Symptom- and Prevention-Based Testing of COVID-19 in Nursing Home Residents: A Retrospective Cohort Study.

Nursing homes (NH) residents with COVID-19 can either be tested because of presence of core symptoms (S-based) or because of transmission prevention (TP-based). The investigated study sample included all NH residents who underwent SARS-CoV-2 RT-PCR testing between March 16, 2020 and May 31, 2020 (n = 380). Clinical symptoms, temperature, and oxygen saturation were extracted from medical records, 7 days before to 14 days after testing. COVID-19 was confirmed in 81 (21%) residents; 36 (44%) S-based and 45 (56%) TP-based: 45. Cycle threshold (CT) values did not differ between the groups. In the 7 days prior to the test falling (32%), somnolence (25%) and fatigue (21%) occurred in both groups. Two days before the test, we observed a stronger decrease in oxygen saturation and an increase in temperature for the S-based group compared to the T-based group that remained up to 10 days after testing. Residents within the S-based group were 2.5 times more likely to increased mortality within 30 days than residents in the TP-based group (HR, 2.56; 95% 1.3-5.2). Although, 73% of the T-based group did eventually develop core symptoms. Thus, attention to falling and daily measures of temperature and oxygen saturation can contribute to earlier detection.

Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.

Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E deficient mice (Apoe-/- ) with advanced atherosclerotic plaques. This resulted in rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an eight-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.

HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation.

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.