Tuberculosis (Edinb). 2021 Oct 8;131:102138. doi: 10.1016/j.tube.2021.102138. Online ahead of print.

ABSTRACT

The clinical utility of blood transcriptomic biosignatures for the treatment monitoring and outcome prediction of tuberculosis (TB) remains limited. In this study, we aimed to discover and validate biomarkers for pulmonary TB treatment monitoring and outcome prediction based on kinetic responses of gene expression during treatment. In particular, differentially expressed genes (DEGs) were identified by time-series comparison. Subsequently, DEGs with the monotonic expression alterations during the treatment were selected. Ten consistently down-regulated genes (CD274, KIF1B, IL15, TLR1, TLR5, FCGR1A, GBP1, NOD2, GBP2, EGF) exhibited significant potential in treatment monitoring, demonstrated via biological and technical validation. Additionally, the biosignature showed potential in predicting the cured versus relapsed patients. Furthermore, the biosignature could be utilized for TB diagnosis, latent tuberculosis infection/active TB differential diagnosis, and risk of progression to active TB. Benchmarking analysis of the 10-gene biosignature with other biosignatures showed equivalent performance in tested data sets. In conclusion, we established a 10-gene transcriptomic biosignature that represents the kinetic responses of TB treatment. Subsequent studies are warranted to validate, refine and translate the biosignature into a precise assay to assist clinical decisions in a broad spectrum of TB management.

PMID:34801869 | DOI:10.1016/j.tube.2021.102138

Environ Pollut. 2021 Nov 18:118542. doi: 10.1016/j.envpol.2021.118542. Online ahead of print.

ABSTRACT

Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10-1, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.

PMID:34801623 | DOI:10.1016/j.envpol.2021.118542

J Biol Chem. 2021 Nov 18:101413. doi: 10.1016/j.jbc.2021.101413. Online ahead of print.

ABSTRACT

Naturally occurring missense variants of G protein-coupled receptors (GPCRs) with loss-of-function have been linked to metabolic disease in case studies and in animal experiments. The glucagon receptor, one such GPCR, is involved in maintaining blood glucose and amino acid homeostasis; however, loss-of-function mutations of this receptor have not been systematically characterized. Here, we observed fewer glucagon receptor missense variants than expected, as well as lower allele diversity and fewer variants with trait associations as compared to other class B1 receptors. We performed molecular pharmacological phenotyping of 38 missense variants located in the receptor extracellular domain, at the glucagon interface, or with previously suggested clinical implications. These variants were characterized in terms of cAMP accumulation to assess glucagon-induced Gɑs coupling, and of recruitment of β-arrestin-1/2. Fifteen variants were impaired in at least one of these downstream functions, with six variants affected in both cAMP accumulation and β-arrestin 1/2 recruitment. For the eight variants with decreased Gɑs signaling (D63ECDN, P86ECDS, V96ECDE, G125ECDC, R2253.30H, R3085.40W, V3686.59M, and R3787.35C) binding experiments revealed preserved glucagon affinity, although with significantly reduced binding capacity. Finally, using the UK Biobank, we found that variants with wildtype-like Gɑs signaling did not associate with metabolic phenotypes, whereas carriers of cAMP accumulation-impairing variants displayed a tendency towards increased risk of obesity and increased body mass and blood pressure. These observations are in line with the essential role of the glucagon system in metabolism and support that Gɑs is the main signaling pathway effecting the physiological roles of the glucagon receptor.

PMID:34801547 | DOI:10.1016/j.jbc.2021.101413

J Am Pharm Assoc (2003). 2021 Nov 3:S1544-3191(21)00462-3. doi: 10.1016/j.japh.2021.10.033. Online ahead of print.

ABSTRACT

BACKGROUND: Variability in individual drug response may delay time to relief of symptoms for various disease states. As pharmacogenomic (PGx) testing becomes more widespread, providers are tasked with determining when and in who PGx testing is most appropriate. The use of PGx testing in patients with depressive symptoms has shown some utility, but how this translates to a general population within a primary care setting has yet to be determined.

OBJECTIVE: The objective of this pilot study was to determine the effect of PGx testing on treatment decisions in patients with depressive symptoms in an interprofessional primary care setting.

METHODS: This was a retrospective observational study in which patients who underwent PGx testing for psychotropic medications between April 2019 and March 2021 at a private interprofessional primary care clinic were identified. Charts were reviewed to determine whether a resultant change was made to the prescribed psychotropic medication regimen based on PGx testing results. The number of antidepressants trialed before and after testing was also reviewed. Data were analyzed using descriptive statistics and t test where appropriate.

RESULTS: A total of 78 patients were included in the study. A total of 42 patients (53.8%) experienced a change to their antidepressant regimen after PGx testing. The most frequent change identified was the addition of another antidepressant (50%). This was followed by switching the antidepressant and then by an increase in dose of the prescribed antidepressant. No difference between the number of antidepressants trialed before and after testing was identified.

CONCLUSION: PGx testing in an interprofessional primary care setting leads to a medication change in most patients in this study. Based on the changes identified, testing may be most useful in those beginning treatment with an antidepressant or in those who experience an inadequate response to their prescribed regimen.

PMID:34801407 | DOI:10.1016/j.japh.2021.10.033

Mol Psychiatry. 2021 Nov 19. doi: 10.1038/s41380-021-01383-9. Online ahead of print.

ABSTRACT

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.

PMID:34799694 | DOI:10.1038/s41380-021-01383-9

Curr Pharm Teach Learn. 2021 Nov;13(11):1438-1444. doi: 10.1016/j.cptl.2021.09.047. Epub 2021 Sep 25.

ABSTRACT

INTRODUCTION: With community pharmacy transitioning from a fee-for-service model to a value-based care focus, the desired skills of pharmacist graduates is an evolving paradigm. As active stakeholders in community practice, pharmacist preceptors are in a unique position to compare the ever-changing dichotomy between pharmacy practice and training. Examining preceptors' assessments of these essential contemporary practice skills may provide useful insights.

METHODS: A survey was emailed to all regional, active college of pharmacy community advanced pharmacy practice experiences preceptors. Participating preceptors were given 30 days to complete the online survey. Weekly reminders were provided.

RESULTS: Of the 168 preceptors invited to participate, 42 (25%) completed the survey. Descriptive analysis compared preceptors' perceptions of transformative services vs. their relative implementation in practice. This revealed service areas such as health screenings that were proportionate in their prevalence of offering and perception as contemporary. In contrast, services such as pharmacogenomic testing were more widely perceived as contemporary compared to their low prevalence as an offering. Participants showed broad consensus in the importance of most skills listed in the survey, predominantly indicating these skills were either "very important" or "extremely important." Only a few specific skills areas were identified that showed less consensus, with a minority of respondents specifying that these skills were of less importance.

CONCLUSIONS: Preceptor surveys may offer insights on the progression of community practice curricula. Continued monitoring of changes in service parameters over time may reveal trends in practice transformation, identifying service areas being more widely adopted.

PMID:34799056 | DOI:10.1016/j.cptl.2021.09.047

Rheum Dis Clin North Am. 2022 Feb;48(1):305-330. doi: 10.1016/j.rdc.2021.09.010.

ABSTRACT

Despite an increase in the number of available therapeutics, many children with rheumatic disease continue to experience active inflammatory disease and treatment failure. One reason for treatment failure is the lack of dosing paradigms to account for the wide between-patient variability in drug pharmacokinetics because of developmental changes or genetic polymorphisms that effect drug absorption, distribution, metabolism, and elimination. This review highlights several strategies to optimize dosing for biologic and nonbiologic disease-modifying antirheumatic drugs, including therapeutic drug monitoring, pharmacogenomics, and the use of pharmacokinetic/pharmacodynamic modeling.

PMID:34798954 | DOI:10.1016/j.rdc.2021.09.010

BMC Genom Data. 2021 Nov 19;22(1):51. doi: 10.1186/s12863-021-00999-8.

ABSTRACT

BACKGROUND: The variation of drug responses and target does among individuals is mostly determined by genes. With the development of pharmacogenetics and pharmacogenomics, the differences in drug response between different races seem to be mainly caused by the genetic diversity of pharmacodynamics and pharmacokinetics genes. Very important pharmacogenetic (VIP) variants mean that genes or variants play important and vital roles in drug response, which have been listed in pharmacogenomics databases, such as Pharmacogenomics Knowledge Base (PharmGKB). The information of Chinese ethnic minorities such as the Wa ethnic group is scarce. This study aimed to uncover the significantly different loci in the Wa population in Yunnan Province of China from the perspective of pharmacogenomics, to provide a theoretical basis for the future medication guidance, and to ultimately achieve the best treatment in the future.

RESULTS: In this study, we recruited 200 unrelated healthy Wa adults from the Yunnan province of China, selected 52 VIP variants from the PharmGKB for genotyping. We also compared the genotype frequency and allele distribution of VIP variants between Wa population and the other 26 populations from the 1000 Genomes Project ( http://www.1000Genomes.org/ ). Next, χ2 test was used to determine the significant points between these populations. The study results showed that compared with the other 26 population groups, five variants rs776746 (CYP3A5), rs4291 (ACE), rs3093105 (CYP4F2), rs1051298 (SLC19A1), and rs1065852 (CYP2D6) had higher frequencies in the Wa population. The genotype frequencies rs4291-TA, rs3093105-CA, rs1051298-AG and rs1065852-GA were higher than those of the other populations, and the allele distributions of rs4291-T and rs3093105-C were significantly different. Additionally, the difference between the Wa ethnic group and East Asian populations, such as CDX, CHB, and CHS, was the smallest.

CONCLUSIONS: Our research results show that there is a significant difference in the distribution of VIP variants between the Wa ethnic group and the other 26 populations. The study results will have an effect on supplementing the pharmacogenomics information for the Wa population and providing a theoretical basis for individualised medication for the Wa population.

PMID:34798807 | DOI:10.1186/s12863-021-00999-8

PLoS One. 2021 Nov 19;16(11):e0260431. doi: 10.1371/journal.pone.0260431. eCollection 2021.

ABSTRACT

BACKGROUND: Regular visit to psychiatric clinic is essential for successful treatment of any psychiatric condition including attention-deficit/hyperactivity disorder (AD/HD). However, cancellation of outpatient appointments in patients with AD/HD, which represents a significant medical loss, has not been systematically investigated to our knowledge.

METHODS: A systematic chart review was conducted for patients visiting the Shimada Ryoiku medical Center for Challenged Children in Japan at the age of ≤15 years from January to December 2013. The primary outcome measure was the cancellation rate, defined as the number of missed visits divided by the number of scheduled visits. The cancellation rates during 24 months after the first visit were compared between outpatients with AD/HD and other psychiatric disorders, including pervasive developmental disorders (PDD), and developmental coordination disorders and/or communication disorders (DCD-CD). A generalized linear model with binomial distribution was used to examine factors associated with cancellation rates exclusively in the AD/HD group.

RESULTS: We included 589 patients (mean ± SD age, 5.6 ± 3.4 years; 432 males) in the analysis. The cancellation rate in patients with AD/HD was 12.3% (95% confidence interval [CI]: 10.0-15.1), which was significantly higher than in those with PDD (5.6%, 95% CI: 3.8-8.3) and DCD-CD (5.3%, 95% CI: 3.6-7.8). Prescriptions of osmotic-release oral system-methylphenidate (OROS-MPH) and antipsychotics were associated with fewer cancellations in AD/HD patients (odds ratios: 0.61, 95% CI: 0.39-0.95 and 0.49, 95% CI: 0.25-0.95, respectively), although these significances did not find in the subgroup analysis including only patients with ≥ 6 years old.

CONCLUSIONS: Patients with AD/HD were more likely to miss appointments compared to those with other psychiatric disorders. The impact of AD/HD medications as well as potential psychiatric symptoms of their parents or caregivers on appointment cancellations needs to be evaluated in more detail in future investigations.

PMID:34797891 | DOI:10.1371/journal.pone.0260431

Medicine (Baltimore). 2021 Nov 19;100(46):e27858. doi: 10.1097/MD.0000000000027858.

ABSTRACT

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, and methylphenidate (MPH) is considered one of the first-line medicine for ADHD. Unfortunately, this medication is only effective for some children with ADHD. This meta-analysis was conducted to evaluate whether noradrenergic gene polymorphisms impact the efficacy of MPH in children with ADHD.

METHODS: Candidate gene studies published in English until March 1, 2020, were identified through literature searches on PubMed, Web of Science, and Embase. Data were pooled from individual clinical trials considering MPH pharmacogenomics. According to the heterogeneity, the odds ratio and mean differences were calculated by applying fixed-effects or random-effects models.

RESULTS: This meta-analysis includes 15 studies and 1382 patients. Four polymorphisms of the NET gene (rs5569, rs28386840, rs2242446, rs3785143) and 2 polymorphisms of the α2A-adrenergic receptor gene (ADRA2A) gene (MspI and DraI) were selected for the analysis. In the pooled data from all studies, T allele carriers of the rs28386840 polymorphism were significantly more likely to respond to MPH (P < .001, ORTcarriers = 2.051, 95% confidence interval [CI]:1.316, 3.197) and showed a relationship with significantly greater hyperactive-impulsive symptoms improvement (P < .001, mean difference:1.70, 95% CI:0.24, 3.16). None of the ADRA2A polymorphisms correlated significantly with MPH response as a whole. However, G allele carriers of the MspI polymorphism showed a relationship with significantly inattention symptoms improvement (P < .001, mean difference:0.31, 95% CI: 0.15, 0.47).

CONCLUSION: Our meta-analysis results indicate that the noradrenergic gene polymorphisms may impact MPH response. The NET rs28386840 is linked to improved MPH response in ADHD children. And the ADRA2A MspI is associated with inattention symptom improvements. Further investigations with larger samples will be needed to confirm these results.Registration: PROSPERO (no. CRD42021265830).

PMID:34797323 | DOI:10.1097/MD.0000000000027858

J Oncol Pharm Pract. 2021 Nov 19:10781552211049144. doi: 10.1177/10781552211049144. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity.

METHODS: Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay.

RESULTS: Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities.

CONCLUSIONS: Our results indicate that a combined genotype-phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.

PMID:34797200 | DOI:10.1177/10781552211049144

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2021 Aug;29(Special Issue):1258-1263. doi: 10.32687/0869-866X-2021-29-s2-1258-1263.

ABSTRACT

PURPOSE: To investigate the possibilities of pharmacoeconomic and pharmacogenetic factors monitoring to assess the effectiveness of treatment of a cardiological profile patients as a part of the implementation of a personalized approach.

MATERIAL AND METHODS: 200 patients with arterial hypertension and CHD were examined. Pharmacotherapy was analyzed. ABC/VEN and DDD analysis, pharmacoeconomic analysis were applied. Genetic analysis of the polymorphism of the genes CYP2D6*4 and CYP2D6*10 encoding the subfamily of the cytochrome isoenzyme Р-450 was carried out. An original monitoring method was used to assess the effect of pharmacoeconomic and pharmacogenetic factors on the performance of cardiac care.

RESULTS: When conducting a pharmacoeconomic analysis of cases of cardiac care, it was found that the costs of drug therapy are significant and take over 10% of the total costs. However, its effectiveness is insufficient in 58% of cases in inpatient and 37% in outpatient care. The analysis showed that there is an inverse mean correlation between gene polymorphism and clinical performance of cardiac care (r = -0.62) and a direct strong correlation between polypharmacy in pharmacotherapy, not accounting for interdrug interaction and clinical performance (r = 0.89).

PMID:34792874 | DOI:10.32687/0869-866X-2021-29-s2-1258-1263

Pharmacopsychiatry. 2021 Nov 18. doi: 10.1055/a-1681-2047. Online ahead of print.

ABSTRACT

OBJECTIVES: Partial response to pharmacotherapy is common in major depressive disorder (MDD) and many patients require alternative pharmacotherapy or augmentation, including adjunctive L-methylfolate. Given that L-methylfolate augmentation is rarely included in major clinical practice guidelines, we sought to systematically review evidence for L-methylfolate augmentation in adults with MDD and to examine its efficacy meta-analytically.

METHODS: We systematically searched PubMed for articles up to December 31, 2020, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Included studies were published in peer-reviewed, English-language journals and examined L-methylfolate adjunctive therapy in depressive disorders or its effect on antidepressant response. A fixed- and random-effects meta-analysis and risk of bias assessment using the Cochrane Risk of Bias Tool were conducted.

RESULTS: Qualitative assessment of nine articles (N=6,707 patients) suggests that adjunctive L-methylfolate improved antidepressant response. In the meta-analysis of categorical Hamilton Rating Scale for Depression-17 response, (three studies, N=483) adjunctive L-methylfolate was associated with a small effect versus antidepressant monotherapy (relative risk: 1.25, 95% confidence interval [CI]=1.08 to 1.46, p=0.004). A meta-analysis of four studies (N=507) using a continuous measure of depressive symptoms showed a similar effect of adjunctive L-methylfolate (standardized mean difference=- 0.38, 95% CI=- 0.59 to-0.17, p=0.0003).

CONCLUSION: Adjunctive L-methylfolate may have modest efficacy in antidepressant-treated adults with MDD.

PMID:34794190 | DOI:10.1055/a-1681-2047

Bioinformatics. 2021 Nov 18:btab783. doi: 10.1093/bioinformatics/btab783. Online ahead of print.

ABSTRACT

MOTIVATION: Identifying sample mix-ups in biobanks is essential to allow the repurposing of genetic data for clinical pharmacogenetics. Pharmacogenetic advice based on the genetic information of another individual is potentially harmful. Existing methods for identifying mix-ups are limited to datasets in which additional omics data (e.g., gene expression) is available. Cohorts lacking such data can only use sex, which can reveal only half of the mix-ups. Here, we describe Idéfix, a method for the identification of accidental sample mix-ups in biobanks using polygenic scores.

RESULTS: In the Lifelines population-based biobank we calculated polygenic scores (PGSs) for 25 traits for 32,786 participants. Idéfix then compares the actual phenotypes to PGSs and uses the relative discordance that is expected for mix-ups, compared to correct samples. In a simulation, using induced mix-ups, Idéfix reaches an AUC of 0.90 using 25 polygenic scores and sex. This is a substantial improvement over using only sex, which has an AUC of 0.75. Subsequent simulations present Idéfix's potential in varying datasets with more powerful PGSs. This suggests its performance will likely improve, when more highly powered GWASs for commonly measured traits will become available. Idéfix can be used to identify a set of high-quality participants for whom it is very unlikely that they reflect sample mix-ups, and for these participants we can use genetic data for clinical purposes, such as pharmacogenetic profiles. For instance, in Lifelines we can select 34.4% of participants, reducing the sample mix-up rate from 0.15% to 0.01%.

AVAILABILITY: Idéfix is freely available at https://github.com/molgenis/systemsgenetics/wiki/Idefix.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:34792549 | DOI:10.1093/bioinformatics/btab783

Pharmacogenomics. 2021 Nov 18. doi: 10.2217/pgs.10.77e1. Online ahead of print.

NO ABSTRACT

PMID:34792412 | DOI:10.2217/pgs.10.77e1

Curr Drug Saf. 2021 Nov 18. doi: 10.2174/157488631602211118122907. Online ahead of print.

ABSTRACT

BACKGROUND: Phenytoin is the most commonly reported aromatic Anti-Epileptic Drug (AED) to cause Cutaneous Adverse Drug Reactions (CADRs). Cutaneous adverse drug reactions may be immune or non-immune mediated. It has been observed that predisposition is multifactorial and that gene mutations alone cannot be the cause.

OBJECTIVES: In this study, we investigated the patient, disease, and drug-related risk factors associated with phenytoin-induced cutaneous adverse drug reactions in South Indian epileptic patients.

METHODOLOGY: This study was conducted as a single-center prospective case-control study over a period of 13 months. The Fisher's exact test and multivariate binary logistic regression analysis were used to test the association of single and multiple variables, respectively.

RESULTS: This study comprised 26 patients with phenytoin-induced cutaneous adverse drug reactions (PHT-CARDs) and 32 phenytoin-tolerant controls with a mean age of 40.60±18.15 and 36.21±14.71 years, respectively. Among 26 phenytoin-induced cutaneous adverse drug reactions, 76.92% cases were mild-moderate reactions and 23.07% were severe. The onset latency period of these reactions ranged from 7-42 days. The multivariate analysis showed that multiple AEDs (OR =18.62, 95% CI 4.28-80.87, p=<.001) and comorbidities (OR= 5.98, 95% CI 1.33-26.78, p=.01) are risk factors for PHT-CADRs. PHT-SCARs were shown to be associated with previous allergy history (OR= 31, % CI 2.40-398.8, p=.008).

CONCLUSION: The risk factors found to be associated with CARDs in South Indian Epileptic patients are multiple AEDs, comorbidities, and past allergic history. Therefore, physicians and other associated health care professionals should closely monitor the patients when phenytoin is employed.

PMID:34792004 | DOI:10.2174/157488631602211118122907

Addiction. 2021 Nov 17. doi: 10.1111/add.15742. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: CYP2B6, a genetically variable enzyme, converts bupropion to its active metabolite hydroxybupropion. CYP2B6 activity and bupropion-aided cessation differ between women and men. The aim of this study was to determine whether genetically normal (vs. reduced) CYP2B6 activity increases bupropion-aided cessation in African American smokers via higher hydroxybupropion concentration, and whether this differs by sex.

DESIGN AND SETTING: Secondary analysis of a smoking cessation clinical trial (NCT00666978).

PARTICIPANTS/CASES: African American light-smokers (≤10 cigarettes/day).

INTERVENTIONS: Participants were treated with bupropion for 7 weeks.

MEASUREMENTS: Participants with detectable bupropion and/or hydroxybupropion concentrations were divided into normal (n=64) and reduced (n=109) CYP2B6 activity groups based on the presence of reduced-function CYP2B6*6 and CYP2B6*18 alleles. Biochemically-verified smoking cessation was assessed at week 3, end-of-treatment (7 weeks), and follow-up (26 weeks).

FINDINGS: Normal (vs. reduced) CYP2B6 activity was associated with increased cessation at week 7, which was mediated by higher hydroxybupropion concentration (odds ratio (OR)=1.25, 95% confidence interval (CI)=1.03, 1.78); this mediation effect persisted at week 26 (OR=1.23, 95% CI=1.02, 1.70). The mediation effect was similar in women (n=116; OR=1.33, 95% CI=1.01, 2.30) and men (n=57; OR=1.33, 95% CI=0.92, 3.87). Moreover, sex did not appear to moderate the mediation effect, although this should be tested in a larger sample.

CONCLUSIONS: In African American light-smokers with verified early bupropion use, genetically normal CYP2B6 activity appears to be indirectly associated with greater smoking cessation success in a relationship mediated by higher hydroxybupropion concentration. The mediating effect of higher hydroxybupropion concentration on smoking cessation persists beyond the active treatment phase and does not appear to differ by sex.

PMID:34791718 | DOI:10.1111/add.15742

Int J Mol Med. 2022 Jan;49(1):9. doi: 10.3892/ijmm.2021.5064. Epub 2021 Nov 18.

ABSTRACT

RNA modifications have recently become the focus of attention due to their extensive regulatory effects in a vast array of cellular networks and signaling pathways. Just as epigenetics is responsible for the imprinting of environmental conditions on a genetic level, epitranscriptomics follows the same principle at the RNA level, but in a more dynamic and sensitive manner. Nevertheless, its impact in the field of cardiovascular disease (CVD) remains largely unexplored. CVD and its associated pathologies remain the leading cause of death in Western populations due to the limited regenerative capacity of the heart. As such, maintenance of cardiac homeostasis is paramount for its physiological function and its capacity to respond to environmental stimuli. In this context, epitranscriptomic modifications offer a novel and promising therapeutic avenue, based on the fine‑tuning of regulatory cascades, necessary for cardiac function. This review aimed to provide an overview of the most recent findings of key epitranscriptomic modifications in both coding and non‑coding RNAs. Additionally, the methods used for their detection and important associations with genetic variations in the context of CVD were summarized. Current knowledge on cardiac epitranscriptomics, albeit limited still, indicates that the impact of epitranscriptomic editing in the heart, in both physiological and pathological conditions, holds untapped potential for the development of novel targeted therapeutic approaches in a dynamic manner.

PMID:34791505 | DOI:10.3892/ijmm.2021.5064

Front Pharmacol. 2021 Nov 1;12:753845. doi: 10.3389/fphar.2021.753845. eCollection 2021.

ABSTRACT

Background: Understanding the prescription pattern of medications in a population can help reveal the potential usage scenarios, including off-label prescriptions, and the need for precision medicine implementation. Therefore, the aim of this study was to assess the prescription pattern and off-label use of antipsychotics in the Qatari population. Methods: We performed a cross-sectional study of Qatari patients who received antipsychotic prescriptions from the major healthcare providers in the country during the 2-year period between June 2018 and May 2020. The number of patients, prescriptions dispensed, and clinical indications were collected and statistical analysis using chi-square test was conducted. Results: Among the 9,349 Qatari patients prescribed with antipsychotics during the study period, the majority were female (57%; p < 0.001) and were in the age categories 20-39 and 30-39 years (both 22%; p < 0.001). Among the 35,938 antipsychotic prescriptions dispensed, second-generation antipsychotics were the most highly prescribed (59%), specifically, quetiapine (16%) and olanzapine (12%), but the first-generation antipsychotic prochlorperazine (13%) was also highly prescribed. Most of the indications of antipsychotics (69%) were for off-label use such as for controlling chronic diseases, sleeping disorders, benign paroxysmal positional vertigo and irritable bowel syndrome. Conclusion: Non-mental health and off-label prescriptions of several antipsychotics were observed. Integration of this data with pharmacogenomic and clinical outcome data will help in determining the course of action for implementing personalized and precision medicine in the country and beyond.

PMID:34790126 | PMC:PMC8591163 | DOI:10.3389/fphar.2021.753845

Ann Rheum Dis. 2021 Nov 17:annrheumdis-2021-220578. doi: 10.1136/annrheumdis-2021-220578. Online ahead of print.

ABSTRACT

OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.

METHODS: In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied.

RESULTS: Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2×10-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still's controls (p=6.3×10-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.

CONCLUSIONS: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

PMID:34789453 | DOI:10.1136/annrheumdis-2021-220578