J Crohns Colitis. 2022 Aug 27:jjac127. doi: 10.1093/ecco-jcc/jjac127. Online ahead of print.

ABSTRACT

BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).

METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.

RESULTS: A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).

CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

PMID:36029471 | DOI:10.1093/ecco-jcc/jjac127

Biomed Pharmacother. 2022 Aug 23;154:113555. doi: 10.1016/j.biopha.2022.113555. Online ahead of print.

ABSTRACT

Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a bioactive compound, a natural anthraquinone aglycone, present mainly in herbaceous species of the families Fabaceae, Polygonaceae and Rhamnaceae, with a physiological role in protection against abiotic stress in vegetative tissues. Emodin is mainly used in traditional Chinese medicine to treat sore throats, carbuncles, sores, blood stasis, and damp-heat jaundice. Pharmacological research in the last decade has revealed other potential therapeutic applications such as anticancer, neuroprotective, antidiabetic, antioxidant and anti-inflammatory. The present study aimed to summarize recent studies on bioavailability, preclinical pharmacological effects with evidence of molecular mechanisms, clinical trials and clinical pitfalls, respectively the therapeutic limitations of emodin. For this purpose, extensive searches were performed using the PubMed/Medline, Scopus, Google scholar, TRIP database, Springer link, Wiley and SciFinder databases as a search engines. The in vitro and in vivo studies included in this updated review highlighted the signaling pathways and molecular mechanisms of emodin. Because its bioavailability is low, there are limitations in clinical therapeutic use. In conclusion, for an increase in pharmacotherapeutic efficacy, future studies with carrier molecules to the target, thus opening up new therapeutic perspectives.

PMID:36027610 | DOI:10.1016/j.biopha.2022.113555

J Hypertens. 2022 Jun 1;40(Suppl 1):e311. doi: 10.1097/01.hjh.0000838772.03800.3c.

ABSTRACT

OBJECTIVE: Inadequate adherence to anti-hypertensive prescription is one of the major obstacles for blood pressure control in patients with arterial hypertension. It is estimated that 40% of patients with hypertension have partial or absent compliance, with more than 80% of non-adherence when blood pressure targets are not achieved. However, in clinical practice the assessment of therapeutic adherence is still challenging. The available methods for the assessment of anti-hypertensive compliance are costly, low accurate or time consuming.

DESIGN AND METHOD: We designed a prospective observational study to evaluate the therapeutic adherence to inhibitors of renin-angiotensin-aldosterone system (RAAS) in patients with hypertension through serial measurement of aldosterone-to-direct renin ratio (ARR), before and after treatment.We enrolled 80 patients, including 40 patients with arterial hypertension and 40 healthy controls. Patients with arterial hypertension underwent three visits: at baseline and 2 and 8 weeks after initiation of RAAS inhibitors. Patients of the control group underwent two visits: at baseline and after 2 weeks. At each visit we collected blood specimens for hormonal assays and therapeutic drug monitoring, used as gold standard for therapeutic adherence. We used delta ARR (ARR), defined as the relative change in ARR before and after treatment, for assessment of therapeutic compliance.

RESULTS: After initiation of RAAS inhibitor, aldosterone significantly decreased and renin levels significantly increased, with consequent ARR reduction. The use ARR provided high accuracy for determination of therapeutic compliance, with an area under the curve (AUC) of 0.900 and 0.886, at 2 and 8 weeks respectively. A cut-off of -48% of ARR was adopted, providing 90% sensitivity and 75% specificity, both at 2 and 8 weeks.

CONCLUSIONS: The ARR measurement, is an innovative, cheap and highly sensitive method to predict compliance to RAAS inhibitors in patients with hypertension. We hence propose the implementation of ARR as screening test for identification of patients suspected to be non-adherent, reserving therapeutic drug monitoring for non-adherence confirmation.

PMID:36027462 | DOI:10.1097/01.hjh.0000838772.03800.3c

J Hypertens. 2022 Jun 1;40(Suppl 1):e200-e201. doi: 10.1097/01.hjh.0000837484.58272.76.

ABSTRACT

OBJECTIVE: Current guidelines recommend to withdraw interfering antihypertensive drugs before to perform a screening test for primary aldosteronism (PA). Recent studies suggested that diagnostic work-up of PA might be performed without withdrawing mineralocorticoid receptor antagonist (MRA) treatment in selected patients, especially when severe hypertension and hypokalemia are difficult to control.We designed a prospective study to evaluate the effects of MRA treatment on aldosterone to renin ratio (ARR) in patients with PA.

DESIGN AND METHOD: We prospectively recruited 121 patients with confirmed PA and started on canrenone treatment. Eighteen patients were enrolled in a short-term treatment cohort to assess the effects of MRA on aldosterone to renin ratio (ARR) and potassium after 2 and 8 weeks of canrenone therapy. One hundred and two patients were recruited in the long-term treatment cohort to evaluate the effects of canrenone on ARR after 2 to 12 months of MRA therapy.

RESULTS: Plasma renin activity and potassium displayed a significant increase, and ARR showed a significant reduction compared with baseline in patients with PA after MRA initiation. These effects were observed both after a short- and a long-term treatment with canrenone, and were progressively more significant after longer periods of therapy and with greater doses of MRA. We demonstrated that canrenone assumption severely impacts on the rate of false-negative screening tests for PA, which raised from 16.7% to 72.5% after 2 weeks and 7-12 months of MRA treatment, respectively.

CONCLUSIONS: ARR testing for PA screening should not be performed under MRA therapy.

PMID:36027140 | DOI:10.1097/01.hjh.0000837484.58272.76

Front Genet. 2022 Aug 9;13:960731. doi: 10.3389/fgene.2022.960731. eCollection 2022.

ABSTRACT

Background and aims: Albeit several factors which influence the outcome of corona virus disease (COVID-19) are already known, genetic markers which may predict the outcome of the disease in hospitalized patients are still very sparse. Thus, in this study, we aimed to analyze whether the single-nucleotide polymorphism (SNP) rs5443 in the gene GNB3, which was associated with higher T cell responses in previous studies, might be a suitable biomarker to predict T cell responses and the outcome of COVID-19 in a comprehensive German cohort. Methods: We analyzed the influence of demographics, pre-existing disorders, laboratory parameters at the time of hospitalization, and GNB3 rs5443 genotype in a comprehensive cohort (N = 1570) on the outcome of COVID-19. In a sub cohort, we analyzed SARS-CoV-2-specific T cell responses and associated GNB3 rs5443 genotypes. We investigated the influence of all factors on COVID-19 fatality in multivariable analysis. Results: We found a younger patient age, normotension or absence of diabetes mellitus or cardiovascular diseases, normal blood cell counts, and low inflammatory markers at hospital admission were protective factors against fatal course of disease. In addition, the rs5443 TT genotype was significantly associated with protection against COVID-19 fatality (OR: 0.60, 95% CI: 0.40-0.92, p = 0.02). We also observed significantly increased SARS-CoV-2-specific T cell responses in rs5443 TT genotype carriers (p = 0.01). Although we observed a significant association of the factors described previously in univariate analysis, only a younger age of the patients, normal blood cell counts, and the GNB3 rs5443 TT genotype remained independent predictors against COVID-19 fatality in multivariable analysis. Conclusion: Immutable predictors for COVID-19 fatality are relatively rare. In this study we could show that the TT genotype of the SNP rs5443 in the gene GNB3 is associated with protection against COVID-19 fatality. It was as well correlated to higher SARS-CoV-2-specific T cell responses, which could result in a milder course of disease in those patients. Based on those observations we hereby provide a further prognostic biomarker, which might be used in routine diagnostics as a predictive factor for COVID-19 mortality already upon hospitalization.

PMID:36017493 | PMC:PMC9395599 | DOI:10.3389/fgene.2022.960731

Complex Psychiatry. 2021 Dec;7(3-4):60-70. doi: 10.1159/000518926. Epub 2021 Aug 24.

ABSTRACT

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute's Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

PMID:36017067 | PMC:PMC8740081 | DOI:10.1159/000518926

Pharmaceutics. 2022 Aug 21;14(8):1744. doi: 10.3390/pharmaceutics14081744.

ABSTRACT

Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl &lt; 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study's findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication's dose in accordance with renal function.

PMID:36015370 | DOI:10.3390/pharmaceutics14081744

Pharmaceutics. 2022 Aug 14;14(8):1692. doi: 10.3390/pharmaceutics14081692.

ABSTRACT

Melanoma is a skin cancer characterized by rapid growth and spread for which current therapies produce both resistance and increased risk of infection. To develop new anti-melanoma biocompatible species, the series of complexes Cu(N-N)(bzac)(X)⋅nH2O (N-N: 1,10-phenanthroline/2,2'-bipyridine, Hbzac: 1-phenyl-1,3-butanedione, X: NO3/ClO4, and n = 0, 1) was studied. Single-crystal X-ray diffraction revealed a mononuclear structure for all complexes. The ability of the complexes to scavenge or trap reactive oxygen species such as O2⋅- and HO⋅ was proved by EPR spectroscopy experiments. All complexes inhibited B16 murine melanoma cells in a dose-dependent and nanomolar range, but the complexes with 1,10-phenanthroline were more active. Moreover, comparative activity on B16 and healthy BJ cells revealed a therapeutic index of 1.27-2.24. Bioinformatic methods were used to calculate the drug-likeness, pharmacokinetic, pharmacogenomic, and pharmacodynamic profiles of the compounds. The results showed that all compounds exhibit drug-likeness features, as well as promising absorption, distribution, metabolism, and excretion (ADME) properties, and no toxicity. The pharmacodynamics results showed that the neutral species appear to be good candidates for antitumor molecular targets (Tyrosyl-DNA phosphodiesterase 1, DNA-(apurinic or apyrimidinic site) lyase or Kruppel-like factor 5). Furthermore, the pharmacogenomic results showed a good affinity of the copper(II) complexes for the human cytochrome. These results recommend complexes bearing 1,10-phenanthroline as good candidates for developing drugs to melanoma alternative treatment.

PMID:36015318 | DOI:10.3390/pharmaceutics14081692

Pharmaceutics. 2022 Aug 4;14(8):1627. doi: 10.3390/pharmaceutics14081627.

ABSTRACT

The objective of this prospective study was to examine the exposure to the main active metabolites of ciprofloxacin in critically ill patients and to examine the factors (demographic, laboratory and genetic) that could potentially affect the drug metabolic conversion of ciprofloxacin. The secondary aim was to develop a population pharmacokinetic model for the metabolite showing the most associations with the abovementioned factors. A total of 29 patients were treated with intravenous infusion of ciprofloxacin and enrolled on this trial. Blood samples for pharmacokinetic analysis were taken at 1, 4, and 11.5 h following the completion of the infusion. Sex, age, body weight, height, serum creatinine and bilirubin levels, and creatinine clearance (CLCR) were recorded, and polymorphisms rs2032582 and rs1045642 in the ABCB1 gene, rs4148977 in the SLCO1A2 gene and rs762551 in the CYP1A2 gene were analyzed. A three-stage parent drug-metabolite population pharmacokinetic model was developed. Median (IQR) metabolite/parent ratios of the desethylene ciprofloxacin, formyl ciprofloxacin and oxociprofloxacin were 5.86 (4.09-9.87)%, 4.08 (3.38-6.92)% and 5.91 (3.42-13.65)%, respectively. The desethylene ciprofloxacin metabolic ratio was positively associated with height (r2 = 0.2277, p = 0.0089) and CLCR (r2 = 0.2023, p = 0.0144) and negatively associated with age (r2 = 0.2227, p = 0.0112). Males had a significantly higher oxociprofloxacin metabolic ratio than females (9.14 vs 3.42%, p = 0.0043). In the desethylene ciprofloxacin population PK model, the volume of distribution decreased with age, the parent drug-metabolite transfer rate constant increased with CLCR, and the metabolite elimination rate constant decreased with age and is increased in CYP1A2 rs762551 variant allele carriers. We therefore hypothesized that the CYP1A2 inhibition by ciprofloxacin is mediated by its metabolite desethylene ciprofloxacin.

PMID:36015253 | DOI:10.3390/pharmaceutics14081627

Pharmaceuticals (Basel). 2022 Aug 11;15(8):990. doi: 10.3390/ph15080990.

ABSTRACT

Pediatric cancer treatment has evolved significantly in recent decades. The implementation of risk stratification strategies and the selection of evidence-based chemotherapy combinations have improved survival outcomes. However, there is large interindividual variability in terms of chemotherapy-related toxicities and, sometimes, the response among this population. This variability is partly attributed to the functional variability of drug-metabolizing enzymes (DME) and drug transporters (DTS) involved in the process of absorption, distribution, metabolism and excretion (ADME). The DTS, being ubiquitous, affects drug disposition across membranes and has relevance in determining chemotherapy response in pediatric cancer patients. Among the factors affecting DTS function, ontogeny or maturation is important in the pediatric population. In this narrative review, we describe the role of drug uptake/efflux transporters in defining pediatric chemotherapy-treatment-related toxicities and responses. Developmental differences in DTS and the consequent implications are also briefly discussed for the most commonly used chemotherapeutic drugs in the pediatric population.

PMID:36015138 | DOI:10.3390/ph15080990

Nutrients. 2022 Aug 10;14(16):3275. doi: 10.3390/nu14163275.

ABSTRACT

BACKGROUND: Vitamin D deficiency has been associated with the severity of COVID-19. The role of vitamin D in pregnant women with COVID-19 has been poorly investigated to date. The aim of this study was to evaluate the influence of vitamin D in affecting some clinical features in pregnancy between SARS-CoV-2 positive and negative patients.

METHODS: Vitamin D pathway related polymorphisms and 25-hydroxyvitamin D levels were quantified in pregnant women followed from the first to the third trimester of pregnancy. Vitamin D deficiency was considered with values ≤ 30 ng/mL.

RESULTS: In total, 160 women were enrolled: 23 resulted positive for at least one SARS-CoV-2 related test (molecular swab or antibody tests). Vitamin D-associated polymorphisms were able to affect vitamin D levels in SARS-CoV-2 negative and positive subjects: remarkably, all the VDR TaqICC genotype patients were negative for SARS-CoV-2. In a sub-population (118 patients), vitamin D levels correlated with pregnancy-related factors, such as alpha-fetoprotein levels. Third-trimester vitamin D levels were lower in preterm births compared to full-term pregnancy: this trend was highlighted for SARS-CoV-2 positive patients.

CONCLUSIONS: This is the first study demonstrating a role of vitamin D in affecting the clinical characteristics of pregnant women during the COVID-19 era. Further studies in larger and different cohorts of patients are required to confirm these findings.

PMID:36014781 | DOI:10.3390/nu14163275

J Pers Med. 2022 Aug 22;12(8):1353. doi: 10.3390/jpm12081353.

ABSTRACT

The CYP2D6 gene encodes an enzyme responsible for the metabolism of ~20% of clinically prescribed drugs. In this study, 18 SNPs from the enhancer and promoter regions of CYP2D6 in 323 Roma from Croatia were genotyped, to find out whether the demographic history of Roma affected the distribution of the studied SNPs and their linkage disequilibrium (LD) values, with the major SNPs defining the CYP2D6 star alleles. No differences were found between the three Roma groups in allele and genotype frequencies. The distribution of LD values of Roma was compared with LD values of European and Asian populations. Regulatory CYP2D6 SNPs (rs5758550, rs28624811, rs1080985 and rs1080983) showed similar distribution and the highest LDs with rs16947 from the gene-coding region in all populations. In the promoter region, a complete LD between rs1080989 and rs28588594, and between rs1080983 and rs28624811, was found in Croatian Roma and investigated populations from 1000 genomes. A high LD was also found between rs1080985 from the promoter and rs5758550 from the enhancer region. SNP rs28735595 from the gene promoter region had the highest LD, with two gene region SNPs, rs1058164 and rs1135840. To conclude, the Croatian Roma population shows an LD pattern of the CYP2D6 gene region similar to the 1000 Genomes European and Asian populations.

PMID:36013302 | DOI:10.3390/jpm12081353

J Pers Med. 2022 Aug 21;12(8):1348. doi: 10.3390/jpm12081348.

ABSTRACT

(1) Background: Uptake of pharmacogenomic testing in routine clinical practices is currently slow in China. Pharmacists might play an important role in leveraging care through applying pharmacogenomics, therefore, it is important to better understand clinical pharmacists' knowledge of and attitudes toward pharmacogenomic testing, which has not been well-studied. (2) Methods: A self-administered survey was developed based on previous knowledge of pharmacogenomic testing and its uptake in China. Participants were recruited through the Committee of Pharmaceutical Affairs Management under the Chinese Hospital Association. (3) Results: A total of 1005 clinical pharmacists completed the questionnaire, among whom 996 (99.10%) had heard of pharmacogenomic testing before participation. More than half of respondents (60.0%, n = 597) rated their knowledge of pharmacogenomic testing as "average", while 25% rated it "good" or "excellent". "Guidelines, consensus and treatment paths for disease diagnosis and treatment" (78.7%) were the most preferred sources of information about pharmacogenomic testing. Most respondents (77.0%) believed that pharmacogenomics could "help to improve efficacy and reduce the incidence of adverse reactions". Our participants also believed that patients would benefit most from pharmacogenomic testing through better prediction of individual drug responses and thus informed treatment decisions. The top challenge for the uptake of pharmacogenomic testing was its high cost or lack of insurance coverage (76.7%). (4) Conclusions: Most Chinese clinical pharmacists who participated in our study had a positive attitude toward pharmacogenomic testing, while the knowledge of pharmacogenomic testing was generally self-assessed as average.

PMID:36013297 | DOI:10.3390/jpm12081348

J Pers Med. 2022 Aug 13;12(8):1313. doi: 10.3390/jpm12081313.

ABSTRACT

Using a patient's genetic information to inform medication prescriptions can be clinically effective; however, the practice has not been widely implemented. Health systems need guidance on how to engage with providers to improve pharmacogenetic test utilization. Approaches from the field of implementation science may shed light on the complex factors affecting pharmacogenetic test use in real-world settings and areas to target to improve utilization. This paper presents an approach to studying the application of precision medicine that utilizes mixed qualitative and quantitative methods and implementation science frameworks to understand which factors or combinations consistently account for high versus low utilization of pharmocogenetic testing. This approach involves two phases: (1) collection of qualitative and quantitative data from providers-the cases-at four clinical institutions about their experiences with, and utilization of, pharmacogenetic testing to identify salient factors; and (2) analysis using a Configurational Comparative Method (CCM), using a mathematical algorithm to identify the minimally necessary and sufficient factors that distinguish providers who have higher utilization from those with low utilization. Advantages of this approach are that it can be used for small to moderate sample sizes, and it accounts for conditions found in real-world settings by demonstrating how they coincide to affect utilization.

PMID:36013262 | DOI:10.3390/jpm12081313

J Pers Med. 2022 Aug 8;12(8):1297. doi: 10.3390/jpm12081297.

ABSTRACT

Hereditary factors contribute to disease development and drug pharmacokinetics. The risk of hereditary disease development can be attenuated or eliminated by early screening or risk reducing interventions. The purpose of this study was to assess the clinical utility of germline medical exome sequencing in patients recruited from a family medicine clinic and compare the mutation frequency of hereditary predisposition genes to established general population frequencies. At the University of Kentucky, 205 family medicine patients underwent sequencing in a Clinical Laboratory Improvement Amendments of 1988-compliant laboratory to identify clinically actionable genomic findings. The study identified pathogenic or likely pathogenic genetic variants-classified according to the American College of Medical Genetics and Genomics variant classification guidelines-and actionable pharmacogenomic variants, as defined by the Clinical Pharmacogenetics Implementation Consortium. Test results for patients with pharmacogenomic variants and pathogenic or likely pathogenic variants were returned to the participant and enrolling physician. Hereditary disease predisposition gene mutations in APOB, BRCA2, MUTYH, CACNA1S, DSC2, KCNQ1, LDLR, SCN5A, or SDHB were identified in 6.3% (13/205) of the patients. Nine of 13 (69.2%) underwent subsequent clinical interventions. Pharmacogenomic variants were identified in 76.1% (156/205) of patients and included 4.9% (10/205) who were prescribed a medication that had pharmacogenomic implications. Family physicians changed medications for 1.5% (3/205) of patients to prevent toxicity. In this pilot study, we found that with systemic support, germline genetic screening initiatives were feasible and clinically beneficial in a primary care setting.

PMID:36013246 | DOI:10.3390/jpm12081297

J Pers Med. 2022 Jul 31;12(8):1267. doi: 10.3390/jpm12081267.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) testing is increasingly used in clinical practice to optimize drug therapies. This study aims to understand the involvement of clinical pharmacists in PGx testing at tertiary hospitals in China and their self-assessed capacity to deliver such services.

METHODS: We developed a questionnaire exploring clinical pharmacists' involvement and self-assessed level of capacity of performing PGx tests. A random sample was obtained from the Pharmaceutical Affairs Management Professional Committee of the Chinese Hospital Association.

RESULTS: A total of 1005 clinical pharmacists completed the survey. Of these, 996 (99.1%) had heard of PGx tests and 588 (59.0%) had been involved in PGx testing and related services. Some clinical pharmacists (28.9%) provided PGx services at the rate of "1-5 cases/year" while 21.9% of clinical pharmacists provided PGx services at the rate of "&gt;30 cases/year". Clinical pharmacists most frequently provided PGx testing for cardiovascular diseases. "Consult relevant guidelines/literature" (90.1%) was the most frequently used method to familiarize oneself with PGx testing. About 60% of the pharmacists considered themselves to have poor or fair capacity to provide PGx testing and related services.

CONCLUSIONS: More than half of the pharmacists had been involved in PGx testing and related services. However, pharmacists generally had little confidence in their knowledge level of and capacity to provide PGx-related services.

PMID:36013216 | DOI:10.3390/jpm12081267

J Pers Med. 2022 Jul 31;12(8):1265. doi: 10.3390/jpm12081265.

ABSTRACT

Precision medicine refers to a highly individualized and personalized approach to patient care. Pharmacogenomics is the study of how an individual's genomic profile affects their drug response, enabling stable and effective drug selection, minimizing side effects, and maximizing therapeutic efficacy. Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation in the joints. It mainly starts in peripheral joints, such as the hands and feet, and progresses to large joints, which causes joint deformation and bone damage due to inflammation of the synovial membrane. Here, we review various pharmacogenetic studies investigating the association between clinical response to monoclonal antibody therapy and their target genetic polymorphisms. Numerous papers have reported that some single nucleotide polymorphisms (SNPs) are related to the therapeutic response of several monoclonal antibody drugs including adalimumab, infliximab, rituximab, and tocilizumab, which target tumor necrosis factor (TNF), CD20 of B-cells, and interleukin (IL)-6. Additionally, there are some pharmacogenomic studies reporting on the association between the clinical response of monoclonal antibodies having various mechanisms, such as IL-1, IL-17, IL-23, granulocyte-macrophage colony-stimulating factor (GM-CSF) and the receptor activator of nuclear factor-kappa B (RANK) inhibition. Biological therapies are currently prescribed on a "trial and error" basis for RA patients. If appropriate drug treatment is not started early, joints may deform, and long-term treatment outcomes may worsen. Pharmacogenomic approaches that predict therapeutic responses for RA patients have the potential to significantly improve patient quality of life and reduce treatment costs.

PMID:36013214 | DOI:10.3390/jpm12081265

Int J Mol Sci. 2022 Aug 15;23(16):9124. doi: 10.3390/ijms23169124.

ABSTRACT

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.

PMID:36012390 | DOI:10.3390/ijms23169124

Int J Environ Res Public Health. 2022 Aug 17;19(16):10173. doi: 10.3390/ijerph191610173.

ABSTRACT

TTN encodes the third myofilament, titin, which plays structural, mechanical, regulatory, and developmental roles in sarcomeres. The aim of this research was to determine the interaction between novel and previously described TTN variants and athletic performance, as well as competition level, in Caucasians. Firstly, 100 athletes and 47 controls were recruited, and whole-genome sequencing was performed. Secondly, 348 athletes (108 endurance, 100 sprint/power, 140 mixed-sport athletes) and 403 volunteers were included, and real-time PCR was performed. We found a significant overrepresentation of the rs10497520 CT and TT genotypes in the sprint/power athlete group (95% CI, 1.41-3.66, p = 0.0013). The rs10497520 T carriers were 2.17 times more likely to become sprint/power athletes (95% CI 1.35-3.49, p = 0.0021). We also found that the likelihood of having the TT genotype was higher for the highly elite and sub-elite sprint/power athletes. Possessing at least one TAA (rs10497520, rs55837610, rs72648256) haplotype resulted in an increase in the log-odds ratio by 0.80 (p = 0.0015), 1.42 (p = 0.003), and 0.77 (p = 0.044) for all, highly elite, and sub-elite sprint/power athletes, respectively. We demonstrated that harbouring the rs10497520 T allele, individually and in a haplotype combination, increased the chance of being an elite sprint/power athlete, indicating that this allele may be favourable for sprint/power performance.

PMID:36011809 | DOI:10.3390/ijerph191610173

Int J Environ Res Public Health. 2022 Aug 15;19(16):10073. doi: 10.3390/ijerph191610073.

ABSTRACT

BACKGROUND: Pharmacogenomics (PGx) and personalized medicine embrace the potential to optimize drug treatment and improve the patient's quality of life. Pharmacists' roles include contributing to genetic testing, patient counseling, and pharmacotherapies selection for superior treatment outcomes. The aim of this study is to assess the pharmacists' knowledge, insight, and self-confidence toward PGx testing, identify their future preferred education patterns, and determine the barriers to pharmacogenomic testing implementation.

METHOD: A cross-sectional study was conducted using a previously validated questionnaire among pharmacists working in the Kingdom of Saudi Arabia (KSA). The questionnaire was designed in seven major categories, consisting of 26 questions.

RESULTS: A total of 671 pharmacists participated in this survey. As for knowledge, only 29.8% of pharmacists had good knowledge regarding PGx, while 42.9% had poor knowledge levels. Respectable PGx knowledge was significantly higher among outpatient dispensing pharmacists (33.6%; p = 0.049) and among pharmacists who had completed PGx testing-related training or education (40.3%; p = 0.001). Considering perception, it was positive among 50% of pharmacists and negative among 19.8%. With regard to self-confidence, it was high among 39.2% of male pharmacists (p = 0.042), among 43% of clinical pharmacists (p = 0.006), and among 44.8% of pharmacists who had extra credentials (p = 0.001). The utmost favored continuing-education learning approaches were workshops or seminars. The barriers to the implementation of PGx testing included a lack of testing devices, clinical guidelines, training or education, and personnel.

CONCLUSION: The present study revealed that pharmacists in KSA had inadequate knowledge and understanding of PGx. Nevertheless, the majority established that PGx is a valuable tool for augmenting drug efficacy and safety.

PMID:36011723 | DOI:10.3390/ijerph191610073