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Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation.

Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.

As digital access and education have become increasingly widespread, rural Appalachia, a historically marginalized region of the eastern United States, remains heavily impacted by the digital divide, with lower levels of digital access and use than average rates throughout the US. The digital divide is well-established from a rural-urban perspective. However, intra-rural digital divides, which I define as differences in access, use, experiences, skills, and outcomes between closely located rural areas and/or rural areas that have been designated as having a similar level of rurality, remain largely unexplored. Without an understanding of intra-rural digital divides, development efforts may perpetuate inequity if investments are inadvertently focused on already advantaged areas, to the detriment of smaller, more remote, and less privileged rural communities. In this dissertation, I qualitatively investigate the presence and impacts of intra-rural digital divides through four weeks of multi-sited ethnographic fieldwork at public libraries throughout one rural Appalachian county.In addition to rural-urban and intra-rural views of digital divides, digital divides can also exist along multiple domains such as access, use, experience, skills, and outcomes. As digital access divides close, digital skills divides may persist between those with varying ability to effectively use of digital technology. Thus, digital inequities cannot close through increased digital access alone. Considering Appalachia's historical marginalization, it is important that digital interventions in the region are driven by the community and align with local culture and needs. In this work I present two approaches to digital literacy education, digital storytelling and one-on-one tech tutoring, developed alongside community members and informed by tenets of Appalachian culture. These approaches leverage Appalachian cultural practices to offset inexperienced users' discomfort learning new digital skills, and are designed to increase learners' digital self-efficacy.My contributions in this work provide new perspectives to counter the rural deficit model, which positions rural areas as deficient compared to non-rural areas, and defined in terms of what they lack rather than their assets. I highlight how the deficits in digital experience in this community are driven by factors outside of the community and how leveraging local assets is key for improving digital experiences. Through this work, I build upon rural public libraries’ established role as drivers of digital equity and inclusion to highlight how rural public libraries may be a key asset to resolve intra-rural digital divides in Appalachia. Contributions of locally-informed digital literacy education and depictions of intra-rural digital divides can create pathways for equitable digital development that empowers Appalachian residents, rather than perpetuating extraction and exploitation through digital means.

Software platform technology solutions now enable artificial intelligence guided and quantitative cardiac computed tomography angiography (CCTA) for coronary artery plaque quantification and characterization and vascular morphology assessment. As most patients referred for invasive coronary angiography (ICA) are found not to have actionable coronary artery disease, artificial intelligence guided CCTA measures of vascular morphology may allow for improved referral management to ICA in a manner that is safe and lower in costs.

It is unknown whether gender influences the atherosclerotic plaque characteristics (APCs) of lesions of varying angiographic stenosis severity. This study evaluated the imaging data of 303 symptomatic patients from the derivation arm of the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial, all of whom underwent coronary computed tomographic angiography and clinically indicated nonemergent invasive coronary angiography upon study enrollment. Index tests were interpreted by 2 blinded core laboratories, one of which performed quantitative coronary computed tomographic angiography using an artificial intelligence application to characterize and quantify APCs, including percent atheroma volume (PAV), low-density noncalcified plaque (LD-NCP), noncalcified plaque (NCP), calcified plaque (CP), lesion length, positive arterial remodeling, and high-risk plaque (a combination of LD-NCP and positive remodeling ≥1.10); the other classified lesions as obstructive (≥50% diameter stenosis) or nonobstructive (<50% diameter stenosis) based on quantitative invasive coronary angiography. The relation between APCs and angiographic stenosis was further examined by gender. The mean age of the study cohort was 64.4 ± 10.2 years (29.0% female). In patients with obstructive disease, men had more LD-NCP PAV (0.5 ± 0.4 vs 0.3 ± 0.8, p = 0.03) and women had more CP PAV (11.7 ± 1.6 vs 8.0 ± 0.8, p = 0.04). Obstructive lesions had more NCP PAV compared with their nonobstructive lesions in both genders, however, obstructive lesions in women also demonstrated greater LD-NCP PAV (0.4 ± 0.5 vs 1.0 ± 1.8, p = 0.03), and CP PAV (17.4 ± 16.5 vs 25.9 ± 18.7, p = 0.03) than nonobstructive lesions. Comparing the composition of obstructive lesions by gender, women had more CP PAV (26.3 ± 3.4 vs 15.8 ± 1.5, p = 0.005) whereas men had more NCP PAV (33.0 ± 1.6 vs 26.7 ± 2.5, p = 0.04). Men had more LD-NCP PAV in nonobstructive lesions compared with women (1.2 ± 0.2 vs 0.6 ± 0.2, p = 0.02). In conclusion, there are gender-specific differences in plaque composition based on stenosis severity.

ObjectiveThe study evaluates the relationship of coronary stenosis, atherosclerotic plaque characteristics (APCs) and age using artificial intelligence enabled quantitative coronary computed tomographic angiography (AI-QCT).MethodsThis is a post-hoc analysis of data from 303 subjects enrolled in the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial who were referred for invasive coronary angiography and subsequently underwent coronary computed tomographic angiography (CCTA). In this study, a blinded core laboratory analysing quantitative coronary angiography images classified lesions as obstructive (≥50%) or non-obstructive (<50%) while AI software quantified APCs including plaque volume (PV), low-density non-calcified plaque (LD-NCP), non-calcified plaque (NCP), calcified plaque (CP), lesion length on a per-patient and per-lesion basis based on CCTA imaging. Plaque measurements were normalised for vessel volume and reported as % percent atheroma volume (%PAV) for all relevant plaque components. Data were subsequently stratified by age <65 and ≥65 years.ResultsThe cohort was 64.4±10.2 years and 29% women. Overall, patients >65 had more PV and CP than patients <65. On a lesion level, patients >65 had more CP than younger patients in both obstructive (29.2 mm3 vs 48.2 mm3; p<0.04) and non-obstructive lesions (22.1 mm3 vs 49.4 mm3; p<0.004) while younger patients had more %PAV (LD-NCP) (1.5% vs 0.7%; p<0.038). Younger patients had more PV, LD-NCP, NCP and lesion lengths in obstructive compared with non-obstructive lesions. There were no differences observed between lesion types in older patients.ConclusionAI-QCT identifies a unique APC signature that differs by age and degree of stenosis and provides a foundation for AI-guided age-based approaches to atherosclerosis identification, prevention and treatment.

The value of a coin may affect people's judgment of its size and the size of a coin affects the judgment of its worth. A study of this possibility is presented by comparing the probability that a person would pick up an old five pence coin with the probability of a person picking up a new five pence coin, which is smaller.

NLRP3 is an intracellular sensor protein that when activated by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis 1 , 2 . The conformational states of NLRP3 and the way antagonistic small molecules act at the molecular level remain poorly understood 2 , 3 . Here we report the cryo-electron microscopy structures of full-length human NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950) 4 . Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined leucine-rich repeat (LRR) domains that assemble back-to-back as pentamers. The NACHT domain is located at the apical axis of this spherical structure. One pyrin domain dimer is in addition formed inside the LRR cage. Molecular contacts between the concave sites of two opposing LRR domains are mediated by an acidic loop that extends from an LRR transition segment. Binding of CRID3 considerably stabilizes the NACHT and LRR domains relative to each other. CRID3 binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginine residues, which explains the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this key therapeutic agent, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization is within reach. Cryo-electron microscopy structures of human NLRP3 in its resting state and bound to the inhibitor CRID3 provide insight into the binding mechanism of CRID3 and its mode of antagonism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and the outbreak rapidly evolved into the current coronavirus disease pandemic. SARS-CoV-2 is a respiratory virus that causes symptoms similar to those caused by influenza A and B viruses. On July 2, 2020, the US Food and Drug Administration granted emergency use authorization for in vitro diagnostic use of the Influenza SARS-CoV-2 Multiplex Assay. This assay detects influenza A virus at 102.0, influenza B virus at 102.2, and SARS-CoV-2 at 100.3 50% tissue culture or egg infectious dose, or as few as 5 RNA copies/reaction. The simultaneous detection and differentiation of these 3 major pathogens increases overall testing capacity, conserves resources, identifies co-infections, and enables efficient surveillance of influenza viruses and SARS-CoV-2.