The pivotal role of cholesterol absorption inhibitors in the management of dyslipidemia

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease. Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. It impairs the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol. Ezetimibe is an effective and safe agent for lowering LDL-C and non HDL-C. Short term clinical trials have established the role of ezetimibe monotherapy and its use in combination with statins. Furthermore, ezetimibe and statin combination therapy increased the percentage of patients who achieved their LDL-C treatment goal. Studies using surrogate markers of atherosclerosis have suggested a possible role of ezetimibe in combating atherosclerosis. Ezetimibe provides an effective therapeutic strategy for the management of homozygous familial hypercholesterolemia (HoFH) and sitosterolemia. The lack of outcomes and long term safety data is attributed to the relatively recent introduction of this medication

AN INTEGRATIVE APPROACH FOR TRANSLATING RESOLVIN E1 TO IMPROVE OBESITY-RELATED OUTCOMES

Chronic inflammation contributes toward the pathogenesis of numerous diseases including, but not limited to, obesity, autoimmunity, cardiovascular diseases, and cancers. The discovery of specialized pro-resolving mediators (SPMs), critical molecules for resolving inflammation, initiated investigation into targeting pathways of inflammation resolution to improve physiological outcomes. To determine mechanisms by which SPMs target inflammation resolution in obesity we conducted RNA-sequencing on hepatic tissue on mice treated with resolvin E1 (RvE1), an SPM synthesized from eicosapentaenoic (EPA) that we previously showed attenuates hyperinsulinemia and hyperglycemia in obese mice. We included mice that are either wildtype or knockouts of the ChemR23 gene, the receptor for RvE1. We were able to establish gene and exon-level splicing variants that altered the hepatic genomic landscape, providing potential novel mechanisms of action for RvE1 and its metabolic/inflammatory effects. Next, we conducted studies that focused on the translation of RvE1 for obesity-related metabolic outcomes. We studied RvE1 with diversity outbred mice fed a high-fat diet to model the heterogeneity of obesity in the human population. We first found SNPs that significantly increased risk of weight gain with diet-induced obesity and then showed that upon RvE1 treatment there were positive and negative responders to RvE1 for insulin, glucose, glucagon, resistin, leptin, and gastric inhibitory peptide. RvE1’s effects were most pronounced with positive responders for RvE1 in the lowest fat mass in relation to hyperleptinemia. Lastly, to translate our findings at the human level, we conducted a non-randomized uncontrolled clinical trial where we gave subjects with obesity an enriched marine oil dietary supplement that contains the parent molecule to RvE1, 18-hydroxyeicosapentaenoic. After participants took 2g of the supplement for one month, we found an increase in several SPMs including a 3-fold increase in plasma RvE1. Here we showed that SPM bioavailability in individuals with obesity, who are at higher risk for SPM deficiencies, can be improved upon supplementation. These results establish integrative approaches for translating RvE1 and other SPM therapeutics for improvement of obesity-related outcomes.Doctor of Philosoph

Markov modeling of moving target defense games

We introduce a Markov-model-based framework for Moving Target Defense (MTD) analysis. The framework allows modeling of broad range of MTD strategies, provides general theorems about how the probability of a successful adversary defeating an MTD strategy is related to the amount of time/cost spent by the adversary, and shows how a multi-level composition of MTD strategies can be analyzed by a straightforward combination of the analysis for each one of these strategies. Within the proposed framework we define the concept of security capacity which measures the strength or effectiveness of an MTD strategy: the security capacity depends on MTD specific parameters and more general system parameters. We apply our framework to two concrete MTD strategies

Inflammation and Metabolism of Influenza-Stimulated Peripheral Blood Mononuclear Cells From Adults With Obesity Following Bariatric Surgery

BACKGROUND: Obesity dysregulates immunity to influenza infection. Therefore, there is a critical need to investigate how obesity impairs immunity and to establish therapeutic approaches that mitigate the impact of increased adiposity. One mechanism by which obesity may alter immune responses is through changes in cellular metabolism. METHODS: We studied inflammation and cellular metabolism of peripheral blood mononuclear cells (PBMCs) isolated from individuals with obesity relative to lean controls. We also investigated if impairments to PBMC metabolism were reversible upon short-term weight loss following bariatric surgery. RESULTS: Obesity was associated with systemic inflammation and poor inflammation resolution. Unstimulated PBMCs from participants with obesity had lower oxidative metabolism and adenosine triphosphate (ATP) production compared to PBMCs from lean controls. PBMC secretome analyses showed that ex vivo stimulation with A/Cal/7/2009 H1N1 influenza led to a notable increase in IL-6 with obesity. Short-term weight loss via bariatric surgery improved biomarkers of systemic metabolism but did not improve markers of inflammation resolution, PBMC metabolism, or the PBMC secretome. CONCLUSIONS: These results show that obesity drives a signature of impaired PBMC metabolism, which may be due to persistent inflammation. PBMC metabolism was not reversed after short-term weight loss despite improvements in measures of systemic metabolism

Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250 mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h(-1); elimination rate constant, 0.69 (0.46) h(-1); volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500 mg or more was needed for >= 90% attainment of the 1.0-log kill target at a MIC of 1 mg/liter, and 2,250 mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5 mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the pre-defined targets supporting the current recommendations for ETA deprioritization

Human-Computer Interaction and the Future ofWork

Advances in computing technology, changing policies, and slow crises are rapidly changing the way we work. Human-computer interaction (HCI) is a critical aspect of these trends, to understand how workers contend with emerging technologies and how design might support workers and their values and aspirations amidst technological change. This SIG invites HCI researchers across diverse domains to reflect on the range of approaches to future of work research, recognize connections and gaps, and consider how HCI can support workers and their wellbeing in the future

Analysis of the impact of sex and age on the variation in the prevalence of antinuclear autoantibodies in Polish population : a nationwide observational, cross-sectional study

The detection of antinuclear autoantibody (ANA) is dependent on many factors and varies between the populations. The aim of the study was first to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cutoff threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA-staining patterns. We tested 1731 patient samples using commercially available IIFA using two cutoff thresholds of 1:100 and 1:160. We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cutoff level. For a cutoff threshold 1:100, the positive population was 19.5% and for the 1:160 cutoff threshold, it was 11.7%. The most prevalent ANA-staining pattern was AC-2 Dense Fine speckled (50%), followed by AC-21 Reticular/AMA (14.38%) ANA more common in women (72%); 64% of ANA-positive patients were over 50 years of age. ANA prevalence in the Polish population is at a level observed in other highly developed countries and is more prevalent in women and elderly individuals. To reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cutoff threshold. © 2021, The Author(s). **Please note that there are multiple authors for this article therefore only the name of the first 30 including Federation University Australia affiliate “Fadi Charchar" is provided in this record*