Eur Neuropsychopharmacol. 2021 Nov 26;55:86-95. doi: 10.1016/j.euroneuro.2021.11.005. Online ahead of print.

ABSTRACT

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p = 0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11-1.98, p = 0.007). Nominal associations were also found between MDD-PRS and non-response (p = 0.013), as well as between SCZ-PRS and non-remission (p = 0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.

PMID:34844152 | DOI:10.1016/j.euroneuro.2021.11.005

Epilepsy Res. 2021 Nov 19;178:106814. doi: 10.1016/j.eplepsyres.2021.106814. Online ahead of print.

ABSTRACT

Despite the best possible medication and treatment protocols, one-third of epilepsy patients have drug resistance which is associated with an elevated risk of mortality and debilitating psychological consequences. P-glycogen encoded by ABCB1 is major drug transporter for a wide variety of AED. To evaluate the complex haplotypic association, genetic and allelic frequency distribution of rs1128503, rs1045642, and rs2032582 polymorphisms of ABCB1 gene with drug resistance in Pakistani pediatric epilepsy patients, we performed this study. A total of 337 individuals including 100 healthy control, 110 drug-resistant patients, and 127 drug-responsive patients were enrolled and genotyped for three polymorphisms. PCR and direct sequencing of DNA were done for genotyping. All the studied SNPs showed a statistically significant association with drug-resistant epilepsy at p < 0.01. In addition, we identified a novel variant at c 0.2678C > A (SCV001712095) position. The haplotype analysis indicated strong linkage disequilibrium between three SNPs. The in-silico analysis indicated that rs2032582 polymorphism at c 0.2677T > A is benign while c 0.2677T > G and c 0.2678C > A are possibly damaging. Our findings showed that pharmacogenetic variants play a key role in disease. Our findings shed light on the pharmacogenomic association of ABCB1 with epilepsy which might facilitate study on pharmacokinetics concerning ethnology.

PMID:34844091 | DOI:10.1016/j.eplepsyres.2021.106814

J Psychiatr Res. 2021 Nov 23;145:27-34. doi: 10.1016/j.jpsychires.2021.11.036. Online ahead of print.

ABSTRACT

Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning.

PMID:34844049 | DOI:10.1016/j.jpsychires.2021.11.036

Microb Pathog. 2021 Nov 26:105311. doi: 10.1016/j.micpath.2021.105311. Online ahead of print.

ABSTRACT

Hepatitis C virus (HCV) is the leading cause of liver diseases worldwide. At present, drug combinations of different classes of direct-acting antiviral agents (DAAs) are used as treatment options for HCV, in which sofosbuvir (SOF) is the common DAA among different therapeutic regimes. In Egypt, SOF plus daclatasvir (DCV) is the widely used anti-HCV treatment protocol. Herein, we aimed to assess the association between 3 single-nucleotide polymorphisms (SNPs) at the genes coding for 2 SOF metabolizing enzymes: histidine triad nucleotide-binding protein 1 (HINT1) rs4696/rs7728773 and nucleoside diphosphate kinase 1 (NME1) rs3760468, together with the most potent anti-HCV innate molecule, i.e., Interferon lambda 3 (IFNL3) rs12979860 and the response to SOF/DCV in Egyptian patients chronically infected with genotype 4 (GT4). SNPs were genotyped using real-time PCR in DNA from patients who achieved sustained virological response (SVR) at 12 weeks post-SOF/DCV treatment (i.e., responders; n = 188) and compared with patients who failed to achieve SVR12 (i.e., non-responders; n = 109) or healthy controls (n = 62). Our results demonstrated that patients bearing HINT1 rs7728773 CT/TT (odds ratio 2.119, 95% CI 1.263-3.559, p = 0.005) and IFNL3 rs12979860 CC (odds ratio 3.995, 95% CI 2.126-7.740, p = 0.0001) were more likely to achieve SVR12. However, neither HINT1 rs4696 nor NME1 rs3760468 seems to contribute to the responsiveness to SOF/DCV. Binary regression analysis defined 5 predictor factors independently associated with SVR12: age, bilirubin, HB, early stages of fibrosis, and combined HINT1 rs7728773 and IFNL3 rs12979860 favorable and mixed genotypes (odds ratio 3.134, 95% CI 1.518-6.47, p = 0.002), and that was confirmed by the combined ROC curve for the 5 predictor factors (AUC = 0.91, 95% CI 0.869-0.95, P = 0.0001). In conclusion, these data suggest that the two SNPs have the potential in predicting the response rate to SOF/DCV treatment in patients infected with HCV GT4. This study is the first to investigate the pharmacogenetics of SOF metabolizing enzyme and introduce HINT1 rs7728773 as a novel SNP that predict the treatment efficacy.

PMID:34843922 | DOI:10.1016/j.micpath.2021.105311

Lancet Child Adolesc Health. 2021 Nov 26:S2352-4642(21)00305-9. doi: 10.1016/S2352-4642(21)00305-9. Online ahead of print.

ABSTRACT

BACKGROUND: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms.

METHODS: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996).

FINDINGS: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group).

INTERPRETATION: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants.

FUNDING: EU Seventh Framework Programme for research, technological development and demonstration.

PMID:34843669 | DOI:10.1016/S2352-4642(21)00305-9

Pharmacogenomics. 2021 Nov 29. doi: 10.2217/pgs-2021-0140. Online ahead of print.

NO ABSTRACT

PMID:34842441 | DOI:10.2217/pgs-2021-0140

CPT Pharmacometrics Syst Pharmacol. 2021 Nov 29. doi: 10.1002/psp4.12735. Online ahead of print.

ABSTRACT

Intravenous (i.v.) morphine is a safe, robust, and recommended treatment for severe pain using the titration principle. Despite its high efficacy, it is impacted by organizational constraints related to venous access. Nebulized (NEB) morphine may represent an alternative for titration but pharmacokinetic (PK) properties of short nebulization using routine devices need evaluation. Twenty-seven healthy volunteers were included to receive NEB or i.v. morphine administration using increasing amounts according to Dixon's reference method. Plasma morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were quantified. PK modeling and simulations were performed using Monolix. Dixon's method exhibited a significantly higher morphine dose regimen in the NEB group versus the i.v. group (6.2 [5.3-7.1] vs. 3.0 [2.0-4.0] mg, p < 0.001). Morphine, M3G, and M6G dose-normalized exposure were significantly lower in the NEB group versus the i.v. group: morphine (19 [13-23] vs. 1044 [702-1266] µg min/L, p < 0.001), M3G (245 [162-287] vs. 3752 [2487-5165] µg min/L, p < 0.001) and M6G (28 [21-43] vs. 466 [370-723] µg min/L, p < 0.001). The model that best fitted the data consisted in a transit compartment for morphine absorption, three compartments for morphine distribution followed by multiple transit compartments (8.2 and 57.5-min transit time for M3G and M6G, respectively) and a first order elimination for M3G and M6G. Morphine bioavailability in the NEB group was 3.5% using the i.v. group as reference. Administration route and sex significantly influenced morphine and metabolite PKs. This work aimed to evaluate the PKs of NEB morphine compared with the i.v. route. Despite a bioavailability to improve, NEB morphine administration using a routine device is suitable to plan morphine titration.

PMID:34842366 | DOI:10.1002/psp4.12735

Clin Transl Med. 2021 Nov;11(11):e586. doi: 10.1002/ctm2.586.

NO ABSTRACT

PMID:34841710 | DOI:10.1002/ctm2.586

BMC Rheumatol. 2021 Nov 29;5(1):52. doi: 10.1186/s41927-021-00222-2.

ABSTRACT

BACKGROUND: Precision medicine, as a personalized medicine approach based on biomarkers, is a booming field. In general, physicians and patients have a positive attitude toward precision medicine, but their knowledge and experience are limited. In this study, we aimed at assessing the expectations and educational needs for precision medicine among rheumatologists, rheumatology fellows and patients with rheumatic diseases in Canada.

METHODS: We conducted two anonymous online surveys between June and August 2018, one with rheumatologists and fellows and one with patients assessing precision medicine expectations and educational needs. Descriptive statistics were performed.

RESULTS: 45 rheumatologists, 6 fellows and 277 patients answered the survey. 78% of rheumatologists and fellows and 97.1% of patients would like to receive training on precision medicine. Most rheumatologists and fellows agreed that precision medicine tests are relevant to medical practice (73.5%) with benefits such as helping to determine prognosis (58.9%), diagnosis (79.4%) and avoid treatment toxicity (61.8%). They are less convinced of their usefulness in helping to choose the most effective treatment and to improve patient adherence (23.5%). Most patients were eager to take precision medicine tests that could predict disease prognosis (92.4%), treatment response (98.1%) or drug toxicity (93.4%), but they feared potential negative impacts like loss of insurability (62.2%) and high cost of the test (57.5%).

CONCLUSIONS: Our study showed that rheumatologists and patients in Canada are overall interested in getting additional precision medicine education. Indeed, while convinced of the potential benefits of precision medicine tests, most physicians don't feel confident in their abilities and consider their training insufficient to incorporate them into clinical practice.

PMID:34839831 | DOI:10.1186/s41927-021-00222-2

Addict Sci Clin Pract. 2021 Nov 27;16(1):70. doi: 10.1186/s13722-021-00278-y.

ABSTRACT

BACKGROUND: Patients with opioid use disorder (OUD) display an interindividual variability in their response to medications for opioid use disorder (MOUD). A genetic basis may explain the variability in this response. However, no consensus has been reached regarding which genetic variants significantly contribute to MOUD outcomes.

OBJECTIVES: This systematic review aims to summarize genome-wide significant findings on MOUD outcomes and critically appraise the quality of the studies involved.

METHODS: Databases searched from inception until August 21st, 2020 include: MEDLINE, Web of Science, EMBASE, CINAHL and Pre-CINAHL, GWAS Catalog and GWAS Central. The included studies had to be GWASs that assessed MOUD in an OUD population. All studies were screened in duplicate. The quality of the included studies was scored and assessed using the Q-Genie tool. Quantitative analysis, as planned in the protocol, was not feasible, so the studies were analyzed qualitatively.

RESULTS: Our search identified 7292 studies. Five studies meeting the eligibility criteria were included. However, only three studies reported results that met our significance threshold of p ≤ 1.0 × 10-7. In total, 43 genetic variants were identified. Variants corresponding to CNIH3 were reported to be associated with daily heroin injection in Europeans, OPRM1, TRIB2, and ZNF146 with methadone dose in African Americans, EYS with methadone dose in Europeans, and SPON1 and intergenic regions in chromosomes 9 and 3 with plasma concentrations of S-methadone, R-methadone, and R-EDDP, respectively, in Han Chinese.

LIMITATIONS: The limitations of this study include not being able to synthesize the data in a quantitative way and a conservative eligibility and data collection model.

CONCLUSION: The results from this systematic review will aid in highlighting significant genetic variants that can be replicated in future OUD pharmacogenetics research to ascertain their role in patient-specific MOUD outcomes. Systematic review registration number CRD42020169121.

PMID:34838141 | DOI:10.1186/s13722-021-00278-y

BMC Bioinformatics. 2021 Nov 27;22(1):571. doi: 10.1186/s12859-021-04481-1.

ABSTRACT

BACKGROUND: In-depth analysis of regulation networks of genes aberrantly expressed in cancer is essential for better understanding tumors and identifying key genes that could be therapeutically targeted.

RESULTS: We developed a quantitative analysis approach to investigate the main biological relationships among different regulatory elements and target genes; we applied it to Ovarian Serous Cystadenocarcinoma and 177 target genes belonging to three main pathways (DNA REPAIR, STEM CELLS and GLUCOSE METABOLISM) relevant for this tumor. Combining data from ENCODE and TCGA datasets, we built a predictive linear model for the regulation of each target gene, assessing the relationships between its expression, promoter methylation, expression of genes in the same or in the other pathways and of putative transcription factors. We proved the reliability and significance of our approach in a similar tumor type (basal-like Breast cancer) and using a different existing algorithm (ARACNe), and we obtained experimental confirmations on potentially interesting results.

CONCLUSIONS: The analysis of the proposed models allowed disclosing the relations between a gene and its related biological processes, the interconnections between the different gene sets, and the evaluation of the relevant regulatory elements at single gene level. This led to the identification of already known regulators and/or gene correlations and to unveil a set of still unknown and potentially interesting biological relationships for their pharmacological and clinical use.

PMID:34837938 | DOI:10.1186/s12859-021-04481-1

Nutrients. 2021 Nov 9;13(11):3988. doi: 10.3390/nu13113988.

ABSTRACT

BACKGROUND: A total colectomy and a frequent life-long endoscopic surveillance are guaranteed to patients with Familial Adenomatous Polyposis (FAP) to reduce their risk of duodenal and rectal stump cancers. However, after surgery, individuals with FAP suffer from an increased number of diarrheal discharges that force them to dietary restrictions. A non-randomized pilot study was conducted to assess whether a three-month low-inflammatory Mediterranean dietary intervention reduces gastro-intestinal markers of inflammation in FAP individuals. The aim of the present work is to evaluate the participant's adherence to the proposed dietary recommendations and the change in their number of diarrheal discharges.

METHODS: 26 FAP individuals aged >18 years, who underwent a total colectomy with ileo-rectal anastomosis and were involved in the surveillance program at the Fondazione IRCCS Istituto Nazionale Tumori of Milan, were included in the present analysis.

RESULTS: FAP individuals significantly reduced the Not recommended foods (p-value: 0.002) and increased the consumption of the Recommended ones (p-value: 0.075). The adherence to the proposed dietary recommendations was accompanied by a significant decrease in the number of diarrheal discharges (p-value: 0.008).

CONCLUSIONS: This study suggests that adhering to a low-inflammatory Mediterranean diet has a potential protective effect on the number of diarrheal discharges in FAP individuals.

PMID:34836243 | DOI:10.3390/nu13113988

Nutrients. 2021 Oct 25;13(11):3783. doi: 10.3390/nu13113783.

ABSTRACT

Vitamin D has been associated with risk, development, and progression of cancer. However, the genes involved in its metabolism are highly polymorphic, compromising its activity. The aim of this study is to evaluate the association between the gene polymorphisms involved in the metabolic pathway of vitamin D and survival in patients with non-small-cell lung cancer (NSCLC). The study was designed as an observational cohort which included 194 Caucasians patients from southern Spain with NSCLC. Real-time polymerase chain reaction was used to analyze the following polymorphisms: CYP27B1 rs4646536, rs3782130, and rs10877012; CYP24A1 rs6068816 and rs4809957; GC rs7041; CYP2R1 rs10741657; VDR rs1544410 (BsmI), rs11568820 (Cdx-2), rs2228570 (FokI), rs7975232 (ApaI), and rs731236 (TaqI). Progression-free survival (PFS) and overall survival were assessed. Cox regression showed that rs4646536 was associated with PFS in the general population (p = 0.0233) and in the non-resected NSCLC subgroup (p = 0.0233). In the resected NSCLC subgroup, rs11568820 was associated with OS (p = 0.0129) and rs7041 with PFS (p = 0.0447). In the non-resected NSCLC subgroup, rs6068816 was associated with PFS (p = 0.0048) and OS (p = 0.0089) and rs731236 and rs7975232 were associated with OS (p = 0.0005) and PFS (p = 0.0002), respectively. The other polymorphisms showed no effect on the results. The rs4646536, rs6068816, rs7041, rs11568820, rs731236, and rs7975232 polymorphisms are associated with survival in NSCLC and may have a substantial role as prognostic markers of the disease.

PMID:34836039 | DOI:10.3390/nu13113783

Plants (Basel). 2021 Nov 19;10(11):2522. doi: 10.3390/plants10112522.

ABSTRACT

Dermatophyte infections represent a significant public health concern, with an alarming negative impact caused by unsuccessful therapeutic regimens. Natural products have been highlighted as a promising alternative, due to their long-standing traditional use and increasing scientific recognition. In this study, honokiol and magnolol, the main bioactives from Magnolia spp. bark, were investigated for their antidermatophytic activity. The antifungal screening was performed using dermatophyte standard strains and clinical isolates. The minimal inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) were determined in accordance with EUCAST-AFST guidelines, with minor modifications. The effects on ergosterol biosynthesis were assessed in Trichophyton rubrum cells by HPLC-DAD. Putative interactions with terbinafine against T. rubrum were evaluated by the checkerboard method. Their impact on cells' viability and pro-inflammatory cytokines (IL-1β, IL-8 and TNF-α) was shown using an ex vivo human neutrophils model. Honokiol and magnolol were highly active against tested dermatophytes, with MIC and MFC values of 8 and 16 mg/L, respectively. The mechanism of action involved the inhibition of ergosterol biosynthesis, with accumulation of squalene in T. rubrum cells. Synergy was assessed for binary mixtures of magnolol with terbinafine (FICI = 0.50), while honokiol-terbinafine combinations displayed only additive effects (FICI = 0.56). In addition, magnolol displayed inhibitory effects towards IL-1β, IL-8 and TNF-α released from lipopolysaccharide (LPS)-stimulated human neutrophils, while honokiol only decreased IL-1β secretion, compared to the untreated control. Overall, honokiol and magnolol acted as fungicidal agents against dermatophytes, with impairment of ergosterol biosynthesis.

PMID:34834886 | DOI:10.3390/plants10112522

Plants (Basel). 2021 Nov 4;10(11):2378. doi: 10.3390/plants10112378.

ABSTRACT

Dermatophyte infections represent an important public health concern, affecting up to 25% of the world's population. Trichophyton rubrum and T. mentagrophytes are the predominant dermatophytes in cutaneous infections, with a prevalence accounting for 70% of dermatophytoses. Although terbinafine represents the preferred treatment, its clinical use is hampered by side effects, drug-drug interactions, and the emergence of resistant clinical isolates. Combination therapy, associating terbinafine and essential oils (EOs), represents a promising strategy in the treatment of dermatophytosis. In this study, we screened the potential of selected Apiaceae EOs (ajowan, coriander, caraway, and anise) to improve the antifungal activity of terbinafine against T. rubrum ATCC 28188 and T. mentagrophytes ATCC 9533. The chemical profile of EOs was analyzed by gas chromatography. The minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) of EOs/main compounds were determined according to EUCAST-AFST guidelines, with minor modifications. The checkerboard microtiter method was used to identify putative synergistic combinations of EOs/main constituents with terbinafine. The influence of EOs on the viability and pro-inflammatory cytokine production (IL-1β, IL-8 and TNF-α) was determined using an ex vivo human neutrophils model. The binary associations of tested EOs with terbinafine were found to be synergistic against T. rubrum, with FICI values of 0.26-0.31. At the tested concentrations (6.25-25 mg/L), EOs did not exert cytotoxic effects towards human neutrophils. Anise EO was the most potent inhibitor of IL-1β release (46.49% inhibition at 25 mg/L), while coriander EO displayed the highest inhibition towards IL-8 and TNF-α production (54.15% and 54.91%, respectively). In conclusion, the synergistic combinations of terbinafine and investigated Apiaceae EOs could be a starting point in the development of novel topical therapies against T. rubrum-related dermatophytosis.

PMID:34834740 | DOI:10.3390/plants10112378

Plants (Basel). 2021 Oct 30;10(11):2347. doi: 10.3390/plants10112347.

ABSTRACT

Fruits of Cornus mas and Cornus officinalis are representative plant materials traditionally used in Europe and Asia, respectively, in the treatment of diabetes and diabetes-related complications, which are often mediated by pathogenic inflammatory agents. Additionally, due to the fact of mutual infiltration of Asian and European medicines, the differentiation as well as standardization of traditional prescriptions seem to be crucial for ensuring the quality of traditional products. The objective of this study was a comparison of biological activity of extracts from fruits of C. mas and C. officinalis by an assessment of their effect on reactive oxygen species (ROS) generation in human neutrophils as well as cytokines secretion both in neutrophils (tumor necrosis factor α, TNF- α; interleukin 8, IL-8; interleukin 1β, IL-1β) and in human colon adenocarcinoma cell line Caco-2 (IL-8). To evaluate the phytochemical differences between the studied extracts as well as to provide a method for standardization procedures, a quantitative analysis of iridoids, such as loganin, sweroside, and loganic acid, found in extracts of Cornus fruits was performed with HPLC-DAD. All standardized extracts significantly inhibited ROS production, whereas the aqueous-alcoholic extracts were particularly active inhibitors of IL-8 secretion by neutrophils. The aqueous-methanolic extract of C. officinalis fruit, decreased IL-8 secretion by neutrophils to 54.64 ± 7.67%, 49.68 ± 6.55%, 50.29 ± 5.87% at concentrations of 5, 50, and 100 µg/mL, respectively, compared to LPS-stimulated control (100%). The aqueous extract of C. officinalis fruit significantly inhibited TNF-α release by neutrophils at concentrations of 50 and 100 µg/mL. On the other hand, the aqueous-ethanolic extract of C. mas fruit showed the propensity to increase TNF-α and IL-1β secretion. The modulatory activity of the Cornus extracts was noted in the case of secretion of IL-8 in Caco-2 cells. The effect was comparable with dexamethasone. The content of loganin in aqueous and aqueous-methanolic extract of C. officinalis fruit was higher than in the aqueous-ethanolic extract of C. mas fruit, which was characterized by a significant quantity of loganic acid. In conclusion, the immunomodulatory effect observed in vitro may partially confirm the traditional use of Cornus fruits through alleviation of the development of diabetes-derived inflammatory complications. Loganin and loganic acid are significant markers for standardization of C. mas and C. officinalis fruit extracts, respectively.

PMID:34834710 | DOI:10.3390/plants10112347

J Pers Med. 2021 Nov 20;11(11):1233. doi: 10.3390/jpm11111233.

ABSTRACT

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10-8) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10-7) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

PMID:34834585 | DOI:10.3390/jpm11111233

J Pers Med. 2021 Nov 19;11(11):1230. doi: 10.3390/jpm11111230.

ABSTRACT

The increasing availability of next generation sequencing (NGS) for personal genomics could promote pharmacogenomics (PGx) discovery and application. However, current tools for analysis and interpretation of pharmacogenomic variants from NGS data are inadequate, as none offer comprehensive analytic functions in a simple, web-based platform. In addition, no tools exist to analyze human leukocyte antigen (HLA) genes for determining potential risks of immune-mediated adverse drug reaction (IM-ADR). We describe PharmVIP, a web-based PGx tool, for one-stop comprehensive analysis and interpretation of genome-wide variants obtained from NGS platforms. PharmVIP comprises three main interpretation modules covering analyses of pharmacogenes involved in pharmacokinetics, pharmacodynamics and IM-ADR. The Guideline module provides Clinical Pharmacogenetics Implementation Consortium (CPIC) drug guideline recommendations based on the translation of genotypic data in genes having guidelines. The HLA module reports HLA genotypes, potential adverse drug reactions, and the relevant drug guidelines. The Pharmacogenes module is employed for prioritizing variants according to variant effect on gene function. Detailed, customizable reports are provided as exportable files and as an interactive web version. PharmVIP is a new integrated NGS workflow for the PGx community to facilitate discovery and clinical application.

PMID:34834582 | DOI:10.3390/jpm11111230

J Pers Med. 2021 Nov 18;11(11):1227. doi: 10.3390/jpm11111227.

ABSTRACT

A formal assessment of pharmacogenomics clinical decision support (PGx-CDS) by providers is lacking in the literature. The objective of this study was to evaluate the usability of PGx-CDS tools that have been implemented in a healthcare setting. We enrolled ten prescribing healthcare providers and had them complete a 60-min usability session, which included interacting with two PGx-CDS scenarios using the "Think Aloud" technique, as well as completing the Computer System Usability Questionnaire (CSUQ). Providers reported positive comments, negative comments, and suggestions for the two PGx-CDS during the usability testing. Most provider comments were in favor of the current PGx-CDS design, with the exception of how the genotype and phenotype information is displayed. The mean CSUQ score for the PGx-CDS overall satisfaction was 6.3 ± 0.95, with seven strongly agreeing and one strongly disagreeing for overall satisfaction. The implemented PGx-CDS at our institution was well received by prescribing healthcare providers. The feedback collected from the session will guide future PGx-CDS designs for our healthcare system and provide a framework for other institutions implementing PGx-CDS.

PMID:34834578 | DOI:10.3390/jpm11111227

J Pers Med. 2021 Nov 18;11(11):1226. doi: 10.3390/jpm11111226.

ABSTRACT

The Clinical Pharmacogenetics Implementation Consortium (CPIC®) establishes evidence-based guidelines for utilizing pharmacogenetic information for certain priority drugs. Warfarin, clopidogrel and simvastatin are cardiovascular drugs that carry strong prescribing guidance by CPIC. The respective pharmacogenes for each of these drugs exhibit considerable variability amongst different ethnic/ancestral/racial populations. Race and ethnicity are commonly employed as surrogate biomarkers in clinical practice and can be found in many prescribing guidelines. This is controversial due to the large variability that exists amongst different racial/ethnic groups, lack of detailed ethnic information and the broad geographic categorization of racial groups. Using a retrospective analysis of electronic health records (EHR), we sought to determine the degree to which self-reported race/ethnicity contributed to the probability of adverse drug reactions for these drugs. All models used individuals self-reporting as White as the comparison group. The majority of apparent associations between different racial groups and drug toxicity observed in the "race only" model failed to remain significant when we corrected for covariates. We did observe self-identified Asian race as a significant predictor (p = 0.016) for warfarin hemorrhagic events in all models. In addition, patients identifying as either Black/African-American (p = 0.001) or Other/Multiple race (p = 0.019) had a lower probability of reporting an adverse reaction than White individuals while on simvastatin even after correcting for other covariates. In both instances where race/ethnicity was predictive of drug toxicity (i.e., warfarin, simvastatin), the findings are consistent with the known global variability in the pharmacogenes described in the CPIC guidelines for these medications. These results confirm that the reliability of using self-identified race/ethnic information extracted from EHRs as a predictor of adverse drug reactions is likely limited to situations where the genes influencing drug toxicity display large, distinct ethnogeographic variability.

PMID:34834577 | DOI:10.3390/jpm11111226