide Association Results

<p>Abstract</p> <p>Background</p> <p>The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results.</p> <p>Methods</p> <p>We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS.</p> <p>Results</p> <p>Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., <it>APOE</it>, <it>LPL</it>). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (<it>SLC16A7, CSMD1, OAS1</it>), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 × 10^-14), a finding which was not perturbed by a sensitivity analysis.</p> <p>Conclusion</p> <p>We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.</p

A Curated Database of miRNA Mediated Feed-Forward Loops Involving MYC as Master Regulator

BACKGROUND: The MYC transcription factors are known to be involved in the biology of many human cancer types. But little is known about the Myc/microRNAs cooperation in the regulation of genes at the transcriptional and post-transcriptional level. METHODOLOGY/PRINCIPAL FINDINGS: Employing independent databases with experimentally validated data, we identified several mixed microRNA/Transcription Factor Feed-Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions, in human. We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving E2F1, PTEN, RB1 and VEGF. CONCLUSIONS/SIGNIFICANCE: We have assembled and characterized a catalogue of human mixed Transcription Factor/microRNA Feed-Forward Loops, having Myc as master regulator and completely defined by experimentally verified regulatory interactions

HDP—A Novel Heme Detoxification Protein from the Malaria Parasite

When malaria parasites infect host red blood cells (RBC) and proteolyze hemoglobin, a unique, albeit poorly understood parasite-specific mechanism, detoxifies released heme into hemozoin (Hz). Here, we report the identification and characterization of a novel Plasmodium Heme Detoxification Protein (HDP) that is extremely potent in converting heme into Hz. HDP is functionally conserved across Plasmodium genus and its gene locus could not be disrupted. Once expressed, the parasite utilizes a circuitous “Outbound–Inbound” trafficking route by initially secreting HDP into the cytosol of infected RBC. A subsequent endocytosis of host cytosol (and hemoglobin) delivers HDP to the food vacuole (FV), the site of Hz formation. As Hz formation is critical for survival, involvement of HDP in this process suggests that it could be a malaria drug target

The Worksite Health Promotion Capacity Instrument (WHPCI): development, validation and approaches for determining companies' levels of health promotion capacity

<p>Abstract</p> <p>Background</p> <p>The Worksite Health Promotion Capacity Instrument (WHPCI) was developed to assess two key factors for effective worksite health promotion: collective willingness and the systematic implementation of health promotion activities in companies. This study evaluates the diagnostic qualities of the WHPCI based on its subscales Health Promotion Willingness and Health Promotion Management, which can be used to place companies into four different categories based on their level of health promotion capacity.</p> <p>Methods</p> <p>Psychometric evaluation was conducted using exploratory factor and reliability analyses with data taken from a random sample of managers from n = 522 German information and communication technology (ICT) companies. Receiver operating characteristic (ROC) analyses were conducted to determine further diagnostic qualities of the instrument and to establish the cut-off scores used to determine each company's level of health promotion capacity.</p> <p>Results</p> <p>The instrument's subscales, Health Promotion Willingness and Health Promotion Management, are based on one-dimensional constructs, each with very good reliability (Cronbach's alpha = 0.83/0.91). ROC analyses demonstrated satisfactory diagnostic accuracy with an area under the curve (AUC) of 0.76 (SE = 0.021; 95% CI 0.72-0.80) for the Health Promotion Willingness scale and 0.81 (SE = 0.021; 95% CI 0.77-0.86) for the Health Promotion Management scale. A cut-off score with good sensitivity (71%/76%) and specificity (69%/75%) was determined for each scale. Both scales were found to have good predictive power and exhibited good efficiency.</p> <p>Conclusions</p> <p>Our findings indicate preliminary evidence for the validity and reliability of both subscales of the WHPCI. The goodness of each cut-off score suggests that the scales are appropriate for determining companies' levels of health promotion capacity. Support in implementing (systematic) worksite health promotion can then be tailored to each company's needs based on their current capacity level.</p

Plasmodium falciparum Merozoite Invasion Is Inhibited by Antibodies that Target the PfRh2a and b Binding Domains

Plasmodium falciparum, the causative agent of the most severe form of malaria in humans invades erythrocytes using multiple ligand-receptor interactions. The P. falciparum reticulocyte binding-like homologue proteins (PfRh or PfRBL) are important for entry of the invasive merozoite form of the parasite into red blood cells. We have analysed two members of this protein family, PfRh2a and PfRh2b, and show they undergo a complex series of proteolytic cleavage events before and during merozoite invasion. We show that PfRh2a undergoes a cleavage event in the transmembrane region during invasion consistent with activity of the membrane associated PfROM4 protease that would result in release of the ectodomain into the supernatant. We also show that PfRh2a and PfRh2b bind to red blood cells and have defined the erythrocyte-binding domain to a 15 kDa region at the N-terminus of each protein. Antibodies to this receptor-binding region block merozoite invasion demonstrating the important function of this domain. This region of PfRh2a and PfRh2b has potential in a combination vaccine with other erythrocyte binding ligands for induction of antibodies that would block a broad range of invasion pathways for P. falciparum into human erythrocytes