20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/11/18

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

The Urinary Microbiome and Bladder Cancer: Susceptibility and Immune Responsiveness.

Bladder Cancer. 2020 Sep 21;6(3):225-235

Authors: Andolfi C, Bloodworth JC, Papachristos A, Sweis RF

Abstract
Bladder cancer is a highly prevalent disease worldwide and is associated with a high mortality rate. Across all stages of bladder cancer, immunotherapy has now become the cornerstone of treatment. The commensal microbiome has become a major focus of research given its impact on numerous states of human health and disease. Many links between commensal microbes and immune function have been reported. Recently a commensal urinary microbiome has been identified and characterized in healthy individuals by several research groups. The urinary microbiome is now emerging as an important factor influencing bladder cancer development and therapeutic responsiveness. In this report, we identify findings from important clinical and mechanistic studies on the urinary microbiome and future opportunities to impact prevention and treatment of bladder cancer.

PMID: 33195783 [PubMed]

Genetic Warfarin-Resistance Resulting in Surgery to Change a Prosthetic Valve.

Eur J Case Rep Intern Med. 2020;7(11):001851

Authors: Malik J, Ishaq U, Javed N, Baig MA, Javaid M

Abstract
Warfarin is a readily available anticoagulant used worldwide in a variety of clinical scenarios. Patients who need more than 15 mg/day are considered to be warfarin resistant. Numerous genes have been implicated in warfarin pharmacogenetics, with genes encoding CYP2C9 and VKORC1 shown to be the most important determinants of drug dosage requirements. A 27-year-old woman was admitted as she had a sub-therapeutic international normalized ratio (INR) after prosthetic mitral valve replacement. Even after a warfarin dose of 50 mg/day, her INR was not in the therapeutic range, so the heart team decided to replace her metallic valve with a bioprosthetic valve, thus alleviating the need for anticoagulation.
LEARNING POINTS: Genetic warfarin resistance is rare and mainly associated with two genes encoding CYP2C9 and VKORC1.In addition to dietary counselling and drug compliance, options in warfarin-resistant patients include increasing the warfarin dose, which carries a risk of bleeding complications, or switching to novel oral anticoagulants, which increases the risk of prosthetic valve thrombosis.We replaced a metallic valve with a bioprosthetic valve, which is the first time this has been documented in a patient with warfarin resistance.

PMID: 33194861 [PubMed]

Tre2-Bub2-Cdc16 Family Proteins Based Nomogram Serve as a Promising Prognosis Predicting Model for Melanoma.

Front Oncol. 2020;10:579625

Authors: Tang L, Peng C, Zhu SS, Zhou Z, Liu H, Cheng Q, Chen X, Chen XP

Abstract
Tre2-Bub2-Cdc16 (TBC) proteins are conserved in eukaryotic organisms and function as negative feedback dominating the GAPs for Rab GTPases, while the function of TBC proteins in melanoma remains unclear. In this study, we observed the differential expression of 33 TBC genes in TCGA datasets classified by clinical features. Seven prognostic-associated TBC genes were identified by LASSO Cox regression analysis. Mutation analysis revealed distinctive frequency alteration in the seven prognostic-associated TBCs between cases with high and low scores. High-risk score and cluster 1 based on LASSO Cox regression and consensus clustering analysis were relevant to clinical features and unfavorable prognosis. GSVA analysis showed that prognostic-associated TBCs were related to metabolism and protein transport signaling pathway. Correlation analysis indicated the relationship between the prognostic-associated TBCs with RAB family members, invasion-related genes and immune cells. The prognostic nomogram model was well established to predict survival in melanoma. What's more, interference of one of the seven TBC proteins TBC1D7 was confirmed to inhibit the proliferation, migration and invasion of melanoma cells in vitro. In summary, we preliminarily investigated the impact of TBCs on melanoma through multiple bioinformatics analysis and experimental validation, which is helpful for clarifying the mechanism of melanoma and the development of anti-tumor drugs.

PMID: 33194704 [PubMed]

Pharmacogenetics of Statin-Induced Myotoxicity.

Front Genet. 2020;11:575678

Authors: Kee PS, Chin PKL, Kennedy MA, Maggo SDS

Abstract
Statins, a class of lipid-lowering medications, have been a keystone treatment in cardiovascular health. However, adverse effects associated with statin use impact patient adherence, leading to statin discontinuation. Statin-induced myotoxicity (SIM) is one of the most common adverse effects, prevalent across all ages, genders, and ethnicities. Although certain demographic cohorts carry a higher risk, the impaired quality of life attributed to SIM is significant. The pathogenesis of SIM remains to be fully elucidated, but it is clear that SIM is multifactorial. These factors include drug-drug interactions, renal or liver dysfunction, and genetics. Genetic-inferred risk for SIM was first reported by a landmark genome-wide association study, which reported a higher risk of SIM with a polymorphism in the SLCO1B1 gene. Since then, research associating genetic factors with SIM has expanded widely and has become one of the foci in the field of pharmacogenomics. This review provides an update on the genetic risk factors associated with SIM.

PMID: 33193687 [PubMed]

Review of Genetic Variation as a Predictive Biomarker for Chronic Graft-Versus-Host-Disease After Allogeneic Stem Cell Transplantation.

Front Immunol. 2020;11:575492

Authors: Partanen J, Hyvärinen K, Bickeböller H, Bogunia-Kubik K, Crossland RE, Ivanova M, Perutelli F, Dressel R

Abstract
Chronic graft-versus-host disease (cGvHD) is one of the major complications of allogeneic stem cell transplantation (HSCT). cGvHD is an autoimmune-like disorder affecting multiple organs and involves a dermatological rash, tissue inflammation and fibrosis. The incidence of cGvHD has been reported to be as high as 30% to 60% and there are currently no reliable tools for predicting the occurrence of cGvHD. There is therefore an important unmet clinical need for predictive biomarkers. The present review summarizes the state of the art for genetic variation as a predictive biomarker for cGvHD. We discuss three different modes of action for genetic variation in transplantation: genetic associations, genetic matching, and pharmacogenetics. The results indicate that currently, there are no genetic polymorphisms or genetic tools that can be reliably used as validated biomarkers for predicting cGvHD. A number of recommendations for future studies can be drawn. The majority of studies to date have been under-powered and included too few patients and genetic markers. Like in all complex multifactorial diseases, large collaborative genome-level studies are now needed to achieve reliable and unbiased results. Some of the candidate genes, in particular, CTLA4, HSPE, IL1R1, CCR6, FGFR1OP, and IL10, and some non-HLA variants in the HLA gene region have been replicated to be associated with cGvHD risk in independent studies. These associations should now be confirmed in large well-characterized cohorts with fine mapping. Some patients develop cGvHD despite very extensive immunosuppression and other treatments, indicating that the current therapeutic regimens may not always be effective enough. Hence, more studies on pharmacogenetics are also required. Moreover, all of these studies should be adjusted for diagnostic and clinical features of cGvHD. We conclude that future studies should focus on modern genome-level tools, such as machine learning, polygenic risk scores and genome-wide association study-transcription meta-analyses, instead of focusing on just single variants. The risk of cGvHD may be related to the summary level of immunogenetic differences, or whole genome histocompatibility between each donor-recipient pair. As the number of genome-wide analyses in HSCT is increasing, we are approaching an era where there will be sufficient data to incorporate these approaches in the near future.

PMID: 33193367 [PubMed - in process]

Long-Term Effects of Maternal Deprivation on the Volume of Dopaminergic Nuclei and Number of Dopaminergic Neurons in Substantia Nigra and Ventral Tegmental Area in Rats.

Front Neuroanat. 2020;14:578900

Authors: Kapor S, Aksić M, Puškaš L, Jukić M, Poleksić J, Milosavljević F, Bjelica S, Filipović B

Abstract
Early life adversities leave long-lasting structural and functional consequences on the brain, which may persist later in life. Dopamine is a neurotransmitter that is extremely important in mood and motor control. The aim of this study was to investigate the effect of maternal deprivation during the ninth postnatal day on the volume of dopaminergic nuclei and the number of dopaminergic neurons in adolescence and adulthood. Maternally deprived and control Wistar rats were sacrificed on postnatal day 35 or 60, and the dopaminergic neurons were stained in coronal histological sections of ventral midbrain with the tyrosine hydroxylase antibody. The volume of dopaminergic nuclei and the number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were analyzed in three representative coordinates. Maternal deprivation caused weight loss on postnatal day 21 (weaning) and corticosterone blood level elevation on postnatal days 35 and 60 in stressed compared to control rats. In maternally deprived animals, the volumes of SN and VTA were increased compared to the controls. This increase was accompanied by an elevation in the number of dopaminergic neurons in both nuclei. Altogether, based on somatic and corticosterone level measurements, maternal deprivation represents a substantial adversity, and the phenotype it causes in adulthood includes increased volume of the dopaminergic nuclei and number of dopaminergic neurons.

PMID: 33192342 [PubMed]

[Network analysis by systemic text excavation of the concept of personalized psychiatry and precision].

Encephale. 2020 Nov 12;:

Authors: Gauld C, Micoulaud-Franchi JA

Abstract
OBJECTIVES: The current challenges of psychiatric nosology and semiology are part of an interdisciplinary and integrative framework. The paradigm of the personalized and precision psychiatry proposes to study this discipline according to new approaches and methodologies. Personalized and precision psychiatry therefore requires clarification of its concepts. To our knowledge, there is no systematic exploration of the literature on the application of the concepts of personalized and precision medicine in the field of psychiatry. This article proposes thus to explore the framework of personalized and precision medicine applied to psychiatry.
METHODS: We explored the framework of personalized and precision medicine applied to psychiatry by a textual network analysis. Firstly, we performed a systematic text-mining (Natural Language Processing) from an exhaustive review of the international literature with the terms "precision psychiatry" and "personalized psychiatry". Secondly, this analysis of textual data allowed us to build a textual network which made it possible to visualize the most proximal terms (the most frequently associated in the literature). Finally, we extracted from the network the main dimensions explored in the scientific literature, and we studied the relative importance of each term by analyzing the network centrality. In addition, a brief bibliometric analysis was conducted.
RESULTS: We show that personalized and precision psychiatry refers to six dimensions found in the textual network analysis which correspond to the scientific fields which study personalized and precision psychiatry: genetics, pharmacogenetics, artificial intelligence, therapeutic trials, biomarkers and staging. We explore how each dimension relates to the mechanization of psychiatric disorders. However, precision and personalized psychiatry, which tries to refine the levels of mechanistic explanations for psychiatry, suffers from a conceptual heterogeneity. Indeed, textual analysis also allows us to find terms referring to a set of heterogeneous concepts. Many methodological fields and epistemological concepts are invoked in this literature, without standardization.
CONCLUSIONS: The paradox of personalized and precision psychiatry is to associate a strong conceptual heterogeneity with a well-defined mechanistic component. Heterogeneity found in literature on personalized and precision psychiatry testifies to the lack of a pluralist and integrative theoretical framework. This framework could be based on a naturalizing but non-reducing formalism, aware of the societal challenges of the sciences and their implementation in the research and clinical systems of psychiatry.

PMID: 33190818 [PubMed - as supplied by publisher]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/11/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Higher polygenic risk scores for schizophrenia may be suggestive of treatment non-response in major depressive disorder.

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Nov 09;:110170

Authors: Fanelli G, Benedetti F, Kasper S, Zohar J, Souery D, Montgomery S, Albani D, Forloni G, Ferentinos P, Rujescu D, Mendlewicz J, Serretti A, Fabbri C

Abstract
Up to 60% of patients with major depressive disorder (MDD) do not respond to the first treatment with antidepressants. Response to antidepressants is a polygenic trait, although its underpinning genetics has not been fully clarified. This study aimed to investigate if Polygenic Risk Scores (PRSs) for major psychiatric disorders and trait neuroticism (NEU) were associated with non-response or resistance to antidepressants in MDD. PRSs for bipolar disorder, MDD, NEU, and schizophrenia (SCZ) were computed in 1148 patients with MDD. Summary statistics from the largest meta-analyses of genome-wide association studies were used as base data. Patients were classified as responders, non-responders to one treatment, non-responders to two or more treatments (treatment-resistant depression or TRD). Regression analyses were adjusted for population stratification and recruitment sites. PRSs did not predict either non-response vs response or TRD vs response after Bonferroni correction. However, SCZ-PRS was nominally associated with non-response (p = 0.003). Patients in the highest SCZ-PRS quintile were more likely to be non-responders than those in the lowest quintile (OR = 2.23, 95% CI = 1.21-4.10, p = 0.02). Patients in the lowest SCZ-PRS quintile showed higher response rates when they did not receive augmentation with second-generation antipsychotics (SGAs), while those in the highest SCZ-PRS quintile had a poor response independently from the treatment strategy (p = 0.009). A higher genetic liability to SCZ may reduce treatment response in MDD, and patients with low SCZ-PRSs may show higher response rates without SGA augmentation. Multivariate approaches and methodological refinements will be necessary before clinical implementations of PRSs.

PMID: 33181205 [PubMed - as supplied by publisher]

The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation.

Br J Clin Pharmacol. 2020 Nov 11;:

Authors: Ji Q, Zhang C, Xu Q, Wang Z, Li X, Lv Q

Abstract
AIMS: Our study aimed to determine the impact of genetic polymorphisms of ABCB1 and CES1 on the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in patients with non-valvular atrial fibrillation (NVAF).
METHODS: We conducted a prospective study and enrolled NVAF patients treated with dabigatran. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration (PDC) and coagulation parameters including activated partial thromboplastin time (APTT) and thrombin time (TT). Patients' demographics and clinical outcomes from scheduled follow-up visits were all recorded. Statistical analysis was performed to identify the impact of genetic polymorphisms on the PK/PD and bleeding risk of dabigatran.
RESULTS: A total of 198 patients were included in analysis. For the ABCB1 polymorphisms rs4148738 and rs1045642, no significant association was found with dabigatran PK/PD. For the CES1 polymorphism rs8192935, the minor allele(C) was associated with increased trough PDCs (ANOVA: P<0.001; CC vs. TT genotype, P<0.001; CT vs. TT genotype, P=0.014) and with APTT values at trough level(P=0.015). For the CES1 polymorphism rs2244613, the minor allele(A) carriers had higher levels of trough PDC than non-carriers (ANOVA: P<0.001; AA vs. CC genotype, P<0.001; CA vs. CC genotype, P=0.004) and increased risk for minor bleeding(P=0.034; OR=2.71, 95% CI 1.05-7.00).
CONCLUSIONS: Our study indicated that the minor allele(C) on the CES1 SNP rs8192935 was associated with PDCs and APTT values at trough level. The minor allele(A) on the CES1 SNP rs2244613 was associated with increased trough PDCs and higher risk for minor bleeding in NVAF patients treated with dabigatran.

PMID: 33179295 [PubMed - as supplied by publisher]

Aberrant RNA Splicing Events Driven by Mutations of RNA-Binding Proteins as Indicators for Skin Cutaneous Melanoma Prognosis.

Front Oncol. 2020;10:568469

Authors: Mei C, Song PY, Zhang W, Zhou HH, Li X, Liu ZQ

Abstract
The worldwide incidence of skin cutaneous melanoma (SKCM) is increasing at a more rapid rate than other tumors. Aberrant alternative splicing (AS) is found to be common in cancer; however, how this process contributes to cancer prognosis still remains largely unknown. Mutations in RNA-binding proteins (RBPs) may trigger great changes in the splicing process. In this study, we comprehensively analyzed DNA and RNA sequencing data and clinical information of SKCM patients, together with widespread changes in splicing patterns induced by RBP mutations. We screened mRNA expression-related and prognosis-related mutations in RBPs and investigated the potential affections of RBP mutations on splicing patterns. Mutations in 853 RBPs were demonstrated to be correlated with splicing aberrations (p < 0.01). Functional enrichment analysis revealed that these alternative splicing events (ASEs) may participate in tumor progress by regulating the modification process, cell-cycle checkpoint, metabolic pathways, MAPK signaling, PI3K-Akt signaling, and other important pathways in cancer. We also constructed a prediction model based on overall survival-related AS events (OS-ASEs) affected by RBP mutations, which exhibited a good predict efficiency with the area under the curve of 0.989. Our work highlights the importance of RBP mutations in splicing alterations and provides effective biomarkers for prediction of prognosis of SKCM.

PMID: 33178596 [PubMed]

Diagnostic procedures & practices in drug allergy/hypersensitivity: a survey of 13 Asian countries.

Asia Pac Allergy. 2020 Oct;10(4):e36

Authors: Tang MM, Fok JS, Thong BY, Yun J, Li PH, Kang HR, Thien F, Yamaguchi M, Lucas M, Chang YS, Kim BK, Nagao M, Rengganis I, Tsai YG, Chung WH, Rerkpattanapipat T, Kamchaisatian W, Leung TF, Ho JY, Zhang L, Latiff AHA, Fujisawa T, Castells MC, Demoly P, Wang JY, Pawankar R

Abstract
Background: The issues and challenges in the diagnosis of drug allergy/hypersensitivity among children and adults in Asia are likely to be different from non-Asian countries.
Objective: To study the diagnostic modalities used in the evaluation and management of drug allergy/drug hypersensitivity reactions (DHRs) among member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI).
Methods: A questionnaire comprising 41 questions was circulated electronically to member societies and individual members of APAAACI between January 23, 2020 and March 6, 2020.
Results: Twenty-six respondents from 15 member societies and 1 individual member responded. European DHR guidelines were most commonly used. Skin prick and intradermal testing was used by 100%, with only 60% having access to commercial penicillin skin test reagents. In vitro-specific IgE tests were used by 75%, and basophil activation test by 56.3% for immediate DHR. Patch tests were used by 75% in contrast to lymphocyte transformation tests by 25% for nonimmediate DHR. Drug provocation tests were used by 68.8%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (93.3%). Human leukocyte antigen (HLA) genotype testing was mandatory among 25% respondents before new carbamazepine prescriptions, and 8.3% for allopurinol prescriptions.
Conclusions: There was increased use of skin testing for iodinated contrast media hypersensitivity and patch testing for nonimmediate DHR. HLA genotype testing prior to new carbamazepine, allopurinol and abacavir prescriptions remain variable despite strong associations for severe cutaneous adverse reactions with Asian ethnicity. Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across APAAACI member societies.

PMID: 33178561 [PubMed]

CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia.

Pharmgenomics Pers Med. 2020;13:543-551

Authors: Chamnanphon M, Wainipitapong S, Wiwattarangkul T, Chuchuen P, Nissaipan K, Phaisal W, Tangwongchai S, Sukasem C, Wittayalertpanya S, Gaedigk A, Aniwattanapong D, Chariyavilaskul P

Abstract
Purpose: Donepezil, a drug frequently used to treat dementia, is mainly metabolized by cytochrome P450 2D6 (CYP2D6). This study investigated the relationships between CYP2D6 genotype and activity scores as well as predicted phenotype of plasma donepezil concentrations in 86 Thai dementia participants.
Materials and Methods: CYP2D6 was genotyped using bead-chip technology (Luminex xTAG® v.3). Steady-state trough plasma donepezil concentrations were measured using high-performance liquid chromatography.
Results: Sixteen genotypes were found but the most frequent genotypes detected among our participants were CYP2D6*10/*10 (27.9%) and *1/*10 (26.7%). One-third of the participants had an activity score of 1.25 which predicted that they were normal metabolizers. The overall median (interquartile range) of plasma donepezil concentration was 51.20 (32.59-87.24) ng/mL. Normal metabolizers (NMs) had lower plasma donepezil concentrations compared to intermediate metabolizers (IMs) (41.15 (28.44-67.65) ng/mL vs 61.95 (35.25-97.00) ng/mL). Multivariate analysis showed that CYP2D6 activity score (r2 = 0.50) and the predicted phenotype (independent of dose) could predict the plasma donepezil concentration (r2 = 0.49).
Conclusion: Plasma donepezil concentration in NMs was lower compared to IMs. Additional studies with larger sample size and use of next-generation sequencing as well as its outcomes are warranted to confirm the benefit of using pharmacogenetic-guided treatment for donepezil.

PMID: 33177862 [PubMed]

Towards safer risperidone prescribing in Alzheimer's disease.

Br J Psychiatry. 2020 Nov 12;:1-8

Authors: Reeves S, Bertrand J, Uchida H, Yoshida K, Otani Y, Ozer M, Liu KY, Bramon E, Bies R, Pollock BG, Howard R

Abstract
BACKGROUND: In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to 'use the lowest possible dose' of antipsychotic drugs, but provide no information on optimal dosing.
AIMS: This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).
METHOD: A statistical model, which described the concentration-time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and 'active moiety' (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.
RESULTS: The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann-Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.
CONCLUSIONS: Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.

PMID: 33176899 [PubMed - as supplied by publisher]

Rapid Serological Assays and SARS-CoV-2 Real-Time Polymerase Chain Reaction Assays for the Detection of SARS-CoV-2: Comparative Study.

J Med Internet Res. 2020 10 30;22(10):e19152

Authors: Paradiso AV, De Summa S, Loconsole D, Procacci V, Sallustio A, Centrone F, Silvestris N, Cafagna V, De Palma G, Tufaro A, Garrisi VM, Chironna M

Abstract
BACKGROUND: Real-time polymerase chain reaction (RT-PCR) testing for the identification of viral nucleic acid is the current standard for the diagnosis of SARS-CoV-2 infection, but technical issues limit its utilization for large-scale screening. Serological immunoglobulin M (IgM)/IgG testing has been proposed as a useful tool for detecting SARS-CoV-2 exposure.
OBJECTIVE: The objective of our study was to compare the results of the rapid serological VivaDiag test for SARS-CoV-2-related IgM/IgG detection with those of the standard RT-PCR laboratory test for identifying SARS-CoV-2 nucleic acid.
METHODS: We simultaneously performed both serological and molecular tests with a consecutive series of 191 symptomatic patients. The results provided by a new rapid serological colorimetric test for analyzing IgM/IgG expression were compared with those of RT-PCR testing for SARS-CoV-2 detection.
RESULTS: Of the 191 subjects, 70 (36.6%) tested positive for SARS-CoV-2 based on RT-PCR results, while 34 (17.3%) tested positive based on serological IgM/IgG expression. Additionally, 13 (6.8%) subjects tested positive based on serological test results, but also tested negative based on RT-PCR results. The rapid serological test had a sensitivity of 30% and a specificity of 89% compared to the standard RT-PCR assay. Interestingly, the performance of both assays improved 8 days after symptom appearance. After 10 days had passed since symptom appearance, the predictive value of the rapid serological test was higher than that of the standard molecular assay (proportion of positive results: 40% vs 20%). Multivariate analysis showed that age >58 years (P<.01) and period of >15 days after symptom onset (P<.02) were significant and independent factors associated with serological test positivity.
CONCLUSIONS: The rapid serological test analyzed in this study seems limited in terms of usefulness when diagnosing SARS-CoV-2 infection. However, it may be useful for providing relevant information on people's immunoreaction to COVID-19 exposure.

PMID: 33031048 [PubMed - indexed for MEDLINE]

ABCG2 Deficiency Does Not Alter Dolutegravir Metabolism and Pharmacokinetics.

J Pharmacol Exp Ther. 2020 07;374(1):38-43

Authors: Zhu J, Tian X, Shehu AI, McMahon DK, Ma X

Abstract
Dolutegravir (DTG) is a potent integrase inhibitor of human immunodeficiency virus. Because DTG is a substrate of the efflux transporter ABCG2 and ABCG2 is highly polymorphic, we asked whether dose adjustment of DTG is needed for ABCG2-deficient individuals. Using Abcg2-null mice, the current work investigated the impact of ABCG2 deficiency on DTG metabolism and pharmacokinetics. Compared with wild-type mice, no statistically significant difference was found in the systemic and tissue-specific (liver, kidney, and brain) pharmacokinetics of DTG in Abcg2-null mice. In addition, ABCG2 deficiency had no statistically significant impact on the production and excretion of DTG metabolites. In summary, this study demonstrated that deficiency of ABCG2 does not alter DTG metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency. SIGNIFICANCE STATEMENT: The current work demonstrated that deficiency of ATP-binding cassette subfamily G member 2 (ABCG2) does not alter Dolutegravir (DTG) metabolism and pharmacokinetics, suggesting that dose adjustment of DTG is not needed for individuals with ABCG2 deficiency.

PMID: 32303561 [PubMed - indexed for MEDLINE]

Optimal sampling strategies for darunavir and external validation of the underlying population pharmacokinetic model.

Eur J Clin Pharmacol. 2020 Nov 11;:

Authors: Stillemans G, Belkhir L, Vandercam B, Vincent A, Haufroid V, Elens L

Abstract
PURPOSE: A variety of diagnostic methods are available to validate the performance of population pharmacokinetic models. Internal validation, which applies these methods to the model building dataset and to additional data generated through Monte Carlo simulations, is often sufficient, but external validation, which requires a new dataset, is considered a more rigorous approach, especially if the model is to be used for predictive purposes. Our first objective was to validate a previously published population pharmacokinetic model of darunavir, an HIV protease inhibitor boosted with ritonavir or cobicistat. Our second objective was to use this model to derive optimal sampling strategies that maximize the amount of information collected with as few pharmacokinetic samples as possible.
METHODS: A validation dataset comprising 164 sparsely sampled individuals using ritonavir-boosted darunavir was used for validation. Standard plots of predictions and residuals, NPDE, visual predictive check, and bootstrapping were applied to both the validation set and the combined learning/validation set in NONMEM to assess model performance. D-optimal designs for darunavir were then calculated in PopED and further evaluated in NONMEM through simulations.
RESULTS: External validation confirmed model robustness and accuracy in most scenarios but also highlighted several limitations. The best one-, two-, and three-point sampling strategies were determined to be pre-dose (0 h); 0 and 4 h; and 1, 4, and 19 h, respectively. A combination of samples at 0, 1, and 4 h was comparable to the optimal three-point strategy. These could be used to reliably estimate individual pharmacokinetic parameters, although with fewer samples, precision decreased and the number of outliers increased significantly.
CONCLUSIONS: Optimal sampling strategies derived from this model could be used in clinical practice to enhance therapeutic drug monitoring or to conduct additional pharmacokinetic studies.

PMID: 33175180 [PubMed - as supplied by publisher]

Editorial: The Genetic and Environmental Basis for Diseases in Understudied Populations.

Front Genet. 2020;11:559956

Authors: Mulder N, Lombard Z, Owolabi MO, Ofori-Acquah SF

PMID: 33173534 [PubMed]

Individual variation in unfractionated heparin dosing after pediatric cardiac surgery.

Sci Rep. 2020 Nov 10;10(1):19438

Authors: Hikino K, Koido M, Ide K, Nishimura N, Terao C, Mushiroda T, Nakagawa S

Abstract
We aimed to identify attributing factors to the interindividual variabilities of the infusion rates in unfractionated heparin therapy. We included patients who required unfractionated heparin therapy to achieve the target APTT after cardiac surgery between May 2014 and February 2018. Fifty-nine patients were included, of whom 8 underwent Blalock-Taussig shunt; 27, Glenn procedure; 19, Fontan procedure; 3, mechanical valve replacement; and 2, Rastelli procedure. Previously reported variables that influenced the response to unfractionated heparin treatment were initially compared, which included age; weight; sex; type of surgery; platelet count; fibrinogen, antithrombin III, total protein, albumin, alanine transaminase, and creatinine levels; and use of fresh frozen plasma. The type of surgical procedure was found to be significantly associated with the differences in heparin infusion rate (P = 0.00073). Subsequently, the variance explained by these factors was estimated through a selection based on the minimum Akaike information criterion value; models constructed by various combinations of the surgery types were compared. The model including the Blalock-Taussig shunt, Glenn procedure, and mechanical valve replacement showed the highest summed variance explained (29.1%). More than 70% of the interindividual variability in initial heparin maintenance dosing was unexplained.

PMID: 33173059 [PubMed - in process]