Biomarkers: how to consolidate them in clinical practice.

An inadequate biomarker validation can affect many patients' diagnosis, treatment, and follow-up. Therefore, special interest should be placed on performing these analyses correctly so that biomarkers can be applicable to patients and evidence of their clinical usefulness can be generated. A methodological work on the concept of biomarkers is presented, as well as the difficulties associated with the methodological approach to their development, validation, and implementation in clinical practice.

Exploring the impact of pharmacogenetics on personalized medicine: A systematic review. / [Artículo traducido] Exploración del impacto de la farmacogenética en la medicina personalizada: una revisión sistemática.

INTRODUCTION: Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine. MATERIALS AND METHODS: A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualized dosing", "clinical routine" and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis. RESULTS: 49 articles were included for the final analysis following review by two investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNF-α agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found. CONCLUSION: The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.

Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) / Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis

El tratamiento de la enfermedad inflamatoria intestinal (EII) ha sufrido una gran transformación tras la introducción de los fármacos biológicos. Gracias a ellos, los objetivos del tratamiento han evolucionado desde la respuesta y remisión clínica a objetivos más ambiciosos, como la remisión endoscópica o radiológica. Sin embargo, aunque los biológicos son muy eficaces, un porcentaje importante de pacientes no obtendrá una respuesta inicial o la perderá a lo largo del tiempo. Sabemos que existe una relación directa entre las concentraciones valle del biológico y su eficacia terapéutica, que cuanto más exigente sea el objetivo terapéutico serán necesarios niveles superiores del fármaco y que es frecuente la exposición insuficiente al mismo. La monitorización terapéutica de medicamentos biológicos, así como los modelos farmacocinéticos, nos brindan la posibilidad de ofrecer un enfoque personalizado del abordaje en pacientes con EII. Durante los últimos años se ha acumulado información relevante respecto a su utilidad durante o después de la inducción, así como en el mantenimiento del tratamiento biológico, en estrategias reactivas o proactivas y antes de la retirada o desintensificación del esquema.El objetivo de este documento es establecer recomendaciones sobre la utilidad de la monitorización terapéutica de biológicos en pacientes con EII, en los diferentes escenarios de la práctica clínica e identificar las áreas donde su utilidad es evidente, prometedora o controvertida. (AU)

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common.Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation.The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial. (AU)

Artificial intelligence in paediatrics: Current events and challenges.

This article examines the use of artificial intelligence (AI) in the field of paediatric care within the framework of the 7P medicine model (Predictive, Preventive, Personalized, Precise, Participatory, Peripheral and Polyprofessional). It highlights various applications of AI in the diagnosis, treatment and management of paediatric diseases as well as the role of AI in prevention and in the efficient management of health care resources and the resulting impact on the sustainability of public health systems. Successful cases of the application of AI in the paediatric care setting are presented, placing emphasis on the need to move towards a 7P health care model. Artificial intelligence is revolutionizing society at large and has a great potential for significantly improving paediatric care.

Inteligencia artificial en pediatría: actualidad y retos / Artificial intelligence in paediatrics: Current events and challenges

Se examina el uso de la inteligencia artificial (IA) en el campo de la atención a la salud pediátrica dentro del marco de la «Medicina de las 7P» (Predictiva, Preventiva, Personalizada, Precisa, Participativa, Periférica y Poliprofesional). Se destacan diversas aplicaciones de la IA en el diagnóstico, el tratamiento y el control de enfermedades pediátricas, así como su papel en la prevención y en la gestión eficiente de los recursos médicos con su repercusión en la sostenibilidad de los sistemas públicos de salud. Se presentan casos de éxito de la aplicación de la IA en el ámbito pediátrico y se hace un gran énfasis en la necesidad de caminar hacia la Medicina de las 7P. La IA está revolucionando la sociedad en general ofreciendo un gran potencial para mejorar significativamente el cuidado de la salud en pediatría.(AU)

This article examines the use of artificial intelligence (AI) in the field of paediatric care within the framework of the 7P medicine model (Predictive, Preventive, Personalized, Precise, Participatory, Peripheral and Polyprofessional). It highlights various applications of AI in the diagnosis, treatment and management of paediatric diseases as well as the role of AI in prevention and in the efficient management of health care resources and the resulting impact on the sustainability of public health systems. Successful cases of the application of AI in the paediatric care setting are presented, placing emphasis on the need to move towards a 7P health care model. Artificial intelligence is revolutionizing society at large and has a great potential for significantly improving paediatric care.(AU)

Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. / Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU).

The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.

Exploring the impact of pharmacogenetics on personalized medicine: A systematic review.

INTRODUCTION: Pharmacogenetics evaluates how genetic variations influence drug responses. Nowadays, genetic tests have advanced, becoming more affordable, and its integration is supported by stronger clinical evidence. Guidelines such as those from CPIC (Clinical Pharmacogenetics Implementation Consortium) and resources like PharmGKB facilitate genotype-based prescribing; and organizations like the FDA promote genetic testing before initiating certain medications. Preventive pharmacogenetic panels seem promising, but further research on biomarkers and diverse populations is needed. The aim of this review is to analyze recent evidence on the genotype-drug response relationship to examine how the genetic profile of patients influences the clinical response to treatments, and analyze the areas of research that need further study to advance towards a genetic-based precision medicine. MATERIALS AND METHODS: A systematic search was conducted on PubMed to identify articles investigating the genotype-drug response relationship. The search strategy included terms such as "pharmacogenetics", "personalized treatment", "precision medicine", "dose adjustment", "individualizing dosing", "clinical routine", and "clinical practice." Clinical trials, observational studies, and meta-analyses published in English or Spanish between 2013 and 2023 were included. The initial search resulted in a total of 136 articles for analysis. RESULTS: 49 articles were included for the final analysis following review by 2 investigators. A relationship between genetic polymorphisms and drug response or toxicity was found for drugs such as opioids, GLP-1 agonists, tacrolimus, oral anticoagulants, antineoplastics, atypical antipsychotics, efavirenz, clopidogrel, lamotrigine, anti-TNFα agents, voriconazole, antidepressants, or statins. However, for drugs like metformin, quetiapine, irinotecan, bisoprolol, and anti-VEGF agents, no statistically significant association between genotype and response was found. CONCLUSION: The studies analyzed in this review suggest a strong correlation between genetic variability and individual drug responses, supporting the use of pharmacogenetics for treatment optimization. However, for certain drugs like metformin or quetiapine, the influence of genotype on their response remains unclear. More studies with larger sample sizes, greater ethnic diversity, and consideration of non-genetic factors are needed. The lack of standardization in analysis methods and accessibility to genetic testing are significant challenges in this field. As a conclusion, pharmacogenetics shows immense potential in personalized medicine, but further research is required.

Puntuaciones de riesgo poligénico (PRS): una herramienta en la predicción de enfermedades y la medicina personalizada / Polygenic risk scores (PRS) - A tool for disease prediction and personalized medicine

En la última década, la genómica y la secuenciación de alto rendimiento han revolucionado la comprensión de las enfermedades complejas. las puntuaciones de riesgo poligénico (PRS) surgen como una prometedora herramienta para predecir enfermedades y personalizar tratamientos. Sin embargo, su implementación requiere confirmar la utilidad real y plantea importantes desafíos éticos y de privacidad. Las PRS se utilizan para identificar individuos de alto riesgo y guiar tratamientos personalizados. Su potencial es evidente en enfermedades como el cáncer o la osteoporosis, donde mejoran la estratificación de riesgo y permiten seleccionar tratamientos más efectivos. Sin embargo, las PRS tienen múltiples limitaciones, incluyendo la falta de precisión individual, la variabilidad en diferentes poblaciones y la incapacidad de considerar la influencia de los factores ambientales. La interpretación clínica y las implicaciones éticas, legales y sociales (ELSI) representan cuestiones muy relevantes en este campo. En el futuro, presumiblemente las PRS mejorarán su precisión predictiva, con la combinación de factores clínicos de riesgo y la adaptación a poblaciones de diversas etnias. Consecuentemente, se prevé que las PRS desempeñen un papel central en la medicina personalizada. (AU)

Over the past decade, genomics and high-throughput sequencing have revolutionized our understanding of complex diseases. Polygenic risk scores (PRS) have emerged as a promising tool for predicting diseases and personalizing treatments. However, their implementation requires confirmation of real utility, which raises significant ethical and privacy challenges. PRS are used to identify high-risk individuals and guide personalized treatments. Their potential is evident in diseases such as cancer or osteoporosis, where they improve risk stratification and enable the selection of more effective treatments. However, PRS have multiple limitations, including lack of individual accuracy, variability among different populations, and the inability to account for the impact of environmental factors. Clinical interpretation and ethical, legal, and social implications (ELSI) are highly relevant issues in this field. In the future, PRS are expected to improve their predictive accuracy by combining clinical risk factors and adapting to populations of various ethnicities. Consequently, PRS are expected to play a central role in personalized medicine. (AU)

Advancements in multi-omics strategies in personalized medicine and the ethical, legal and criminological considerations

Los avances en las estrategias multiómicas, tanto a nivel analítico como computacional, han llevado al desarrollo de la medicina personalizada, que adapta el tratamiento médico al individuo basado en la comprensión de su composición biológica. Este enfoque tiene el potencial de revolucionar la atención médica, al proporcionar tratamientos más efectivos y eficientes. Sin embargo, la implementación de la medicina personalizada plantea importantes cuestiones éticas, legales y sociales. Las consideraciones éticas y legales en torno a las pruebas multiómicas, los desafíos de implementar la medicina personalizada en países de rentas bajas y el papel de las leyes de propiedad intelectual en la configuración del acceso a tratamientos personalizados son temas de creciente preocupación. Algunas consideraciones incluyen cuestiones de privacidad, consentimiento informado y posibles discriminaciones. Consideraciones relevantes, en términos penales, por los importantes avances que se van a producir en los próximos años en el análisis multiómico. Los estudios ómicos van a conllevar una mayor comprensión de los mecanismos biológicos que contribuyen a enfermedades mentales y comportamientos agresivos (Jakovljevic and Jakovljevic 2019). La biología humana, que subyace a determinados trastornos que tienen gran influencia en la cuestión penal, va a ser explicada mejor por el sistema multicapa que las pruebas multiómicas propician y va a posibilitar biomarcadores bioquímicos de la agresión que nos proporcionarán gran información en los ámbitos penal y criminológico. Un aspecto ético importante es el derecho a la privacidad de la información genética. Los pacientes pueden dudar en someterse a pruebas genéticas si temen que su información sea compartida o utilizada de formas que no pretendían. El consentimiento informado es otra consideración ética y legal importante. ... (AU)

Advances in multi-omics strategies, both analytical and computational, have led to the development of personalized medicine, which tailors medical treatment to the individual based on an understanding of their biological makeup. This approach has the potential to revolutionize medical care by providing more effective and efficient treatments. However, the implementation of personalized medicine raises important ethical, legal, and social issues. Ethical and legal considerations surrounding multiomics testing, the challenges of implementing personalized medicine in low-income countries, and the role of intellectual property laws in shaping access to personalized treatments are issues of growing concern. Some considerations include issues of privacy, informed consent, and possible discrimination, considerations that may apply in criminal terms because of the significant advances that will be made in the coming years in multi-omics analysis. Omics studies are going to lead to a greater understanding of the biological mechanisms that contribute to mental illness and aggressive behaviors (Jakovljevic and Jakovljevic 2019). Human biology, which underlies certain disorders that have a great influence on the criminal issue, will be better explained by the multi-layered system that multi-omics testing provides and will reveal biochemical biomarkers of aggression that will provide us with vital information in the criminal and criminological fields. An important ethical aspect is the right to privacy of genetic information. Patients may hesitate to undergo genetic testing if they fear that their information will be shared or used in ways they did not intend. Informed consent is another important ethical and legal consideration. The potential for discrimination is also an important legal consideration surrounding genetic testing. ... (AU)

Valor pronóstico del intervalo Tpeak-Tend en el desarrollo de arritmias ventriculares subagudas intrahospitalarias en el síndrome de tako-tsubo / Prognostic value of the Tpeak-Tend interval for in-hospital subacute ventricular arrhythmias in tako-tsubo syndrome

Introducción y objetivos El valor de los parámetros del electrocardiograma (ECG) de repolarización asociados al riesgo de arritmias ventriculares (AVs) en el síndrome de tako-tsubo es controvertido. Nuestro objetivo fue identificar predictores ECG de AVs subagudas, definidas como aquellas ocurridas después de las primeras 48 horas desde el ingreso. Métodos Estudio observacional unicéntrico de pacientes ingresados en el servicio de cardiología entre 2012 y 2018 con diagnóstico de síndrome de tako-tsubo. La recogida de datos incluyó el ECG de 12 derivaciones al ingreso y a las 48 horas, registros de telemetría continua, analíticas, ecocardiografía transtorácica y angiografía coronaria durante la hospitalización. Los eventos de AVs se definieron como: extrasístoles ventriculares ≥ 2.000 en registros de telemetría de 24 horas, fibrilación ventricular, taquicardia ventricular (TV) sostenida, TV polimórfica y TV no sostenida. Resultados Se incluyeron 87 pacientes (edad 72±12 años). Durante una hospitalización mediana de 8 días se registraron AVs subagudas en 22 pacientes (25%) tras una mediana de 91 horas desde el ingreso. Las AVs subagudas se asociaron a aumento de la mortalidad hospitalaria (p=0,030). El intervalo Tpeak-Tend corregido global (promedio de las 12 derivaciones del ECG) a las 48 horas del ingreso fue un predictor independiente de AVs subagudas, superior al intervalo QT corregido (p=0,040). Un valor de corte 108ms en el Tpeak-Tend corregido global mostró una sensibilidad del 71% y especificidad del 72% para AVs subagudas. Conclusiones En pacientes con síndrome de tako-tsubo, las AVs subagudas se asocian a alteraciones de la repolarización que pueden detectarse en el ECG convencional mediante el intervalo Tpeak-Tend (AU)

Introduction and objectives The clinical value of electrocardiogram (ECG) repolarization parameters associated with ventricular arrhythmias (VAs) in tako-tsubo syndrome is still under debate. We aimed to evaluate ECG predictors of subacute VAs, defined as those occurring after the first 48hours from admission. Methods This single-center observational study enrolled patients admitted to the cardiology department between 2012 and 2018 with a confirmed diagnosis of tako-tsubo syndrome. Data collection included a 12-lead ECG on admission and at 48hours, continuous telemetry monitoring, blood testing, transthoracic echocardiography, and coronary angiography during hospitalization. VAs events were defined as: premature ventricular contractions ≥ 2000 within a 24-hour window of telemetry monitoring, ventricular fibrillation, sustained ventricular tachycardia (VT), polymorphic VT, and non-sustained VT. Results A total of 87 patients (age 72±12 years) were enrolled. During a median of 8 days of hospitalization, subacute VAs were documented in 22 patients (25%) after a median of 91hours from admission. Subacute VAs were associated with an increase in mortality during hospitalization (P=.030). The corrected global (mean of the 12-lead ECG values) Tpeak-Tend interval at 48hours from admission was an independent predictor of subacute VAs and was statistically superior to the standard corrected QT interval (Z test, P=.040). A cut-off of 108 msec for the corrected global Tpeak-Tend yielded a 71% sensitivity and 72% specificity for subacute VAs. Conclusions In patients with tako-tsubo syndrome, subacute VAs are associated with repolarization alterations that can be identified on conventional ECG using the Tpeak-Tend interval (AU)

PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma.

INTRODUCTION: Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s). MATERIAL AND METHODS: Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin-eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted. RESULTS: Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype. DISCUSSION: Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.

PD-L1 immunoexpression and molecular characterization of histological subtypes in urothelial carcinoma / Inmunoexpresión de PD-L1 y caracterización molecular de subtipos histológicos de carcinoma urotelial

Introduction: Urothelial carcinoma (UC) has histological subtypes whose phenotype reflects their molecular diversity, behavior and response to conventional therapy. Immune checkpoint inhibitors (ICIs) have improved the management of UC by evaluation of PD-L1. In the case of PD-L1 22C3, the initiation of ICI is considered from a combined positive score (CPS) greater than 10. However, UC subtypes with absent PD-L1 22C3 expression in cases with CPS>10 may not respond to these treatments. This study aims to establish a correlation between the PD-L1 immunoexpression and molecular alterations in divergent differentiation and histological subtypes of UC (UC-s). Material and methods: Twenty-six samples of UC were detected from a total of 24 patients. Two pathologists performed separately an assessment of UC-s on hematoxylin–eosin as well as PD-L1 expression. Molecular study of each case was performed by next generation sequencing (NGS). A descriptive analysis of the variables included was conducted. Results: Nine cases (34.61%) showed a CPS>10, some with negative PD-L1 immunoexpression in aggressive UC-s. The molecular study revealed alterations in genes belonging to the p53/cell cycle control, RAS, and DNA repair pathways, among others. None of the alterations were exclusive to any histological subtype. Discussion: Special attention should be paid to CPS>10 cases that include histological subtypes of UC with divergent expression for PD-L1 as they may not respond to treatment with ICI. We recommend examining the proportion and PD-L1 status of each subtype, especially if it has aggressive behavior.(AU)

Introducción: El carcinoma urotelial (CU) presenta subtipos histológicos cuyo fenotipo refleja su diversidad molecular, su comportamiento y su respuesta al tratamiento. Los inhibidores de puntos de control inmunitario (ICI) han mejorado el manejo del CU mediante la evaluación de PD-L1. En el caso de PD-L1 22C3, se considera el inicio de ICI a partir de una puntuación positiva combinada (combined positive score [CPS]) mayor de 10. Sin embargo, los subtipos de CU con ausencia de expresión de PD-L1 22C3 en casos con CPS>10 podrían no responder a estos tratamientos. Este estudio pretende establecer una correlación entre la inmunoexpresión de PD-L1 y las alteraciones moleculares en áreas con diferenciación divergente y subtipos histológicos de CU (CU-s). Material y métodos: Se obtuvieron 26 muestras con CU de 24 pacientes. Dos patólogos evaluaron de manera independiente las CU-s en hematoxilina-eosina y la expresión de PD-L1. Se realizó el estudio molecular mediante Next Generation Sequencing (NGS). Se realizó un análisis descriptivo de las variables incluidas. Resultados: Nueve casos (34,61%) mostraron un CPS>10, algunos con PD-L1 negativo en los CU-s de comportamiento agresivo. El estudio molecular reveló alteraciones en genes de las vías de p53/control del ciclo celular, RAS y reparación del ADN, entre otras. Ninguna alteración fue exclusiva de algún CU-s. Discusión: Debe prestarse especial atención a los casos con CPS>10 que incluyan subtipos histológicos con expresión divergente para PD-L1, ya que podrían no responder al tratamiento con ICI. Se recomienda cuantificar la proporción y el estado de PD-L1 de cada subtipo, especialmente si es de comportamiento agresivo.(AU)

Prognostic value of the Tpeak-Tend interval for in-hospital subacute ventricular arrhythmias in tako-tsubo syndrome.

INTRODUCTION AND OBJECTIVES: The clinical value of electrocardiogram (ECG) repolarization parameters associated with ventricular arrhythmias (VAs) in tako-tsubo syndrome is still under debate. We aimed to evaluate ECG predictors of subacute VAs, defined as those occurring after the first 48hours from admission. METHODS: This single-center observational study enrolled patients admitted to the cardiology department between 2012 and 2018 with a confirmed diagnosis of tako-tsubo syndrome. Data collection included a 12-lead ECG on admission and at 48hours, continuous telemetry monitoring, blood testing, transthoracic echocardiography, and coronary angiography during hospitalization. VAs events were defined as: premature ventricular contractions ≥ 2000 within a 24-hour window of telemetry monitoring, ventricular fibrillation, sustained ventricular tachycardia (VT), polymorphic VT, and non-sustained VT. RESULTS: A total of 87 patients (age 72±12 years) were enrolled. During a median of 8 days of hospitalization, subacute VAs were documented in 22 patients (25%) after a median of 91hours from admission. Subacute VAs were associated with an increase in mortality during hospitalization (P=.030). The corrected global (mean of the 12-lead ECG values) Tpeak-Tend interval at 48hours from admission was an independent predictor of subacute VAs and was statistically superior to the standard corrected QT interval (Z test, P=.040). A cut-off of 108 msec for the corrected global Tpeak-Tend yielded a 71% sensitivity and 72% specificity for subacute VAs. CONCLUSIONS: In patients with tako-tsubo syndrome, subacute VAs are associated with repolarization alterations that can be identified on conventional ECG using the Tpeak-Tend interval.

Organoides de cérebro como modelos de doenças de Alzheimer e Parkinson: uma revisão narrativa sobre as perspectivas para medicina regenerativa e personalizada / Brain organoids as models of Alzheimer's and Parkinson's diseases: a narrative review on perspectives for regenerative and personalized medicine

Há muitos anos a cultura celular bidimensional (2D) é utilizada como modelo de estudo de doenças, possuindo grande importância na medicina regenerativa, apesar de ainda conter limitações significativas. A fim de contornar essas limitações, a cultura celular tridimensional (3D) propõe uma organização mais complexa e sustentável que pode ser produzida a partir de células-tronco adultas (ASCs), células-tronco embrionárias (ESCs) ou células-tronco pluripotentes induzidas (iPSCs). A cultura 3D possibilitou o cultivo de células em um ambiente mais próximo do fisiológico, levando à formação de distintos tecidos órgãos-específicos. Em outras palavras, a cultura de células 3D possibilita a criação de estruturas orgânicas muito semelhantes aos órgãos de um ser humano, tanto estruturalmente, quanto funcionalmente. Desse modo, tem-se o que é chamado de organoides. O uso dos organoides tem crescido exponencialmente em ambientes in vitro, permitindo a análise e observação dos diversos fenômenos fisiológicos existentes. Como exemplo, pode-se citar os organoides cerebrais ("mini-brains") reproduzidos in vitro buscando delinear as peculiaridades e complexidades do cérebro humano, com o objetivo de compreender algumas disfunções neurológicas que acometem esse sistema, como as duas principais doenças neurodegenerativas: Doenças de Alzheimer e Parkinson. Portanto, os organoides cerebrais podem permitir notável avanço da medicina regenerativa aplicada a doenças neurodegenerativas, já que esses "mini-brains" podem ser produzidos a partir de células do próprio paciente. Isso permitirá intervenções personalizadas, como testagens farmacológicas, a fim de definir qual seria o melhor tratamento medicamentoso. Consequentemente, essa tecnologia pode permitir terapias mais eficientes e individualizadas - o que é fundamental para a Medicina Personalizada (AU).

For many years, two-dimensional (2D) cell culture has been used as a model to study diseases, having great importance in regenerative medicine, despite still having significant limitations. In order to circumvent these limitations, three-dimensional (3D) cell culture proposes a more complex and sustainable organization that can be produced from adult stem cells (ASCs), embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). The 3D culture enabled the cultivation of cells in an environment closer to the physiological one, leading to the formation of different organ-specific tissues. In other words, 3D cell culture makes it possible to create organic structures very similar to the organs of a human being, both structurally and functionally. In this way, we have what are called organoids. The use of organoids has grown exponentially in in vitro environments, allowing the analysis and observation of the various existing physiological phenomena. As an example, we can mention the brain organoids ("mini-brains") reproduced in vitro, seeking to delineate the peculiarities and complexities of the human brain, in order to understand some neurological dysfunctions that affect this system, such as the two main neurodegenerative diseases: Alzheimer's and Parkinson's Diseases. Therefore, brain organoids may allow a remarkable advance in regenerative medicine applied to neurodegenerative diseases, as these "mini-brains" can be produced from the patient's own cells. This will allow for personalized interventions, such as drug testing, in order to define what would be the best drug treatment. Consequently, this technology can enable more efficient and individualized therapies - which is fundamental for Personalized Medicine (AU).

Un tratamiento "a la carta" para los pacientes con adenocarcinoma pancreático / An "à la carte" treatment for patients with pancreatic adenocarcinoma

Resumen El adenocarcinoma pancreático es una enfermedad heterogénea. Sin dudas la aparición y la acumulación de mutaciones genéticas promueven el desarrollo del adenocarcinoma pancreático. Sin embargo, de manera contra-intuitiva, los análisis genéticos, por más precisos y profundos que sean, no permi ten la estratificación de los pacientes para predecir la evolución clínica ni para seleccionar el tratamiento más eficaz para cada paciente. Esto es debido a que la evolución clínica y la sensibilidad a los tratamientos están asociadas con su fenotipo, el que, a su vez, está determinado por la expresión global de los genes, es decir están regulados a nivel transcriptómico. Por lo tanto, la estratificación de esos pacientes debe hacerse a través de la lectura transcriptómica y no a través de su análisis genético. Los datos obtenidos sobre grandes cohortes de pacientes indican que el estudio de un conjunto de transcriptos seleccionados podría predecir la evolución clínica y ayudar a decidir el tratamiento más apropiado. Se está avanzando rápidamente hacia una medicina personalizada para esta enfermedad, que de por sí tiene un mal pronóstico, pero que es aún peor si la deci sión terapéutica no es la más adaptada a cada paciente. Estamos convencidos de que en un futuro próximo el tratamiento de los cánceres estará precedido por una caracterización transcriptómica extensa con el fin de seleccionar los tratamientos "a la carta" más adecuados.

Abstract Pancreatic adenocarcinoma is a heterogeneous disease. Undeniably, the appearance and accumulation of genetic muta tions promote the development of pancreatic adenocarcinoma. However, counterintuitively, genetic analyzes, no matter how precise and in-depth they may be, do not allow stratification of patients to predict their clinical evolution or to select the most effective treatment in each case. This is due to the fact that the clinical evolution and sensitivity to treatments are associated with the tumoral phenotype, which, in turn, is determined by the global expression of genes that is regulated at the transcriptomic level. Therefore, the stratification of these patients must be done by analysis at the transcriptomic level and not by genetic analysis. The data obtained from large cohorts of patients indicate that studying the transcription of a selected set of genes could predict the clinical outcome and can help to decide about the most appropriate treatment. We are moving very rapidly towards a personalized medicine for this disease, which in itself has a poor prognosis, even worse if the therapeutic deci sion is not the most adapted to each patient. We are convinced that in the near future the treatment of cancers will be preceded by an extensive transcriptomic characterization in order to select the most suitable "à la carte" treatments.

Abordaje farmacológico del dolor neuropático: pasado, presente y futuro / Pharmacological approach to neuropathic pain: past, present and future

Introducción: El dolor neuropático (DN) es difícil de tratar debido a la heterogeneidad de causas, síntomas y mecanismos subyacentes. Constituye una gran necesidad médica que no está cubierta y cuenta con un número elevado de fracasos terapéuticos en ensayos clínicos aleatorizados recientes. Desarrollo: En esta revisión narrativa se presenta una actualización sobre el tratamiento farmacológico del DN con énfasis en las nuevas guías clínicas publicadas, los nuevos fármacos en desarrollo y los nuevos retos que se presentan en el manejo terapéutico de esta entidad. Conclusiones: Los fármacos propuestos como primera línea incluyen antidepresivos tricíclicos (particularmente amitriptilina), inhibidores de la recaptación de la serotonina y la noradrenalina (particularmente duloxetina), pregabalina y gabapentina. Sin embargo, las últimas recomendaciones siguen siendo relevantes y los estudios clínicos más recientes incluso cuestionan el papel de la pregabalina como tratamiento de primera línea. Por tanto, consideramos necesarias las actualizaciones periódicas de las guías clínicas en DN para guiar mejor nuestra práctica clínica diaria y racionalizar el uso de todas las opciones terapéuticas disponibles. Por otro lado, la expansión del conocimiento en DN ha generado una serie de desafíos, como el desarrollo de nuevos fármacos basados en mecanismos fisiopatológicos investigados en animales y el desarrollo de planteamientos terapéuticos óptimos en ensayos clínicos, más basados en enfoques personalizados que etiológicos.(AU)

Introduction: Neuropathic pain (NP) is difficult to treat due to the heterogeneity of causes, symptoms and underlying mechanisms. It constitutes a great medical need that is not covered, and has a high number of therapeutic failures in recent randomized clinical trials. Development: This narrative review presents an update on the pharmacological treatment of NP with emphasis on the new published clinical guidelines, new drugs in development, and the new challenges that arise in the therapeutic management of this entity. Conclusions: First-line drugs proposed include tricyclic antidepressants (particularly amitriptyline), serotonin and norepinephrine reuptake inhibitors (particularly duloxetine), pregabalin, and gabapentin. However, the latest recommendations are still relevant and the most recent clinical studies even question the role of pregabalin as a first-line treatment. Therefore, we consider that periodic updates of the clinical guidelines in NP are necessary to better guide our daily clinical practice and rationalize the use of all available therapeutic options. Furthermore, the expansion of knowledge in NP has generated a series of challenges, such as the development of new drugs based on pathophysiological mechanisms investigated in animals, and the development of optimal therapeutic approaches in clinical trials, based more on personalized than etiological approaches.(AU)

Defining the Heterogeneity of Sleep Apnea Syndrome: A Cluster Analysis With Implications for Patient Management / Definiendo la heterogeneidad del Síndrome de Apneas del Sueño: un análisis de clúster con implicaciones en el manejo del paciente

Introduction Obstructive sleep apnea (OSA) is a complex pathology with heterogeneity that has not been fully characterized to date. Our objective is to identify groups of patients with common clinical characteristics through cluster analysis that could predict patient prognosis, the impact of comorbidities and/or the response to a common treatment. Methods Cluster analysis was performed using the hierarchical cluster method in 2025 patients in the apnea-HUGU cohort. The variables used for building the clusters included general data, comorbidity, sleep symptoms, anthropometric data, physical exam and sleep study results. Results Four clusters were identified: (1) young male without comorbidity with moderate apnea and otorhinolaryngological malformations; (2) middle-aged male with very severe OSA with comorbidity without cardiovascular disease; (3) female with mood disorder; and (4) symptomatic male with established cardiovascular disease and severe OSA. Conclusions The characterization of these four clusters in OSA can be decisive when identifying groups of patients who share a special risk or common therapeutic strategies, orienting us toward personalized medicine and facilitating the design of future clinical trials.

Introducción La Apnea Obstructiva del Sueño (AOS) es una patología compleja en la que su heterogeneidad no ha sido completamente caracterizada hasta la fecha. Nuestro objetivo es identificar grupos de pacientes con características clínicas comunes, por medio de análisis de clúster, que pudieran se predictivos de un pronóstico, impacto de comorbilidades y/o respuesta a un tratamiento común. Métodos Se realizó un análisis de clúster por el método de conglomerados jerárquico en 2025 pacientes de la cohorte apnea-HUGU. Las variables utilizadas para la construcción de los clúster incluían datos generales, comorbilidad, síntomas de sueño, datos antropométricos, exploración física y resultados del estudio de sueño. Resultados Se identificaron 4 clúster: 1) varón joven sin comorbilidad con apnea moderada y alteraciones de la esfera otorrinolaringológica (ORL) 2) Varón de edad media con AOS muy grave sintomático con comorbilidad sin enfermedad cardiovascular desarrollada. 3) Mujer con alteraciones en el estado de ánimo 4) Varón sintomático con enfermedad cardiovascular establecida y AOS grave. Conclusiones La caracterización de estos cuatro clúster en la AOS puede ser determinante a la hora de identificar grupos de pacientes que comparten un especial riesgo o estrategias terapéuticas comunes orientándonos hacia la medicina personalizada y facilitando el diseño de futuros ensayos clínicos.

Deconstruyendo los fenotipos en la EPOC: un análisis de la cohorte TRACE / Deconstructing Phenotypes in COPD: an Analysis of the TRACE Cohort

Objetivos: En una estrategia de manejo de la enfermedad pulmonar obstructiva crónica (EPOC) basada en fenotipos clínicos sería deseable que todos los pacientes pudieran adscribirse al menos a un fenotipo sin adscribirse a otro. El objetivo de este trabajo fue evaluar si todos los pacientes tienen un fenotipo y sólo uno asignado según la actual guía española de la EPOC (GesEPOC 2017) y evaluar los criterios que los definen. Método: El estudio Time-based Register and Analysis of COPD Endpoints (TRACE; clinicaltrials.gov NCT03485690) es una cohorte prospectiva de pacientes con EPOC en visitas anuales desde 2012 que recoge los fenotipos GesEPOC. A pesar de que GesEPOC recomienda no fenotipar a los pacientes considerados de bajo riesgo, se realizó un análisis de los criterios de identifican los fenotipos en alto y bajo riesgo, comparando la distribución de los fenotipos y sus criterios en estos dos grupos. Resultados: La cohorte incluye 970 pacientes con diagnóstico confirmado de EPOC, divididos en 427 (44,02%) pacientes de bajo riesgo y 543 (55,9%) de alto riesgo. El fenotipo más frecuente fue el no agudizador (44,9% de los pacientes de alto riesgo). Un 20,6% de los pacientes de bajo riesgo cumplían criterios de solapamiento entre EPOC y asma. Un 9,2% de la cohorte no cumplía los criterios diagnósticos de ningún fenotipo y el 19,1% cumplía los criterios de dos fenotipos, sin diferencias entre grupos de riesgo. Conclusiones: Nuestros datos ponen de manifiesto algunas de las debilidades de la actual estrategia basada en fenotipos clínicos, existiendo solapamiento en algunos casos y pacientes sin fenotipos.

Objectives: In a clinical phenotype-based management strategy for COPD, it would be preferable to at least assign all patients to a phenotype, but to a single phenotype only. The aim of this study was to evaluate whether all patients are assigned to one and only one phenotype using the Spanish COPD guidelines (GesEPOC) and to evaluate the criteria that define these categories. Method: The Time-based Register and Analysis of COPD Endpoints study (TRACE; clinicaltrials.gov NCT03485690) is a prospective cohort of COPD patients attending annual visits since 2012, which collects GesEPOC phenotypes. Although the GesEPOC recommends that patients considered to be at low risk are not phenotyped, an analysis of the criteria for identifying high- and low-risk phenotypes was performed, comparing the distribution of phenotypes and the criteria applied between these 2 groups. Results: The cohort included 970 patients with a confirmed diagnosis of COPD, divided into 427 (44.02%) low-risk and 543 (55.9%) high-risk patients. The most frequent phenotype was the non-exacerbator (44.9% of high-risk patients). Overall, 20.6% of low-risk patients met criteria for asthma-COPD overlap syndrome, while 9.2% of the cohort did not meet the diagnostic criteria for any phenotype, and 19.1% met the criteria for 2 phenotypes, with no differences between risk groups.Conclusions: Our data highlight some of the weaknesses of the current clinical phenotype strategy, revealing overlapping categories in some cases, and patients to whom no phenotype was assigned.