Pharmacogenomics. 2022 Jan 10. doi: 10.2217/pgs-2021-0099. Online ahead of print.

ABSTRACT

Imaging and tissue biopsies represent the current gold standard for breast cancer diagnosis and patient management. However, these practices are time-consuming, expensive and require invasive procedures. Moreover, tissue biopsies do not capture spatial and temporal tumor heterogeneity. Conversely, liquid biopsy, which includes circulating tumor cells, circulating free nucleic acids and extracellular vesicles, is minimally invasive, easy to perform and can be repeated during a patient's follow-up. Increasing evidence also suggests that liquid biopsy can be used to efficiently screen and diagnose tumors at an early stage, and to monitor changes in the tumor molecular profile. In the present review, clinical applications and prospects are discussed.

PMID:35006002 | DOI:10.2217/pgs-2021-0099

Front Cardiovasc Med. 2021 Dec 24;8:726694. doi: 10.3389/fcvm.2021.726694. eCollection 2021.

ABSTRACT

Aim: To explore the diverse target distribution and variable mechanisms of different fangjis prescriptions when treating arrhythmias based on the systems pharmacology. Methods: The active ingredients and their corresponding targets were acquired from the three fangjis [Zhigancao Tang (ZT), Guizhigancao Longgumuli Tang (GLT), and Huanglian E'jiao Tang (HET)] and the arrhythmia-related genes were identified based on comprehensive database screening. Networks were constructed between the fangjis and arrhythmia and used to define arrhythmia modules. Common and differential gene targets were identified within the arrhythmia network modules and the cover rate (CR) matrix was applied to compare the contributions of the fangjis to the network and modules. Comparative pharmacogenetics analyses were then conducted to define the arrhythmia-related signaling pathways regulated by the fangjis prescriptions. Finally, the divergence and convergence points of the arrhythmia pathways were deciphered based on databases and the published literature. Results: A total of 187, 105, and 68 active ingredients and 1,139, 1,195, and 811 corresponding gene targets of the three fangjis were obtained and 102 arrhythmia-related genes were acquired. An arrhythmia network was constructed and subdivided into 4 modules. For the target distribution analysis, 65.4% of genes were regulated by the three fangjis within the arrhythmia network. ZT and GLT were more similar to each other, mainly regulated by module two, whereas HET was divided among all the modules. From the perspective of signal transduction, calcium-related pathways [calcium, cyclic guanosine 3',5'-monophosphate (cGMP)-PKG, and cyclic adenosine 3',5'-monophosphate (cAMP)] and endocrine system-related pathways (oxytocin signaling pathway and renin secretion pathways) were associated with all the three fangjis prescriptions. Nevertheless, heterogeneity existed between the biological processes and pathway distribution among the three prescriptions. GLT and HET were particularly inclined toward the conditions involving abnormal hormone secretion, whereas ZT tended toward renin-angiotensin-aldosterone system (RAAS) disorders. However, calcium signaling-related pathways prominently feature in the pharmacological activities of the decoctions. Experimental validation indicated that ZT, GLT, and HET significantly shortened the duration of ventricular arrhythmia (VA) and downregulated the expression of CALM2 and interleukin-6 (IL-6) messenger RNAs (mRNAs); GLT and HET downregulated the expression of CALM1 and NOS3 mRNAs; HET downregulated the expression of CRP mRNA. Conclusion: Comparing the various distributions of the three fangjis, pathways provide evidence with respect to precise applications toward individualized arrhythmia treatments.

PMID:35004871 | PMC:PMC8739471 | DOI:10.3389/fcvm.2021.726694

J Pediatr Pharmacol Ther. 2022;27(1):4-11. doi: 10.5863/1551-6776-27.1.4. Epub 2021 Dec 22.

NO ABSTRACT

PMID:35002553 | PMC:PMC8717621 | DOI:10.5863/1551-6776-27.1.4

Pharmacogenomics. 2022 Jan 10. doi: 10.2217/pgs-2021-0109. Online ahead of print.

ABSTRACT

Aim: We evaluated the clinical acceptance and feasibility of a pharmacist-guided personalized consult service following its transition from a mandatory (mPGx) to optional (oPGx) CYP2C9/VKORC1/CYP4F2 genotyping for warfarin. Methods: A total of 1105 patients were included. Clinical acceptance and feasibility outcomes were analyzed using bivariate and multivariable analyses. Results: After transitioning to optional genotyping, genotype testing was still ordered in a large segment of the eligible population (52.1%). Physician acceptance of pharmacist-recommended doses improved from 83.9% (mPGx) to 86.6% (oPGx; OR: 1.3; 95% CI: 1.1-1.5; p = 0.01) with a shorter median genotype result turnaround time (oPGX: 23.6 hr vs mPGX: 25.1 hr ; p < 0.01). Conclusion: Ordering of genotype testing and provider acceptance of dosing recommendations remained high after transitioning to optional genotyping.

PMID:35001645 | DOI:10.2217/pgs-2021-0109

Am J Health Syst Pharm. 2022 Jan 6:zxab489. doi: 10.1093/ajhp/zxab489. Online ahead of print.

ABSTRACT

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PMID:34999758 | DOI:10.1093/ajhp/zxab489

Eur J Cancer. 2022 Jan 5;162:148-157. doi: 10.1016/j.ejca.2021.12.009. Online ahead of print.

ABSTRACT

AIM: To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan.

PATIENTS AND METHODS: In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1∗28 and UGT1A1∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs.

RESULTS: Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient.

CONCLUSION: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety.

PMID:34998046 | DOI:10.1016/j.ejca.2021.12.009

Br J Clin Pharmacol. 2022 Jan 7. doi: 10.1111/bcp.15216. Online ahead of print.

ABSTRACT

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates, and infants, is limited by a paucity of good quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts, by complementary information about targeted and non-targeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis-generating allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a sub-division into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as well as type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, non-invasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (e.g. liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, like artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to identify complex phenotypes and subpopulations of patients to improve development of medicines for children with potential economic advantages.

PMID:34997627 | DOI:10.1111/bcp.15216

Res Social Adm Pharm. 2021 Dec 15:S1551-7411(21)00387-9. doi: 10.1016/j.sapharm.2021.12.002. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenetic testing enhances patient safety by improving medical treatment and reducing side effects. It has shown potential in both primary and secondary care. However, implementation in healthcare, particularly in primary care, is slow.

OBJECTIVE: The objective was to review articles published on the attitudes towards, and knowledge on pharmacogenetic testing in primary care, among general practitioners, pharmacists, and patients.

METHODS: The review was performed according to the PRISMA checklist. A systemized literature search was followed by a 2-step screening process. Apart from the content of articles being within the scope of the review, inclusion criteria included: articles in English; primary research articles; qualitative, quantitative, or mixed methods. Content analysis was conducted as a qualitative meta-synthesis. The methodological rigor of included articles was assessed.

RESULTS: Fifteen studies were included. The analysis resulted in the following main themes: i) benefits of pharmacogenetic testing, ii) barriers to pharmacogenetic testing, iii) pharmacists' role in pharmacogenetic counselling, and iv) pharmacists' knowledge on pharmacogenetics. Methodological rigor was generally medium/high.

CONCLUSIONS: More studies are needed in this area, and there is a need for more education on pharmacogenetic testing for healthcare professionals. Issues like patient autonomy, economy, and access to tests also need to be addressed.

PMID:34996718 | DOI:10.1016/j.sapharm.2021.12.002

Expert Opin Drug Metab Toxicol. 2022 Jan 7. doi: 10.1080/17425255.2021.2027367. Online ahead of print.

ABSTRACT

INTRODUCTION: Therapeutic drug monitoring (TDM) is useful for optimizing monoclonal antibodies (mAbs) for the treatment of immune-mediated inflammatory disorders including inflammatory bowel disease (IBD). However, TDM in clinical practice is still restricted by long turnaround times between sampling and results and the fact that dosing of mAbs to a target drug concentration is challenging due to high pharmacokinetic (PK) variability at both a population and patient level. Overcoming these barriers may be addressed by point-of-care (POC) assays, model-informed precision dosing (MIPD) and pharmacogenetics/pharmacogenomics.

AREAS COVERED: This review provides an overview of the optimization of TDM of mAbs in IBD including POC testing, MIPD and pharmacogenetics.

EXPERT OPINION: Recent advances in sampling, quantification, and support of clinical decisions include POC assays and PK dashboards which may allow for prompt and precise application of TDM in clinical practice. Future perspectives towards a more personalized implementation of TDM could include the incorporation of pharmacogenetics/pharmacogenomics to identify subgroups of patients who would benefit more from proactive TDM or combination therapy such as those prone to immunogenicity and/or accelerated drug clearance. However, there are still challenges regarding the implementation of these innovative approaches and more data from prospective studies and randomized controlled trials are needed.

PMID:34996330 | DOI:10.1080/17425255.2021.2027367

Mol Inform. 2022 Jan 6. doi: 10.1002/minf.202100261. Online ahead of print.

ABSTRACT

The Metabolovigilance database (https://pharmacogenomics.clas.ucdenver.edu/pharmacogenomics/side-effect/) is a single repository of information on over 15,920 pharmaceuticals and the compounds expected to result from metabolism of these drugs. Metabolovigilance functions as both a web server, providing data directly to users and as a web application, applying user inputs to create logic statements that curate the data presented or downloaded. Using this tool, it is easy to collect information on drugs, their side effects, and the metabolites associated with specific side effects. Information on these compounds can be sorted based on physical properties of the drugs and their metabolites. All of this information can be viewed, sorted, and downloaded for use in other applications. This open-access tool will facilitate molecular studies on the causes of adverse drug reactions and is well suited to integrate with genomic data furthering the goals of personalized medicine.

PMID:34994061 | DOI:10.1002/minf.202100261

Hum Psychopharmacol. 2022 Jan 6:e2830. doi: 10.1002/hup.2830. Online ahead of print.

ABSTRACT

OBJECTIVE: Significant challenges in the management of major depressive disorder include the lag period from treatment initiation to an evident response, low response rates and unpredictable disparities in outcome between patients. As a large part of these has been linked to genetic mechanisms, we tried to establish a relationship between genes associated with serotonin neurotransmission and outcome to selective serotonin reuptake inhibitor (SSRI) treatment.

METHODS: One hundred and twenty-five patients with moderate to severe depression [at least 15 on the Hamilton Depression (HAM-D) Rating Scale] being started on SSRI were recruited. Those with a reduction of at least 50% from baseline or an absolute score of 7 or less after 8 weeks of treatment were considered as responders. The serotonin transporter linked polymorphic region 5HTTLPR, serotonin transporter intron 2 (STin2) polymorphism and the 5-HT receptor 1A rs6295 polymorphisms were studied in association with outcome.

RESULTS: The l/l genotype of the 5HTTLPR was associated with greater likelihood of response (OR: 4.65, CI: 1.74-12.38, p = 0.003). Patients with the 12/12 repeat variant of the STin2 VNTR polymorphism showed a greater reduction in HAM-D score, compared to patients with the 10/10 genotype (OR: 0.12, CI: 0.03-0.44, p = 0.001). We found no association of the 5HTR1Ars6295 polymorphism with response.

CONCLUSIONS: The 5HTTLPR polymorphism and the SLC6A4 intron 2 polymorphism were associated with treatment response, with the l/l genotype and 12-copy allele showing a tendency towards better outcomes, respectively.

PMID:34994008 | DOI:10.1002/hup.2830

Inflammation. 2022 Jan 7. doi: 10.1007/s10753-021-01601-0. Online ahead of print.

ABSTRACT

Interleukin 6 (IL-6) is a moderately heritable pleiotropic cytokine whose elevated concentrations in coronary artery disease, peripheral arterial disease, pulmonary arterial hypertension, Eales' disease, Sjògren's syndrome, osteoarthritis, adenocarcinoma, neuroblastoma, polymyalgia rheumatica, pulmonary tuberculosis, and enterovirus 71 infection, and following coronary artery bypass graft show larger genetic effects than in unaffected low IL-6 controls. We hypothesize that genetic effects may depend upon whether average IL-6 concentrations are high or low, i.e., quantile-dependent expressivity. Quantile-specific offspring-parent (βOP) and full-sib regression slopes (βFS) were estimated by applying quantile regression to the age- and sex-adjusted serum IL-6 concentrations in families surveyed in the Framingham Heart Study. Quantile-specific heritabilities were calculated as h2 = 2βOP / (1 + rspouse) and h2 = {(1 + 8rspouseβFS)0.5 -1} / (2rspouse)). Heritability (h2 ± SE) of IL-6 concentrations increased from 0.01 ± 0.01 at the 10th percentile (NS), 0.02 ± 0.01 at the 25th (P = 0.009), 0.03 ± 0.01 at the 50th (P = 0.007), 0.04 ± 0.02 at the 75th (P = 0.004), and 0.13 ± 0.05 at the 90th percentile (P = 0.03), or 0.0005 ± 0.0002 for each 1% increase in the offspring's phenotype distribution (Plinear trend = 0.02) when estimated from βOP and from 0.02 ± 0.02 at the 10th (NS), 0.02 ± 0.02 at the 25th (NS), 0.06 ± 0.02 at the 50th (P = 0.01), 0.12 ± 0.04 at the 75th (P = 0.001), and 0.30 ± 0.03 at the 90th percentile (P < 10-16), or 0.0015 ± 0.0007 for each 1% increase in the sibling phenotype distribution (Plinear trend = 0.02) when estimated from βFS. Thus the heritability of serum IL-6 concentrations is quantile dependent, which may contribute in part to the larger genetic effect size reported for diseases and environmental conditions that elevate IL-6 concentrations vis-à-vis unaffected controls.

PMID:34993731 | DOI:10.1007/s10753-021-01601-0

Oxid Med Cell Longev. 2021 Dec 28;2021:1602437. doi: 10.1155/2021/1602437. eCollection 2021.

ABSTRACT

Lasia spinosa (L.) is used ethnobotanically for the treatment of various diseases, including rheumatoid arthritis, inflammation of the lungs, bleeding cough, hemorrhoids, intestinal diseases, stomach pain, and uterine cancer. This review is aimed at summarizing phytochemistry and pharmacological data with their molecular mechanisms of action. A search was performed in databases such as PubMed, Science Direct, and Google Scholar using the keywords: "Lasia spinosa," then combined with "ethnopharmacological use," "phytochemistry," and "pharmacological activity." This updated review included studies with in vitro, ex vivo, and in vivo experiments with compounds of known concentration and highlighted pharmacological mechanisms. The research results showed that L. spinosa contains many important nutritional and phytochemical components such as alkanes, aldehydes, alkaloids, carotenoids, flavonoids, fatty acids, ketones, lignans, phenolics, terpenoids, steroids, and volatile oil with excellent bioactivity. The importance of this review lies in the fact that scientific pharmacological evidence supports the fact that the plant has antioxidant, anti-inflammatory, antimicrobial, cytotoxic, antidiarrheal, antihelminthic, antidiabetic, antihyperlipidemic, and antinociceptive effects, while protecting the gastrointestinal system and reproductive. Regarding future toxicological and safety data, more research is needed, including studies on human subjects. In light of these data, L. spinosa can be considered a medicinal plant with effective bioactives for the adjuvant treatment of various diseases in humans.

PMID:34992714 | PMC:PMC8727140 | DOI:10.1155/2021/1602437

Front Genet. 2021 Dec 21;12:781451. doi: 10.3389/fgene.2021.781451. eCollection 2021.

ABSTRACT

Background: African Americans (AAs) suffer a higher stroke burden due to hypertension. Identifying genetic contributors to stroke among AAs with hypertension is critical to understanding the genetic basis of the disease, as well as detecting at-risk individuals. Methods: In a population comprising over 10,700 AAs treated for hypertension from the Genetics of Hypertension Associated Treatments (GenHAT) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) studies, we performed an inverse variance-weighted meta-analysis of incident stroke. Additionally, we tested the predictive accuracy of a polygenic risk score (PRS) derived from a European ancestral population in both GenHAT and REGARDS AAs aiming to evaluate cross-ethnic performance. Results: We identified 10 statistically significant (p < 5.00E-08) and 90 additional suggestive (p < 1.00E-06) variants associated with incident stroke in the meta-analysis. Six of the top 10 variants were located in an intergenic region on chromosome 18 (LINC01443-LOC644669). Additional variants of interest were located in or near the COL12A1, SNTG1, PCDH7, TMTC1, and NTM genes. Replication was conducted in the Warfarin Pharmacogenomics Cohort (WPC), and while none of the variants were directly validated, seven intronic variants of NTM proximal to our target variants, had a p-value <5.00E-04 in the WPC. The inclusion of the PRS did not improve the prediction accuracy compared to a reference model adjusting for age, sex, and genetic ancestry in either study and had lower predictive accuracy compared to models accounting for established stroke risk factors. These results demonstrate the necessity for PRS derivation in AAs, particularly for diseases that affect AAs disproportionately. Conclusion: This study highlights biologically plausible genetic determinants for incident stroke in hypertensive AAs. Ultimately, a better understanding of genetic risk factors for stroke in AAs may give new insight into stroke burden and potential clinical tools for those among the highest at risk.

PMID:34992631 | PMC:PMC8724550 | DOI:10.3389/fgene.2021.781451

J Clin Oncol. 2022 Jan 6:JCO2101422. doi: 10.1200/JCO.21.01422. Online ahead of print.

ABSTRACT

PURPOSE: To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.

MATERIALS AND METHODS: Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial.

RESULTS: In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low v high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; P = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; P = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, P = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, P = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms).

CONCLUSION: Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.

PMID:34990262 | DOI:10.1200/JCO.21.01422

Cancer Chemother Pharmacol. 2022 Jan 6. doi: 10.1007/s00280-021-04374-3. Online ahead of print.

ABSTRACT

PURPOSE: Large interindividual variability in the pharmacokinetic properties of docetaxel has been reported, with the clearance of docetaxel varying nearly six fold, in which pharmacogenetics of docetaxel may play an essential role in addition to physiological factors. The association between the gene polymorphism and risk of adverse clinical effects in docetaxel treated patients has been examined in several studies, but their conclusions are, to some extent, controversial. To clarify the role of gene polymorphism in the clinical outcomes of docetaxel treatment, a meta-analysis was performed in the present study.

METHODS: Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were employed to evaluate the impact of gene polymorphisms of CYP3A4, CYP3A5 and ABCB1. Four studies with 485 subjects were included in this study. Fixed or random-effects model was chosen according to heterogeneity to conduct the meta-analysis. Publication bias was evaluated by fail-safe numbers.

RESULTS: Significant association was identified between the ABCB1 C3435T (rs1045642) polymorphism and risk of short-term recurrent hematological toxicity (TT vs. CC + TC OR = 2.91, 95% CI 1.30-6.52, P = 0.009; TT vs. CC OR = 4.23, 95% CI 1.69-10.57 P = 0.002). The association of the ABCB1 G2677T/A (rs2032582) polymorphism with risk of fluid retention was statistically significant (T(A)/T(A) vs. GG + GT(A) OR = 2.08, 95% CI 1.16-3.73, P = 0.01). No statistically significant association between the CYP3A5 A6986G (rs776746) polymorphism and adverse effects was observed in this study. Due to the limitations of included literature, we did not conduct meta-analysis on CYP3A4 gene polymorphism and adverse effects.

CONCLUSION: An association between the ABCB1 C3435T (rs1045642), ABCB1 G2677T/A (rs2032582) polymorphism and risk of adverse effects of docetaxel was found by our meta-analysis. Namely, the TT homozygotes of the ABCB1 C3435T polymorphism may be associated with the risk of hematological toxicity. ABCB1 G2677T T(A)/T(A) genotype may be associated with the fluid retention.

TRAIL REGISTRATION: PROSPERO 2020 CRD42020203132.

PMID:34988655 | DOI:10.1007/s00280-021-04374-3

Front Psychiatry. 2021 Dec 20;12:756403. doi: 10.3389/fpsyt.2021.756403. eCollection 2021.

ABSTRACT

Objective: We first sought to examine the relationship between plasma levels of methylxanthines (caffeine and its metabolites) and sleep disorders, and secondarily between polygenic risk scores (PRS) of caffeine consumption or sleep duration with methylxanthine plasma levels and/or sleep disorders in a psychiatric cohort. Methods: Plasma levels of methylxanthines were quantified by ultra-high performance liquid chromatography/tandem mass spectrometry. In inpatients, sleep disorder diagnosis was defined using ICD-10 "F51.0," sedative drug intake before bedtime, or hospital discharge letters, while a subgroup of sedative drugs was used for outpatients. The PRS of coffee consumption and sleep duration were constructed using publicly available GWAS results from the UKBiobank. Results: 1,747 observations (1,060 patients) were included (50.3% of observations with sleep disorders). Multivariate analyses adjusted for age, sex, body mass index, setting of care and psychiatric diagnoses showed that patients in the highest decile of plasma levels of methylxanthines had more than double the risk for sleep disorders compared to the lowest decile (OR = 2.13, p = 0.004). PRS of caffeine consumption was associated with plasma levels of caffeine, paraxanthine, theophylline and with their sum (β = 0.1; 0.11; 0.09; and 0.1, pcorrected = 0.01; 0.02; 0.02; and 0.01, respectively) but not with sleep disorders. A trend was found between the PRS of sleep duration and paraxanthine levels (β = 0.13, pcorrected = 0.09). Discussion: Very high caffeine consumption is associated with sleep disorders in psychiatric in- and outpatients. Future prospective studies should aim to determine the benefit of reducing caffeine consumption in high caffeine-consuming patients suffering from sleep disorders.

PMID:34987426 | PMC:PMC8721597 | DOI:10.3389/fpsyt.2021.756403

Psychiatry Res. 2021 Dec 22;308:114354. doi: 10.1016/j.psychres.2021.114354. Online ahead of print.

ABSTRACT

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.

PMID:34986431 | DOI:10.1016/j.psychres.2021.114354

JCO Clin Cancer Inform. 2022 Jan;6:e2100152. doi: 10.1200/CCI.21.00152.

ABSTRACT

PURPOSE: The rapid growth of biomedical data ecosystems has catalyzed research for oncology and precision medicine. We leverage federal cloud-based precision medicine databases and tools to better understand the current landscape of precision medicine and genomic testing for patients with cancer.

METHODS: Retrospective observational study of genomic testing for patients with cancer in the National Institutes of Health All of Us Research Program, with the cancer cohort defined as having at least two documented or reported cancer diagnoses.

RESULTS: There were 5,678 (1.8%) All of Us participants in the cancer cohort, with a significant difference between cancer status by age category, sex, race, and ethnicity (P < .001 for all). There were 295 (5.2%) patients with cancer who received genomic testing compared with 6,734 (2.2%) of noncancer patients, with 752 genomic tests commonly focused on gene mutations (primarily pharmacogenomics), molecular pathology, or clinical cytogenetic reports.

CONCLUSION: Although not yet ubiquitous, diverse clinical genomic analyses in oncology can set the stage to grow the practice of precision medicine by integrating research patient data repositories, cancer data ecosystems, and biomedical informatics.

PMID:34985965 | DOI:10.1200/CCI.21.00152

Per Med. 2022 Jan 5. doi: 10.2217/pme-2021-0064. Online ahead of print.

ABSTRACT

Aim: Patient knowledge and attitudes toward pharmacogenetic (PGx) testing may impact adoption of clinical testing. Methods: Questionnaires regarding knowledge, attitudes and ethics of PGx testing were distributed to 504 patients enrolled in the ADAPT study conducted at two urban hospitals in Philadelphia, Pennsylvania, USA. Responses were assessed using multivariable logistic regression. Results: 311 completed the survey (62% response rate). 74% were unaware of PGx testing, but 79% indicated using PGx results to predict medication efficacy was important. In a multivariable model, higher education level (p = 0.031) and greater genetics knowledge (p < 0.001) were associated with more positive attitudes toward PGx testing. Conclusion: Greater patient knowledge of genetics was associated with a more positive attitude toward PGx testing, indicating that educational strategies aimed at increasing genetics knowledge may enhance adoption of PGx testing in the clinic.

PMID:34984913 | DOI:10.2217/pme-2021-0064