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

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

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 /

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

Challenges in the diagnosis and management of acromegaly : a focus on comorbidities

Q2Q1Introduction: Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life. Methods: We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment. Findings and conclusions: Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.https://orcid.org/0000-0002-8433-5435N/

Applying agroclimatic seasonal forecasts to improve rainfed maize agronomic management in Colombia

Climate variability affects crop production in multiple and often complex ways. The development and use hybrid crops with greater productivity and tolerance to climate shocks is one of the approaches to climate adaptation and agricultural intensification. Since hybrid crops are more expensive for the producer, risk management is of paramount importance. Here, we pose that there is high potential for the Colombian maize sector to use crop-specific climate services for risk reduction. We used the CERES-Maize crop model connected to seasonal climate forecasts developed via Canonical Correlation Analysis (CCA) across key maize growing areas in Colombia to assess the performance of a maize-specific agroclimatic forecast to inform two key decisions, namely, the choice of sowing dates and genotypes. We find that the agroclimatic models perform well at discriminating yield categories (above, below, and normal) with discrimination capacity of up to 70–80 % for the ‘below normal’ and ‘above + below normal’ categories. Consistent with this, agroclimatic forecasts typically predict the optimal planting date with an error of 3 pentads or less. They also predict the optimal choice of genotype correctly around 50–70 % of the time depending on the site or season of interest. Notably, we identify specific cases in which the agroclimatic forecast is misleading but argue that the overall value of the forecasts outweighs these cases. Future work should focus on expanding the scope of the agroclimatic prediction to include other relevant farming decisions that are influenced by climate, and on the improvement of climate forecast performance

Multi-site investigation of strategies for the implementation of CYP2C19 genotype-guided antiplatelet therapy

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes which are both related to CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions. This article is protected by copyright