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Comparison of coronavirus disease (COVID-19) case numbers over time and between locations is complicated by limits to virologic testing to confirm severe acute respiratory syndrome coronavirus 2 infection. The proportion of tested individuals who have tested positive (test-positive proportion, TPP) can potentially be used to inform trends in incidence. We propose a model for testing in a population experiencing an epidemic of COVID-19, and derive an expression for TPP in terms of well-defined parameters related to testing and presence of other pathogens causing COVID-19 like symptoms. In the absence of dramatic shifts of testing practices in time or between locations, the TPP is positively correlated with the incidence of infection. We show that the proportion of tested individuals who present COVID-19 like symptoms encodes similar information to the TPP but has different relationships with the testing parameters, and can thus provide additional information regarding dynamic changes in TPP and incidence. Finally, we compare data on confirmed cases and TPP from US states up to October 2020. We conjecture why states may have higher or lower TPP than average. Collection of symptom status and age/risk category of tested individuals can increase the utility of TPP in assessing the state of the pandemic in different locations and times.

Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and anti-inflammatory treatment strategies are currently pursued to lower cardiovascular disease burden. Modulation of recently discovered inactive rhomboid protein 2 (iRhom2) attenuates shedding of tumor necrosis factor-alpha (TNF-α) selectively from immune cells. The present study aims at investigating the impact of iRhom2 deficiency on the development of atherosclerosis.

Low-density lipoprotein receptor (LDLR)-deficient mice with additional deficiency of iRhom2 (LDLR-/-iRhom2-/-) and control (LDLR-/-) mice were fed a Western type diet (WD) for 8 or 20 weeks to induce early or advanced atherosclerosis. Deficiency of iRhom2 resulted in a significant decrease in the size of early atherosclerotic plaques as determined in aortic root cross sections. LDLR-/-iRhom2-/- mice exhibited significantly lower serum levels of TNF-α and lower circulating and hepatic levels of cholesterol and triglycerides compared to LDLR-/- mice at 8 weeks mation as observed with diabetes mellitus or rheumatoid arthritis.

iRhom2 attenuates shedding of TNF-α selectively from immune cells and therefore has emerged as a potential new target for the treatment of inflammatory diseases. In the present study, we identified iRhom2 as a critical link between inflammation, lipid metabolism, and atherogenesis. Selective iRhom2 inhibition represents a potential treatment strategy to modify atherosclerosis, particularly in the presence of enhanced inflammation as observed with diabetes mellitus or rheumatoid arthritis.Atrial fibrillation (AF) is an important clinical problem. Chronic pressure/volume overload of the atria promotes AF, particularly via enhanced extracellular matrix (ECM) accumulation manifested as tissue fibrosis. Loading of cardiac cells causes cell-stretch that is generally considered to promote fibrosis by directly activating fibroblasts, the key cell-type responsible for ECM-production. The primary purpose of this article is to review the evidence regarding direct effects of stretch on cardiac fibroblasts, specifically (i) the similarities and differences among studies in observed effects of stretch on cardiac-fibroblast function; (ii) the signaling-pathways implicated; and (iii) the factors that affect stretch-related phenotypes. Our review summarizes the most important findings and limitations in this area and gives an overview of clinical data and animal models related to cardiac stretch, with particular emphasis on the atria. We suggest that the evidence regarding direct fibroblast activation by stretch is weak and inconsistent, in part because of variability among studies in key experimental conditions that govern the results. Further work is needed to clarify whether, in fact, stretch induces direct activation of cardiac fibroblasts and if so, to elucidate the determining factors to ensure reproducible results. PF-07321332 If mechanical load on fibroblasts proves not to be clearly profibrotic by direct actions, other mechanisms like paracrine influences, the effects of systemic mediators and/or the direct consequences of myocardial injury or death, might account for the link between cardiac stretch and fibrosis. Clarity in this area is needed to improve our understanding of AF pathophysiology and assist in therapeutic development.Rapid initiation of antiretroviral therapy (ART) is recommended for people living with HIV, with the option to start treatment on the day of diagnosis (same-day-ART). However, the effect of same-day-ART remains unknown in realistic public sector settings. We established a cohort of ≥16-year-old patients who initiated first-line ART under Treat-All in Nhlangano (Eswatini) between 2014-2016, either on the day of HIV care enrolment (same-day-ART) or 1-14 days thereafter (early-ART). Directed acyclic graphs, flexible parametric survival analysis and targeted maximum likelihood estimation (TMLE) were used to estimate the effect of same-day-ART initiation on the composite unfavourable treatment outcome (loss to follow-up;death;viral failure). Of 1328 patients, 839 (63.2%) initiated same-day ART. The adjusted hazard ratio of the unfavourable outcome was increased by 1.48 (95% CI1.16-1.89) for same-day-ART compared with early-ART. TMLE suggested that after 1 year, 28.9% of patients would experience the unfavourable outcome under same-day-ART compared with 21.2% under early-ART (difference 7.7%; 1.3-14.1%). This estimate was driven by loss to follow-up and varied over time, with a higher hazard during the first year after HIV care enrolment and a similar hazard thereafter. We found an increased risk with same-day-ART. A limitation was possible silent transfers that were not captured.

The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, β-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery.

In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction. The impact of rAAV6-delivered O-GlcNAc transferase (rAAV6-OGT, facilitating protein O-GlcNAcylation), O-GlcNAcase (rAAV6-OGA, facilitating de-O-GlcNAcylation) and empty vector (null) were determined in non-diabetic and diabetic mice. In non-diabetic mice, rAAV6-OGT was sufficient to impair LV diastolic function and induce maladaptive cardiac remodelling, including cardiac fibrosis and increased Myh-7 and Nppa pro-hypertrophic gene expression, recapitulating characteristics of diabetic cardiomyopathy.