Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library's nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe −/− ) mouse model of atherosclerosis, we quantitatively evaluated the library's immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases.nanomedicine | drug delivery | immunotherapy | molecular imaging | atherosclerosis

The pharmacological manipulation of Liver X Receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. In this study, we present the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands were employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules were systematically optimized. In vitro studies indicated that the GW-encapsulated NPs upregulated the LXR target genes and downregulated pro-inflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV-GW-NPs) successfully reached atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (~30%) compared to the PBS group, which was with greater efficacy vs. non-targeting NPs encapsulating GW (GW-NPs) (~18%). In addition, mice administered the Col IV-GW-NPs did not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.

Aim To compare glycaemic control, hypoglycaemia and treatment discontinuation of insulin glargine 300 units/mL (Gla‐300) and insulin degludec (IDeg) in a real‐world study of insulin‐naïve adults with type 2 diabetes (T2D). Materials and methods DELIVER Naive D was a retrospective observational study that used electronic medical record data from the IBM Watson Health Explorys database. Insulin‐naïve adults with T2D who started Gla‐300 or IDeg between March 2015 and September 2017 were identified. Patients were active in the system for ≥12 months before and ≥6 months after starting Gla‐300 or IDeg and had HbA1c measurements during 6‐month baseline and 3‐ to 6‐month follow‐up. Outcomes were compared among 1:1 propensity score‐matched cohorts. Results In the matched cohorts (n = 638 each), the mean age was 59 years, approximately 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). Mean (SD) HbA1c decreases were comparable in the Gla‐300 and IDeg cohorts (−1.67% [2.22] and −1.58% [2.20]; P = 0.51), as were HbA1c target attainment [<7% (53 mmol/mol): 23.8% and 27.4%; P = 0.20; <8% (64 mmol/mol): 55.0% and 57.1%; P = 0.63] and treatment discontinuation (29.2% and 32.6%; P = 0.14). Overall and inpatient/emergency department‐associated hypoglycaemia incidences and event rates were similar in both cohorts using fixed 6‐month or variable on‐treatment follow‐up. Conclusions Among real‐world insulin‐naïve adults with T2D, initiation of Gla‐300 or IDeg resulted in comparable improvements in glycaemic control and similar rates of hypoglycaemia. These real‐world data complement and confirm a randomized trial and other real‐world studies.

The new EuroSCORE II does not improve risk prediction in high-risk patients undergoing adult cardiac surgery when compared with original additive and logistic EuroSCOREs. The key problem of risk stratification in high-risk patients has not been addressed by this new model. Future iterations of the score should explore more advanced statistical methods and focus on developing procedure-specific algorithms. Moreover, models that predict complications in addition to mortality may prove to be of increasing value.