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1.
Expert Opin Drug Metab Toxicol ; : 1-10, 2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-33896324

RESUMO

Introduction: Antipsychotic medications are used to treat a number of conditions in children and adolescents. While side effect profiles from second generation antipsychotics (SGAs) may differ from older antipsychotics, they do not come without risk. Knowing which children may be at higher risk for specific outcomes is important clinical information for prescribers. Common side effects and toxicities of SGAs in children include movement disorders, weight gain, and hormonal changes. There are also rare, but potentially dangerous adverse events including neuroleptic malignant syndrome, hypersensitivity and suicidal ideation.Areas covered: This review will summarize and comment on clinical, pharmacological, and genetic factors having evidence as predictors of SGA-associated side effects and toxicities in children.Expert opinion: Observations across studies note that older children and those that do not respond early in treatment may be more at risk for movement disorders, while younger, antipsychotic naive children are at increased risk for weight gain. Relatively fewer studies have looked at pharmacogenetic relationships, although variations in pharmacokinetic and pharmacodynamic genes hold promise to advance drug dosing or selection strategies. Future efforts to assimilate multiple clinical, pharmacological, and genetic factors to facilitate predictive analytics and clinical decision support for prescribers will advance precision care to patients.

2.
Neuropsychopharmacology ; 46(1): 143-155, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32979849

RESUMO

Focusing on biomarker identification and using biomarkers individually or in clusters to define biological subgroups in psychiatry requires a re-orientation from behavioral phenomenology to quantifying brain features, requiring big data approaches for data integration. Much still needs to be accomplished, not only to refine but also to build support for the application and customization of such an analytical phenotypic approach. In this review, we present some of what Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has learned so far to guide future applications of multivariate phenotyping and their analyses to understanding psychosis. This paper describes several B-SNIP projects that use phenotype data and big data computations to generate novel outcomes and glimpse what phenotypes contribute to disease understanding and, with aspiration, to treatment. The source of the phenotypes varies from genetic data, structural neuroanatomic localization, immune markers, brain physiology, and cognition. We aim to see guiding principles emerge and areas of commonality revealed. And, we will need to demonstrate not only data stability but also the usefulness of biomarker information for subgroup identification enhancing target identification and treatment development.

3.
JAMA Netw Open ; 3(12): e2029411, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33315113

RESUMO

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, Setting, and Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures: Prescription of 38 level A medications based on electronic health records. Main Outcomes and Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.


Assuntos
Serviços de Saúde da Criança , Cálculos da Dosagem de Medicamento , Testes Farmacogenômicos , Padrões de Prática Médica , Medicamentos sob Prescrição , Criança , Serviços de Saúde da Criança/normas , Serviços de Saúde da Criança/estatística & dados numéricos , Estudos Transversais , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Perfil Genético , Humanos , Masculino , Pediatria/métodos , Pediatria/normas , Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/estatística & dados numéricos , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Medicina de Precisão/métodos , Medicamentos sob Prescrição/classificação , Medicamentos sob Prescrição/uso terapêutico , Estados Unidos
4.
Pharmacotherapy ; 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33202062

RESUMO

INTRODUCTION: Warfarin's narrow therapeutic index and high variability in dosage requirements make dosage selection critical. Genetic factors are known to impact warfarin dosage selection. The Hmong are a unique Asian sub-population numbering over 278,000 in the United States whose participation in genetic-based research is virtually non-existent. The translational significance of early reports of warfarin pharmacogene differences in Hmong has not been evaluated. OBJECTIVES: 1): To validate previously identified allele frequency differences relevant to warfarin dosing in Hmong versus East Asians; and 2): To compare predicted warfarin sensitivity and maintenance doses between a Hmong population and an East Asian cohort. METHOD: DNA collected from two independent cohorts (N=236 and N=198) of Hmong adults were genotyped for CYP2C9 (*2,*3), VKORC1 (G-1639A), and CYP4F2 (*3). Allele frequencies between the combined Hmong cohort (N=433) and East Asians (N=1165) from the 2009 International Warfarin Pharmacogenetics Consortium (IWPC) study were compared using a χ2 test. Percentages of Hmong and East Asian participants predicted to be very sensitive to warfarin were compared using a χ2 test, and the predicted mean warfarin maintenance dose was compared with a t test. RESULTS: The allele frequency of CYP2C9*3 in the combined Hmong cohort and CYP4F2*3 in the VIP-Hmong cohort are significantly different from those in East Asians (18.9% versus 3.0%, p<0.001 and 9.8% versus 22.1%, p<0.001, respectively). Comparing the combined Hmong cohort to the East Asian cohort, the percentage of participants predicted to be very sensitive to warfarin was significantly higher (28% versus 5%, p<0.01) and the mean predicted warfarin maintenance dose was significantly lower (19.8 versus 21.3 mg/week, p<0.001), respectively. CONCLUSION: The unique allele frequencies related to warfarin when combined with non-genetic factors observed in the Hmong translate into clinically relevant differences in predicted maintenance dose requirements for Hmong versus East Asians.

5.
Pharmacopsychiatry ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33147643

RESUMO

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

6.
Mol Psychiatry ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060818

RESUMO

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

7.
J Am Med Inform Assoc ; 27(10): 1547-1555, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32940692

RESUMO

OBJECTIVE: We sought to assess the need for additional coverage of dietary supplements (DS) in the Unified Medical Language System (UMLS) by investigating (1) the overlap between the integrated DIetary Supplements Knowledge base (iDISK) DS ingredient terminology and the UMLS and (2) the coverage of iDISK and the UMLS over DS mentions in the biomedical literature. MATERIALS AND METHODS: We estimated the overlap between iDISK and the UMLS by mapping iDISK to the UMLS using exact and normalized strings. The coverage of iDISK and the UMLS over DS mentions in the biomedical literature was evaluated via a DS named-entity recognition (NER) task within PubMed abstracts. RESULTS: The coverage analysis revealed that only 30% of iDISK terms can be matched to the UMLS, although these cover over 99% of iDISK concepts. A manual review revealed that a majority of the unmatched terms represented new synonyms, rather than lexical variants. For NER, iDISK nearly doubles the precision and achieves a higher F1 score than the UMLS, while maintaining a competitive recall. DISCUSSION: While iDISK has significant concept overlap with the UMLS, it contains many novel synonyms. Furthermore, almost 3000 of these overlapping UMLS concepts are missing a DS designation, which could be provided by iDISK. The NER experiments show that the specialization of iDISK is useful for identifying DS mentions. CONCLUSIONS: Our results show that the DS representation in the UMLS could be enriched by adding DS designations to many concepts and by adding new synonyms.

8.
Schizophr Res ; 223: 236-241, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32829984

RESUMO

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype.

11.
Ment Health Clin ; 10(4): 254-258, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32685338

RESUMO

Pharmacogenomic (PGx) testing aided by therapeutic drug monitoring (TDM) has the potential to improve medication-related outcomes in some individuals prescribed psychiatric medications. Many commonly prescribed psychiatric medications are metabolized through polymorphic drug metabolizing enzymes such as cytochrome p450 (CYP) 2D6 (CYP2D6) and CYP2C19. Through PGx testing, clinicians can make biologically informed choices when selecting a new medication, and TDM may help inform dose adjustments or assess exposures to current treatments. Herein, we describe 2 complex case reports of individuals with multiple psychiatric diagnoses and extensive histories of medication failures who underwent PGx testing in addition to TDM as part of a pharmacist-led comprehensive medication therapy management evaluation in a community mental health clinic setting.

12.
Pharmacotherapy ; 40(7): 632-647, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32519344

RESUMO

BACKGROUND: Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified. OBJECTIVE: A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system. METHODS: A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone + 9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens. RESULTS: A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies. CONCLUSION: Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone + 9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.

13.
Curr Psychiatry Rep ; 22(5): 26, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32377970

RESUMO

PURPOSE OF REVIEW: This paper aims to acquaint child and adolescent psychiatrists with the field of pharmacogenomics (PGX) and review the most up-to-date evidence-based practices to guide the application of this field in clinical care. RECENT FINDINGS: Despite much research being done in this area, the field of PGX continues to yield controversial findings. In the adult world, studies have focused on the impact of combinatorial gene panels that guide medication selection by providing reports that estimate the impact of multiple pharmacodynamic and pharmacokinetic genes, but to date, these have not been directly examined in younger patient populations. Pharmacokinetic genes, CYP2D6 and CYP2C19, and hypersensitivity genes, HLA-A and HLA-B, have the strongest evidence base for application to pharmacotherapy in children. Although the field is evolving, and the evidence is mixed, there may be a role for PGX testing in children to help guide dosing and monitoring strategies. However, evidence-based medicine, rather than PGX testing, continues to play the lead role in guiding medication selection in pediatric psychopharmacology.


Assuntos
Farmacogenética , Psiquiatria , Adolescente , Psiquiatria do Adolescente , Adulto , Criança , Citocromo P-450 CYP2D6/genética , Medicina Baseada em Evidências , Humanos
14.
J Am Med Inform Assoc ; 27(4): 539-548, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068839

RESUMO

OBJECTIVE: To build a knowledge base of dietary supplement (DS) information, called the integrated DIetary Supplement Knowledge base (iDISK), which integrates and standardizes DS-related information from 4 existing resources. MATERIALS AND METHODS: iDISK was built through an iterative process comprising 3 phases: 1) establishment of the content scope, 2) development of the data model, and 3) integration of existing resources. Four well-regarded DS resources were integrated into iDISK: The Natural Medicines Comprehensive Database, the "About Herbs" page on the Memorial Sloan Kettering Cancer Center website, the Dietary Supplement Label Database, and the Natural Health Products Database. We evaluated the iDISK build process by manually checking that the data elements associated with 50 randomly selected ingredients were correctly extracted and integrated from their respective sources. RESULTS: iDISK encompasses a terminology of 4208 DS ingredient concepts, which are linked via 6 relationship types to 495 drugs, 776 diseases, 985 symptoms, 605 therapeutic classes, 17 system organ classes, and 137 568 DS products. iDISK also contains 7 concept attribute types and 3 relationship attribute types. Evaluation of the data extraction and integration process showed average errors of 0.3%, 2.6%, and 0.4% for concepts, relationships and attributes, respectively. CONCLUSION: We developed iDISK, a publicly available standardized DS knowledge base that can facilitate more efficient and meaningful dissemination of DS knowledge.

15.
Neuropsychopharmacology ; 45(4): 666-674, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31812151

RESUMO

Abnormal neuroanatomic brain networks have been reported in schizophrenia, but their characterization across patients with psychotic disorders, and their potential alterations in nonpsychotic relatives, remain to be clarified. Participants recruited by the Bipolar and Schizophrenia Network for Intermediate Phenotypes consortium included 326 probands with psychotic disorders (107 with schizophrenia (SZ), 87 with schizoaffective disorder (SAD), 132 with psychotic bipolar disorder (BD)), 315 of their nonpsychotic first-degree relatives and 202 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the participant groups. Compared with healthy controls, psychotic probands showed decreased nodal efficiency mainly in bilateral superior temporal regions. These regions had altered morphological relationships primarily with frontal lobe regions, and their network-level alterations were associated with positive symptoms of psychosis. Nonpsychotic relatives showed lower nodal centrality metrics in the prefrontal cortex and subcortical regions, and higher nodal centrality metrics in the left cingulate cortex and left thalamus. Diagnosis-specific analysis indicated that individuals with SZ had lower nodal efficiency in bilateral superior temporal regions than controls, probands with SAD only exhibited lower nodal efficiency in the left superior and middle temporal gyrus, and individuals with psychotic BD did not show significant differences from healthy controls. Our findings provide novel evidence of clinically relevant disruptions in the anatomic association of the superior temporal lobe with other regions of whole-brain networks in patients with psychotic disorders, but not in their unaffected relatives, suggesting that it is a disease-related trait. Network disorganization primarily involving frontal lobe and subcortical regions in nonpsychotic relatives may be related to familial illness risk.

16.
Annu Rev Pharmacol Toxicol ; 60: 311-331, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31283429

RESUMO

Pharmacogenetics is a key component of precision medicine. Genetic variation in drug metabolism enzymes can lead to variable exposure to drugs and metabolites, potentially leading to inefficacy and drug toxicity. Although the evidence for pharmacogenetic associations in children is not as extensive as for adults, there are several drugs across diverse therapeutic areas with robust pediatric data indicating important, and relatively common, drug-gene interactions. Guidelines to assist gene-based dose optimization are available for codeine, thiopurine drugs, selective serotonin reuptake inhibitors, atomoxetine, tacrolimus, and voriconazole. For each of these drugs, there is an opportunity to clinically implement precision medicine approaches with children for whom genetic test results are known or are obtained at the time of prescribing. For many more drugs that are commonly used in pediatric patients, additional investigation is needed to determine the genetic factors influencing appropriate dose.


Assuntos
Preparações Farmacêuticas/administração & dosagem , Farmacogenética/métodos , Medicina de Precisão/métodos , Criança , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Preparações Farmacêuticas/metabolismo
17.
Pharmacotherapy ; 40(2): 142-152, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31884695

RESUMO

OBJECTIVES: Implementing pharmacogenetics for very important pharmacogenes (VIPs) holds the promise of improving clinical outcomes through optimal medication selection and dosing. However, significant differences in the frequency of actionable variants in VIPs may exist within subpopulations of a given ancestral group. Furthermore, these differences can potentially impact drug selection and dosing. The purpose of this study was to ascertain allele frequencies for VIPs and to predict medication requirements using Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines in Hmong and compare with published data for East Asians. METHODS: Using a community-based participatory action research approach, DNA collected from 194 Hmong adults living in the United States was analyzed for 22 genetic variants within eight VIPs (CYP2C9, CYP2C19, CYP4F2, DPYD, G6PD, SLCO1B1, TPMT, VKORC1). Allele frequencies for VIPs and predicted medication requirements using CPIC guidelines were compared between Hmong participants and East Asians. RESULTS: Significant differences in allele frequencies between the Hmong and East Asians were found for 23% (5/22) of the CPIC-actionable variants tested. Allele frequencies for VIPs in Hmong versus East Asians were 16.6% versus 3.4% in CYP2C9*3A, 42.2% versus 29.0% for CYP2C19*2, 0.3% versus 8.3% in CYP2C19*3, 6.5% versus 22.1% in CYP4F2*3, and 3.6% versus 0.1% in SLCO1B1*5, respectively. These differences significantly influenced predicted medication usage recommendations in warfarin, simvastatin, and phenytoin between Hmong and East Asians. CONCLUSIONS: Important differences in allele frequencies for key genetic variants influencing selection of medications and dosages were found between the Hmong and East Asians. The magnitude and nature of these differences can be expected to result in different medication recommendations for the Hmong relative to East Asians.

19.
Transl Psychiatry ; 9(1): 230, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530798

RESUMO

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Ventrículos Laterais/diagnóstico por imagem , Moléculas de Adesão de Célula Nervosa/genética , Transtornos Psicóticos/genética , Adulto , Alelos , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/diagnóstico por imagem , Adulto Jovem
20.
Am J Cardiol ; 124(7): 1038-1043, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31375243

RESUMO

Guideline-recommended anticoagulation is frequently omitted in high-risk patients with atrial fibrillation (AF) for reasons not fully understood, which may result in suboptimal care. A nationally representative, expert group of physicians (cardiology, neurology, and general medicine), and clinical pharmacists participated in a consensus-seeking, modified Delphi method to identify key clinical decision-making factors driving anticoagulant prescribing in real-world AF patients. Representing >2,500 anticoagulation-related patient encounters per month, 27 of 30 participants completed the study (90% overall response rate). In Round-1, experts rated their level of agreement with factors and suggested modifications or additional factors. Of 66 factors entering Round-1, 21 met and 4 partially met consensus, 41 did not meet consensus, and 7 were newly suggested. Of 32 factors advanced for scoring in Round-2, 16 met consensus criteria. In Round-3, experts were given the option to rescue up to 2 of the 16 nonconsensus factors from Round-2. Including a concomitant need for dual antiplatelet therapy, no factor was successfully rescued into consensus. The most important factors related to risk of infarction rather than bleeding risk or other patient-specific considerations. Among factors not independently addressed in current guidelines, these included baseline hematologic indicators of potential bleeding risk, previous bleeding episodes by specific type, other risk factors for bleeding, and adherence. In conclusion, when determining anticoagulation strategies in AF, there is a need for further research on the clinical implications of these emerging factors as well as the reasons behind divergent opinions toward nonconsensus factors.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Tomada de Decisão Clínica , Seleção de Pacientes , Padrões de Prática Médica , Adulto , Consenso , Técnica Delfos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle
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