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Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment. [ABSTRACT FROM AUTHOR]

Background: The ratio of neutrophils to lymphocytes [NLR] is one of the most accepted prognostic indices and demonstrates a positive correlation with the severity of a disease. Given that probiotics exerted immunomodulatory properties and thus positively affected lymphocytopenia induction in severely ill patients, we performed a post hoc analysis in the ProVAP protocol to investigate whether probiotics affected the prognostication of NLR in respect to ventilator-associated pneumonia in multi-trauma patients. This cohort mandatorily involved severe traumatic brain injury patients. Methods: The white blood cell data of all patients, after being retrieved for the days 0 and 7, were statistically assessed in respect to neutrophils, lymphocytes and NLR among the 4 sub-groups of the study: placebo/no-VAP, placebo/VAP, probiotics/no-VAP, and probiotics/VAP. Results: Lymphopenia was dominant in placebo sub-groups, while an increased level of lymphocytes was prominent in probiotics sub-groups. This resulted in an increase [p = 0.018] in the NLR value in the probiotics/VAP group in relation to the probiotics/no-VAP cohort; this was an increase of half the value of the placebo/VAP [p < 0.001], while the NLR value in placebo/no-VAP group increased almost four-fold in relation to probiotics/no-VAP [p < 0.001]. Additionally, the ROC curve for probiotic-treated patients revealed a NLR7 cut-off value of 7.20 as a prognostic factor of VAP (AUC: 78.6%, p = 0.015, 95% CI: 62.6–94.5%), having a high specificity of 90.2% and a sensitivity of 42.9%. Conclusions: NLR may considered a credible prognostic biomarker in multi-trauma patients since it can evaluate the immunomodulatory benefits of probiotic treatment. However, the results of the present post hoc analysis should be interpreted meticulously until further evaluation, since they may be basically species- or strain-specific. [ABSTRACT FROM AUTHOR]

Postoperative pain is the unpleasant sensory and emotional experience after surgery, its origin being both the inflammatory reaction induced by the surgical trauma on the abdominal wall and the splanchnic pain induced by the activation of nociceptors of the viscera, which are highly sensitive to distension, ischemia, and inflammation. Nowadays, it is well recognized that there is a close relationship between the gut microbiome and pain perception, and that microbiome is highly affected by both anesthesia and surgical manipulation. Thus, efforts to restore the disturbed microbiome via supplementation with beneficial bacteria, namely probiotics, seem to be effective. In this article, the knowledge gained mainly from experimental research on this topic is analyzed, the concluding message being that each probiotic strain works in its own way towards pain relief. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms in cytochrome P450 genes can cause variation in metabolism. Thus, single nucleotide variants significantly impact drug pharmacokinetics, toxicity factors, and efficacy and safety of medicines. The distribution of CYP450 alleles varies drastically across ethnicities, with significant implications for personalized medicine and the healthcare system. We combined whole-genome and exome sequencing data to provide a review of CYP450 allele polymorphisms with clinical importance. Data were collected from 800 unrelated Iranians (100 subjects from 8 major ethnicities of Iran), more than 32,000 unrelated Europeans (other than Caucasian), and four Middle Eastern countries. We analyzed the frequencies and similarities of 17 CYP450 frequent alleles related to nine important CYP450 isoenzymes and homozygous and heterozygous genotypes based on these alleles in eight major Iranian ethnics by integrating these data with population-specific linkage information and compared these datasets with mentioned populations. [ABSTRACT FROM AUTHOR]

Background: The coexistence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) has been defined as overlap syndrome (OVS). Recently, a link between OSA, COPD and Vitamin D (Vit D) serum concentration was reported, however, evidence regarding Vit D status in patients with OVS is scarce. The aim of the present study was to evaluate Vit D serum levels and to explore the association of those levels with anthropometric, pulmonary function and sleep parameters in patients with OVS. Methods: Vit D serum levels were measured in patients diagnosed with OVS, as confirmed by overnight polysomnography and pulmonary function testing. Results: A total of 90 patients (79 males and 11 females) were included in the analysis. The patients were divided into three groups matched for age, gender, and BMI: the control group that included 30 patients (27 males and 3 females), the OSA group that included 30 patients (26 males and 4 females), and the OVS group that included 30 patients (26 males and 4 females). Patients with OVS exhibited decreased serum 25(OH)D levels compared with OSA patients and controls (14.5 vs. 18.6 vs. 21.6 ng/mL, p < 0.001). In the OVS group, multiple linear regression analysis identified AHI and FEV1, as predictors of serum 25(OH)D levels (p = 0.041 and p = 0.038, respectively). Conclusions: Lower Vit D levels have been observed in patients with OVS compared with OSA patients and non-apneic controls, indicating an increased risk of hypovitaminosis D in this population which might be associated with disease severity. [ABSTRACT FROM AUTHOR]

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies (n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research. [ABSTRACT FROM AUTHOR]

CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare 'variants of uncertain significance', which are increasingly detected as more exome and genome sequencing of diverse populations is conducted. [ABSTRACT FROM AUTHOR]

Over 90% of deaths in cancer patients are attributed to tumor drug resistance. Resistance to therapeutic agents can be due to an innate property of cancer cells or can be acquired during chemotherapy. In recent years, it has become increasingly clear that regulation of membrane ion channels is an important mechanism in the development of chemoresistance. Here, we review the contribution of ion channels in drug resistance of various types of cancers, evaluating their potential in clinical management. Several molecular mechanisms have been proposed, including evasion of apoptosis, cell cycle arrest, decreased drug accumulation in cancer cells, and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. Thus, targeting ion channels might represent a good option for adjuvant therapies in order to counteract chemoresistance development. [ABSTRACT FROM AUTHOR]

Anticoagulants play an important role in reducing complications and mortality associated with thromboembolic disorders, and anticoagulant therapy has been progressively enriched over the last few years with numerous new options. On the contrary, the pharmacogenetic aspects are still poorly understood and still under investigation, despite the increasing use of DOACs and an ascertained variability in response to therapy with these drugs. The authors described, for each drug, the approved indications, mechanism of action, pharmacokinetics, pharmacodynamic, side effects, antidotes, drug-drug interactions, and particularly, the relationship between SNPs of common genetic variants and plasma drug levels [[6]]. [Extracted from the article]

The exponential expansion of genomic data coupled with the lack of appropriate clinical categorization of the variants is posing a major challenge to conventional medications for many common and rare diseases. To narrow this gap and achieve the goals of personalized medicine, a collaborative effort should be made to characterize the genomic variants functionally and clinically with a massive global genomic sequencing of "healthy" subjects from several ethnicities. Familial-based clustered diseases with homogenous genetic backgrounds are amongst the most beneficial tools to help address this challenge. This review will discuss the diagnosis, management, and clinical monitoring of familial hypercholesterolemia patients from a wide angle to cover both the genetic mutations underlying the phenotype, and the pharmacogenomic traits unveiled by the conventional and novel therapeutic approaches. Achieving a drug-related interactive genomic map will potentially benefit populations at risk across the globe who suffer from dyslipidemia. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated. [ABSTRACT FROM AUTHOR]

Dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban are direct oral anticoagulants (DOACs). Their inter-individual variability in pharmacodynamics and pharmacokinetics (transport and metabolism) is high, and could result from genetic polymorphisms. As recommended by the French Network of Pharmacogenetics (RNPGx), the management of some treatments in cardiovascular diseases (as antiplatelet agents, oral vitamin K antagonists, and statins) can rely on genetic testing in order to improve healthcare by reducing therapeutic resistance or toxicity. This paper is a review of association studies between single nucleotide polymorphisms (SNPs) and systemic exposure variation of DOACs. Most of the results presented here have a lot to do with some SNPs of CES1 (rs2244613, rs8192935, and rs71647871) and ABCB1 (rs1128503, rs2032582, rs1045642, and rs4148738) genes, and dabigatran, rivaroxaban, and apixaban. Regarding edoxaban and betrixaban, as well as SNPs in the CYP3A4 and CYP3A5 genes, literature is scarce, and further studies are needed. [ABSTRACT FROM AUTHOR]

Medical and health science students represent future health professionals, and their perceptions are essential to increasing awareness on genomic medicine and pharmacogenomics. Lack of education is one of the significant barriers that may affect health professional's ability to interpret and communicate pharmacogenomics information and results to their clients. Our aim was to assess medical and health science students' knowledge, attitudes and perception for a better genomic medicine and pharmacogenomics practice in the United Arab Emirates (UAE). A cross-sectional study was conducted using a validated questionnaire distributed electronically to students recruited using random and snowball sampling methods. A total of 510 students consented and completed the questionnaire between December 2018 and October 2019. The mean knowledge score (SD) for students was 5.4 (±2.7). There were significant differences in the levels of knowledge by the year of study of bachelor's degree students, the completion status of training or education in pharmacogenomics (PGX) or pharmacogenetics and the completion of an internship or study abroad program (p-values < 0.05. The top two barriers that students identified in the implementation of genomic medicine and pharmacogenomics were lack of training or education (59.7%) and lack of clinical guidelines (58.7%). Concerns regarding confidentiality and discrimination were stated. The majority of medical and health science students had positive attitudes but only had a fair level of knowledge. Stakeholders in the UAE must strive to acquaint their students with up-to-date knowledge of genomic medicine and pharmacogenomics. [ABSTRACT FROM AUTHOR]

Pharmacogenetics and biomarkers are becoming normalised as important technologies to improve drug efficacy rates, reduce the incidence of adverse drug reactions, and make informed choices for targeted therapies. However, their wider clinical implementation has been limited by a lack of robust evidence. Suitable evidence is required before a biomarker's clinical use, and also before its use in a clinical trial. We have undertaken a review of five pharmacogenetic biomarker-guided randomised controlled trials (RCTs) and evaluated the evidence used by these trials to justify biomarker inclusion. We assessed and quantified the evidence cited in published rationale papers, or where these were not available, obtained protocols from trial authors. Very different levels of evidence were provided by the trials. We used these observations to write recommendations for future justifications of biomarker use in RCTs and encourage regulatory authorities to write clear guidelines. [ABSTRACT FROM AUTHOR]

In this endeavour, inspired by the Odyssey, we aim to embark with the reader on a journey on a ship from Troy to Ithaca, coursing through the history of the momentous events and achievements that paved the way for personalised medicine. We will set sail amidst important genetic discoveries, beginning with the discovery of the first human genome, and voyage through the projects that contributed to the progress of pharmacogenomic studies. Concurrently, we will propose methods to overcome the obstacles that are slowing the potential full implementation of accumulated knowledge into everyday practice. This journey aims to reflect on the frontiers of current genetic knowledge and the practical use of this knowledge in preventive, diagnostic and pharmacogenomic approaches to directly impact the socio-economic aspects of public health. [ABSTRACT FROM AUTHOR]

Oral anticoagulants are required for both treatment and prophylaxis in many different diseases. Clinicians and patients now have a choice of oral anticoagulants, including the vitamin K antagonists (of which warfarin is the most widely used and is used as the exemplar in this paper), and direct oral anticoagulants (DOACs: dabigatran, apixaban, rivaroxaban, and edoxaban). This paper explores the recent advances and controversies in oral anticoagulation. While some commentators may favour a complete switchover to DOACs, this paper argues that warfarin still has a place in therapy, and a stratified approach that enables the correct choice of both drug and dose would improve both patient outcomes and affordability. [ABSTRACT FROM AUTHOR]