In this paper, we introduce fractional-order into a model of HIV-1 infection of CD4+ T cells. We study the effect of the changing the average number of viral particles N with different sets of initial conditions on the dynamics of the presented model. Generalized Euler method (GEM) will be used to find a numerical solution of the HIV-1 infection fractional order model.

Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. The importance of the CYP metabolism has led to the adoption of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment in major medical centers. Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin-norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.

The dependence of net atomic charges, as derived from least‐squares fitting to electrostatic potentials, on molecular orientation and potential site location is critically examined. A unique rotationally invariant algorithm, in which the charges may be constrained to reproduce the molecular dipole moment, is presented and the results for several basis sets compared to previous work. Significant improvements in dipole moments derived from the unconstrained charges are noted.

PURPOSE The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.

Abstract-Atherosclerosis is distinguished by the accumulation of lipoprotein lipid within the arterial wall. An ionic interaction of positively charged regions of apolipoprotein (apo) B with matrix proteins, including proteoglycans, collagen, and fibronectin, is thought to initiate this process. Proteoglycans are complex glycoproteins containing highly negatively charged carbohydrate chains. These proteins are abundant in atherosclerosis lesions, and they associate with apoB-containing lipoproteins. Several specific regions of apoB may mediate this process. Other lipoprotein-associated proteins, including apoE and lipases, might also participate in this process. In addition, retention may occur via lipoprotein association with other matrix molecules or as a consequence of intra-arterial lipoprotein aggregation. Key Words: atherosclerosis Ⅲ lipoproteins Ⅲ apolipoproteins Ⅲ proteoglycans C holesterol was recognized as the lipid present in atheromatous plaques in the 19th century. 1 The epidemiological association between plasma cholesterol or, more precisely, low-density lipoprotein (LDL) and coronary heart disease was well-established by the 1960s. 2 Subsequently, studies of patients with familial hypercholesterolemia demonstrated that increased plasma concentrations of LDL, without other coronary heart disease risk factors, could cause accelerated atherosclerosis. 3 Cholesterol in atheromatous lesions is derived from LDL cholesterol. 4 Raised serum triglyceride levels, a reflection of very-low-density lipoprotein (VLDL) concentrations, are also thought to be risk factors for coronary heart disease. 5 Zilversmit proposed that postprandial lipoproteins, especially chylomicron remnants, are also harmful. 6 High plasma concentrations of remnant lipoproteins created using diet or genetic manipulation in animals are atherogenic in animals. Moreover, remnant lipoproteins have been identified within arteries. 7 The commonality between these atherogenic lipoproteins is the presence of apolipoprotein (apo) B. For this reason, a quest to understand atherogenesis has focused on the biochemistry of apoB interaction with vascular wall molecules.The theories of how lipoproteins enter and accumulate within the artery have remained rather consistent for decades. Nearly 50 years ago, Page 8 summarized the extant theories in his Connor lecture: lipoproteins infiltrate the artery wall, the lipid is altered to a toxic form, and this promotes an inflammatory response (Figure 1). Increased infiltration could result from alterations in the wall of the vessel caused by endothelial denudation. 9 However, developing atheroma are usually covered by an intact endothelial layer throughout most stages of lesion progression: lipoprotein retention, fatty streak formation, and formation of advanced lesions. 10 Endothelial injuries that are insufficient to cause gross denudation may cause functional modifications leading to reduced barrier functions, ie, increased permeability. This could lead not only to greater amounts of arterial lipoproteins ...