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Background Complex percutaneous coronary intervention (PCI) is increasingly performed in older adults (age ≥75 years) with stable ischemic heart disease. However, little is known about clinical outcomes. Methods and Results We derived a cohort of older adults undergoing elective PCI for stable ischemic heart disease across a large health system. We compared 12-month event-free survival (freedom from all-cause death, nonfatal myocardial infarction, stroke, and major bleeding), all-cause death, target lesion revascularization, and bleeding events for patients receiving complex versus noncomplex PCI and derived risk estimates with Cox regression models. We included 513 patients (mean age, 81±5 years). Patients receiving complex PCI versus noncomplex PCI did not significantly differ across a host of clinical characteristics including cardiovascular disease features, noncardiac comorbidities, guideline-directed medical therapy use, and frailty. Patients receiving complex PCI versus noncomplex PCI experienced worse event-free survival (80.4% versus 86.8%), which was not significant in adjusted analyses (hazard ratio [HR], 1.38 [95% CI, 0.88-2.16]). All-cause death at 1 year for patients undergoing complex PCI was nearly double that seen for patients receiving noncomplex PCI (10.2% versus 5.9%), and the risk was significant in models adjusted for clinical characteristics (HR, 1.97 [95% CI, 1.02-3.79]). Target lesion revascularization risk was lower for patients receiving complex PCI (2.2% versus 3.5%, adjusted HR), but bleeding events were not statistically different between groups (25.3% versus 20.5%; P=0.19). Conclusions Complex PCI in older adults with stable ischemic heart disease was associated with lower risk of target lesion revascularization but higher all-cause death compared with noncomplex PCI.

Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin-1β (IL-1β), TNF, and IL-6. The bioactivity of IL-1β is classically dependent on NLRP3 inflammasome activation, which culminates in caspase-1 activation and pyroptosis. Recent studies suggest a role for NLRP3 inflammasome activation in lung inflammation and fibrosis in both COVID-19 and SARS, and there is evidence of NLRP3 involvement in HIV-1 disease. Here, we show that GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1, and HIV-1 trigger a TLR8-dependent pro-inflammatory cytokine response from human macrophages in the absence of pyroptosis, with GU-rich RNA from the SARS-CoV-2 spike protein triggering the greatest inflammatory response. Using genetic and pharmacological inhibition, we show that the induction of mature IL-1β is through a non-classical pathway dependent on caspase-1, caspase-8, the NLRP3 inflammasome, potassium efflux, and autophagy while being independent of TRIF (TICAM1), vitamin D3, and pyroptosis.

Therapeutic strategies that provide effective and broad-spectrum neutralization against HIV-1 infection are highly desirable. Here, we investigate the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) to neutralize a broad range of HIV-1 strains. TNP displayed outstanding neutralizing breadth and potency; they neutralized all 125 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, and transmitted/founder viruses, with a geometric mean 80% inhibitory concentration (IC80) of 819 μg ml-1 (range, 72 to 8,570 μg ml-1). TNP also selectively bound to and induced autophagy in HIV-1-infected CD4+ T cells and macrophages, while having no effect on uninfected cells. This TNP-mediated autophagy inhibited viral release and reduced cell-associated HIV-1 in a dose- and phospholipase D1-dependent manner. Genetic or pharmacological inhibition of autophagy ablated this effect. Thus, we can use TNP as therapeutic agents to neutralize cell-free HIV-1 and to target HIV-1 gp120-expressing cells to decrease the HIV-1 reservoir.IMPORTANCE HIV-1 is a major global health challenge. The development of an effective vaccine and/or a therapeutic cure is a top priority. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 hinders this progress. Here we developed an approach using nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP). Not only do TNP effectively neutralize all strains of HIV-1, but they also selectively bind to infected cells and decrease the release of HIV-1 particles through an autophagy-dependent mechanism with no drug-induced off-target or cytotoxic effects on bystander cells.

This paper addresses the redevelopment of the Nassau Airport in The Bahamas and how this airport is constantly adapting to meet the needs of a tourism-dependent country while protecting itself from potential shocks that may disrupt tourism demand. By diversifying its revenue streams and expanding its physical footprint, the airport is positioning itself to provide commercial opportunities and generate sustainable income beyond passenger traffic. [ABSTRACT FROM AUTHOR]

Background: Percutaneous coronary intervention (PCI) for stable ischemic heart disease (SIHD) in older adults requires a meticulous assessment of procedural risks and benefits, but contemporary data on outcomes in this population is lacking. Therefore, we examined the risk of near-term readmission, bleeding, and mortality in high-risk cohort of older adults undergoing inpatient PCI for SIHD. METHODS: We analyzed the National Readmissions Database from 2017 to 2018 to identify index hospitalizations in which PCI was performed for SIHD. Patients were stratified into those ≥ 75 years old (older adults) and those < 75 years old. The primary outcome was 90-day readmission. Secondary outcomes included in-hospital mortality, hospital length of stay (LOS), and total hospital charge. RESULTS: A total of 74,516 patients underwent inpatient PCI for SIHD, of whom 24,075 were older adults. Older adult patients had higher odds of in-hospital mortality (OR = 2.00, 95% CI: 1.68-2.38), intracranial hemorrhage (OR = 2.03, 95% CI: 1.24-3.34), and gastrointestinal hemorrhage (OR = 1.72, 95% CI: 1.43-2.07) during index hospitalization, with longer LOS and in-hospital charge. Older adults also experienced a higher hazard of 90-day readmission for any cause (HR = 1.61, 95% CI: 1.57-1.66) and cardiovascular causes (HR = 1.84, 95% CI: 1.77-1.91). CONCLUSION: Older adults undergoing inpatient PCI for SIHD were at increased risk for in-hospital mortality, periprocedural morbidities, higher cost, and readmissions compared with younger adults. Understanding these differences may improve shared decision-making for patients with SIHD being considered for PCI. [ABSTRACT FROM AUTHOR]

The influence of Niccolò Machiavelli’s thought on John Adams’s political theory and principal writings has received not insubstantial attention in history and political science scholarship. This research both builds upon and departs from previous studies by focusing on Adams’s other major works, namely, “A Dissertation on the Canon and Feudal Law” and the “Novanglus” essays, to illustrate Adams’s alignment with, and profound intellectual debt to, Machiavelli’s principles as delineated in the latter’s major work, Discourses on Livy. This study supplements the scholarly understanding of Adams’s theorizing by examining the American statesman and Machiavelli together in the overlooked early stages of Adams’s Revolutionary career. Furthermore, it challenges interpretations of Adams with respect to how he has been ideologically framed in contemporary historical discourses assessing the Enlightenment. [ABSTRACT FROM AUTHOR]

This study employs an ideal free distribution (IFD) model to conduct a fine-grained analysis of environmental factors affecting the pre-Columbian colonisation sequence and settlement patterning in the southern Lesser Antilles of the Eastern Caribbean. We compiled a database of all known archaeological site locations and associated chronological data from St. Vincent, the Grenadines, and Grenada, and vetted this dataset for accuracy. We then performed multivariate statistical analysis of the vetted site data and 24 environmental variables hypothesised to influence settlement habitat quality, including soil attributes, proximity to freshwater/stream beds, structure and sizes of marine environments, and net primary productivity (NPP) layers. Iterative testing and refinement of the model allowed for the creation of a predictive map of pre-Columbian archaeological sites over time. Results indicate proximity to freshwater wetlands, NPP, and reef size were important variables influencing habitat choice. Additionally, latitude (distance from the equator) was also a significant variable, indicating support for a proposed colonisation of the southern Lesser Antilles that began in the northern Caribbean, rather than the south. Lastly, we provide a site inventory and map of predicted site locations that can aid in the management of threatened archaeological resources within the study region. [ABSTRACT FROM AUTHOR]

Background There are limited and nonconcordant data on the rapidity and safety of blood pressure response to clonidine in the setting of asymptomatic severe hypertension. We evaluated the blood pressure response to clonidine in hospitalized patients with asymptomatic severe hypertension. Methods We performed a review of hospitalized, noncritically ill patients receiving clonidine within 6 hours of developing asymptomatic severe hypertension (systolic blood pressure [SBP] >180 or diastolic blood pressure [DBP] >110 mm Hg in the absence of acute hypertension-mediated target organ damage). The incidence of mean arterial pressure (MAP) reduction by ≥30% at 4 hours after clonidine was the primary endpoint. Results We identified 200 relevant patient encounters (median age 63 years, 48.5% women). Median time to clonidine following asymptomatic severe hypertension was 2.8 hours. A total of 20 (10%) patients had ≥30% MAP reduction within 4 hours after clonidine, and 32 (16%) patients had ≥30% reduction in either SBP, DBP, or MAP. Older age, female sex, and preexisting vascular disease were associated with ≥30% MAP reductions (P < 0.05). Only patient sex and clonidine dose of 0.3 mg were significant in multivariable models. There were 14 adverse events observed within 24 hours of administration of clonidine; most (9) were acute kidney injury. There were no ischemic (myocardial, cerebrovascular) events. Conclusions A substantial minority of hospitalized patients with asymptomatic severe hypertension experience precipitous blood pressure decline with clonidine, and though blood pressure declines more precipitously in women and those receiving higher doses (0.3 mg specifically), the response to clonidine is generally not predictable on clinical grounds. [ABSTRACT FROM AUTHOR]