Pharmacogenetics of Bleeding and Thromboembolic Events in Direct Oral Anticoagulant Users

Publisher Copyright: © 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and TherapeuticsThis study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.Peer reviewe

Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. However, its molecular pathogenesis is incompletely characterized and clinical biomarkers remain scarce. The aims of these experiments were to identify and characterize liver protein alterations in an animal model of early, diet-related, liver injury and to assess novel candidate biomarkers in NAFLD patients. Methods: Liver membrane and cytosolic protein fractions from high fat fed apolipoprotein E knockout (ApoE−/−) animals were analyzed by quantitative proteomics, utilizing isobaric tags for relative and absolute quantitation (iTRAQ) combined with nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). Differential protein expression was confirmed independently by immunoblotting and immunohistochemistry in both murine tissue and biopsies from paediatric NAFLD patients. Candidate biomarkers were analyzed by enzyme-linked immunosorbent assay in serum from adult NAFLD patients. Results: Through proteomic profiling, we identified decreased expression of hepatic glyoxalase 1 (GLO1) in a murine model. GLO1 protein expression was also found altered in tissue biopsies from paediatric NAFLD patients. In vitro experiments demonstrated that, in response to lipid loading in hepatocytes, GLO1 is first hyperacetylated then ubiquitinated and degraded, leading to an increase in reactive methylglyoxal. In a cohort of 59 biopsy-confirmed adult NAFLD patients, increased serum levels of the primary methylglyoxal-derived advanced glycation endproduct, hydroimidazolone (MG-H1) were significantly correlated with body mass index (r = 0.520, p < 0.0001). Conclusion: Collectively these results demonstrate the dysregulation of GLO1 in NAFLD and implicate the acetylation-ubquitination degradation pathway as the functional mechanism. Further investigation of the role of GLO1 in the molecular pathogenesis of NAFLD is warranted. Keywords: Non-alcoholic fatty liver disease, Glyoxalase, Methylglyoxal, Proteomics, iTRA

Metrics That Suit for Dichotomy, Well Conditioning and Object Oriented Design on Measure Chains

The paper deals with Dichotomy, well conditioning of two-point boundary value problems on time scale dynamical systems using a suitable norm on $R^{n}$. The results presented in this paper on Dichotomy and well conditions of two-point boundary value problems unify both continuous and discrete systems and generalizes these results on time scale dynamical systems. We also present empirical validation of a set of theoretical-grounded metrics on object-oriented design. Fixed point theory on metric spaces is used as a tool to obtain the required object in object oriented designs and in designing flows

Fundamental Theory of Control of General First-order Matrix Difference Systems

This paper presents the general solution of the first-order matrix difference/discrete system T(n + 1) = A(n)T(n)B(n) + D(n)U(n) R(n) = C(n)T(n) in terms of two fundamental matrix solutions of T(n + 1) = A(n)T(n) and T(n + 1) = B*(n)T(n). Then questions are addressed related to controllability, observability, and realizability. Further, more general criteria are presented for complete controllability and complete observability of time-invariant systems

Qualitative Properties of A System of Differential Equations Involving Kronecker Product of Matrices

A new approach is presented for solving a system of differential equations given by the Kronecker product of two matrices that present linear differential equations of different orders. We discuss the qualitative properties such as stability, controllability and observability

B2B online sales pushes: whether, when, and why they enhance sales performance

Business-to-business (B2B) sellers are increasingly transitioning to hybrid sales structures, by augmenting an in-person field sales force with a direct online channel. During this transition, sellers frequently experience a cold-start problem, wherein existing customers are either not acquainted with the online channel or unconvinced of its usefulness and are therefore reluctant to adopt it. To overcome the cold-start problem, B2B sellers are increasingly relying on online sales pushes, which are efforts to encourage salespeople to nudge customers to adopt the online channel for certain buying tasks. Yet, because salespeople may fear that the online channel adoption jeopardizes the very relationships that they painstakingly built, the salespeople's compliance with an online sales push remains unclear. To glean insight into this dilemma, we empirically investigate an online sales push's impact on salesperson effort (re)allocation and sales performance. Based on an econometric analysis of archival data from a B2B seller and a scenario-based experiment, we conclude that salespeople generally tend to comply with an online sales push because it frees up their time and allows them to pursue new selling opportunities that have the potential to increase their compensation. The results also indicate that following an online sales push, salespeople expend their effort based on a customer's online proclivity and potential prior to the push. Moreover, the effort expended varies over time and across communication channels. Additionally, the analysis reveals (a) asymmetric carryover and cross-channel effects of communication effort and sales performance and (b) asymmetric synergistic effects of communication effort on sales performance