Virulence Associated Gene 8 of Bordetella pertussis Enhances Contact System Activity by Inhibiting the Regulatory Function of Complement Regulator C1 Inhibitor.

Bordetella pertussis is a Gram-negative bacterium and the causative agent of whooping cough. Whooping cough is currently re-emerging worldwide and, therefore, still poses a continuous global health threat. B. pertussis expresses several virulence factors that play a role in evading the human immune response. One of these virulence factors is virulence associated gene 8 (Vag8). Vag8 is a complement evasion molecule that mediates its effects by binding to the complement regulator C1 inhibitor (C1-INH). This regulatory protein is a fluid phase serine protease that controls proenzyme activation and enzyme activity of not only the complement system but also the contact system. Activation of the contact system results in the generation of bradykinin, a pro-inflammatory peptide. Here, the activation of the contact system by B. pertussis was explored. We demonstrate that recombinant as well as endogenous Vag8 enhanced contact system activity by binding C1-INH and attenuating its inhibitory function. Moreover, we show that B. pertussis itself is able to activate the contact system. This activation was dependent on Vag8 production as a Vag8 knockout B. pertussis strain was unable to activate the contact system. These findings show a previously overlooked interaction between the contact system and the respiratory pathogen B. pertussis. Activation of the contact system by B. pertussis may contribute to its pathogenicity and virulence

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study

Background: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling

Genetically Predicted Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From Mendelian Randomization.

Inflammation contributes to atherosclerosis and coronary artery disease (CAD). In order to help identify therapeutic targets, it is important to ascertain whether biomarkers associated with CAD risk are causal. In a recent meta-analysis of clinical trials, neutrophil-to lymphocyte ratio (NLR) was associated with increased cardiovascular risk 1 . We investigate a potential causal nature of this relationship by performing Mendelian randomization (MR) analyse

Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

Aims: Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL-6 signalling perturbation through IL-6 or IL-6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL-6 or IL-6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL-6 and IL-6 receptor on cardiometabolic risk and potential side effects. // Methods: We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL-6 or IL-6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. // Results: A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL-filtered results were in concordance with the main results, but with wider confidence intervals. // Conclusions: IL-6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL-6 and IL-6R are potential therapeutic targets to lower CVD. Moreover, IL-6 rather than IL-6R inhibition might have a more favourable pneumonia risk

Effects of oral semaglutide on cardiovascular outcomes in individuals with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease: Design and baseline characteristics of SOUL, a randomized trial

Aim: To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. Materials and methods: In SOUL, the effects of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double-blind, parallel-group, placebo-controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). The primary outcome is time from randomization to first occurrence of a major adverse CV event (MACE; a composite of CV death, nonfatal myocardial infarction or nonfatal stroke). This event-driven trial will continue until 1225 first adjudication-confirmed MACEs have occurred. Enrolment has been completed. Results: Overall, 9650 participants were enrolled between June 17, 2019 and March 24, 2021 (men 71.1%, White ethnicity 68.9%, mean age 66.1 years, diabetes duration 15.4 years, body mass index 31.1 kg/m2, glycated haemoglobin 63.5 mmol/mol [8.0%]). The most frequently used antihyperglycaemic medications at baseline were metformin (75.7%), insulin and insulin analogues (50.5%), sulphonylureas (29.1%), sodium-glucose cotransporter-2 inhibitors (26.7%) and dipeptidyl peptidase-4 inhibitors (23.0%). At randomization, 70.7% of participants had CAD, 42.3% had CKD, 21.1% had cerebrovascular disease and 15.7% had symptomatic PAD (categories not mutually exclusive). Prevalent heart failure was reported in 23.0% of participants. Conclusion: SOUL will provide evidence regarding the CV effects of oral semaglutide in individuals with type 2 diabetes and established ASCVD and/or CKD

Bescherming gegeven? Evaluatie UAVG, meldplicht datalekken en de boetebe- voegdheid

De overkoepelende vraag die in het onderzoek centraal staat luidt als volgt: Hoe werden in de periode 2018 - 2020 de normen van de Uitvoeringswet Algemene Verordening Gegevensbescherming (UAVG) nageleefd en in hoeverre heeft de UAVG bijgedragen aan een doelmatige en doeltreffende uitvoering en handhaving van de Algemene Verordening Gegevensbescherming (AVG)? Het onderzoek is uitgevoerd langs de lijnen van de volgende zestiental onderzoeksvragen: Hoe beoordelen juristen, de Autoriteit Persoonsgegevens (AP) en verwerkers van persoonsgegevens de duidelijkheid en toegankelijkheid van de UAVG? In hoeverre worden de normen van de UAVG verduidelijkt door de AP en de jurisprudentie? Welke informatie wordt op welk moment aan de verschillende doelgroepen gegeven en op welke manier? Wat is de rol van de AP hierbij? Hoe beoordelen juristen, de AP en verwerkers van persoonsgegevens de uitvoerbaarheid van de UAVG? Hoe beoordelen juristen, de AP en verwerkers van persoonsgegevens de handhaafbaarheid van de UAVG? Hoe leven verwerkers van persoonsgegevens de bepalingen van de UAVG na? In welke mate wordt de meldplicht datalekken nageleefd door verwerkers van persoonsgegevens? Wat is de rol van de Functionaris voor Gegevensbescherming binnen organisaties, onder meer bij de naleving van de meldplicht? In hoeverre heeft de jurisprudentie preventieve werking voor de naleving van de bepalingen van de UAVG en de meldplicht datalekken en hoe zou deze kunnen worden vergroot? Hoe ziet de toezichtstrategie van de AP er uit? Hoe luidt het handhavingsbeleid van de AP? Op welke wijze vinden toezicht en handhaving door de AP in de praktijk plaats? Hoe worden bij het uitoefenen van de boetebevoegdheid door de AP de ernst van de normschending, de mate van verwijtbaarheid en een passende wijze van optreden bepaald? In hoeverre draagt de boetebevoegdheid en het toepassen daarvan door de AP bij aan een doelmatige en doeltreffende uitvoering en handhaving van de AVG? Is er aanleiding tot een wijziging van de toepassing van de bevoegdheden door de AP en zo ja, in welk opzicht? Hoe beoordelen juristen, de AP en verwerkers van persoonsgegevens de mate waarin de UAVG de ruimte heeft benut die de AVG laat voor nationale keuzes bij de uitvoering van de AVG? INHOUD: 1. Inleiding, 2. Juridisch kader, 3. Jurisprudentieonderzoek, 4. Vragenlijstonderzoek en interviews: FG’s aan het woord, 5. De meldplicht datalekken en de bestuurlijke boete in de praktijk, 6. Het functioneren van de UAVG, 7. Conclusies en aanbevelingen

Nasopharyngeal Myoepithelial Carcinoma Mimicking Nasopharyngeal Carcinoma

AbstractMyoepithelial carcinoma (malignant myoepithelioma) (MC) is a rare tumor, defined as a malignant salivary neoplasm composed almost exclusively of tumor cells with myoepithelial differentiation. It can arise in unusual location sites, such as the nasopharynx, and may be difficult to approach. Nasopharyngeal MC can sometimes present as a nasopharyngeal mass which may be mistaken for primary nasopharyngeal carcinoma (NPC). The treatment strategy for nasopharyngeal MC is different from NPC, and maximal surgical resection of the main lesion is still considered as the mainstay of therapy. Herein we present a 32-year-old man with a nasopharyngeal mass which was initially mistaken as NPC, and which was later confirmed as MC after a comprehensive review of the pathology

Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: The EPIC-Norfolk prospective population study

BACKGROUND AND AIMS: Lipoprotein(a) (Lp[a]) is a strong genetic risk factor for cardiovascular disease (CVD). The American Heart Association has prioritised seven cardiovascular health metrics to reduce the burden of CVD: body mass index, healthy diet, physical activity, smoking status, blood pressure, diabetes and cholesterol levels (together also known as ideal cardiovascular health). Our objective was to determine if individuals with high Lp(a) levels could derive cardiovascular benefits if characterized by ideal cardiovascular health. METHODS: A total of 14,051 participants of the EPIC-Norfolk study were stratified according to the cardiovascular health score (based on the number of health metrics with an ideal, intermediate or poor status). Of them, 1732 had a CVD event during a mean follow-up of 11.5 years. Cox proportional hazards models were used to describe the association between the cardiovascular health score and Lp(a) level or genotype (as estimated by the rs10455872 variant) with the risk of CVD. RESULTS: We observed little or no differences in serum Lp(a) levels across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels ≥50 mg/dl), those in the highest (i.e. healthiest) cardiovascular health score category (10-14) had an adjusted hazard ratio for cardiovascular disease of 0.33 (95% CI = 0.17-0.63, p = 0.001) compared to participants in the lowest (i.e. unhealthiest) cardiovascular health score category(0-4). Similar results were obtained when we replaced Lp(a) with rs10455872. CONCLUSIONS: Although Lp(a) levels are only slightly influenced by cardiovascular health metrics, an ideal cardiovascular health could substantially reduce CVD risk associated with high Lp(a) levels or genotype.EPIC-Norfolk is supported by program grants from the Medical Research Council UK and Cancer Research UK and with additional support from the European Union, Stroke Association, British Heart Foundation, and Research into Ageing. RV is supported by a grant from the European Union [TransCard: FP7-603091-2]. BJA holds a junior scholar award from the Fonds de recherche du Québec: Santé (FRQS)