Big Data to Knowledge Analytics Reveals the Zika Virus Epidemic as Only One of Multiple Factors Contributing to a Year-Over-Year 28-Fold Increase in Microcephaly Incidence.

During the 2015-2016 Zika Virus (ZIKV) epidemic in Brazil, the geographical distributions of ZIKV infection and microcephaly outbreaks did not align. This raised doubts about the virus as the single cause of the microcephaly outbreak and led to research hypotheses of alternative explanatory factors, such as environmental variables and factors, agrochemical use, or immunizations. We investigated context and the intermediate and structural determinants of health inequalities, as well as social environment factors, to determine their interaction with ZIKV-positive- and ZIKV-negative-related microcephaly. The results revealed the identification of 382 associations among 382 nonredundant variables of Zika surveillance, including multiple determinants of environmental public health factors and variables obtained from 5565 municipalities in Brazil. This study compared those factors and variables directly associated with microcephaly incidence positive to ZIKV and those associated with microcephaly incidence negative to ZIKV, respectively, and mapped them in case and control subnetworks. The subnetworks of factors and variables associated with low birth weight and birthweight where birth incidence served as an additional control were also mapped. Non-significant differences in factors and variables were observed, as were weights of associations between microcephaly incidence, both positive and negative to ZIKV, which revealed diagnostic inaccuracies that translated to the underestimation of the scope of the ZIKV outbreak. A detailed analysis of the patterns of association does not support a finding that vaccinations contributed to microcephaly, but it does raise concerns about the use of agrochemicals as a potential factor in the observed neurotoxicity arising from the presence of heavy metals in the environment and microcephaly not associated with ZIKV. Summary: A comparative network inferential analysis of the patterns of variables and factors associated with Zika virus infections in Brazil during 2015-2016 coinciding with a microcephaly epidemic identified multiple contributing determinants. This study advances our understanding of the cumulative interactive effects of exposures to chemical and non-chemical stressors in the built, natural, physical, and social environments on adverse pregnancy and health outcomes in vulnerable populations.

Local deliberative approach to the bioethical controversies: An opportunity for the proper implementation of neonatal screening / [Enfoque local deliberativo de las controversias bioéticas: una oportunidad para la adecuada implementación de la tamización neonatal].

Introduction: The controversial characteristics of neonatal screening influenced by bioethical considerations make its implementation complex. Colombia is not an exception in this sense and local circumstances complicate the panorama. Objective: To establish how bioethical controversies on neonatal screening are approached at a local level as a basis for deliberating on the must-be of this activity in Colombia. Materials and methods: A survey immersed in an interpretative investigation with descriptive and deliberative components of analysis was applied to approach the values exposed by officials of the Colombian Instituto Nacional de Salud. Results: The compulsory offer of screening by the nation, regardless of its opportunity cost and the consent for the use in research of results and residual samples, were not controversial, but, in contrast, the type of information and the consent to authorize screening did arise controversy. The more experienced officials preferred mandatory screening (17.7 vs. 11.79 years on average, p=0.007). Surprisingly, despite the risk of discrimination, keeping the neonate as the purpose, there was agreement on giving all the information to parents and medical records. Another controversial aspect was the follow-up of cases without hiding their identification where officials with more experience in bioethical aspects preferred the use of codes (4.5 vs. 1.26 years on average, p=0.009). In this context, strategies such as informed dissent, specialized advice or public health programs that appreciate diversity would allow to rescue even seemingly opposite values. Conclusion: A local approach regarding what ought to be in neonatal screening based on a deliberative bioethical perspective allowed to present an implementation proposal for this activity

Introducción. Las características controversiales de la tamización neonatal influenciadas por consideraciones bioéticas hacen compleja su implementación. Colombia no es ajena a esta situación y las circunstancias locales complican el panorama. Objetivo. Determinar cómo se abordan en el contexto local las controversias bioéticas en torno a la tamización neonatal como fundamento de las deliberaciones sobre el deber ser de esta actividad en Colombia. Materiales y métodos. Se aplicó una encuesta en el marco de un estudio interpretativo con dos componentes de análisis, uno descriptivo y otro deliberativo, en torno a los valores expuestos por funcionarios del Instituto Nacional de Salud. Resultados. La oferta obligatoria de la tamización por parte de la nación, independientemente del costo de oportunidad y el consentimiento para el uso de sus resultados y de las muestras residuales en la investigación, no suscitaron controversias, pero sí el tipo de información y la autorización para hacer la tamización. Los funcionarios con mayor experiencia expresaron su preferencia por una tamización obligatoria (17,7 Vs. 11,79 años en promedio; p=0,007). Sorpresivamente, a pesar del riesgo de discriminación, teniendo como fin el neonato, hubo acuerdo en entregar toda la información a padres e historia clínica. Otro aspecto controversial fue la identificación de los pacientes en el seguimiento, frente a lo cual los funcionarios de mayor experiencia en aspectos bioéticos prefirieron el uso de códigos (4,5 Vs. 1,26 años en promedio; p=0,009). En este contexto, estrategias como el disentimiento informado, el asesoramiento especializado o los programas de salud pública que aprecien la diversidad permitirían rescatar valores, incluso aquellos aparentemente opuestos. Conclusión. La aproximación local al deber ser de la tamización neonatal desde una perspectiva bioética deliberativa permitió ajustar una propuesta para su implementación.

Enfoque local deliberativo de las controversias bioéticas: una oportunidad para la adecuada implementación de la tamización neonatal / Local deliberative approach to the bioethical controversies: An opportunity for the proper implementation of neonatal screening

Resumen: Introducción. Las características controversiales de la tamización neonatal influenciadas por consideraciones bioéticas hacen compleja su implementación. Colombia no es ajena a esta situación y las circunstancias locales complican el panorama. Objetivo. Determinar cómo se abordan en el contexto local las controversias bioéticas en torno a la tamización neonatal como fundamento de las deliberaciones sobre el deber ser de esta actividad en Colombia. Materiales y métodos. Se aplicó una encuesta en el marco de un estudio interpretativo con dos componentes de análisis, uno descriptivo y otro deliberativo, en torno a los valores expuestos por funcionarios del Instituto Nacional de Salud. Resultados. La oferta obligatoria de la tamización por parte de la nación, independientemente del costo de oportunidad y el consentimiento para el uso de sus resultados y de las muestras residuales en la investigación, no suscitaron controversias, pero sí el tipo de información y la autorización para hacer la tamización. Los funcionarios con mayor experiencia expresaron su preferencia por una tamización obligatoria (17,7 Vs. 11,79 años en promedio; p=0,007). Sorpresivamente, a pesar del riesgo de discriminación, teniendo como fin el neonato, hubo acuerdo en entregar toda la información a padres e historia clínica. Otro aspecto controversial fue la identificación de los pacientes en el seguimiento, frente a lo cual los funcionarios de mayor experiencia en aspectos bioéticos prefirieron el uso de códigos (4,5 Vs. 1,26 años en promedio; p=0,009). En este contexto, estrategias como el disentimiento informado, el asesoramiento especializado o los programas de salud pública que aprecien la diversidad permitirían rescatar valores, incluso aquellos aparentemente opuestos. Conclusión. La aproximación local al deber ser de la tamización neonatal desde una perspectiva bioética deliberativa permitió ajustar una propuesta para su implementación.

Abstract: Introduction: The controversial characteristics of neonatal screening influenced by bioethical considerations make its implementation complex. Colombia is not an exception in this sense and local circumstances complicate the panorama. Objective: To establish how bioethical controversies on neonatal screening are approached at a local level as a basis for deliberating on the must-be of this activity in Colombia. Materials and methods: A survey immersed in an interpretative investigation with descriptive and deliberative components of analysis was applied to approach the values exposed by officials of the Colombian Instituto Nacional de Salud. Results: The compulsory offer of screening by the nation, regardless of its opportunity cost and the consent for the use in research of results and residual samples, were not controversial, but, in contrast, the type of information and the consent to authorize screening did arise controversy. The more experienced officials preferred mandatory screening (17.7 vs. 11.79 years on average, p=0.007). Surprisingly, despite the risk of discrimination, keeping the neonate as the purpose, there was agreement on giving all the information to parents and medical records. Another controversial aspect was the follow-up of cases without hiding their identification where officials with more experience in bioethical aspects preferred the use of codes (4.5 vs. 1.26 years on average, p=0.009). In this context, strategies such as informed dissent, specialized advice or public health programs that appreciate diversity would allow to rescue even seemingly opposite values. Conclusion: A local approach regarding what ought to be in neonatal screening based on a deliberative bioethical perspective allowed to present an implementation proposal for this activity.

Bioethics and public policies in neonatal screening in the United States, United Kingdom, and Colombia / Bioética y políticas públicas de tamización neonatal en los Estados Unidos, el Reino Unido y Colombia

Introduction: Thinking about how neonatal screening should be done requires explaining the relevance of the bioethical factors involved. Objective: To understand the relationship between bioethical considerations and the way neonatal screening is done and to identify its relevance in the Colombian legislation. Materials and methods: A comparative study of public policies in the United States and the United Kingdom was done, as they exemplify extreme cases of neonatal screening. The influence of bioethical principles was interpreted based on similarities and differences. With this information, locally affected bioethical considerations were identified in the Colombian legislation on neonatal screening. Results: In the United Kingdom, paternal autonomy prevails allowing parents to deny obligatory beneficence. In the USA, beneficence prevails and a significant number of anomalies must be screened for. This increases the likelihood of false positives and causes a high opportunity cost. Both countries have similarities which are also partially accepted in Colombia, such as the demand for equity of access. Others, such as specialized professional advice or the right to refuse screening, are not considered in the Colombian legislation on neonatal screening. Additionally, there are circumstances in Colombia such as different perspectives on what respecting justice means and how to apply that in choosing which abnormalities are screened for and lack of harmony between norms that prevents efficacious detection. Conclusion: Bioethical considerations explain the differences between countries and sometimes prevail in the development of public policies on neonatal screening. Their inclusion in high-level norms in Colombia for effective screening is proposed.

Introducción. La reflexión sobre cómo deber ser la tamización neonatal requiere revelar la relevancia de los factores bioéticos involucrados. Objetivo. Comprender la relación de las consideraciones bioéticas con la forma en que se efectúa la tamización neonatal e indicar la relevancia de esta actividad en las normas colombianas. Materiales y métodos. Se hizo un estudio comparado de las políticas públicas en Estados Unidos y el Reino Unido, las cuales representan casos extremos de la tamización neonatal. Con base en las similitudes y las diferencias, se interpretó la influencia de los principios bioéticos. Con esta información, se indicaron en la normatividad colombiana sobre tamización neonatal las consideraciones bioéticas pertinentes. Resultados. En el Reino Unido prevalece la autonomía de los padres, lo que ocasiona riesgos al no cumplirse con las acciones obligatorias de beneficencia. En los Estados Unidos prevalece la beneficencia, con un amplio y obligatorio cubrimiento de anomalías sujetas a tamización, lo cual incrementa la probabilidad de falsos positivos y ocasiona un alto costo de oportunidad. Hay similitudes entre los procedimientos de los dos países que también están parcialmente contemplados en Colombia, como la pretensión de equidad en el acceso. Otras, como el asesoramiento profesional especializado o la posibilidad de rechazar la tamización, no se tienen en cuenta en la normatividad colombiana sobre tamización neonatal. Además, hay diferentes enfoques de justicia frente a la inclusión de las anomalías en la tamización y falta de armonía entre las normas, lo que impide una detección eficaz. Conclusión. Las consideraciones bioéticas no solo explican las diferencias entre países, sino que algunas veces prevalecen en la concepción de las políticas públicas de tamización neonatal. En Colombia, se propone su inclusión en las normas de mayor jerarquía para hacerlas más efectivas.

Bioética y políticas públicas de tamización neonatal en los Estados Unidos, el Reino Unido y Colombia / Bioethics and public policies in neonatal screening in the United States, United Kingdom, and Colombia

Resumen Introducción. La reflexiónsobre cómo deber ser la tamización neonatal requiere revelar la relevancia de los factores bioéticos involucrados. Objetivo. Comprender la relación de las consideraciones bioéticas con la forma en que se efectúa la tamización neonatal e indicar la relevancia de esta actividad en las normas colombianas. Materiales y métodos. Se hizo un estudio comparado de las políticas públicas en Estados Unidos y el Reino Unido, las cuales representan casos extremos de la tamización neonatal. Con base en las similitudes y las diferencias, se interpretó la influencia de los principios bioéticos. Con esta información, se indicaron en la normatividad colombiana sobre tamización neonatal las consideraciones bioéticas pertinentes. Resultados. En el Reino Unido prevalece la autonomía de los padres, lo que ocasiona riesgos al no cumplirse con las acciones obligatorias de beneficencia. En los Estados Unidos prevalece la beneficencia, con un amplio y obligatorio cubrimiento de anomalías sujetas a tamización, lo cual incrementa la probabilidad de falsos positivos y ocasiona un alto costo de oportunidad. Hay similitudes entre los procedimientos de los dos países que también están parcialmente contemplados en Colombia, como la pretensión de equidad en el acceso. Otras, como el asesoramiento profesional especializado o la posibilidad de rechazar la tamización, no se tienen en cuenta en la normatividad colombiana sobre tamización neonatal. Además, hay diferentes enfoques de justicia frente a la inclusión de las anomalías en la tamización y falta de armonía entre las normas, lo que impide una detección eficaz. Conclusión. Las consideraciones bioéticas no solo explican las diferencias entre países, sino que algunas veces prevalecen en la concepción de las políticas públicas de tamización neonatal. En Colombia, se propone su inclusión en las normas de mayor jerarquía para hacerlas más efectivas.

Abstract Introduction: Thinking about how neonatal screening should be done requires explaining the relevance of the bioethical factors involved. Objective: To understand the relationship between bioethical considerations and the way neonatal screening is done and to identify its relevance in the Colombian legislation. Materials and methods: A comparative study of public policies in the United States and the United Kingdom was done, as they exemplify extreme cases of neonatal screening. The influence of bioethical principles was interpreted based on similarities and differences. With this information, locally affected bioethical considerations were identified in the Colombian legislation on neonatal screening. Results: In the United Kingdom, paternal autonomy prevails allowing parents to deny obligatory beneficence. In the USA, beneficence prevails and a significant number of anomalies must be screened for. This increases the likelihood of false positives and causes a high opportunity cost. Both countries have similarities which are also partially accepted in Colombia, suchas the demand for equity of access. Others, suchas specialized professional advice or the right to refuse screening, are not considered in the Colombian legislation on neonatal screening. Additionally, there are circumstances in Colombia such as different perspectives on what respecting justice means and how to apply that in choosing which abnormalities are screened for and lack of harmony between norms that prevents efficacious detection. Conclusion: Bioethical considerations explain the differences between countries and sometimes prevail in the development of public policies on neonatal screening. Their inclusion in high-level norms in Colombia for effective screening is proposed.

Creating and validating a warfarin pharmacogenetic dosing algorithm for Colombian patients.

PURPOSE: Warfarin is an oral anticoagulant associated with adverse reaction to drugs due to wide inter- and intra-individual dosage variability. Warfarin dosage has been related to non-genetic and genetic factors. CYP2C9 and VKORC1 gene polymorphisms affect warfarin metabolism and dosage. Due to the central role of populations' ethnical and genetic origin on warfarin dosage variability, novel algorithms for Latin American subgroups are necessary to establish safe anticoagulation therapy. PATIENTS AND METHODS: We genotyped CYP2C9*2 (c.430C > T), CYP2C9*3 (c.1075A > C), CYP4F2 (c.1297G > A), and VKORC1 (-1639 G > A) polymorphisms in 152 Colombian patients who received warfarin. We evaluated the impact on the variability of patients' warfarin dose requirements. Multiple linear regression analysis, using genetic and non-genetic variables, was used for creating an algorithm for optimal warfarin maintenance dose. RESULTS: Median weekly prescribed warfarin dosage was significantly lower in patients having the VKORC1-1639 AA genotype and poor CYP2C9*2/*2,*2/*3 metabolizers than their wild-type counterparts. We found a 2.3-fold increase in mean dose for normal sensitivity patients (wild-type VKORC1/CYP2C9 genotypes) compared to the other groups (moderate and high sensitivity); 31.5% of the patients in our study group had warfarin sensitivity-related genotypes. The estimated regression equation accounted for 44.4% of overall variability in regard to warfarin maintenance dose. The algorithm was validated, giving 45.9% correlation (R 2=0.459). CONCLUSION: Our results describe and validate the first algorithm for predicting warfarin maintenance in a Colombian mestizo population and have contributed toward the understanding of pharmacogenetics in a Latin American population subgroup.

Generalización diagnóstica fractal de la morfología cardiaca ventricular izquierda: anormalidades moderadas y severas a partir del ventriculograma / Fractal Diagnostic Generalization of Left Ventricular Cardiac Morphology: Moderate and Severe Anormalities from Ventriculography

Introducción: La irregularidad cardiaca es adecuadamente descrita mediante geometría fractal, la cual fue base para el desarrollo de un diagnóstico del ventriculograma izquierdo. Métodos: Se simularon la totalidad de permutaciones posibles de grados de similitud de las dimensiones fractales del ventrículo en sístole, diástole y totalidad, definidas entre los valores mínimos y máximos de los grados de similitud para anormalidad moderada y severa previamente establecidos. Resultados: Se estableció el número total de prototipos ventriculares entre anormalidad moderada y severa. El número total de prototipos de estructura ventricular posibles fue de 1614: 794 ventrículos con anonnalidad moderada y 820 con anonnalidad severa. Medidas previas de ventrículos con diagnóstico de anonnalidad moderada y severa se encontraron incluidas dentro de la generalización. Conclusiones: Se desarrolló una metodología geométrica objetiva y de ayuda diagnóstica a nivel clínico, que determinó todas las posibles estructuras ventriculares izquierdas con anonnalidad moderada y severa, independientemente de clasificaciones clínicas.

Introduction: The cardiac irregularity is adequately described by means of fractal geometry, which was the basis for the development of a diagnosis of left ventriculography. Methods: All possible pennutations of similarity degrees from fractal dimensions were done for the ventricle in systole. diastole and the totality. Pennutations were defined between the previously established mínimum and máximum valúes of similarity degrees for modérate and severe anonnality. Results: It was established the total number of possible ventricular prototypes between modérate and severe anonnality. The total number of possible ventricular structure prototypes is 1614: 794 of ventricles with modérate anonnality and 820 of ventricles with severe anonnality. Practical measures made previously were found within the generalization. Conclusions: It was developed an objective geometric methodology. which is of diagnostic aid in the clinical practice. It detennined all possible left ventricular structures with modérate and severe anonnality independent of clinical classifications.

Theoretical geometric generalization of left ventriculogram during cardiac dynamic of clinical application / Generalización geométrica teórica del ventriculograma izquierdo durante la dinámica cardíaca de aplicación clínica

Abstract: Fractal geometry has proven to be adequate for mathematical description of irregular objects such as the human body. Based on this geometry, an objective and reproducible representation of a left ventricle was previously developed. The aim of this research was to develop a simulation based on this methodology that allows establishing all possible left ventricular dynamics from normality to severe disease. All possible combinations for each state were determined from maximum and minimum values of similarity degrees previously found for normal ventricular structures with mild, moderate and severe disease. The whole spectrum of ventricular dynamics between normality and disease during cardiac dynamic was quantified. There were found out 2,165 possible prototypes of ventricular structure: 551 of healthy states, 794 of mild and moderate disease, and 820 of severe disease. It was found that the similarity degrees of ventricle measures observed in previous studies were included within the identified prototypes. Thus, a generalization that establishes all possible ventricular fractal prototypes that may be found in clinical practice was developed, which is able to differentiate a normal state from several degrees of disease.

Resumen: La geometría fractal ha probado ser adecuada para la descripción de objetos irregulares tales como el cuerpo humano. Con base en esta geometría, se desarrolló previamente una representación objetiva y reproducible de un ventrículo izquierdo. El objetivo de esta investigación fue desarrollar una simulación basada en esta metodología que permita establecer todas las dinámicas posibles del ventrículo izquierdo desde la normalidad hasta la enfermedad severa. Todas las combinaciones posibles para cada estado se determinaron a partir de los valores máximos y mínimos de los grados de similitud previamente encontrados para las estructuras ventriculares normales con enfermedad leve, moderada y grave. Se cuantificó todo el espectro de la dinámica ventricular entre la normalidad y la enfermedad durante la dinámica cardíaca. Se encontraron 2,165 posibles prototipos de estructura ventricular: 551 de estados sanos, 794 de enfermedad leve y moderada y 820 de enfermedad severa. Se encontró que los grados de similitud de las medidas de ventrículo observadas en estudios previos se incluyeron dentro de los prototipos identificados. De esta manera, se desarrolló una generalización que establece todos los posibles prototipos de ventrículo fractal que se pueden encontrar en la práctica clínica, que es capaz de diferenciar un estado normal de varios grados de enfermedad.

Prediction of sensitivity to warfarin based on VKORC1 and CYP2C9 polymorphisms in patients from different places in Colombia.

INTRODUCTION: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin.  OBJECTIVE: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients' sensitivity to warfarin at the Hospital Militar Central, a reference center for patients born in different parts of Colombia.  MATERIALS AND METHODS: Demographic and clinical data were obtained from 130 patients with stable doses of warfarin for more than two months. Next, their genotypes were obtained through a melting curve analysis. After verifying the Hardy-Weinberg equilibrium of the genotypes from the polymorphisms, a statistical analysis was done, which included multivariate and predictive approaches.  RESULTS: A pharmacogenetic model that explained 52.8% of dose variation (p<0.001) was built, which was only 4% above the performance resulting from the same data using the International Warfarin Pharmacogenetics Consortium algorithm. The model predicting the sensitivity achieved an accuracy of 77.8% and included age (p=0.003), polymorphisms *2 and *3 (p=0.002) and polymorphism 1639G>A (p<0.001) as predictors.  CONCLUSIONS: These results in a mixed population support the prediction of sensitivity to warfarin based on polymorphisms in VKORC1 and CYP2C9 as a valid approach in Colombian patients.

Predicción de la sensibilidad a la warfarina con base en polimorfismos de los genes VKORC1 y CYP2C9 en pacientes colombianos / Prediction of sensitivity to warfarin based on VKORC1 and CYP2C9 polymorphisms in patients from different places in Colombia

Introducción. La validación de los factores predictores de la sensibilidad a la warfarina es importante para evitar las hemorragias asociadas con la terapia anticoagulante. En los estudios previos hechos en Colombia con polimorfismos de los genes VKORC1 y CYP2C9 , se reportaban algoritmos con rendimientos diferentes para explicar la variación de las dosis, pero no se evaluaba la predicción de la sensibilidad a la warfarina. Objetivo. Determinar la exactitud del análisis farmacogenético de los polimorfismos *2 y *3 en el gen CYP2C9 y 1639G>A en el gen VKORC1 para predecir la sensibilidad a la warfarina en pacientes del Hospital Militar Central, un centro de referencia que atiende pacientes de diferentes lugares de Colombia. Materiales y métodos. Se recopilaron los datos demográficos y clínicos de 130 pacientes que habían recibido una dosis estable de warfarina durante más de dos meses. Se obtuvieron sus genotipos mediante un análisis de curvas de fusión , y, después de verificar el equilibrio de Hardy-Weinberg de los polimorfismos, se hizo un análisis estadístico con enfoque multivariado y predictivo. Resultados. Se construyó un modelo farmacogenético que explicó el 52,8 % de la variación de la dosis (p<0,001), solo 4 % por encima del rendimiento obtenido con los mismos datos usando el algoritmo del International Warfarin Pharmacogenetics Consortium . El modelo predictivo de sensibilidad logró 77,8 % de exactitud e incluyó como factores la edad (p=0,003), los polimorfismos *2 y *3 (p=0,002) y el polimorfismo 1639G>A (p<0,001). Conclusiones. Estos resultados en una población mestiza colombiana respaldan la validez de la predicción de la sensibilidad a la warfarina basada en los polimorfismos de los genes VKORC1 y CYP2C9.

Introduction: In the search to prevent hemorrhages associated with anticoagulant therapy, a major goal is to validate predictors of sensitivity to warfarin. However, previous studies in Colombia that included polymorphisms in the VKORC1 and CYP2C9 genes as predictors reported different algorithm performances to explain dose variations, and did not evaluate the prediction of sensitivity to warfarin. Objective: To determine the accuracy of the pharmacogenetic analysis, which includes the CYP2C9 *2 and *3 and VKORC1 1639G>A polymorphisms in predicting patients´ sensitivity to warfarin at the Hospital Militar Central , a reference center for patients born in different parts of Colombia. Materials and methods: Demographic and clinical data were obtained from 130 patients with stable doses of warfarin for more than two months. Next, their genotypes were obtained through a melting curve analysis. After verifying the Hardy-Weinberg equilibrium of the genotypes from the polymorphisms, a statistical analysis was done, which included multivariate and predictive approaches. Results: A pharmacogenetic model that explained 52.8% of dose variation (p<0.001) was built, which was only 4% above the performance resulting from the same data using the International Warfarin Pharmacogenetics Consortium algorithm. The model predicting the sensitivity achieved an accuracy of 77.8% and included age (p=0.003), polymorphisms *2 and *3 (p=0.002) and polymorphism 1639G>A (p<0.001) as predictors. Conclusions: These results in a mixed population support the prediction of sensitivity to warfarin based on polymorphisms in VKORC1 and CYP2C9 as a valid approach in Colombian patients.

Fractales: ayuda diagnóstica para células preneoplásicas y cancerígenas del epitelio escamoso cervical confirmación de aplicabilidad clínica / Fractals: diagnostic help for preneoplastic and canceriginal cells of cervical scalpal epithelium confirmation of clinical applicability / Fractales: ajuda diagnóstica para células preneoplásticas e canceriginas do epitelio do scalpel cervical confirmação da aplicabilidade clínica

Antecedentes: Se desarrolló un método diagnóstico fractal para evaluar células del cuello uterino utilizando el concepto de Armonía Matemática Intrínseca (AMI) y variabilidad celular, el cual diferencia matemáticamente células normales de células L-SIL y H-SIL, haciendo innecesario el diagnóstico de células ASCUS. Objetivo: confirmar la capacidad diagnóstica de la metodología desarrollada mediante un estudio ciego de comparación con el Gold Standard. Método: se tomaron fotografías digitales de 50 preparaciones citológicas de mujeres entre 20 y 55 años: 5 con diagnóstico de citología normal y 45 con diferentes grados de lesión hasta carcinoma, incluyendo 5 ASCUS. Se calculó la dimensión fractal de tres objetos matemáticos: núcleo, citoplasma y totalidad, a partir de la superposición de cinco rejillas. Además, se evaluó su dimensión fractal mediante el concepto de AMI y variabilidad celular. Los resultados obtenidos se compararon con el diagnóstico citopatológico convencional determinando su sensibilidad, especificidad y coeficiente kappa. Resultados: La sensibilidad y especificidad fue del 100%, y el coeficiente Kappa de 1. Conclusiones: Los resultados en una población diferente a la inicial son una evidencia de la capacidad de esta metodología para diagnosticar objetiva y cuantitativamente células normales, L-SIL y H-SIL, así como aclarar el diagnóstico de las células ASCUS con base en la dimensión fractal y el concepto de AMI y variabilidad.

Introduction: A new fractal diagnostic method was applied for assessing cervix cells using the Intrinsic Mathematical Harmony (IMH) concept and cellular variability, which mathematically differentiates normal, L-SIL and H-SIL cells making unnecessary the diagnostic of ASCUS cells. Objective: To confirm the diagnostic capability of developed methodology by a blind study of comparison with Gold Standard. Methods: Digital pictures were taken of 50 cells from cytology of 20 to 55 year-old women; 5 with normal diagnosis and 45 with several lesion degrees until carcinoma, including 5 with ASCUS diagnosis. Fractal dimension of three mathematical objects was calculated by superposing five grids: nucleus, cytoplasm and totality. Moreover, their fractal dimension was assessed through the Intrinsic Mathematical Harmony concept and cellular variability. The obtained diagnosis was compared with conventional cytopathologic diagnosis determining sensibility, specificity and Kappa coefficient. Results: 100% Sensibility and specificity, and a Kappa Coefficient of 1 were obtained. Conclusions: The results, in a population different to the initial one, are an evidence of the ability of this methodology for objectively and quantitatively diagnosing the normal, L-SIL and H-SIL cells, as well as for clarifying the ASCUS cells diagnosis, based on fractal dimension and IMH concept and variability.

Introdução: Um novo método de diagnóstico fractal foi aplicado para avaliar as células do colo do útero usando conceito intrínseco harmonia matemática (IMH) e variabilidade celular, que normalmente diferencia matematicamente, LSIL e HSIL células que fazem o diagnóstico de células desnecessários ASCUS. Objetivo: Para confirmar a capacidade de diagnóstico da metodologia desenvolvida por um estudo cego de comparação com Gold Standard. Métodos: Foram tiradas fotos digitais de 50 células de citologia de mulheres com 20 a 55 anos de idade; 5 com diagnóstico normal e 45 com vários graus de lesão até carcinoma, incluindo 5 com diagnóstico de ASCUS. A dimensão fractal de três objetos matemáticos foi calculada através da superposição de cinco grades: núcleo, citoplasma e totalidade. Além disso, sua dimensão fractal foi avaliada através do conceito de harmonia matemática Intrínseca e da variabilidade celular. O diagnóstico obtido foi comparado com o diagnóstico citopatológico convencional, determinando a sensibilidade, especificidade e coeficiente Kappa. Resultados: Foram obtidos 100% de sensibilidade e especificidade e um Coeficiente Kappa de 1. Conclusões: Os resultados, em uma população diferente da inicial, são uma evidência da habilidade desta metodologia para o diagnóstico objetivo e quantitativo das células normais, L-SIL e H-SIL, bem como para esclarecer o diagnóstico das células ASCUS, Baseado na dimensão fractal e no conceito e variabilidade de IMH.

Alzheimer's disease and HLA-A2: linking neurodegenerative to immune processes through an in silico approach.

There is a controversial relationship between HLA-A2 and Alzheimer's disease (AD). It has been suggested a modifier effect on the risk that depends on genetic loadings. Thus, the aims of this study were to evaluate this relationship and to reveal genes associated with both concepts the HLA-A gene and AD. Consequently, we did first a classical systematic review and a meta-analysis of case-control studies. Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining. The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians), in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1. In contrast, the in silico approach retrieved nonrandomly shared genes by both concepts (P = 0.02), which additionally encode truly interacting proteins. The network of proteins encoded by APP, ICAM-1, ITGB2, ITGAL, SELP, SELL, IL2, IL1B, CD4, and CD8A linked immune to neurodegenerative processes and highlighted the potential roles in AD pathogenesis of endothelial regulation, infectious diseases, specific antigen presentation, and HLA-A2 in maintaining synapses.

Maternal mortality due to pandemic influenza A H1N1 2009 virus in Colombia.

AIMS: The 2009 H1N1 pandemic illustrated the higher morbidity and mortality from viral infections in peripartum women. We describe clinical features of women who recently died of H1N1 in Colombia. METHODS: This is a case series study that was gathered through a retrospective record review of all maternal H1N1 deaths in the country. The national mortality database of confirmed mortality from H1N1 in pregnancy and up to 42 days after delivery was reviewed during the H1N1 season in 2009. Women with H1N1 infections were confirmed by the laboratory of virology. Demographic, clinical, and laboratory data were reviewed. Statistical analyses were performed and median values of non-parametric data were reported with inter-quartile range (IQR). RESULTS: A total of 23 H1N1 maternal deaths were identified. Eighty-three percent occurred in the third trimester. None of the mothers who died had received influenza vaccination. The median time from symptom onset to the initiation of antiviral treatment was 8.8 days (IQR 5.8-9.8). Five fatalities did not receive any anti-viral therapy. Median PaO2/FiO2 on day 1 was 80 (IQR, 60-98.5). All patients required inotropic support and mechanical ventilation with barotrauma-related complications of mechanical ventilation occurring in 35% of patients. CONCLUSION: In Colombia, none of the women suffering H1N1-related maternal deaths had received vaccination against the disease and most had delayed or had no anti-viral therapy. Given the lack of evidence-based clinical predictors to identify women who are prone to die from H1N1 in pregnancy, following international guidelines for vaccination and initiation of antiviral therapy in suspected cases would likely improve outcomes in developing countries.

The autoimmune tautology: an in silico approach.

There is genetic evidence of similarities and differences among autoimmune diseases (AIDs) that warrants looking at a general panorama of what has been published. Thus, our aim was to determine the main shared genes and to what extent they contribute to building clusters of AIDs. We combined a text-mining approach to build clusters of genetic concept profiles (GCPs) from the literature in MedLine with knowledge of protein-protein interactions to confirm if genes in GCP encode proteins that truly interact. We found three clusters in which the genes with the highest contribution encoded proteins that showed strong and specific interactions. After projecting the AIDs on a plane, two clusters could be discerned: Sjögren's syndrome-systemic lupus erythematosus, and autoimmune thyroid disease-type1 diabetes-rheumatoid arthritis. Our results support the common origin of AIDs and the role of genes involved in apoptosis such as CTLA4, FASLG, and IL10.

Human leukocyte antigen class II and type 1 diabetes in Latin America: a combined meta-analysis of association and family-based studies.

Conclusions from association studies could be spurious because of population stratification; therefore we combined association with family studies seeking to confirm which human leukocyte antigen (HLA) class II alleles/haplotypes were associated with type 1 diabetes (T1D) in the admixed Latin America. By calculating the effect summary odds ratios (OR) and their 95% confidence intervals (95% CI), data up to June 2010 showed that risk associations were observed with DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR]: 7.51; 95% confidence interval [CI]: 3.69-15.25) and DQB1*0302 in presence of DRB1*0405 (OR: 11.64; 95% CI: 3.15-43.01) or DRB1*0401 (OR: 5.85; 95% CI: 3.07-11.14). In contrast, DRB1*0404-DQB1*0302 had a nonsignificant TID risk (OR: 2.23; 95% CI: 0.91-5.43). T1D protective associations were observed with DRB1*11-DQA1*0501-DQB1*0301 (OR: 0.24; 95% CI: 0.1-0.56) and DRB1*15-DQA1*0102-DQB1*0602 (OR: 0.35; 95% CI: 0.17-0.73). These results were similar to those observed in Caucasian and other populations, thus highlighting the primary role of class II HLA in T1D regardless of ethnicity. A DRB1*04 risk hierarchy was confirmed with the DRB1*0405 being in the top. A binding prediction analysis disclosed possible receptor-ligand interactions in the HLA-antigenic peptide complex.

Supervised selection of single nucleotide polymorphisms in chronic fatigue syndrome.

INTRODUCTION: The different ways for selecting single nucleotide polymorphisms have been related to paradoxical conclusions about their usefulness in predicting chronic fatigue syndrome even when using the same dataset. OBJECTIVE: To evaluate the efficacy in predicting this syndrome by using polymorphisms selected by a supervised approach that is claimed to be a method that helps identifying their optimal profile. MATERIALS AND METHODS: We eliminated those polymorphisms that did not meet the Hardy-Weinberg equilibrium. Next, the profile of polymorphisms was obtained through the supervised approach and three aspects were evaluated: comparison of prediction accuracy with the accuracy of a profile that was based on linkage disequilibrium, assessment of the efficacy in determining a higher risk stratum, and estimating the algorithm influence on accuracy. RESULTS: A valid profile (p<0.01) was obtained with a higher accuracy than the one based on linkage disequilibrium, 72.8 vs. 62.2% (p<0.01). This profile included two known polymorphisms associated with chronic fatigue syndrome, the NR3C1_11159943 major allele and the 5HTT_7911132 minor allele. Muscular pain or sinus nasal symptoms in the stratum with the profile predicted V with a higher accuracy than those symptoms in the entire dataset, 87.1 vs. 70.4% (p<0.01) and 92.5 vs. 71.8% (p<0.01) respectively. The profile led to similar accuracies with different algorithms. CONCLUSIONS: The supervised approach made it possible to discover a reliable profile of polymorphisms associated with this syndrome. Using this profile, accuracy for this dataset was the highest reported and it increased when the profile was combined with clinical data.

ZC3H12A (MCPIP1): molecular characteristics and clinical implications.

BACKGROUND: ZC3H12A is a gene whose absence is related to autoimmune disorders and to other phenotypical alterations. METHODS: A comprehensive review of the structure, molecular functions and regulation of ZC3H12A gene and its protein MCPIP1 is done in order to understand their clinical implications. RESULTS: ZC3H12A, at 1p34.3, has 9860bp, six exons and 61 described SNPs. Eleven are non-synonymous thus leading to changes in MCPIP1, the protein encoded by ZC3H12A. MCPIP1 is induced by MCP-1 and IL-1 whose signals are transduced through the NF-kß and MAPkinase pathways. This protein acts as an RNAse by degrading chemokine transcripts such as IL-1 as well as its own mRNA and as a transcription factor by reducing the expression of other chemokines induced by NF-kß such as MCP-1. It also up-regulates genes involved in several differentiation processes and apoptosis. Therefore, ZC3H12A is an equilibrium gatekeeper that not only regulates its own inducers but also controls the regulation by degrading its own mRNA. CONCLUSION: Understanding ZC3H12A gives a comprehensive panorama that promises to improve our understanding of processes in which this gene is involved including autoimmune, infectious and cardiovascular diseases.