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Background: For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac)., Methods: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile., Results: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively., Conclusions: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation., Competing Interests: J.D. Momper has received consulting fees from Veloxis Pharmaceuticals, Inc. B.M. Masters and S.J. Patel are employees of Veloxis Pharmaceuticals, Inc. R. Venkataramanan, A.S. Jantz, D.M. Cibrik, and K. Birdwell have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Leukopenia is a serious, frequent side effect associated with azathioprine use. Currently, we use thiopurine methyltransferase (TPMT) testing to predict leukopenia in patients taking azathioprine. We hypothesized that a risk score incorporating additional clinical and genetic variables would improve the prediction of azathioprine-associated leukopenia. In the discovery phase, we developed four risk score models: (1) age, sex, and TPMT metabolizer status; (2) model 1 plus additional clinical variables; (3) sixty candidate single nucleotide polymorphisms; and (4) model 2 plus model 3. The area under the receiver-operating-characteristic curve (AUC) of the risk scores was 0.59 (95% CI: 0.54-0.64), 0.75 (0.71-0.80), 0.66 (0.61-0.71), and 0.78 (0.74-0.82) for models 1, 2, 3, and 4, respectively. During the replication phase, models 2 and 4 (AUC = 0.64, 95% CI: 0.59-0.70 and AUC = 0.63, 95% CI: 0.58-0.69, respectively) were significant in an independent group. Compared with TPMT testing alone, additional genetic and clinical variables improve the prediction of azathioprine-associated leukopenia.

Background: Studies involving organ transplant recipients (OTRs) are often limited to the variables collected in the national Scientific Registry of Transplant Recipients database. Electronic health records contain additional variables that can augment this data source if OTRs can be identified accurately., Objective: The aim of this study was to develop phenotyping algorithms to identify OTRs from electronic health records., Methods: We used Vanderbilt's deidentified version of its electronic health record database, which contains nearly 3 million subjects, to develop algorithms to identify OTRs. We identified all 19,817 individuals with at least one International Classification of Diseases (ICD) or Current Procedural Terminology (CPT) code for organ transplantation. We performed a chart review on 1350 randomly selected individuals to determine the transplant status. We constructed machine learning models to calculate positive predictive values and sensitivity for combinations of codes by using classification and regression trees, random forest, and extreme gradient boosting algorithms., Results: Of the 1350 reviewed patient charts, 827 were organ transplant recipients while 511 had no record of a transplant, and 12 were equivocal. Most patients with only 1 or 2 transplant codes did not have a transplant. The most common reasons for being labeled a nontransplant patient were the lack of data (229/511, 44.8%) or the patient being evaluated for an organ transplant (174/511, 34.1%). All 3 machine learning algorithms identified OTRs with overall >90% positive predictive value and >88% sensitivity., Conclusions: Electronic health records linked to biobanks are increasingly used to conduct large-scale studies but have not been well-utilized in organ transplantation research. We present rigorously evaluated methods for phenotyping OTRs from electronic health records that will enable the use of the full spectrum of clinical data in transplant research. Using several different machine learning algorithms, we were able to identify transplant cases with high accuracy by using only ICD and CPT codes., (©Lee Wheless, Laura Baker, LaVar Edwards, Nimay Anand, Kelly Birdwell, Allison Hanlon, Mary-Margaret Chren. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 10.12.2020.)

Aim: We sought to identify potential pleiotropy involving pharmacogenes., Methods: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients., Results: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10(-7); odds ratio [OR]: 1.73; 95% CI: 1.40-2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10(-4); OR: 1.67; 95% CI: 1.27-2.20)., Conclusion: In this systematic screen for phenotypic associations with functional variants, several novel genotype-phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10(-) (6); OR: 0.61; 95% CI: 0.49-0.75).

Introduction: In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population. Method: Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations. Results: In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans. Conclusion: These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong. [ABSTRACT FROM AUTHOR]

Due to the diversity of image sources, content-based multi-source image fusion and retrieval have shown promising capabilities in computer vision tasks, and especially when applied in Computer-Aided Diagnosis (CAD) to automate and improve the accuracy of medical image analysis. The combination of computer vision and CAD systems has the potential to revolutionize healthcare by augmenting the expertise of clinicians, improving overall diagnostic accuracy and helping experts in the clinical decision-making process by classifying and retrieving similar annotated clinical images to a given query. In the context of multi-view mammography interpretation, the concept of multi-view feature fusion has recently been studied to improve retrieval performance while effectively guaranteeing the complementarity of both MLO and CC views. However, conventional multi-view feature fusion makes descriptors long and lacks to take into consideration the relationship between descriptors. To deal with this issue, we propose two hierarchical multi-view feature fusion methods, for multi-view mammogram retrieval, based on the Canonical Correlation Analysis (CCA), which is the most commonly used multivariate parametric test. In fact, we have adapted CCA to determine the relationship between two descriptors by processing latent correlation factors. Moreover, after extracting descriptors for each view, a comparative study of texture and shape fusion descriptors is proposed in order to identify the more discriminative features for multi-view mammogram retrieval. Then, a query-dependent distance metric preserving both visual resemblance and semantic similarity is carried out to dynamically determine the more appropriate distance measure for each query image. Extensive experiments on the challenging Curated Breast Imaging Subset of Digital Database for Screening Mammography (CBIS-DDSM) have demonstrated the effectiveness of the proposed hierarchical multi-view feature fusion for mammogram retrieval, which outperforms the performance achieved either by conventional fused information or by single view information. To improve the transparency of our paper, the source code of the proposed method and the related dataset (including readme files) are publicly accessible through the following GitHub link: https://github.com/ABDERRAHIMMAR/Multi-View-Feature-Fusion-for-Mammogram-Retrieval. This open-access resource empowers researchers and practitioners to delve deeper into our methodology, fostering collaboration and advancements in the field of computer-aided diagnosis and medical image analysis. [ABSTRACT FROM AUTHOR]

One of the most critical goals in healthcare is safe and effective drug therapy, which is directly related to an individual's response to treatment. Precision medicine can improve drug safety in many scenarios, including polypharmacy, and it requires the development of new genetic characterization methods. In this report, we use real-time PCR, microarray techniques, and mass spectrometry (MALDI-TOF), which allows us to compare them and identify the potential benefits of technological improvements, leading to better quality medical care. These comparative studies, as part of our pharmacogenetic Five-Step Precision Medicine (5SPM) approach, reveal the superiority of mass spectrometry over the other methods analyzed and highlight the importance of updating the laboratory's pharmacogenetic methodology to identify new variants with clinical impact. [ABSTRACT FROM AUTHOR]

Introduction: Ezetimibe inhibits cholesterol uptake by modulation of intestinal sterol absorption. Currently, although some studies have shown alterations in ezetimibe levels caused by alterations in the ABCG5, ABCG8, NPC1L1 or UGT1A1 genes, there are no pharmacogenetic guidelines to confirm these biomarkers. The aim of this work was to evaluate the effect of 49 variants in 22 pharmacogenes related to metabolism and transport. Methods: A total of 96 healthy volunteers from four bioequivalence clinical trials of ezetimibe as monotherapy or in combination with simvastatin were studied. Blood samples were extracted for unconjugated ezetimibe plasma quantification and genotyping. Results and Discussion: No association of metabolizing enzyme variants with ezetimibe pharmacokinetic parameters was found. The results show some trends in the univariate analysis for ABCB1 rs2032582 or ABCC2 rs2273697 and Cmax (p univariate (puv) = 0.056 and 0.087, respectively), which finally reach significance in the multivariate analysis (p multivariate (pmv) = 0.049 and 0.048, respectively). Nevertheless, these results need to be validated in future studies. [ABSTRACT FROM AUTHOR]

Introduction: In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population. Method: Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations. Results: In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans. Conclusion: These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong. [ABSTRACT FROM AUTHOR]

Purpose of Review: Pharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy., Recent Findings: Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant in the kidney transplant field. A potentially clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection being optimized based on CYP3A5 genotype. Although many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes, such as calcineurin inhibitor toxicity and new onset diabetes, is providing new information on patients at risk., Summary: Appropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.

Objective: To investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes. Methods: This retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients' CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs. Results: A total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%-45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 nonexpressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065). Conclusion: CCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs. [ABSTRACT FROM AUTHOR]

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t1/2) (univariate p-value (puv) = 0.018) and incidence of adverse reactions (ADRs) (puv = 0.008, multivariate p (pmv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t1/2 than the T/T genotype (puv = 0.002, pmv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (puv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (puv = 0.007, pmv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics. [ABSTRACT FROM AUTHOR]

Krivova, M.; Olsen, M.; Allan, J.; Parrish, C.; Leshchinsky, B.; Senogles, A.; Herrmann, J., and Dundas, S., 2024. Vulnerability assessment of risk for a coastal highway in Oregon, U.S.A. Journal of Coastal Research, 40(4), 714–739. Charlotte (North Carolina), ISSN 0749-0208. Threading its way through Oregon, U.S. Highway 101 operates as a crucial conduit, intertwining functional necessity with the aesthetic appeal of sweeping coastal vistas. Unfortunately, many locations along this vital route are under constant threat from coastal hazards, such as seacliff erosion, landslides, and recurrent wave runup leading to overtopping and flooding. Given the daunting challenges associated with maintaining functional infrastructure in such rugged, dynamic terrain, as well as the balance between the preservation of the natural state of the coastline and the infrastructure providing access, sites must be prioritized for mitigation. Using quantitative assessment methods, such as the Coastal Vulnerability Index (CVI), can play a pivotal role in systematically identifying high-risk sites in need of remediation. Based on the findings of previous studies, the CVI was tailored to assess the vulnerability of the highway system to coastal geologic hazards. In this study, 71 hazardous sites were pinpointed for evaluation and possible remedial action. To capture the spectrum of hazards faced at each site, 26 parameters were used and classified into three primary categories, namely inundation, erosion, and landslides. This study presents a unique approach in implementing the CVI by considering the potential uncertainties in the calculations. The novelty lies in the usage of a Monte Carlo simulation to assign weights based on the uncertainties of each parameter. This innovative simulation approach enables assessment of the sensitivity of the overall CVI estimation based on the influence of parameter uncertainties. Ultimately, this approach provides a more robust, less subjective, and comprehensive vulnerability assessment process than current implementations of CVI that do not incorporate uncertainty. [ABSTRACT FROM AUTHOR]

Introduction: Post-transplant cardiovascular disease (PTCVD) poses a significant challenge in kidney transplantation, potentially impacting graft outcomes and patient survival. This retrospective study aimed to investigate the incidence, risk factors, and consequential impact of PTCVD in kidney transplant recipients (KTRs) devoid of pre-existing cardiovascular disease (CVD). Method: The cohort comprised 1114 KTRs, with 749 individuals included after excluding those with pre-existing CVD and early graft loss. PTCVD encompasses ischemic heart disease, myocardial infarction, arrhythmias, heart failure, stroke, peripheral vascular disease, and valvular heart disease. Competing risk regression analysis was performed to identify predictors of PTCVD, while Cox proportional hazards analysis assessed the impact of PTCVD on graft and recipient survival. Results: The cumulative incidence of PTCVD at 5, 10, and 20 years was 5.4%, 14.3%, and 22.5%, respectively. Competing risk regression identified increased age (sub-hazard ratio [SHR], 1.22; p = 0.036) per decade, duration of dialysis (SHR, 1.07; p = 0.048) per year on dialysis, and the slope of the estimated glomerular filtration rate (SHR, 1.08; p = 0.008) mL/min/year decline as independent predictors of higher-risk PTCVD. A higher baseline estimated glomerular filtration rate (eGFR) was protective (SHR, 0.98; p = 0.032). PTCVD was not significantly associated with death-censored graft loss (adjusted hazard ratio [aHR] 1.31; p = 0.48) but was correlated with higher all-cause graft loss (aHR, 1.71; p = 0.011) and recipient mortality (aHR, 1.97; p = 0.004). Conclusion: This study provides insights into PTCVD predictors. Although not directly associated with graft loss, PTCVD significantly correlates with heightened mortality in kidney transplant recipients, emphasizing the need for enhanced clinical management and surveillance strategies. [ABSTRACT FROM AUTHOR]

Patients with systemic autoimmune rheumatic diseases are at a high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and effective antiviral treatments including nirmatrelvir/ritonavir can improve their outcomes. However, there might be potential drug-drug interactions when these patients take nirmatrelvir/ritonavir together with immunosuppressants with a narrow therapeutic window, such as tacrolimus and cyclosporine. We present a case of paralytic ileus resulting from tacrolimus toxicity mediated by the use of nirmatrelvir/ritonavir in a patient with systemic lupus erythematosus (SLE). A 37-year-old female SLE patient was prescribed nirmatrelvir/ritonavir without discontinuing tacrolimus. She presented to the emergency room with symptoms of paralytic ileus including persistent abdominal pain, nausea, and vomiting, which were verified to be associated with tacrolimus toxicity. The blood concentration of tacrolimus was measured >30 ng/mL. Urgent medical intervention was initiated, while tacrolimus was withheld. The residual concentration was brought within the appropriate range and tacrolimus was resumed 8 days later. Physicians must be aware of the potential DDIs when prescribing nirmatrelvir/ritonavir, especially to those taking immunosuppresants like tacrolimus. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 (STAT6), CYP2C19, CYP3A4, CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. −75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants. [ABSTRACT FROM AUTHOR]

Mavacamten, the first drug in the class of β-cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 poor metabolizers have increased exposure and are at increased risk of reduced cardiac hypercontractility. To ensure the safety of all patients, European Medicines Agency recommends CYP2C19 preemptive genotyping, and consecutively, to adapt maintenance and initial mavacamten doses, and to manage drug-drug interactions, according to CYP2C19 phenotype. In this article, we summarize evidence from the literature supporting the association between CYP2C19 phenotype and pharmacological features of mavacamten and provide, beyond biologic guidelines, therapeutic recommendations for the use of mavacamten based on CYP2C19 and CYP3A4/CYP3A5 genotype., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aims: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes., Methods: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R., Results: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively., Conclusions: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

What is Known and Objective. Voriconazole (VRC) increases the blood concentration of Tacrolimus (TAC). However, the patterns of changes in TAC trough concentration (TAC C0) and dose-adjustment regimens after VRC discontinuation have not been reported. We aimed to explore the changing pattern of TAC C0 after VRC discontinuation and provide strategies for TAC dose adjustment and blood concentration monitoring in renal transplant recipients. Methods. The clinical data of 46 renal transplant patients pre- and during VRC medication and VRC discontinuation were retrospectively recorded, including doses and concentrations 0 of TAC and VRC; biochemical indicators such as liver and kidney function; and CYP3A5, CYP3A4, and CYP2C19 gene types. Results and Discussion. After discontinuing VRC for 2–4 days, 81% of the patients returned to their initial TAC dose, although TAC C0 and TAC dose-adjusted trough concentration (C/D) were 2.43-fold and 3.35-fold higher, respectively, than pre-VRC administration. After 5–7 days, TAC C0 and C/D gradually recovered. TAC C/D was significantly higher after VRC discontinuation when the VRC trough concentration (VRC C0) was greater than 2.43 mg/L; CYP3A5, CYP3A4, and CYP2C19 genotypes and the administration of erythromycin did not affect the change in TAC C/D. What is New and Conclusion. TAC C/D remains elevated 2–4 days after discontinuing VRC compared to pre-VRC administration, with gradual recovery observed 5–7 days after VRC discontinuation. To avoid excessive blood TAC C0 , the initial TAC dose should not be immediately reinstated upon VRC discontinuation for 2–4 days. VRC C0 are a critical factor influencing the change in TAC C/D ratio after VRC discontinuation. [ABSTRACT FROM AUTHOR]

Background: There is increasing evidence that cardiac screening prior to kidney transplantation does not improve its outcomes. However, risk aversion to perioperative events means that, in practice, testing remains common, limiting the availability of 'real-world' data to support any change. Our objective was to assess perioperative and 1-year post-transplant cardiovascular events in a kidney transplant candidate cohort who received minimal cardiovascular screening. Methods: The retrospective cohort study included all adult kidney-only transplant recipients in a single UK region between January 2015 and December 2021. Kidney transplant recipients asymptomatic of cardiac disease, even those with established risk factors, did not receive cardiac stress testing. The perioperative and 1-year post-transplant cardiovascular event incidences were examined. Logistic regression was used to identify variables of statistical significance that predicted cardiovascular or cerebrovascular events. Results: A total of 895 recipients fulfilled the inclusion criteria. Prior to transplantation, 209 (23%) recipients had an established cardiac diagnosis, and 193 (22%) individuals had a diagnosis of diabetes. A total of 18 (2%) patients had a perioperative event, and there was a 5.7% incidence of cardiovascular events 1 year post-transplantation. The cardiovascular mortality rate was 0.0% perioperatively, 0.2% at 3 months post-transplant, and 0.2% at 1 year post-transplant. Conclusions: This study demonstrates comparable rates of cardiovascular events despite reduced screening in asymptomatic recipients. It included higher risk individuals who may, on the basis of screening results, have been excluded from transplantation in other programmes. It provides further evidence that extensive cardiac screening prior to kidney transplantation is unlikely to be offset by reduced rates of cardiovascular events. [ABSTRACT FROM AUTHOR]

Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT. [ABSTRACT FROM AUTHOR]

Newman, E.D.; Rowland, J.B.; Hammer, T.G.; Frost, L.A.; Lumibao, C.Y., and Henning, J.A. 2024. Trade-offs in arbuscular mycorrhizal fungal responses to drought and salinity stress in Panicum amarum (United States Gulf Coast). Journal of Coastal Research, 40(1), 51–63. Charlotte (North Carolina), ISSN 0749-0208. Arbuscular mycorrhizal fungi (AMF) are soil and plant root-inhabiting fungi that form symbiotic associations with approximately 95% of terrestrial vascular plants and can aid in survival, growth, and stress tolerance of colonized plants. Coastal dune plants face constant environmental stress from high temperatures, sand burial, low moisture and nutrient retention, and frequent saltwater inundation. Instances of both drought and saltwater inundation stress are predicted to increase as sea levels rise and tropical storm frequency, intensity, and duration increases, with more intense periods of drought between storms. To determine whether native AMF from the United States Gulf Coast improve drought or saltwater inundation tolerance of Panicum amarum, a common Gulf Coast dune grass, a manipulative, crossed-factor greenhouse experiment was conducted by growing P. amarum with and without native AMF under drought or across a gradient of saltwater inundation concentrations: 0.25%, 0.50%, 1.00%, and 1.50%. Under 0.25% salinity, P. amarum grown with native AMF had roughly 47% greater survival, although there were no significant differences in biomass of P. amarum between live and sterile sand treatments. Under drought conditions, plants grown with native AMF had 47% lower survival and three times less biomass than those without native AMF communities. Growth differences between sand treatments were diminished under control conditions, and P. amarum grown with and without native AMF had similar survival and biomass. Despite AMF colonization, P. amarum survival was drastically reduced as salinity concentrations surpassed 0.25%. In conclusion, United States Gulf Coast dune AMF improve salinity inundation tolerance of P. amarum at low salt concentrations; however, the results emphasize the context-dependency of plant responses to AMF colonization. [ABSTRACT FROM AUTHOR]

Lack of equitable representation of global genetic diversity has hampered the implementation of genomic medicine in under-represented populations, including those on the African continent. Data from the multi-national Pre-emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE) study suggest that genotype guidance for prescriptions reduced the incidence of clinically relevant adverse drug reactions (ADRs) by 30%. In this study, hospital dispensary trends from a tertiary South African (SA) hospital (Steve Biko Academic Hospital; SBAH) were compared with the drugs monitored in the PREPARE study. Dispensary data on 29 drugs from the PREPARE study accounted for ~10% of total prescriptions and ~9% of the total expenditure at SBAH. VigiLyze data from the South African Health Products Regulatory Authority were interrogated for local ADRs related to these drugs; 27 were listed as being suspected, concomitant, or interacting in ADR reports. Furthermore, a comparison of pharmacogene allele frequencies between African and European populations was used to frame the potential impact of pre-emptive pharmacogenetic screening in SA. Enumerating the benefit of pre-emptive pharmacogenetic screening in SA will only be possible once we initiate its full application. However, regional genomic diversity, disease burden, and first-line treatment options could be harnessed to target stratified PGx today. [ABSTRACT FROM AUTHOR]

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well‐known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post‐anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC‐MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized β coefficients = 0.386 and 0.346, R2 = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized β coefficient = 0.224, R2 = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response. [ABSTRACT FROM AUTHOR]

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of realworld data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice. [ABSTRACT FROM AUTHOR]

Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC∞), maximum plasma concentration (Cmax), and time to reach Cmax (tmax) compared to fasting volunteers; male volunteers also showed higher AUC∞ and Cmax compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC∞, Cmax and tmax compared to fasting individuals. Variants in ABCC3, CYP1A2, CES1, NUDT15, SLC22A1/A2 and UGT2B10 were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as CYP3A4*20 or *22, on tadalafil and finasteride pharmacokinetics. [ABSTRACT FROM AUTHOR]

Tacrolimus is the principal immunosuppressive drug which is administered after heart transplantation. Managing tacrolimus therapy is challenging due to a narrow therapeutic index and wide pharmacokinetic (PK) variability. We aimed to establish a physiologically based pharmacokinetic (PBPK) model of tacrolimus in adult heart transplant recipients to optimize dose regimens in clinical practice. A 15-compartment full-PBPK model (Simbiology® Simulator, version 5.8.2) was developed using clinical observations from 115 heart transplant recipients. This study detected 20 genotypes associated with tacrolimus metabolism. CYP3A5*3 (rs776746), CYP3A4*18B (rs2242480), and IL-10 G-1082A (rs1800896) were identified as significant genetic covariates in tacrolimus pharmacokinetics. The PBPK model was evaluated using goodness-of-fit (GOF) and external evaluation. The predicted peak blood concentration (Cmax) and area under the drug concentration–time curve (AUC) were all within a two-fold value of the observations (fold error of 0.68–1.22 for Cmax and 0.72–1.16 for AUC). The patients with the CYP3A5*3/*3 genotype had a 1.60-fold increase in predicted AUC compared to the patients with the CYP3A5*1 allele, and the ratio of the AUC with voriconazole to alone was 5.80 when using the PBPK model. Based on the simulation results, the tacrolimus dosing regimen after heart transplantation was optimized. This is the first PBPK model used to predict the PK of tacrolimus in adult heart transplant recipients, and it can serve as a starting point for research on immunosuppressive drug therapy in heart transplant patients. [ABSTRACT FROM AUTHOR]

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach it (tmax), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan tmax compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics. [ABSTRACT FROM AUTHOR]

Purpose: Tacrolimus (Tac) is a widely used immunosuppressive agent in kidney transplantation. Cytochrome P450 (CYP), especially CYP3A4 enzymes are responsible for the metabolism of drugs. However, the correlation between plasma Tac concentration and CYP3A4*22 gene variants is controversial. This meta-analysis aims to evaluate the association between CYP3A4*22 polymorphism and the dose-adjusted trough concentration (C0/D) of Tac in adult kidney transplant patients. Methods: We conducted a literature review for qualifying studies using the PubMed, Web of Science, and Embase databases until July 2023. For the continuous variables (C0/D and daily dose), mean difference (MD) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between the CYP3A4*22 and Tac pharmacokinetics. We performed an additional analysis on the relationship of CYP3A5*3 with Tac PKs and analyzed the effects of CYP3A4*22 in CYP3A5 non-expressers. Results: Overall, eight eligible studies with 2,683 renal transplant recipients were included in this meta-analysis. The CYP3A4*22 allele was significantly associated with a higher C0/D (MD 0.57 ng/mL/mg (95% CI: 0.28 to 0.86; p = 0.0001) and lower mean daily dose requirement (MD -2.02 mg/day, 95% CI: -2.55 to -1.50; p < 0.00001). An additional meta-analysis demonstrated that carrying the CYP3A5*3 polymorphism greatly impacted Tac blood concentration. From the result with CYP3A5 non-expressers, CYP3A4*22 showed significant effects on the Tac C0/D and dose requirement even after adjusting the effect of CYP3A5*3. Conclusion: Patients with CYP3A4*22 allele showed significantly higher plasma C0/D of Tac and required lower daily dose to achieve the therapeutic trough level after kidney transplantation. These findings of our meta-analysis may provide further evidence for the effects of genetic polymorphism in CYP3A4 on the PKs of Tac, which will improve individualized treatment in a clinical setting. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients' perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients. Methods: Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained. Results: White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug–gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 (p = 0.012) and CYP2D6 (p = 0.012) activities. The Indigenous American patients had more normal CYP4F2 (p = 0.004) and lower VKORC (p = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts (p = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx. Conclusions: Kidney transplant recipients had several drug–gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients. [ABSTRACT FROM AUTHOR]

Introduction: Pregnancy increases the clearance of CYP3A4 substrate drugs and pregnancy-related hormones (PRHs) induce hepatic CYP3A4 expression and metabolism. However, it remains unclear to what extent the magnitude of PRHevoked changes in hepatic CYP3A metabolism varies across multiple substrates. This study quantified the impact of PRHs on CYP3A protein concentrations and buprenorphine metabolism in human hepatocytes, and compared the magnitude of these effects to nifedipine and midazolam metabolism. Methods: Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRHs, administered in combination across a range of physiologically relevant concentrations, for 72 h. Absolute protein concentrations of CYP3A4, CYP3A5, and CYP3A7 in SCHH membrane fractions were quantified by nanoLC-MS/MS, and norbuprenorphine (nor-BUP), dehydronifedipine (dehydro-NIF), and 1-hydroxy-midazolam (1-OH-MDZ) formation was evaluated. Results: Compared to control, PRH exposure increased CYP3A4, CYP3A7, and total CYP3A protein concentrations, but not CYP3A5 concentrations, and increased nor-BUP, dehydro-NIF, and 1-OH-MDZ formation in a concentration-dependent manner. The formation of nor-BUP, dehydro-NIF, and 1-OH-MDZ each positively correlated with PRH-mediated changes in total CYP3A protein concentrations. The PRH-evoked increase in nor-BUP formation was evident in all donors; however, the PRH induction of dehydro-NIF and 1-OH-MDZformationwas diminished in a hepatocyte donorwith high basal CYP3A5 expression. Discussion: These findings demonstrate that PRHs increase buprenorphine, nifedipine, and midazolam metabolism in SCHH via induction of CYP3A4 and total CYP3A protein concentrations, and the magnitude of these effects vary across hepatocyte donors in a substrate-specific manner. These data provide insight into the contribution of PRH induction of CYP3A4 metabolism to increased buprenorphine clearance during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking. Methods: To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population. Whole genome sequencing was performed using short-read Illumina Novaseq6000 technology. We characterised the pharmacogenomics (PGx) landscape of this population by analysing sequencing results and associated pharmacological treatment data. Results: We observed that every individual in the cohort carry at least one actionable genotype and 77% of them carry at least three clinically actionable genotypes across 19 pharmacogenes. Overall, 41% of the Tiwi cohort were predicted to exhibit impaired CYP2D6 metabolism, with this frequency being much higher than that for other global populations. Over half of the population predicted an impaired CYP2C9, CYP2C19, and CYP2B6 metabolism with implications for the processing of commonly used analgesics, statins, anticoagulants, antiretrovirals, antidepressants, and antipsychotics. Moreover, we identified 31 potentially actionable novel variants within Very Important Pharmacogenes (VIPs), five of which were common among the Tiwi. We further detected important clinical implications for the drugs involved with cancer pharmacogenomics such as thiopurines and tamoxifen, immunosuppressants like tacrolimus and certain antivirals used in the hepatitis C treatment due to potential differences in their metabolic processing. Conclusion: The pharmacogenomic profiles generated in our study demonstrate the utility of pre-emptive PGx testing and have the potential to help guide the development and application of precision therapeutic strategies tailored to Tiwi Indigenous patients. Our research provides valuable insights on pre-emptive PGx testing and the feasibility of its use in ancestrally diverse populations, emphasizing the need for increased diversity and inclusivity in PGx investigations. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to investigate the relationship between cavum septum pellucidum (>6 mm) and cavum septum pellucidum et vergae with psychopathology and neuropsychological functions in individuals with these conditions by comparing them with normal cranial imaging. Methods: Thirty subjects with cavum septum pellucidum and cavum septum pellucidum et vergae on cranial magnetic resonance imaging and 30 controls without pathology on cranial magnetic resonance imaging were included in our study. A sociodemographic data form, Beck Anxiety Inventory, Beck Depression Inventory, and Barratt Impulsivity Scale-11 were applied to the participants. When it comes to neuropsychological functions, digit span test, Boston Naming Test, Verbal Memory Processes Test, Benton Face Recognition Test, Stroop Test, Verbal Fluency Test, and Wisconsin Card Sorting Test were applied to the patients. Results: In the anomaly group, 26 had cavum septum pellucidum et vergae, while 4 had enlarged cavum septum pellucidum, presenting no statistically significant difference in the rates of psychiatric disease between the anomaly and the control group. The group with enlarged cavum septum pellucidum and cavum septum pellucidum et vergae had lower performances in working memory, naming, attention, and executive functions than the controls. Conclusions: Abnormal developmental processes related to the formation and maturation of the septum pellucidum may be responsible for widespread cognitive impairments where these anomalies may act as an indicator for these conditions. In order to better understand the relationship of these anomalies with neuropsychological functions and psychiatric disorders, further studies with larger samples are needed. [ABSTRACT FROM AUTHOR]

Objectives: Obesity is a complex multifactorial disease with recently increasing prevalence and incidence. Several studies have been conducted to explain the ethiology, pathophysiology, epidemiology, molecular and genetic mechanisms, and effective treatments of obesity. Glutathione S-transferase (GST) S1, GSTZ1, and GSTT1 are essential enzymes for oxidative stress and metabolism-related disorders. For this purpose, we aimed to reveal the role of GSTS1, GSTZ1, and GSTT1 in obesity. Methods: The gastric tissue samples were taken from the patients diagnosed with obesity who underwent bariatric surgery in Ankara Keçiören Training and Research Hospital General Surgery Clinic between 2017 and 2019. Immunostaining was performed on paraffin-embedded tissues to evaluate GSTS1, GSTZ1, and GSTT1 expressions. Laboratory data of the patients were recorded. All the results were analyzed statistically. Results: Weak GSTS1 expression was observed in 38.1% of tissues and moderate in 6.3%. 37.3% of the tissues presented weak GSTZ1 expression, and 11 (8.7%) displayed moderate. There were weak GSTT1 expressions in 7.1% of the tissues and moderate 0.8% of them. A positive and statistically significant correlation was observed between GSTS1 and GSTT1 expression levels ((r) = 0.028, p = 0.010; p < 0.05). There were no significant differences between expression levels and gender, age, comorbidities, and medication usage (p > 0.05). Conclusions: GSTs, in particular GSTS1, GSTT1, and GSTZ1, might contribute to molecular mechanisms and the progression of obesity. In our study, GSTS1, GSTT1, and GSTZ1 were found to be moderately expressed in gastric tissues taken from obese patients. However, new studies using more samples and advanced techniques are needed to elucidate the relationship. [ABSTRACT FROM AUTHOR]

Li, W.; Xiang, W.; Wang, H.; Dong, J.; Xu, H.; Zhang, J.; Zuo, C.; Liu, Q.; Lv, J., and Xie, Q., 2023. Preliminary coastal vulnerability assessment for Guangdong province, Southeast China. Journal of Coastal Research, 39(3), 509–518. Charlotte (North Carolina), ISSN 0749-0208. Accelerating sea level rise and intensifying extreme marine and weather events pose unprecedented challenges to coastal areas in the context of climate change. As a hotspot of marine disasters, Guangdong has been suffering from severe marine disasters including storms, flooding, coastal erosion, and saltwater intrusion in the last decades. It is essential for coastal management authorities to distinguish vulnerable areas and optimize coastal planning. To help identify the coastal vulnerability patterns of the Guangdong coast, the coastal vulnerability index was used based on integrated physical and socio-economic indicators including relative sea level rise, mean tide range, significant wave height, coastal slope, geomorphology, population, land use, and coastal gross domestic product. Each indicator was assigned five vulnerability classifications from very low to very high (1–5). Results show that about 36.7% of the coastline in Guangdong is highly vulnerable, of which 18.3% of the coastline is very highly vulnerable. About 63.3% of the coastline is in moderate to low vulnerability. In particular, the coastal areas in east of Zhanjiang, Maoming, Yangjiang, Zhuhai, Zhongshan, Guangzhou, west of Shenzhen, east Shanwei, and Chaozhou are more vulnerable to sea level rise, which calls for urgent planning and protective measures. [ABSTRACT FROM AUTHOR]

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community. [ABSTRACT FROM AUTHOR]

Geographical ancestry has been associated with an increased risk of various genetic conditions. Race and ethnicity often have been used as proxies for geographical ancestry. Despite numerous problems associated with the crude reliance on race and ethnicity as proxies for geographical ancestry, some genetic testing in the clinical, research, and employment settings has been and continues to be race‐ or ethnicity‐based. Race‐based or race‐targeted genetic testing refers to genetic testing offered only or primarily to people of particular racial or ethnic groups because of presumed differences among groups. One current example is APOL1 testing of Black kidney donors. Race‐based genetic testing raises numerous ethical and policy questions. Given the ongoing reliance on the Black race in genetic testing, it is important to understand the views of people who identify as Black or are identified as Black (including African American, Afro‐Caribbean, and Hispanic Black) regarding race‐based genetic testing that targets Black people because of their race. We conducted a systematic review of studies and reports of stakeholder‐engaged projects that examined how people who identify as or are identified as Black perceive genetic testing that specifically presumes genetic differences exist among racial groups or uses race as a surrogate for ancestral genetic variation and targets Black people. Our review identified 14 studies that explicitly studied this question and another 13 that implicitly or tacitly studied this matter. We found four main factors that contribute to a positive attitude toward race‐targeted genetic testing (facilitators) and eight main factors that are associated with concerns regarding race‐targeted genetic testing (barriers). This review fills an important gap. These findings should inform future genetic research and the policies and practices developed in clinical, research, public health, or other settings regarding genetic testing. [ABSTRACT FROM AUTHOR]

The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with R2 values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD. [ABSTRACT FROM AUTHOR]