Leveraging QSP Models for MIPD: A Case Study for Warfarin/INR

Warfarin dosing remains challenging due to substantial inter-individual variability, which can lead to unsafe or ineffective therapy with standard dosing. Model-informed precision dosing (MIPD) can help individualize warfarin dosing, requiring the selection of a suitable model. For models developed from clinical data, the dependence on the study design and population raises questions about generalizability. Quantitative system pharmacology (QSP) models promise better extrapolation abilities; however, their complexity and lack of validation on clinical data raise questions about applicability in MIPD. We have previously derived a mechanistic warfarin/international normalized ratio (INR) model from a blood coagulation QSP model. In this article, we evaluated the predictive performance of the warfarin/INR model in the context of MIPD using an external dataset with INR data from patients starting warfarin treatment. We assessed the accuracy and precision of model predictions, benchmarked against an empirically based reference model. Additionally, we evaluated covariate contributions and assessed the predictive performance separately in the more challenging outpatient data. The warfarin/INR model performed comparably to the reference model across various measures despite not being calibrated with warfarin initiation data. Including CYP2C9 and/or VKORC1 genotypes as covariates improved the prediction quality of the warfarin/INR model, even after assimilating 4 days of INR data. The outpatient INR exhibited higher unexplained variability, and predictions slightly exceeded observed values, suggesting that model adjustments might be necessary when transitioning from an inpatient to an outpatient setting. Overall, this research underscores the potential of QSP-derived models for MIPD, offering a complementary approach to empirical model development

Is evolution faster at ecotones? A test using rates and tempo of diet transitions in Neotropical Sigmodontinae (Rodentia, Cricetidae)

We evaluated whether evolution is faster at ecotones as niche shifts may be needed to persist under unstable environment. We mapped diet evolution along the evolutionary history of 350 sigmodontine species. Mapping was used in three new tipbased metrics of trait evolution – Transition Rates, Stasis Time, and Last Transition Time – which were spatialized at the assemblage level (aTR, aST, aTL). Assemblages were obtained by superimposing range maps on points located at core and ecotone of the 93 South American ecoregions. Using Linear Mixed Models, we tested whether ecotones have species with more changes from the ancestral diet (higher aTR), have maintained the current diet for a shorter time (lower aST), and have more recent transitions to the current diet (lower aLT) than cores. We found lower aTR, and higher aST and aLT at ecotones than at cores. Although ecotones are more heterogeneous, both environmentally and in relation to selection pressures they exert on organisms, ecotone species change little from the ancestral diet as generalist habits are necessary toward feeding in ephemeral environments. The need to incorporate phylogenetic uncertainty in tip-based metrics was evident from large uncertainty detected. Our study integrates ecology and evolution by analyzing how fast trait evolution is across space

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value

Implementation of inpatient models of pharmacogenetics programs

The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted

Genome-wide association study of Tourette Syndrome

Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder

Impactos económicos y ecológicos de la participación en las cadenas globales de valor en los países latinoamericanos, 1995-2011.

En esta tesis se analizan los impactos económicos y ecológicos asociados a la evolución y características de la participación en las Cadenas Globales de Valor (CGV) de siete países latinoamericanos, Argentina, Brasil, Chile, Colombia, Costa Rica, México y Perú, desde una perspectiva multirregional y multisectorial en el periodo 1995-2011. La participación en las CGV y sus impactos económicos se fundamentó en un modelo MRIO denominado GVC income (Timmer et al., 2013, 2015, 2016). Para el análisis de los impactos ecológicos se extiende el modelo MRIO a la consideración de los flujos ambientales (Miller y Blair, 2009; Wiedmann et al., 2011). Nuestra hipótesis es que los países latinoamericanos participan relativamente con mayor intensidad en las etapas iniciales que en las etapas intermedias-finales de las CGV. Esta participación no se concretó en cambios robustos en las estructuras económicas, ni en la configuración de tendencias sostenidas hacia la mejora de los términos de intercambio de los países latinoamericanos. Adicionalmente, los intercambios ecológicos incorporados directa e indirectamente en el comercio internacional se relacionan con mayores presiones sobre la explotación de recursos naturales, como el uso de la superficie agrícola, el consumo de agua, los flujos de materias primas intercambiadas, así como mayores emisiones de carbono. Por ello, analizamos cómo ha evolucionado la participación de los países latinoamericanos en las etapas de producción de las CGV y cuáles han sido sus impactos económicos considerando el rol dinamizador de la industria en el cambio de las estructuras económicas, asimismo se analizó el valor añadido incorporado en los flujos de comercio internacional, para determinar los beneficios/pérdidas del comercio de los países latinoamericanos con el resto del mundo, Norteamérica, Unión Europea, Asia, Otros Países Europeos y Medio Oriente y África. Finalmente, se estudiaron los impactos ecológicos asociados a la participación de los países latinoamericanos en las CGV y sus relaciones con siete regiones desarrolladas, basándonos en indicadores que muestran el uso de la tierra agrícola, el consumo de agua, los flujos de materias primas y las emisiones de carbono en el periodo 1990-2015. La tesis se estructuró en seis capítulos. En el primero se describe el panorama general de los países latinoamericanos en el proceso de transformación estructural de la economía mundial. En el segundo se presentan los elementos teóricos esenciales del concepto CGV como marco articulador en el análisis de la participación de los países en los procesos de integración productiva y comercial, directa e indirectamente, derivadas de la fragmentación internacional de la producción. Esto se complementa con la incorporación del concepto comercio internacional de valor añadido, que es clave en la investigación empírica fundamentada en el marco de análisis input-output bajo los criterios del modelo MRIO denominado GVC income. En los capítulos tres y cuarto, se analizan los impactos económicos de la participación de los países latinoamericanos en las CGV, desde la perspectiva de la estructura de la producción, estimando para ellos indicadores de las capacidades de arrastre e impulso para la clasificación de las industrias en clave, de arrastre, de impulso y no relevantes. En el cuarto capítulo se examinan los términos de intercambio de los países latinoamericanos en diferentes escalas industriales y geográficas con el propósito de determinar cómo han evolucionado las transferencias internacionales de la renta entre países y regiones durante el periodo. El análisis de los impactos ecológicos de la región latinoamericana en el contexto de las CGV se analizó en el capítulo cinco. Finalmente, en el capítulo seis, se enumeran las conclusiones generales.<br /

Genetic variation in RYR1 is associated with heart failure progression and mortality in a diverse patient population

IntroductionHeart failure (HF) is a highly prevalent disease affecting roughly 7 million Americans. A transcriptome-wide analysis revealed RYR1 upregulation in HF patients with severe pulmonary hypertension. Therefore, we aimed to further characterize the role of RYR1 in HF progression and mortality.MethodsIn a mouse model of HF, expression of Ryr1 was compared in cardiac pulmonary, and vascular tissue between HF and control mice. Candidate single nucleotide polymorphisms (SNPs) in the RYR1 gene region were identified, including variants affecting RYR1 expression in relevant tissue types. A Cox proportional hazard model was used to analyze genetic associations of candidate SNPs with all-cause mortality in HF patients. An exploratory analysis assessed significantly associated SNPs with risk of HF and arrhythmia development.ResultsIn the preclinical HF model, left ventricular expression of Ryr1 was increased compared to control (fold change = 2.08; P = 0.01). In 327 HF patients, decreased mortality risk was associated with two RYR1 SNPs: rs12974674 (HR: 0.59; 95% CI: 0.40–0.87; P = 0.007) and rs2915950 (HR: 0.62, 95% CI: 0.43–0.88; P = 0.008). Based on eQTL data, these SNPs were associated with decreased RYR1 expression in vascular tissue. Two missense variants, in linkage disequilibrium with rs2915950 (rs2915952 and rs2071089) were significantly associated with decreased mortality risk (P = 0.03) and decreased risk of atrial fibrillation/flutter (OR: 0.66, 95% CI: 0.44–0.96; P = 0.03 and OR: 0.67, 95% CI: 0.45–0.98; P = 0.04, respectively). Survival associations with these SNPs were replicated in HF patients self-identifying as Black in the UK Biobank, and the arrhythmia associations were replicated in the overall UK Biobank population.ConclusionIncreased RYR1 expression may contribute to HF progression, potentially through the mechanisms associated with calcium handling and arrhythmia development. Our findings suggest that RYR1 should be further studied as a potential therapeutic target for reducing HF-related mortality

CYTOTOXICITY, ANTI-POLIOVIRUS ACTIVITY AND IN SILICO BIOLOGICAL EVALUATION OF CONSTITUENTS FROM MAYTENUS GONOCLADA (CELASTRACEAE)

Objective: The in silico free access web tools PASS online and ChemMapper were used to predict potential biological activities of compounds 1 to 8 isolated from Maytenus gonoclada (Celastraceae). The constituents 4'-O-methylepigalocatequin (6), tingenone (7) and proanthocyanidin A (8), and ethanolic extracts were subjected to in vitro cytotoxicity using VERO cells and anti-Poliovirus assays. Methods: QSAR and molecular superposition, correlating the average number of pharmacophores were used in the prediction studies. Cellular line VERO ATCC CCL-81 was used to determine anti-Poliovirus effect, observed by colorimetric (MTT) method. The annexing V/propidium iodide assay was used to determine the occurrence of apoptosis in the cytotoxicity assays. Results: The experimental results found for constituents 6-8 were in accordance with observed data obtained through PASS online and ChemMapper simulation. Conclusion: Compound 7 showed higher cytotoxic and apoptosis induction properties, and 6 and 8 presented anti-Poliovirus activity

An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers.

Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information. Moreover, current clinical recommendations for cardiovascular pharmacogenetics can be confusing because they are outdated, incomplete, or inconsistent. A myriad of misconceptions about the promise and feasibility of cardiovascular pharmacogenetics among healthcare providers also has halted clinical implementation. Therefore, the main goal of this tutorial is to provide introductory education on the use of cardiovascular pharmacogenetics in clinical practice. The target audience is any healthcare provider (or student) with patients that use or have indications for cardiovascular drugs. This tutorial is organized into the following 6 steps: (1) understand basic concepts in pharmacogenetics; (2) gain foundational knowledge of cardiovascular pharmacogenetics; (3) learn the different organizations that release cardiovascular pharmacogenetic guidelines and recommendations; (4) know the current cardiovascular drugs/drug classes to focus on clinically and the supporting evidence; (5) discuss an example patient case of cardiovascular pharmacogenetics; and (6) develop an appreciation for emerging areas in cardiovascular pharmacogenetics. Ultimately, improved education among healthcare providers on cardiovascular pharmacogenetics will lead to a greater understanding for its potential in improving outcomes for a leading cause of morbidity and mortality

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for <i>CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4</i>, and <i>GRK5 </i>Genotypes and Beta-Blocker Therapy

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).</p