Sci Rep. 2024 Dec 30;14(1):31639. doi: 10.1038/s41598-024-80639-0.

ABSTRACT

Warfarin is the most widely used oral anticoagulant in clinical practice. The cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) genotypes are associated with warfarin dose requirements in China. Accurate genotyping is vital for obtaining reliable genotype-guided warfarin dosing information. The current method for individualized dosing gene polymorphism detection for warfarin has the disadvantages of being easily contaminated, time-consuming, expensive, and unsuitable for clinical use. Herein, we present a novel application, a multiplex fluorescent melting curve assay of whole-blood direct amplification of nested polymerase chain reaction (PCR), to genotyping single-nucleotide polymorphism (SNPs) rapidly that affect warfarin efficacy. This method requires only 1 µL of whole blood, no DNA extraction, takes less than 2 h, costs less than $1, and is able to accurately distinguish between different SNP sites. Polymorphic loci were detected in whole blood specimens of 181 clinical warfarin-administered patients through nested blood direct PCR fluorescence melting curve analysis and gene sequencing. The results of the nested blood direct PCR multiplex fluorescence melting curve technology were 100% consistent with those of sequencing-characterized by high accuracy and high specificity. The allele frequencies were 94.5% for A and 5.5% for C at CYP2C9*3 (rs1057910), 7.5% for G and 92.5% for A at VKORC1 (rs9923231), and 77.1% for G and 22.9% for A at CYP4F2*3 (rs2108622). For CYP2C9*2 (rs1799853), only allele C was detected, with a frequency of 100%. Warfarin doses were lower in the CYP2C9*1*1 genotype population than in the CYP2C9*1*3 population, lower in the VKORC1 (AA) population than in the VKORC1 (GG) population, and higher in individuals with the CYP4F2*3 mutation (GA/AA) compared with those with wild-type (GG). In summary, the detection and genotyping of four polymorphic SNP sites using a multiplex fluorescent melting curve assay of whole blood direct amplification through nested PCR is highly importance for guiding personalized warfarin anticoagulant therapy.

PMID:39738187 | DOI:10.1038/s41598-024-80639-0

Indian J Med Res. 2024 Nov;160(5):489-500. doi: 10.25259/jmr_2382_23.

ABSTRACT

Background & objectives The choice of anesthetic for better perioperative conservation of immune responses has always been contentious. This study investigated the differential impact of the intravenous anesthetic, propofol, and the volatile anesthetic, isoflurane on the T cell immune responses, if any, among individuals going through perioperative breast cancer. Methods Perioperative blood samples (preoperative, intraoperative and postoperative) collected from participants with breast cancer in two arms namely isoflurane arm (n=50) and the propofol arm (n=50) were analyzed for T cell immune response using flow cytometry and ELISA. The interactions of anesthetics with CD4/CD8 were probed with molecular docking and molecular dynamic (MD) simulations. Results Linear mixed model analysis showed that isoflurane in comparison to propofol inhibited CD4+ helper (Th) [β-coefficient: -8.75; 95% CI: -13.00 to -4.51] and CD19+ B cell (β: -7.51; 95% CI: -15.46 to 0.44) frequencies during the intraoperative period in perioperative breast cancer patients. Further, interleukin (IL)-10 and IL-12 were significantly increased during the intra- and postoperative periods in the isoflurane group as compared to the propofol group. Molecular docking (MD) validated propofol's better binding energy with CD4/CD8 than isoflurane. MD simulations propagated that in contrast to isoflurane, propofol formed a more compact and stabilized structure with CD4/CD8, making the amino acid residues on the surface of CD4/CD8 inaccessible for any interaction. Interpretation & conclusions The clinical observations and the in silico findings exhibited that propofol in comparison to isoflurane better regulated T cell immuno-inflammatory response in perioperative breast cancer patients.

PMID:39737515 | DOI:10.25259/jmr_2382_23

Front Pharmacol. 2024 Dec 16;15:1420682. doi: 10.3389/fphar.2024.1420682. eCollection 2024.

ABSTRACT

BACKGROUND: The increasing use of non-specific immunoglobulins (NSIGs) and their current shortage show a need for NSIGs' use prioritization. Data from a clinical perspective are necessary, mainly for pediatric patients.

OBJECTIVES: The aim of the study was to assess the level of clinical evidence (LoE) of the indications that NSIGs are used for, the reasons for discontinuation, and the costs invested.

METHODS: A retrospective multicentric study was conducted on NSIG incident users between September 2019 and December 2021 retrieved from the Registry of Patients and Treatments (RPT) from Catalonia (Spain). LoE was categorized as A) authorized indications, B) unauthorized with scientific support, C) unauthorized without support, and D) unknown (UNK), following local and the United Kingdom's guidelines as a sensitivity analysis. We also estimated overall spending and costs per patient visit.

RESULTS: A total of 400 patients were included (17.3% pediatric), with a mean follow-up of 122.1/person-years for adults. The most frequent indications were nervous system and blood diseases. Almost all pediatric patients (56; 81.2%) were treated under A-level indications, as for 217 (65.6%) adults. In the sensitivity analysis, the A-level usage rate decreased to one-third and the B-level usage rate increased by 2-3 times. Furthermore, 37.8% (151) of individuals discontinued. This was predominantly due to remission or no response. The total costs were 868,462.6€/year, with median spending per visit amounting to 1,500€ for adults and 700€ for pediatric patients.

CONCLUSION: NSIGs are used in clinical practice mainly for approved indications; however, non-approved indications are still an important issue. This could represent a significant economic burden on the healthcare system, focusing on the pediatric population and those at risk for discontinuation with alternative therapeutic options.

PMID:39737065 | PMC:PMC11682906 | DOI:10.3389/fphar.2024.1420682

Cell Biosci. 2024 Dec 30;14(1):156. doi: 10.1186/s13578-024-01336-z.

ABSTRACT

N-myc downstream-regulated gene 1 (NDRG1) is a member of the NDRG family of intracellular proteins and plays a central role in a wide range of biological processes including stress response, differentiation, and metabolism. The overexpression of NDRG1 is an indicator of poor prognosis in various types of cancer. Here, we found that NDRG1 is an independent prognostic marker of poor outcome in breast cancer (BC). Analysis of the TCGA dataset showed a significant positive correlation between NDRG1 and PRKCA expression, suggesting a mechanistic role of protein kinase C (PKC) in the regulation of NDRG1. We then assessed the hypothesis that PKC might modulate the activity of NDRG1, and observed that different acute stress conditions converging on PKC activation lead to enhanced NDRG1 expression. This mechanism was found to be specific for NDRG1 as the expression of other NDRG members was not affected. Moreover, CRISPR-based inhibition of NDRG1 expression was obtained in a BC cell line, and showed that this protein is a key driver of BC cell invasion through the Rho-associated coiled-coil containing protein kinase 1 (ROCK1)/phosphorylated cofilin pathway that regulates stress fiber assembly, and the modulation of extracellular matrix reorganization related genes. Together, our findings highlight the potential of NDRG1 as a new BC biomarker and uncover a novel mechanism of regulation of NDRG1 expression that might lead to innovative therapeutic strategies.

PMID:39736699 | DOI:10.1186/s13578-024-01336-z

Pharmacotherapy. 2024 Dec 29. doi: 10.1002/phar.4638. Online ahead of print.

ABSTRACT

BACKGROUND: Methotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.

METHODS: This study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance therapy were independently reviewed by at least two pediatric oncologists. Germline DNA was genotyped and 97 methotrexate pharmacogenomic variants of interest with at least grade 3 evidence were identified using the Pharmacogenomics Knowledge Base. Associations between variants and neurotoxicity were assessed by logistic regression. Data were randomly split (80/20) and random forest was constructed to estimate the ability of the variants to correctly classify neurotoxicity.

RESULTS: Of the 763 patients included in the study, 8.2% (n = 63) developed methotrexate-associated neurotoxicity. In logistic models, none of the 97 available pharmacogenomic variants reached adjusted statistical significance. However, two variants, rs17222723 (odds ratio [OR] = 2.83 [ref. = T allele], 95% confidence interval [CI]: 1.20-6.15) in ABCC2 and rs1045642 (OR = 0.66 [ref. = minor A allele], 95% CI: 0.44-0.98) in ABCB1, were nominally associated (p-value < 0.05) with neurotoxicity susceptibility. The addition of pharmacogenomic variants did not improve the predictive performance of random forest model (AUC = 0.73) compared to clinical information alone (AUC = 0.74).

CONCLUSION: Overall, our results suggest that associations between neurotoxicity susceptibility and methotrexate pharmacogenomic variants are generally modest and these variants do not significantly improve neurotoxicity risk stratification among children with ALL.

PMID:39734275 | DOI:10.1002/phar.4638

Clin Microbiol Infect. 2024 Dec 27:S1198-743X(24)00601-3. doi: 10.1016/j.cmi.2024.12.015. Online ahead of print.

ABSTRACT

OBJECTIVES: Temocillin is a β-lactam antibiotic used for preventing or treating bacterial infections in liver-transplanted children. We characterized its pharmacokinetics in plasma and ascitic fluid and proposed dosing regimens that maximize achievement of effective drug exposures in this patient group.

METHODS: Patients aged 6-36 months received 25 mg/kg/12h (n=14) or 25 mg/kg/8h (n=23). Total and unbound temocillin concentrations were measured in plasma and ascitic fluid. Drug safety was monitored. Non-compartmental and population pharmacokinetic analyses were performed, together with Monte-Carlo simulations.

RESULTS: No safety concerns were reported. For 25 mg/kg/12h, the unbound mean (±SD) Cmax and Cmin were 38±16 and 2±1 mg/L, respectively. For the 25 mg/kg/8h dose, the unbound Cmax remained similar although the mean Cmin increased to 5±3 mg/L. Protein binding was saturable. Median penetration in ascitic fluid from plasma was 82% (min-max: 63-95%). A three-compartment model with first order elimination best described unbound pharmacokinetic profiles in plasma and ascitic fluid, with body weight and eGFR as significant covariates. Monte-Carlo simulations suggested that 90% Probability of Target Attainment (PTA) was achieved in both fluids with 25 mg/kg/12h for MICs ≤4 mg/L, eGFR ≤180 mL/min/1.73m2 or weight ≥6 kg, and with 25 mg/kg/8h, for MICs ≤8 mg/L, GFR ≤120mL/min/1.73m2 or weight ≥11 kg.

CONCLUSIONS: Although adequate in many instances, the current dosing regimen is likely inadequate for patients with low body weight, high renal function, or bacteria with high MIC, emphasizing the need for patient-specific factors to be considered in dose selection. These data support the importance of paediatric pharmacokinetic studies to optimize drug dosing regimens.

PMID:39734018 | DOI:10.1016/j.cmi.2024.12.015

Sci Rep. 2024 Dec 28;14(1):30683. doi: 10.1038/s41598-024-79018-6.

ABSTRACT

Inter-individual variability in drug responses is significantly influenced by genetic factors, underscoring the importance of population-specific pharmacogenomic studies to optimize clinical outcomes. In this study, we analyzed whole genome sequencing data from 949 unrelated Thai individuals and conducted an in-depth analysis of 3239 genes involved in drug pharmacokinetics, pharmacodynamics, or immune-mediated adverse drug reactions. We identified 43 single nucleotide polymorphisms (SNPs), 134 diplotypes, and 15 human leukocyte antigen (HLA) alleles, all with moderate to high clinical significance. On average, each Thai individual carried 14 SNPs, one to two HLA alleles, and six diplotypes with actionable phenotypic associations. Clinically important diplotypes were present in over 20% of individuals for seven genes (CYP2A6, CYP2B6, CYP2C19, CYP3A5, NAT2, SLCO1B1, and VKORC1). In addition, clinically significant SNPs with allele frequencies exceeding 20% were identified among 15 genes, including VKORC1, CYP4F2, and ABCG2. We also identified 21,211 potentially deleterious variants among 3239 genes. Of these variants, 3746 were novel. The comprehensive dataset from this study serves as a valuable resource of pharmacogenomic variants in the Thai population, which will facilitate the development of personalized drug therapies and enhance patient care in Thailand.

PMID:39730427 | DOI:10.1038/s41598-024-79018-6

Curr Pharm Teach Learn. 2024 Dec 26;17(3):102189. doi: 10.1016/j.cptl.2024.102189. Online ahead of print.

NO ABSTRACT

PMID:39729765 | DOI:10.1016/j.cptl.2024.102189

Eur Arch Psychiatry Clin Neurosci. 2024 Dec 27. doi: 10.1007/s00406-024-01944-3. Online ahead of print.

ABSTRACT

Schizophrenia (SCZ), bipolar (BD) and major depression disorder (MDD) are severe psychiatric disorders that are challenging to treat, often leading to treatment resistance (TR). It is crucial to develop effective methods to identify and treat patients at risk of TR at an early stage in a personalized manner, considering their biological basis, their clinical and psychosocial characteristics. Effective translation of theoretical knowledge into clinical practice is essential for achieving this goal. The Psych-STRATA consortium addresses this research gap through a seven-step approach. First, transdiagnostic biosignatures of SCZ, BD and MDD are identified by GWAS and multi-modal omics signatures associated with treatment outcome and TR (steps 1 and 2). In a next step (step 3), a randomized controlled intervention study is conducted to test the efficacy and safety of an early intensified pharmacological treatment. Following this RCT, a combined clinical and omics-based algorithm will be developed to estimate the risk for TR. This algorithm-based tool will be designed for early detection and management of TR (step 4). This algorithm will then be implemented into a framework of shared treatment decision-making with a novel mental health board (step 5). The final focus of the project is based on patient empowerment, dissemination and education (step 6) as well as the development of a software for fast, effective and individualized treatment decisions (step 7). The project has the potential to change the current trial and error treatment approach towards an evidence-based individualized treatment setting that takes TR risk into account at an early stage.

PMID:39729102 | DOI:10.1007/s00406-024-01944-3

Nurs Rep. 2024 Nov 27;14(4):3689-3705. doi: 10.3390/nursrep14040270.

ABSTRACT

The integration of genetics and genomics into nursing practice is essential for addressing genetic pathologies and providing personalized patient care. This study aims to analyze the nursing education curricula across Spanish universities to understand how genetic and genomic concepts are incorporated. Using the "Qué estudiar y dónde en la Universidad" (QEDU) database, an official source provided by the Spanish Ministry of Universities, a systematic review of 4720 teaching guides from 118 university centers was conducted. Our findings reveal that 12 centers do not include any genetic or genomic content, while 43% of the remaining centers focus solely on basic genetics. In contrast, 57% cover advanced topics, such as genetic counseling and pharmacogenetics. Teaching methodologies predominantly involve lectures and seminars, with limited practical training. On average, three to six ECTS credits out of the total 240 required for the Nursing Degree are dedicated to genetics and genomics. This study highlights the need for curriculum updates and standardization to ensure comprehensive training in these crucial areas. Improved integration of genetic and genomic education will better prepare nursing professionals to meet the evolving demands of modern healthcare. This study was not registered.

PMID:39728631 | DOI:10.3390/nursrep14040270

J Pers Med. 2024 Dec 19;14(12):1157. doi: 10.3390/jpm14121157.

ABSTRACT

Chronic kidney disease (CKD) is a major worldwide health concern because of its progressive nature and complex biology. Traditional diagnostic and therapeutic approaches usually fail to account for disease heterogeneity, resulting in low efficacy. Precision medicine offers a novel approach to studying kidney disease by combining omics technologies such as genomics, transcriptomics, proteomics, metabolomics, and epigenomics. By identifying discrete disease subtypes, molecular biomarkers, and therapeutic targets, these technologies pave the way for personalized treatment approaches. Multi-omics integration has enhanced our understanding of CKD by revealing intricate molecular linkages and pathways that contribute to treatment resistance and disease progression. While pharmacogenomics offers insights into expected responses to personalized treatments, single-cell and spatial transcriptomics can be utilized to investigate biological heterogeneity. Despite significant development, challenges persist, including data integration concerns, high costs, and ethical quandaries. Standardized data protocols, collaborative data-sharing frameworks, and advanced computational tools such as machine learning and causal inference models are required to address these challenges. With the advancement of omics technology, nephrology may benefit from improved diagnostic accuracy, risk assessment, and personalized care. By overcoming these barriers, precision medicine has the potential to develop novel techniques for improving patient outcomes in kidney disease treatment.

PMID:39728069 | DOI:10.3390/jpm14121157

J Pers Med. 2024 Nov 29;14(12):1128. doi: 10.3390/jpm14121128.

ABSTRACT

Background/Objectives: The integration of pharmacogenetic (PGx) testing into primary care has not been widely implemented, despite its benefits for patients and providers. PGx testing could also reduce health disparities as patients with lower healthcare access are prescribed higher proportions of medications with PGx guidelines. Little is known about the preferences of patients who have experienced PGx testing to inform implementation across the care process. This qualitative study aimed to refine implementation by capturing patient preferences on (1) testing and prescription timing, (2) patient-clinician discussion of results during post-test counseling, and (3) usability of a card during results dissemination. Methods: Interviews were conducted with 25 primary care patients from clinics primarily serving medically underserved populations. Interview transcripts were thematically analyzed using a constant comparative approach. Results: While patients supported both reactive and pre-emptive testing, they valued pre-emptive PGx testing because it is proactive for future health needs, expedites treatment, and is convenient. Patients' preferences for receiving prescriptions depended on several factors: having immediate access to needed medications, avoiding experiencing medication side effects and interactions, avoiding taking ineffective medications, and avoiding inconveniences. Patients identified three issues critical to patient-clinician interactions when receiving testing results: information specific to medications, clarification and further information about their results, and enhanced clinician accessibility related to the results. Lastly, they liked that the results card could facilitate discussions with clinicians and was informative and convenient but said it lacked clarity. Conclusions: These findings should inform implementation strategies for integrating PGx testing in primary care for underserved patients.

PMID:39728041 | DOI:10.3390/jpm14121128

J Pers Med. 2024 Nov 27;14(12):1121. doi: 10.3390/jpm14121121.

ABSTRACT

Pharmacogenomics (PGx) has revolutionized personalized medicine by empowering the tailoring of drug treatments based on individual genetic profiles. However, the complexity of drug response mechanisms necessitates the integration of additional biological and environmental factors. This article explores integrating epigenetics, nutrigenomics, microbiomes, protein interactions, exosomes, and metabolomics with PGx to enhance personalized medicine. In addition to discussing these scientific advancements, we examine the regulatory and ethical challenges of translating multi-omics into clinical practice, including considerations of data privacy, regulatory oversight, and equitable access. By framing these factors within the context of Medication Adherence, Medication Appropriateness, and Medication Adverse Events (MA3), we aim to refine therapeutic strategies, improve drug efficacy, and minimize adverse effects, with the goal of improving personalized medicine. This approach has the potential to benefit patients, healthcare providers, payers, and the healthcare system as a whole by enabling more precise and effective treatments.

PMID:39728034 | DOI:10.3390/jpm14121121

Curr Oncol. 2024 Dec 20;31(12):8054-8074. doi: 10.3390/curroncol31120594.

ABSTRACT

The enzyme topoisomerase II alpha (TOP2A) plays a critical role in DNA replication and cell proliferation, making it a promising target for cancer therapy. In epithelial ovarian cancer (EOC), TOP2A overexpression is associated with poor prognosis and resistance to conventional treatments. This review explores the biological functions of TOP2A in EOC and discusses its potential as a therapeutic target. We highlight studies on the mechanisms through which TOP2A contributes to tumor progression and recurrence. Additionally, we evaluate the clinical implications of targeting TOP2A, including the use of TOP2A inhibitors and their combination with novel drugs. We provide a comprehensive overview of the current understanding and future directions for targeting TOP2A in the management of EOC.

PMID:39727717 | DOI:10.3390/curroncol31120594

Pediatr Infect Dis J. 2024 Oct 10. doi: 10.1097/INF.0000000000004582. Online ahead of print.

ABSTRACT

BACKGROUND: Rates of carbapenem-resistant Acinetobacter baumannii are rising in Thailand. Although high-dose (HD) sulbactam is recommended for treating carbapenem-resistant A. baumannii infections, data on plasma sulbactam concentrations in children are limited. We aimed to evaluate plasma sulbactam concentrations and pharmacokinetic-pharmacodynamic (PK-PD) target achievement in pediatric patients.

METHODS: Prospective study data (January-November 2023) on children (1 month-18 years) who received sulbactam every 6-8 hours were analyzed. Mid-dosing (Cmid, 50% fT) and trough (Ctrough, 100% fT) concentrations were evaluated. PK-PD target achievement [50% fT > minimum inhibitory concentration (MIC), 100% fT > MIC] was evaluated using Clinical and Laboratory Standards Institute 2024 MIC cutoffs and MIC data of isolates of Acinetobacter calcoaceticus-baumannii complex from this study.

RESULTS: Thirty-five patients (median age 50 months) were categorized into standard-dose (SD) or HD groups. The geometric mean Cmid was higher in the HD (41.3 mg/L) versus SD (19.5 mg/L) groups (P = 0.006). Among 101 isolates of Acinetobacter calcoaceticus-baumannii complex, the MIC50 and MIC90 (concentrations that inhibit 50% and 90% of isolates of the A. calcoaceticus-baumannii complex) were 16 and 128 mg/L, respectively. The HD group achieved Cmid >MIC50 in 87.5% of the patients compared with 63.6% in SD (P = 0.17). Within the HD group, patients with augmented renal clearance (ARC) had lower Cmid (geometric mean 31.9 mg/L) compared with non-ARC (geometric mean 63.4 mg/L) (P = 0.04).

CONCLUSIONS: HD sulbactam resulted in higher Cmid and PK-PD achievement. ARC significantly compromised plasma sulbactam concentration. HD sulbactam may be preferable for treating critically ill pediatric patients and those with ARC, especially during the empirical period.

PMID:39724654 | DOI:10.1097/INF.0000000000004582

Allergy. 2024 Dec 26. doi: 10.1111/all.16438. Online ahead of print.

ABSTRACT

BACKGROUND: Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are commonly used to treat asthma, however, some children lack response to the addition of LABA. This might be partially due to the presence of the Arg16Gly polymorphism, encoded by rs1042713 G>A in the ADRB2 gene. Carrying the A allele (Arg16) at this variant has been associated with an increased risk of exacerbations despite LABA treatment. We investigated whether genotype-guided treatment improved asthma-related outcomes.

METHODS: We conducted an individual participant data meta-analysis of two randomised controlled trials: PUFFIN (Dutch and Swiss 6-18 year-olds) and PACT (English and Scottish 12-18 year-olds). Children with uncontrolled asthma despite ICS who required a step-up in treatment were included. Participants were randomised to genotype-guided treatment or the control group with a follow-up of at least 6 months. Genotype-guided treatment consisted of adding LABA for children with ADRB2 Gly16/Gly16, whilst children with ADRB2 Arg16/Arg16 or Arg16/Gly16 were treated with double dose ICS (PUFFIN) or add-on montelukast (PACT). The primary outcome was a change in asthma control; secondary outcomes included exacerbation rate and time to exacerbation. Repeated measures mixed models and Cox regression were used.

RESULTS: Fifty-nine out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one Arg (A allele). Amongst all 193 children, no difference was observed in asthma control between the study groups. However, genotype-guided treatment resulted in lower asthma exacerbation rates (-0.08 (95%CI -0.16 to -0.00, p = 0.04)) compared to the control group.

CONCLUSION: Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates and may be useful for personalising asthma care.

PMID:39723595 | DOI:10.1111/all.16438

Addict Behav Rep. 2024 Nov 27;21:100575. doi: 10.1016/j.abrep.2024.100575. eCollection 2025 Jun.

ABSTRACT

BACKGROUND: The substance use crisis continues to progress. Medication for Opioid Use Disorder (MOUD) are prescribed to reduce opioid use and related harms; however, many individuals continue to use substances while on treatment. The objective of this study was to describe the temporal and demographic trends of the agreement between self-reported and urine tested substances.

METHODS: The current study is a retrospective secondary analysis of three phases of a prospective cohort study (Pilot 2011, Genetics of opioid addiction (GENOA) 2013-2017, and Pharmacogenetics of opioid substitution treatment (POST)) 2018-2022) spanning 2011-2022. We compared the self-reported substance use data for opioids, benzodiazepines, amphetamine/methamphetamine (AMP/MET), and cocaine with urine drug results. We compared the positive predictive value (PPV), false omission rate (FOR), sensitivity, and specificity between (i) different drugs; (ii) by sex, and (iii) age group at enrollment in each phase of the study using self-reported substance use at baseline and retrospective electronic health record data on urine drug screenings collected over the same time period.

RESULTS: Overall, the average PPV and FOR for any drug across all phases was 80.7 % and 37.9 %, respectively. Sensitivity and specificity were highest for cocaine and lowest for benzodiazepines. We found no specific trend by sex. Lastly, we found a higher sensitivity for opioids and AMP/MET in those under 25 years of age compared to other age groups. PPV increased over time for benzodiazepines, AMP/MET and cocaine and FOR was higher during the pilot and POST phases than the GENOA phase.

CONCLUSION: Our study highlights the unique challenges associated with ascertaining substance use behaviour for individuals receiving MOUD, indicating many patients will accurately report substance use while others do not. It is therefore important to consider the context of the patient, and the type of the co-substance used to select patient-centred testing as indicated. Therefore, the answer to the question of do we need urine drug screen is yes in some cases.

PMID:39723346 | PMC:PMC11667632 | DOI:10.1016/j.abrep.2024.100575

Front Sports Act Living. 2024 Dec 11;6:1480373. doi: 10.3389/fspor.2024.1480373. eCollection 2024.

ABSTRACT

The presence of a doping substance in an athlete's biological sample may not be only related to intentional pharmacological support. The unintended use of a prohibited substance may be due various reasons. This paper describes the case of a Polish canoeist preparing for the 2024 Summer Olympics in Paris who presented a positive doping test result, as a consequence of administering medication to her injured dog. The athlete used a Trofodermin cutaneous spray (containing clostebol acetate) for pet treatment, which resulted in human transfer during close contact and subsequent detection by doping authorities. To bolster the athlete's defense, it was essential to substantiate the scenario of an unconscious violation of anti-doping rules with scientific evidence. Hence, the decision was made to analyze and compare samples of the athlete's hair and her dog's fur. This investigation confirmed that clostebol absorption occurred through the skin of the hands, transfer during sleeping with the dog on the same bedding and/or inhalation (during the application of the medication, which was dispensed to the animal's paws). This defense was accepted by the Court of Arbitration for the Sport Anti-Doping Division, which subsequently found that the athlete committed an anti-doping rule violation, but under circumstances that amounted to a "no fault" scenario.

PMID:39722740 | PMC:PMC11668582 | DOI:10.3389/fspor.2024.1480373

Clin Oncol (R Coll Radiol). 2024 Dec 9;38:103706. doi: 10.1016/j.clon.2024.103706. Online ahead of print.

ABSTRACT

In 2020, the introduction of pre-emptive DPYD genotyping prior to the administration of systemic fluoropyrimidine-based chemotherapy represented one of the first widespread pharmacogenetic testing programmes to be applied nationally in the United Kingdom. Pharmacogenetic variants in the DPYD gene found in between 3 and 6% of the population are a recognised cause of primary DPD enzyme deficiency and associated increased risk of severe fluoropyrimidine toxicity [1]. Yet, the availability of testing globally is heterogeneous. Despite growing evidence that in addition to reducing drug-induced toxicity, DPYD-guided dosing does not negatively affect outcomes, further research on the impact of routine DPYD genotyping in the UK population is required. With mandatory testing in the UK focussed on four well-characterised variants, there is a need to address the applicability of this strategy across diverse ethnic or ancestral populations. We highlight approaches to identify and characterise rare variants in DPYD and in other genes involved in the pyrimidine metabolic pathway to reduce healthcare inequalities. Finally, we discuss the future of pharmacogenomics within cancer care, and the potential to harness innovative digital and genotyping technologies to streamline prescribing and optimise both systemic anti-cancer therapies and supportive care.

PMID:39721301 | DOI:10.1016/j.clon.2024.103706

Pharmgenomics Pers Med. 2024 Dec 20;17:551-561. doi: 10.2147/PGPM.S482289. eCollection 2024.

ABSTRACT

PURPOSE: Atorvastatin is commonly used to treat dyslipidemia; however, individual responses vary considerably. This study endeavors to evaluate the relationship between polymorphisms in the coding sequence (CDS) of SLCO1B1 gene and blood lipid levels before and after atorvastatin treatment among the Chinese Han adults with dyslipidemia.

PATIENTS AND METHODS: A total of 165 Chinese Han adults undergoing atorvastatin therapy were enrolled in this study and followed up quarterly. The complete CDS of the SLCO1B1 gene was sequenced to detect polymorphisms. Statistical analysis was utilized to assess the impacts of sex, age, body mass index (BMI), and polymorphisms on blood lipid levels before and after atorvastatin treatment.

RESULTS: Fourteen polymorphisms were identified in the SLCO1B1 CDS. Among them, four polymorphisms had mutant alleles present in over 20 patients. No polymorphism was found to correlate with blood lipid levels before treatment; in contrast, age, sex, and BMI did show correlations (P<0.05). Notably, females had higher baseline blood lipid levels than males, indicating that sex had a more significant impact on baseline levels than age and BMI. The polymorphism rs2306283 was significantly correlated with the efficacy of atorvastatin (P<0.05), whereas age, sex, and BMI were not. Carriers of the rs2306283 AA allele experienced a substantially greater reduction in total cholesterol (TC) and triglyceride (TG) levels after atorvastatin treatment. The other polymorphisms did not demonstrate any significant impact on atorvastatin's efficacy.

CONCLUSION: This study delved into the intricate genetic structure of polymorphisms in SLCO1B1 CDS and their roles in lipid metabolism and atorvastatin's efficacy among Chinese Han adults with dyslipidemia. The findings underscore the crucial role of the rs2306283 polymorphism in the response to atorvastatin's efficacy, highlighting the significance of pharmacogenomics in personalized medicine. It is thus advisable to consider genetic testing for SLCO1B1 variants to optimize atorvastatin therapy.

PMID:39720770 | PMC:PMC11668066 | DOI:10.2147/PGPM.S482289