Curr Neuropharmacol. 2023 Aug 9. doi: 10.2174/1570159X21666230808170123. Online ahead of print.

ABSTRACT

Traditional medicine and biomedical sciences are reaching a turning point because of the constantly growing impact and volume of Big Data. Machine Learning (ML) techniques and related algorithms play a central role as diagnostic, prognostic, and decision-making tools in this field. Another promising area becoming part of everyday clinical practice is personalized therapy and pharmacogenomics. Applying ML to pharmacogenomics opens new frontiers to tailored therapeutical strategies to help clinicians choose drugs with the best response and fewer side effects, operating with genetic information and combining it with the clinical profile. This systematic review aims to draw up the state-of-the-art ML applied to pharmacogenomics in psychiatry. Our research yielded fourteen papers; most were published in the last three years. The sample comprises 9,180 patients diagnosed with mood disorders, psychoses, or autism spectrum disorders. Prediction of drug response and prediction of side effects are the most frequently considered domains with the supervised ML technique, which first requires training and then testing. The random forest is the most used algorithm; it comprises several decision trees, reduces the training set's overfitting, and makes precise predictions. ML proved effective and reliable, especially when genetic and biodemographic information were integrated into the algorithm. Even though ML and pharmacogenomics are not part of everyday clinical practice yet, they will gain a unique role in the next future in improving personalized treatments in psychiatry.

PMID:37559539 | DOI:10.2174/1570159X21666230808170123

Ann Rehabil Med. 2023 Aug 9. doi: 10.5535/arm.23067. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the effects of lower limb muscle fatigue on spatiotemporal gait parameters and turning difficulty characteristics during the extended Timed Up and Go (extended TUG) test in individuals with different severity stages of Parkinson's disease (PD).

METHODS: Forty individuals with PD, classified as Hoehn and Yahr (H&Y) stages 2 and 3 participated in this pre- and post-experimental study design. The participants performed a continuous sit-to-stand task from a chair based on 30 cycles/min set-up to induce lower limb muscle fatigue. They performed extended TUG test immediately before and after completing the fatigue protocol. Spatiotemporal gait parameters and turning difficulty characteristics were recorded using two GoPro® Hero 4 Silver cameras. Data were subjected to a repeated-measure ANOVA.

RESULTS: Individuals with PD experience significant changes in spatiotemporal gait parameters, specifically stride velocity and length, under conditions of lower limb muscle fatigue (p=0.001). These changes were more pronounced in individuals with PD in the H&Y stage 3 group. Additionally, both PD groups exhibited difficulty with turning, requiring more than five steps to complete a 180° turn and taking more than 3 seconds to accomplish it.

CONCLUSION: These findings highlight the impact of muscle fatigue on gait performance in PD and suggest that individuals in later stages of the disease may be particularly affected. Further research is needed to explore interventions that can mitigate these gait impairments and improve mobility in individuals with PD.

PMID:37558204 | DOI:10.5535/arm.23067

Cell Rep Med. 2023 Aug 3:101143. doi: 10.1016/j.xcrm.2023.101143. Online ahead of print.

ABSTRACT

Effective triage of high-risk human papillomavirus (hrHPV)+ women is warranted to avoid unnecessary referral and overtreatment. Molecular triage tests have recently begun to impact cervical intraepithelial neoplasia grade 3 (CIN3) or cervical cancer (CC), termed CIN3+, detection. We find that zinc finger protein 671 methylation (ZNF671m) test has superior performance for CIN3+ detection in all single molecular triage tests, including HPV16/18 genotyping, paired box gene 1 methylation (PAX1m), and ZNF671m, in the training set. Using ZNF671m test instead of Thinprep cytologic test (TCT) as a single triage strategy or as a combined triage strategy with HPV16/18 genotyping has achieved comparable sensitivity but higher specificity for CIN3+ detection among 391 hrHPV+ women in the validation set. Little attention has been paid to the women with hrHPV- status but detected CIN3+. We find that the CIN3+ risk after a negative result could be reduced further by triage using ZNF671m in hrHPV- patients.

PMID:37557178 | DOI:10.1016/j.xcrm.2023.101143

Hepatol Commun. 2023 Aug 9;7(9):e0220. doi: 10.1097/HC9.0000000000000220. eCollection 2023 Sep 1.

ABSTRACT

BACKGROUND: We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.

METHODS: We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.

RESULTS: DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.

CONCLUSIONS: YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.

PMID:37556373 | DOI:10.1097/HC9.0000000000000220

Brain Behav. 2023 Aug 8:e3215. doi: 10.1002/brb3.3215. Online ahead of print.

ABSTRACT

OBJECTIVE: To identify the genomics underpinning the increased volume of the hippocampus after long-term administration of lithium (Li) in bipolar disorder patients, hypothesizing the possible contribution of cell growth and differentiation pathways to this complication.

METHODS: RNA-seq profiles of four samples of hippocampal progenitor cells chronically treated with a high dose of Li and three samples chronically treated with the therapeutic dose were retrieved from NCBI-GEO. The raw data underwent filtration, quality control, expression fold change, adjusted significance, functional enrichment, and pharmacogenomic analyses.

RESULTS: CCND1, LOXL2, and PRNP were identified as the genes involved in the drug response and the chronic effects of Li in the hippocampal cells. GSK-3β was also a hub in the pharmacogenomic network of Li. In addition, ZMPSTE24 and DHX35 were identified as the important genes in lithium therapy.

CONCLUSIONS: As shown by gene ontology results, these findings conclude that lithium may increase the size of the hippocampus in bipolar patients by stimulating the generation of new neurons and promoting their differentiation into neuroblasts, neurons, or microglia.

PMID:37553827 | DOI:10.1002/brb3.3215

J Crohns Colitis. 2023 Aug 8:jjad133. doi: 10.1093/ecco-jcc/jjad133. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Anti-TNF treatment failure in patients with inflammatory bowel disease (IBD) is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14.

METHODS: DNA methylation from 1,104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease (PANTS) study were assessed using the Illumina EPIC Beadchip (v1.0) at baseline, weeks 14, 30 and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 and if they were assessed at subsequent time points, were not in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 94), with patients who responded at week 14 and when assessed at subsequent time points, were in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 93).

RESULTS: Overall, between baseline and week 14, we observed 4,999 differentially methylated probes (DMPs) annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses.Epigenome-wide association (EWAS) analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at week 14. Of these, 125 DMPs demonstrated shared associations with other common traits (proportion of shared CpGs compared to DMPs) including body mass index (23.2%), followed by CRP (11.5%), smoking (7.4%), alcohol consumption per day (7.1%) and IBD type (6.8%). EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients (Spearman's rho = -0.94, p < 0.001).

CONCLUSION: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.

PMID:37551994 | DOI:10.1093/ecco-jcc/jjad133

Expert Rev Cardiovasc Ther. 2023 Aug 8. doi: 10.1080/14779072.2023.2245754. Online ahead of print.

ABSTRACT

INTRODUCTION: Cerebrovascular disease is a leading cause of morbidity and mortality in the world and antiplatelet therapy is a main pharmacologic means of secondary prevention. Clinical information has accumulated about benefit of dual antiplatelet therapy in certain clinical scenarios, genetic causes of antiplatelet resistance and its effect on clinical outcomes, and ethnic and geographic distributions of genetic polymorphisms.

AREAS COVERED: This review covers literature related to the pharmacogenomics of antiplatelet agents with a focus on ethnic variability, antiplatelet resistance, and dual antiplatelet therapy in cerebrovascular disease.

EXPERT OPINION: Selecting patients for dual antiplatelet therapy and specific agents require consideration of multiple factors. Ethnic factors should be considered in certain circumstances, but additional research is needed to determine the generalizability of the findings.

PMID:37551687 | DOI:10.1080/14779072.2023.2245754

Future Oncol. 2023 Aug 8. doi: 10.2217/fon-2022-1306. Online ahead of print.

ABSTRACT

Purpose: Previous studies of MMP-3 -1171 5A/6A in cancers have produced inconclusive outcomes. This updated meta-analysis was performed to clarify the link between this variant and cancer. Methods: Databases including PubMed, Google Scholar, EMBASE and Cochrane were searched for data collection. The associations were calculated by odds ratios with 95% CIs. Results: 63 eligible studies with 14,252 cases and 15,176 controls were included. The codominant 2, codominant 3, dominant, recessive and allele models were found to be significantly associated with 1.28-, 1.13-, 1.13-, 1.19- and 1.13-fold enhanced overall risk of cancer, respectively. Stratification analysis revealed a 1.28-times enhanced risk of esophageal cancer (codominant 1), 1.29- and 1.26-fold (codominant 3) and 1.18- and 1.28-fold (recessive model) enhanced risk in colorectal and gastrointestinal cancers, respectively, 1.30-, 1.35- and 1.22-times in codominant model 1, dominant and allele models for breast cancer, 1.56-fold (codominant 2) for gynecological cancer and 2.40-times in codominant model 2 for hepatocellular cancer. Conclusion: This meta-analysis suggests a significant association between the MMP-3 -1171 5A/6A variant and cancer. This meta-analysis was registered at INPLASY (registration number: INPLASY202280049).

PMID:37551683 | DOI:10.2217/fon-2022-1306

Pharmacogenomics. 2023 Aug 8. doi: 10.2217/pgs-2022-0147. Online ahead of print.

ABSTRACT

Sirolimus is an antiproliferative and immunosuppressive compound inhibiting the mTOR pathway, which is often activated in congenital low-flow vascular malformations. Studies have demonstrated the efficacy of sirolimus for this disease. Studies in kidney transplant patients suggest that genetic variants can influence these pharmacokinetic parameters. Therefore, a systematic literature search was performed to gain insight into pharmacogenetic studies with sirolimus. Most studies investigated CYP3A4 and CYP3A5, with inconsistent results. No pharmacogenetic studies focusing on sirolimus have been performed for low-flow vascular malformations. We analyzed two common variants of CYP3A4 and CYP3A5 (CYP3A4*22 and CYP3A5*3, respectively) in patients (n = 59) with congenital low-flow vascular malformations treated with sirolimus. No association with treatment outcome was identified in this small cohort of patients.

PMID:37551646 | DOI:10.2217/pgs-2022-0147

Pharmacogenomics. 2023 Aug 8. doi: 10.2217/pgs-2023-0091. Online ahead of print.

ABSTRACT

Aim: Antimalarial primaquine (PQ) eliminates liver hypnozoites of Plasmodium vivax. CYP2D6 gene variation contributes to PQ therapeutic failure. Additional gene variation may contribute to PQ efficacy. Information on pharmacogenomic variation in Madagascar, with vivax malaria and a unique population admixture, is scanty. Methods: The authors performed genome-wide genotyping of 55 Malagasy samples and analyzed data with a focus on a set of 28 pharmacogenes most relevant to PQ. Results: Mainly, the study identified 110 coding or splicing variants, including those that, based on previous studies in other populations, may be implicated in PQ response and copy number variation, specifically in chromosomal regions that contain pharmacogenes. Conclusion: With this pilot information, larger genome-wide association analyses with PQ metabolism and response are substantially more feasible.

PMID:37551613 | DOI:10.2217/pgs-2023-0091

Int Clin Psychopharmacol. 2023 Aug 7. doi: 10.1097/YIC.0000000000000501. Online ahead of print.

ABSTRACT

This study explored the association of pharmacogenomics with antipsychotic-induced amenorrhea in female patients with schizophrenia. A total of 89 female schizophrenia patients aged 18-40 receiving consistent antipsychotics at a consistent dose for more than 3 months were enrolled in this study. Amenorrhea was defined as the absence of menstrual period for 3 months or three periods in a row. Serum levels of prolactin, estradiol, follicle-stimulating hormone, luteinizing hormone, and thyroid-stimulating hormone were measured and Cytochrome P450 2D6, dopamine receptor D2 (DRD2) and estrogen receptor 1 were genotyped. Twenty-two patients with amenorrhea had higher prolactin levels and lower estradiol levels than those without amenorrhea (94.1 vs. 71.5 ng/ml for prolactin; P = 0.044 and 27.0 vs. 46.7 pg/ml for estradiol; P = 0.007, respectively). Multiple logistic regression analysis identified DRD2-141C deletion [odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.01-4.17; P = 0.049] and drugs increasing prolactin levels (OR = 6.17, 95% CI = 1.28-29.64; P = 0.023) as significant covariates for antipsychotic-induced amenorrhea. This study suggests that DRD2-141C deletion is associated with antipsychotic-induced amenorrhea although further studies are needed.

PMID:37551597 | DOI:10.1097/YIC.0000000000000501

Pharmacogenomics. 2023 Aug 8. doi: 10.2217/pgs-2023-0010. Online ahead of print.

ABSTRACT

Background: The cytokine IL-4 plays vital role in the intercellular signalling network during immune responses to allergen exposure. Methods: This cross-sectional study involved 202 chronic obstructive pulmonary disease (COPD) patients and 203 healthy individuals. The genotyping of IL4RAQ576R gene polymorphism was determined using polymerase chain reaction restriction fragment length polymorphism analysis. Results: Significant association between mutant genotype (GG) and combined (AA+AG) genotype for the risk of COPD was found (odds ratio [OR]: 4.32; p = 0.04). A significant protective effect was observed between the IL4RAQ576R polymorphism and Global Strategy for Obstructive Lung Disease (GOLD) stage four patients in a recessive model (AA+AG vs GG) (p = 0.002). In GOLD A, a substantial relationship was found between the AG and wild-type genotypes (AA) for COPD risk (OR: 2.38; p = 0.03). A strong association was found for COPD duration of 5-10 years (OR: 8.80; p = 0.01). Conclusion: IL4RAQ576R polymorphism is associated with COPD susceptibility.

PMID:37551548 | DOI:10.2217/pgs-2023-0010

Neuropsychopharmacology. 2023 Aug 7. doi: 10.1038/s41386-023-01667-4. Online ahead of print.

ABSTRACT

Pharmacogenomic technology is a developing field with enthusiastic interest and broad application potential. Three large, controlled studies have been published exploring the benefit of pharmacogenomically guided antidepressant treatment selection. Though all three studies did not show significant benefit of using this technology, these studies laid the foundation for further research that should address the limitations of this previous research and currently available commercial platforms. Future research needs to include large scale pharmacogenomic trials with GWAS analytics across diverse groups with attention to cost-effectiveness models, particularly for cases of treatment resistance and polypharmacy. The application of results from these large scale pharmacogenomic trials must also include exploring optimal EHR user interface design.

PMID:37550439 | DOI:10.1038/s41386-023-01667-4

Cancer Res. 2023 Aug 7:CAN-23-0758. doi: 10.1158/0008-5472.CAN-23-0758. Online ahead of print.

ABSTRACT

Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune landscape in relation to protein expression in cancer patients could provide new insights into the functional roles of proteins in cancer. By taking advantage of the genotype data from The Cancer Genome Atlas (TCGA) and protein expression data from The Cancer Proteome Atlas (TCPA), we characterized the effects of genetic variants on protein expression across 31 cancer types and identified approximately 100,000 protein quantitative trait loci (pQTL). Among these, over 8000 pQTL were associated with patient overall survival. Furthermore, characterization of the impact of protein expression on more than 350 imputed anticancer drug responses in patients revealed nearly 230,000 significant associations. In addition, approximately 21,000 significant associations were identified between protein expression and immune cell abundance. Finally, a user-friendly data portal, GPIP (https://hanlaboratory.com/GPIP), was developed featuring multiple modules that enable researchers to explore, visualize, and browse multidimensional data. This detailed analysis reveals the associations between the proteomic landscape and genetic variation, patient outcome, the immune microenvironment, and drug response across cancer types, providing a resource that may offer valuable clinical insights and encourage further functional investigations of proteins in cancer.

PMID:37548539 | DOI:10.1158/0008-5472.CAN-23-0758

Comput Struct Biotechnol J. 2023 Jul 22;21:3705-3714. doi: 10.1016/j.csbj.2023.07.023. eCollection 2023.

ABSTRACT

Large-scale multidimensional cancer genomic and pharmacological profiles have been created by several large consortium projects, including NCI-60, GDSC and DepMap, providing novel opportunities for data mining and further understanding of intrinsic therapeutic response mechanisms. However, it is increasingly challenging for experimental biologists, especially those without a bioinformatic background, to integrate, explore, and analyse these tremendous pharmacogenomics. To address this gap, IMOPAC, an interactive and easy-to-use web-based tool, was introduced to provide rapid visualizations and customizable functionalities on the basis of these three publicly available databases, which may reduce pharmacogenomic profiles from cell lines into readily understandable genetic, epigenetic, transcriptionomic, proteomic, metabolomic, and pharmacological events. The user-friendly query interface together with customized data storage enables users to interactively investigate and visualize multiomics alterations across genes and pathways and to link these alterations with drug responses across cell lines from diverse cancer types. The analyses in our portal include pancancer expression, drug-omics/pathway correlation, cancer subtypes, omics-omics (cis-/trans-regulation) correlation, fusion query analysis, and drug response prediction analysis. The comprehensive multiomics and pharmacogenomic analyses with simple clicking through IMOPAC will significantly benefit cancer precision medicine, contribute to the discoveries of potential biological mechanisms and facilitate pharmacogenomics mining in the identification of clinically actionable biomarkers for both basic researchers and clinical practitioners. IMOPAC is freely available at http://www.hbpding.com/IMOPAC.

PMID:37547083 | PMC:PMC10400808 | DOI:10.1016/j.csbj.2023.07.023

Front Public Health. 2023 Jul 21;11:1183879. doi: 10.3389/fpubh.2023.1183879. eCollection 2023.

ABSTRACT

BACKGROUND: Variants in organic cation transporter (OCT) genes play a crucial role in metformin pharmacokinetics and are critical for diabetes treatment. However, studies investigating the effect of OCT genetic polymorphisms on metformin response have reported inconsistent results. This review and meta-analysis aimed to evaluate the associations between OCT genetic polymorphisms and metformin response and intolerance in individuals with type 2 diabetes mellitus (T2DM).

METHOD: A systematic search was conducted on PubMed, EMBASE, CNKI, WANFANG DATA, and VIP database for identifying potential studies up to 10 November 2022. The Q-Genie tool was used to evaluate the quality of included studies. Pooled odds ratios (OR) or standardized mean differences (SMD) and 95% confidence intervals (95% CI) were calculated to determine the associations between OCT genetic polymorphisms and metformin response and intolerance that were reflected by glycemic response indexes, such as glycated hemoglobin level (HbA1c%) or change in glycated hemoglobin level (ΔHbA1c%), fasting plasma level (FPG) or change in fasting plasma glucose level (ΔFPG), the effectiveness rate of metformin treatment, and the rate of metformin intolerance. A qualitative review was performed for the variants identified just in one study and those that could not undergo pooling analysis.

RESULTS: A total of 30 related eligible studies about OCT genes (SLC22A1, SLC22A2, and SLC22A3) and metformin pharmacogenetics were identified, and 14, 3, and 6 single nucleotide polymorphisms (SNPs) in SLC22A1, SLC22A2, and SLC22A3, respectively, were investigated. Meta-analysis showed that the SLC22A1 rs622342 polymorphism was associated with a reduction in HbA1c level (AA vs. AC: SMD [95% CI] = -0.45 [-0.73--0.18]; p = 0.001). The GG genotype of the SLC22A1 rs628031 polymorphism was associated with a reduction in FPG level (GG vs. AA: SMD [95 %CI] = -0.60 [-1.04-0.16], p = 0.007; GG vs. AG: -0.45 [-0.67-0.20], p < 0.001). No statistical association was found between the remaining variants and metformin response and intolerance.

CONCLUSION: SLC22A1 rs622342 and rs628031 polymorphisms were potentially associated with glycemic response to metformin. This evidence may provide novel insight into gene-oriented personalized medicine for diabetes.

PMID:37546319 | PMC:PMC10400771 | DOI:10.3389/fpubh.2023.1183879

J Hazard Mater. 2023 Aug 2;459:132208. doi: 10.1016/j.jhazmat.2023.132208. Online ahead of print.

ABSTRACT

The adverse effects of silver nanoparticles (AgNPs) have been studied in various models. However, there has been discordance between molecular responses across the literature, attributed to methodological biases and the physicochemical variability of AgNPs. In this study, a gene pathway meta-analysis was conducted to identify convergent and divergent key events (KEs) associated with AgNPs and explore common patterns of these KEs across species. We performed a cross-species analysis of transcriptomic data from multiple studies involving various AgNPs exposure. Pathway enrichment analysis revealed a set of pathways linked to oxidative stress, apoptosis, and metabolite and lipid metabolism, which are considered potentially conserved KEs across species. Subsequently, experiments confirmed that oxidative stress responses could be early KEs in both Caenorhabditis elegans and HepG2 cells. Moreover, AgNPs preferentially impaired the mitochondria, as evidenced by mitochondrial fragmentation and dysfunction. Furthermore, disruption of amino acids, nucleotides, sulfur compounds, glycerolipids, and glycerophospholipids metabolism were in good agreement with gene pathway shreds of evidence. Our findings imply that, although there may be organism-specific responses, potentially conserved events could exist regardless of species and physicochemical factors. These results provide valuable insights into the development of adverse outcome pathways of AgNPs across species and the regulatory toxicity of AgNPs.

PMID:37544172 | DOI:10.1016/j.jhazmat.2023.132208

Med J Aust. 2023 Aug 6. doi: 10.5694/mja2.52065. Online ahead of print.

NO ABSTRACT

PMID:37543844 | DOI:10.5694/mja2.52065

Int J Antimicrob Agents. 2023 Aug 3:106944. doi: 10.1016/j.ijantimicag.2023.106944. Online ahead of print.

ABSTRACT

Nontyphoidal Salmonella (NTS) is a major foodborne pathogen causing from acute gastroenteritis to bacteremia, particularly in pediatric and elderly patients. Antimicrobial resistance of NTS, especially resistance to extended-spectrum cephalosporins, has emerged over the past decades. Thirteen NTS isolates resistant to ceftriaxone or cefotaxime were collected from a teaching hospital in Taipei, and another three from a tertiary hospital, in New Taipei City, Taiwan, from September 2018 to December 2019. Ten other archived isolates from 2000 to 2017 were also obtained. Serogroup B, C2 and E were significantly associated with ampicillin resistance. Over 90% of these 26 isolates are susceptible to carbapenems and colistin. Genomic epidemiology of these isolates shows that blaCMY-2-harboring isolates in different serovars were prevalent over two decades, presumably resulting from highly mobile IncI1 plasmid harboring blaCMY-2. One type of the IncI1 plasmids contained a mobile element, IS26, which might be involved in acquisition of antimicrobial resistance genes. Two emerging serovars, S. Goldcoast ST358 harboring blaCTX-M-55 on IncHI2 plasmids and S. Anatum ST64 harboring blaDHA-1 on IncA/C2 plasmids persisted in Taiwan possibly through clonal spread. Integration of complete or partial plasmid sequences into host chromosomes or multiplications of the antimicrobial resistance genes also appears to be mediated by IS26, in the two emerging clones. The dynamic movement of cephalosporinase genes mediated by IS26 in NTS is of great concern.

PMID:37543120 | DOI:10.1016/j.ijantimicag.2023.106944

Cardiovasc Drugs Ther. 2023 Aug 5. doi: 10.1007/s10557-023-07495-4. Online ahead of print.

ABSTRACT

PURPOSE: This study was designed to investigate the impact of single-nucleotide polymorphism-encoded cytochrome P450 enzymes (CYP3A4/5) on clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) based on pharmacokinetics and pharmacodynamics (PK/PD) aspects.

METHOD: A prospective study enrolling 165 rivaroxaban-treated patients with NVAF was conducted. Genotyping of CYP3A4 (rs2242480, rs2246709, rs3735451, and rs4646440) and CYP3A5 (rs776746) was performed to explore their impact on the trough plasma concentrations (Ctrough) of rivaroxaban, coagulation indicators at the Ctrough including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes.

RESULTS: Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban Ctrough, PT values than that of wild-type. Furthermore, a positive relationship was revealed between Ctrough and PT (r = 0.212, p = 0.007), while no significant correlation was found between Ctrough and APTT. Regarding the clinical outcomes, the minor allele carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were associated with higher incidence of minor bleeding (p = 0.028 and p = 0.038, respectively) and were identified as the independent risk factors of minor bleeding treated with rivaroxaban (p = 0.024 and p = 0.036, respectively), with the receiver operating characteristic (ROC) curve validated (AUC = 0.8956, 95% CI: 0.829-0.962).

CONCLUSION: The CYP3A4 polymorphisms (rs2242480, rs2246709, and rs3735451) and CYP3A5 rs776746 were associated with variations in rivaroxaban PK/PD. The minor allele (C) carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were correlated with clinical outcomes.

PMID:37542618 | DOI:10.1007/s10557-023-07495-4