EBioMedicine. 2024 Dec 31;112:105550. doi: 10.1016/j.ebiom.2024.105550. Online ahead of print.

ABSTRACT

BACKGROUND: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation ('flash freezing') limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions.

METHODS: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene).

FINDINGS: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions.

INTERPRETATION: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples.

FUNDING: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).

PMID:39742562 | DOI:10.1016/j.ebiom.2024.105550

Front Pharmacol. 2024 Dec 16;15:1477485. doi: 10.3389/fphar.2024.1477485. eCollection 2024.

ABSTRACT

Flecainide acetate is a Class 1c anti-arrhythmic with a potent sodium voltage gated channel blockade which is utilized for the second-line treatment of tachyarrhythmias in children and adults. Given its narrow therapeutic index, the individualization of drug therapy is of utmost importance for clinicians. Despite efforts to improve anti-arrhythmic drug therapy, there remain knowledge gaps regarding the impact of variation in the genes relevant to flecainide's disposition and response. This variability is compounded in developing children whose drug disposition and response pathways may remain immature. The purpose of this comprehensive review is to outline flecainide's disposition and response pathways while simultaneously highlighting opportunities for prospective investigation in the pediatric population.

PMID:39741635 | PMC:PMC11686437 | DOI:10.3389/fphar.2024.1477485

BMJ Open. 2024 Dec 31;14(12):e088389. doi: 10.1136/bmjopen-2024-088389.

ABSTRACT

INTRODUCTION: Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for TB preventive therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings.

METHODS: This is an observational cohort study with a nested case-control study. We enrolled consecutive patients who had been initiated on TPT using the 3HP regimen. These are followed up biweekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2, AADAC and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes.

ANALYSIS: The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. χ2 tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modelling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.

ETHICS AND DISSEMINATION: Ethical approval of this study inclusive of all the appropriate documents was obtained from the Infectious Diseases Institute Research and Ethics Committee and the Uganda National Council of Science and Technology. The study adheres to legal, ethical and Good Clinical Practice (GCP) guidelines. Deidentified genotype data from 300 patients will be shared after publication. The protocol and phenotype data will be publicly accessible. Abstracts will be submitted to conferences, and a manuscript will be published poststudy.

PMID:39740953 | DOI:10.1136/bmjopen-2024-088389

J Pharm Biomed Anal. 2024 Dec 25;255:116652. doi: 10.1016/j.jpba.2024.116652. Online ahead of print.

ABSTRACT

Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated. This exploratory multi-omics study investigated the serum molecular profiles of Crohn's disease (CD) and ulcerative colitis (UC), in association with elevated fecal calprotectin and disease activity states. The serum proteome, metabolome, and lipidome of 75 treated IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures for biological interpretations. We found that chronic inflammation, phosphatidylcholines and bile acid homeostasis disturbances underlined the differences between CD and UC. Besides, elevated calprotectin was associated with higher levels of inflammatory proteins and sphingomyelins (SM) and lower levels of bile acids, amino acids, and triacylglycerols (TG). Relative to the remission disease state, the active form was characterized by decreased abundances of SMs and increased abundances of inflammatory proteins and TGs. We also observed that molecular changes upon treatment escalation were putatively related to altered levels of inflammatory response proteins, amino acids, and TGs. ISM1, ANGPTL4, chenodeoxycholate, Cer(18:1;2 O/24:1), and TG were identified as candidates subject to further investigation. Altogether, our study revealed that disturbances in immune response, bile acid homeostasis, amino acids, and lipids potentially underlie the clinically heterogeneous spectrum of IBD.

PMID:39740478 | DOI:10.1016/j.jpba.2024.116652

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