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Objective The aim was to characterise the short-term (up to 12 months) direct economic burden of new cardiovascular (CV) events among adults with type 2 diabetes (T2D) in Israel. Methods In this retrospective cohort study utilising the electronic health records of the Maccabi Healthcare Services, adults aged ≥ 21 years with T2D who experienced their first CV event (2013–2016) were identified via adjudicated enrolment in a CV registry. Wilcoxon rank-sum test estimated excess healthcare resource utilisation in three periods after the CV event: immediate (1 month; for all patients), acute (3 months; for survivors of 1 month of follow-up) and short-term (12 months; for survivors of 3 months of follow-up). Direct healthcare expenditure (2018 United States dollars [USD]) was estimated from unit costs from the State of Israel Ministry of Health price list. Results In total, 5133 adults experienced a qualifying CV event, with a mean (standard deviation [SD]) age of 67.4 (11.8) years, diabetes duration of 17.7 (11.1) years and glycated haemoglobin of 7.4% (1.6%); 38.0% were female. In USD per patient, mean (SD) immediate costs were $10,741 ($11,707) compared with $2820 ($5661) at baseline (cost ratio [CR] 3.81), acute costs were $14,586 ($15,410) compared with $5202 ($8971) at baseline (CR 2.80) and short-term costs were $23,847 ($25,227) compared with $11,123 ($15,990) at baseline (CR 2.14). A sensitivity analysis of survivors only was consistent with the main analysis. Conclusions Our results indicate that CV complications of T2D place a substantial excess economic burden on Israel’s healthcare system over the short term (up to 12 months). Supplementary Information The online version contains supplementary material available at 10.1007/s41669-021-00268-5.

Objectives To evaluate excess healthcare resource utilization (HRU) and costs among patients with both type 2 diabetes (T2D) and established cardiovascular disease (CVD) relative to those with T2D only, in Israel. Methods A retrospective, observational, cohort study of adult patients with T2D from the Maccabi Healthcare Services in Israel who enrolled in a cardiovascular registry between 2013 and 2016 (pre-index date period). Patients with established CVD between 2013 and 2016 were propensity matched 1:2 to control patients without established CVD. HRU and medical costs (2018 US Dollars [USD]) were extracted for a 2-year observation period (January 1, 2017, to December 31, 2018) and analyzed using generalized linear models. Results Overall, 4,582 patients with established CVD were matched 1:2 to 9151 controls (including 13 patients matched to a single control). HRU and costs were significantly higher in patients with established CVD versus controls across a wide range of resources. In total, annual costs per patient (USD) were 10 011.8 (95% confidence interval 9,502.2; 10 548) and 7206.8 (95% confidence interval 6631.8; 7831.7) in patients with established CVD and controls, respectively. Hospitalizations, primary care visits, and medications for any condition were the main cost drivers, with greater utilization and higher costs in the established CVD group versus controls (P Conclusions In a real-world setting, HRU and costs were significantly higher in patients with T2D and established CVD compared with controls across the vast majority of resource types. These up-to-date cost estimates of CVD improve our understanding of the financial implications of established CVD beyond the direct expenses.

Stable nano-sized vesicles with a monolayer encapsulating membrane were prepared from novel bolaamphiphiles with choline ester head groups. The head groups were covalently bound to the alkyl chain of the bolaamphiphiles either via the nitrogen atom of the choline moiety, or via the choline ester's methyl group. Both types of bolaamphiphiles competed with acetylthiocholine for binding to acetylcholine esterase (AChE), yet, only the choline ester head groups bound to the alkyl chain via the nitrogen atom of the choline moiety were hydrolyzed by the enzyme. Likewise, only vesicles composed of bolaamphiphiles with head groups that were hydrolyzed by AChE released their encapsulated material upon exposure to the enzyme. Injection of carboxyfluorescein (CF)-loaded vesicles with cleavable choline ester head groups into mice resulted in the accumulation of CF in tissues that express high AChE activity, including the brain. By comparison, when vesicles with choline ester head groups that are not hydrolyzed by AChE were injected into mice, there was no accumulation of CF in tissues that highly express the enzyme. These results imply that bolaamphiphilic vesicles with surface groups that are substrates to enzymes which are highly expressed in target organs may potentially be used as a drug delivery system with controlled site-directed drug release.

Effective targeted drug delivery by cationic liposomes is difficult to achieve because of their rapid clearance from the blood circulation. Bolaamphiphiles that form monolayer membrane may provide vesicles with improved stability, as shown for archaeosomes. We investigated a series of bolaamphiphiles with acetylcholine head groups and systematic structural changes in their hydrophobic domain for their ability to form stable nanovesicles. Bolaamphiphiles with two aliphatic chains separated by a short amide midsection produced spherical nanovesicles ranging in diameter from 80 to 120 nm. These vesicles lost their encapsulated material within 24 hours of incubation in phosphate-buffered saline (PBS). Similar bolaamphiphiles with a longer midsection produced a mixture of fibers and more stable nanovesicles. Bolaamphiphiles with ester amide midsection produced only spherical nanovesicles that were stable during incubation in PBS for several days. Vesicles made from bolaamphiphiles with acetylcholine head groups conjugated to the aliphatic chain via the amine were less stable than vesicles made from bolaamphiphiles with head groups conjugated to the aliphatic chain via the acetyl group. Vesicles that were stable in vitro showed good stability in the blood circulation after intravenous administration to mice. These results help in elucidating the bolaamphiphile structures needed to form stable cationic vesicles for targeted drug delivery.

Self-assembling nanostructures were prepared from novel cationic amphiphilic compounds synthesized from vernonia oil, a natural epoxydized triglyceride. The presence of a 12,13-epoxy group on the C18 unsaturated fatty acid, vernolic acid, which is the main constituent of vernonia oil, permitted the synthesis of novel amphiphilic derivatives with a hydrogen-bonding hydroxyl and a cationic headgroup moiety on adjacent carbon atoms. The amphiphiles were prepared in a two-stage synthesis that comprised opening of the epoxy groups with a haloacetic acid, followed by quaternization of the halo group with a tertiary amine containing a C12 aliphatic chain. Intact vernonia oil as the starting material gave a triple-headed cationic amphiphile, containing three vernolic acid derived moieties connected through a glycerol backbone. A single-headed amphiphile with two alkyl chains and a single quaternary ammonium headgroup was synthesized from the methyl ester of vernolic acid as the starting material. The triple-headed derivative could form nonencapsulating structures. Cholesterol was required in the formulation (1:1) to make spherical vesicles that could encapsulate a water-soluble marker. The single-headed derivative, however, formed spherical encapsulating vesicles without cholesterol. TEM, NMR, and FT-IR were used to characterize the vesicles, and molecular structure vs morphology relationships were postulated on the basis of these data. The triple-headed amphiphile also formed a DNA complex that was highly resistant to hydrolysis by DNase. This amphiphile-DNA complex was used as vector for gene transfer in cell culture demonstrating efficient DNA transfection.