Cross-Comparison of Inflammatory Skin Disease Transcriptomics Identifies PTEN as a Pathogenic Disease Classifier in Cutaneous Lupus Erythematosus.

Tissue transcriptomics is used to uncover molecular dysregulations underlying diseases. However, the majority of transcriptomics studies focus on single diseases with limited relevance for understanding the molecular relationship between diseases or for identifying disease-specific markers. In this study, we used a normalization approach to compare gene expression across nine inflammatory skin diseases. The normalized datasets were found to retain differential expression signals that allowed unsupervised disease clustering and identification of disease-specific gene signatures. Using the NS-Forest algorithm, we identified a minimal set of biomarkers and validated their use as diagnostic disease classifier. Among them, PTEN was identified as being a specific marker for cutaneous lupus erythematosus and found to be strongly expressed by lesional keratinocytes in association with pathogenic type I IFNs. In fact, PTEN facilitated the expression of IFN-ß and IFN-κ in keratinocytes by promoting activation and nuclear translocation of IRF3. Thus, cross-comparison of tissue transcriptomics is a valid strategy to establish a molecular disease classification and to identify pathogenic disease biomarkers.

Pulmonary injury as a predictor of cerebral hypoxia in traumatic brain injury: from physiology to physiopathology.

Traumatic brain injury is caused by mechanical forces impacting the skull and its internal structures and constitutes one of the main causes of morbidity and mortality in the world. Clinically, severe traumatic brain injury is associated with the development of acute lung injury and so far, few studies have evaluated the cellular, molecular and immunological mechanisms involved in this pathophysiological process. Knowing and investigating these mechanisms allows us to correlate pulmonary injury as a predictor of cerebral hypoxia in traumatic brain injury and to use this finding in decision making during clinical practice. This review aims to provide evidence on the importance of the pathophysiology of traumatic brain injury-acute lung injury, and thus confirm its role as a predictor of cerebral hypoxia, helping to establish an appropriate therapeutic strategy to improve functional outcomes and reduce mortality.

The Role of the Child and Adolescent Psychiatrist in Systems of Care.

To effectively fulfill various roles in systems of care, a child and adolescent psychiatrist must first define "system of care" and become familiar with the child-serving systems that make up the overarching system of care. They should know what roles are currently being fulfilled by child and adolescent psychiatrists, recognize the challenges they may face while fulfilling these roles, and use this knowledge to become catalysts for system improvements. This article discusses these points in greater detail.

Neurogenic pulmonary edema in subarachnoid hemorrhage: relevant clinical concepts.

BACKGROUND: Subarachnoid hemorrhage (SAH) continues to be a condition that carries high rates of morbidity, mortality, and disability around the world. One of its complications is neurogenic pulmonary edema (NPE), which is mainly caused by sympathetic hyperactivity. Due to the complexity of the pathophysiological process and the unspecificity of the clinical presentation, it is little known by general practitioners, medical students and other health care workers not directly related to the neurological part, making the management of this chaotic condition difficult. This review aims to present recent evidence on clinical concepts relevant to the identification and management of NPE secondary to SAH. MAIN BODY OF THE ABSTRACT: NPE is defined as a syndrome of acute onset following significant central nervous system (CNS) injury. Its etiology has been proposed to stem from the release of catecholamines that produce cardiopulmonary dysfunction, with this syndrome being associated with spinal cord injury, cerebrovascular disorders, traumatic brain injury, status epilepticus, and meningitis. NPE has long been considered a rare event; but it may occur more frequently, mainly in patients with SAH. There are two clinical presentations of NPE: the early form develops in the first hours/minutes after injury, while the late form presents 12-24 h after neurological injury. Clinical manifestations consist of non-specific signs of respiratory distress: dyspnea, tachypnea, hypoxia, pink expectoration, crackles on auscultation, which usually resolve within 24-48 h in 50% of patients. Unfortunately, there are no tools to make the specific diagnosis, so the diagnosis is by exclusion. The therapeutic approach consists of two interventions: treatment of the underlying neurological injury to reduce intracranial pressure and control sympathetic hyperactivity related to the lung injury, and supportive treatment for pulmonary edema. SHORT CONCLUSION: SAH is a severe condition that represents a risk to the life of the affected patient due to the possible complications that may develop. NPE is one of these complications, which due to the common manifestation of a respiratory syndrome, does not allow early and accurate diagnosis, being a diagnosis of exclusion. Therefore, in any case of CNS lesion with pulmonary involvement, NPE should be suspected immediately.

Beyond Amitriptyline: A Pediatric and Adolescent Oriented Narrative Review of the Analgesic Properties of Psychotropic Medications for the Treatment of Complex Pain and Headache Disorders.

Children and adolescents with recurrent or chronic pain and headache are a complex and heterogenous population. Patients are best served by multi-specialty, multidisciplinary teams to assess and create tailored, individualized pain treatment and rehabilitation plans. Due to the complex nature of pain, generalizing pharmacologic treatment recommendations in children with recurrent or chronic pains is challenging. This is particularly true of complicated patients with co-existing painful and psychiatric conditions. There is an unfortunate dearth of evidence to support many pharmacologic therapies to treat children with chronic pain and headache. This narrative review hopes to supplement the available treatment options for this complex population by reviewing the pediatric and adult literature for analgesic properties of medications that also have psychiatric indication. The medications reviewed belong to medication classes typically described as antidepressants, alpha 2 delta ligands, mood stabilizers, anti-psychotics, anti-sympathetic agents, and stimulants.

Evidence-Based Data Regarding the Use of Antibiotic-loaded Cement in Hip Arthroplasty. A bibliometric analysis of 50 years / Datos basados en la evidencia sobre el uso de cemento con antibióticos en la artroplastia de cadera. Análisis blbliométrico de 50 años

Introduction: The use of antibiotic-loaded cement is an intraoperative tool that has demonstrated potential benefits in hip arthroplasty. However, the global landscape of research on this topic remains unknown. The objective of this study was to analyze the scientific growth, characteristics, and metrics of global and historical research on the use of antibiotic-loaded cement in hip arthroplasty. Material and methods: A cross-sectional bibliometric study was conducted using Scopus as the data source. Results: A total of 523 documents published between 1973 and 2023 were selected. 89.9% (n=470) of the production consisted of original articles, with 11.85% being multi-center. 84.1% of the authors have published a single article, followed by 10.3% who have published two articles. Research has predominantly focused on adults or the elderly, with an emphasis on outcome evaluation (notably reoperation), assessing various antibiotic agents, and frequently employing retrospective designs. Conclusions: There has been a sustained increase in research on the use of antibiotic-loaded cement in hip arthroplasty over the last 50 years. The research trend has shifted towards the evaluation of adult or elderly patients, exploration of antimicrobial agents, techniques, and health outcomes, primarily using observational and retrospective designs. An emerging research-focus is the study of hip arthroplasty in rheumatoid arthritis patients. (AU)

Introducción: El uso de cemento cargado con antibiótico, es una herramienta intraoperatoria que ha demostrado potenciales beneficios en la artroplastia de cadera. Sin embargo, se desconoce el panorama global de la investigación sobre este tópico. El objetivo de este estudio fue analizar el crecimiento científico, características y métricas de la investigación global e histórica sobre el uso de cemento cargado con antibiótico en artroplastia de cadera. Material y métodos: Estudio bibliométrico de corte transversal, que utilizó como fuente de datos la base Scopus. Resultados: Se seleccionaron 523 documentos publicados entre 1973 y 2023. El 89,9% (n=470) de la producción consistió en artículos originales, siendo el 11,85% multicéntricos. El 84,1% de los autores han publicado un único artículo, seguido de un 10,3% que han publicado dos artículos. La investigación se ha centrado predominantemente en adultos o ancianos, con énfasis en la evaluación de resultados (especialmente la reoperación), evaluando diversos agentes antibióticos y empleando con frecuencia diseños retrospectivos. Conclusiones: En los últimos 50 años se ha producido un aumento sostenido de la investigación sobre el uso de cemento cargado con antibióticos en la artroplastia de cadera. La tendencia de la investigación se ha desplazado hacia la evaluación de pacientes adultos o ancianos, la exploración de los agentes antimicrobianos, las técnicas y los resultados sanitarios, utilizando principalmente diseños observacionales y retrospectivos. Un nuevo foco de investigación es el estudio de la artroplastia de cadera en pacientes con artritis reumatoide. (AU)

Cambio rutinario de instrumental y guantes quirúrgicos en cirugía abdominal: ¿cuál es el impacto sobre el riesgo de infección? / Routine change of surgical instruments and gloves in abdominal surgery: what is the impact on the risk of infection?

Objetivo: Analizar la evidencia más actualizada sobre el cambio rutinario de instrumental y guantes quirúrgicos en cirugía abdominal, y su impacto en el riesgo de infecciones. Métodos: Se realizó una búsqueda bibliográfica, en las bases de datos PubMed, ScienceDirect, Web of Science, y MEDLINE. Resultados: A la fecha, la evidencia sumamente escasa sobre el potencial impacto del cambio rutinario de instrumental y guantes quirúrgicos en cirugía abdominal, y su relación con la incidencia de infección en el sitio operatorio. Sin embargo, no deja de ser un tema de interés en cirugía global. El estudio ChEETAh, ensayo realizado en siete países de bajos y medianos ingresos, que evaluó el cambio rutinario tanto de guantes como de instrumental quirúrgico en cirugía abdominal y su relación con la infección, demostró que, la frecuencia de infección en sitio operatorio fue del 16% (n=931) en el grupo intervención, comparado a un 18,9% (n=1280) en el grupo control (RR 0,87; IC 95%: 0,79 ­ 0,95; p=0,0032). Así, podría existir cierta protección adicional con el cambio rutinario de guantes e instrumental en cirugía abdominal. Conclusión: Aunque la evidencia es limitada y heterogénea, existe una tendencia respecto a un potencial beneficio frente a la incidencia de infección en sitio operatorio, en el cambio rutinario de guantes e instrumental quirúrgico en cirugía abdominal(AU)

Objective: To analyze the most recent evidence regarding the routine change of surgical instruments and gloves in abdominal surgery and its impact on the risk of infections. Methods: A literature search was conducted in the PubMed, ScienceDirect, Web of Science, and MEDLINE databases. Results: To date, the evidence regarding the potential impact of routine changes in surgical instruments and gloves in abdominal surgery and their relationship with the incidence of surgical site infections is extremely scarce. Nevertheless, it remains a topic of interest in global surgery. The ChEETAh study, conducted in seven low and middle-income countries, which assessed the routine change of both gloves and surgical instruments in abdominal surgery and its relation to infection, demonstrated that the frequency of surgical site infection was 16% (n=931) in the intervention group compared to 18.9% (n=1280) in the control group (RR 0.87; 95% CI: 0.79 ­ 0.95; p=0.0032). Thus, there may be some additional protection with the routine change of gloves and instruments in abdominal surgery. Conclusion: Although the evidence is limited and heterogeneous, there is a trend suggesting a potential benefit in reducing the incidence of surgical site infections through the routine change of gloves and surgical instruments in abdominal surgery(AU)

Riesgo cardiovascular en pacientes recuperados de COVID-19 a corto y mediano plazo: ¿qué concluye la evidencia actual?

El riesgo y enfermedades cardiovasculares en pacientes recuperados de COVID-19 es un campo de análisis reciente en la literatura médica mundial y de vital importancia, porque existe una gran cantidad de pacientes con complicaciones una vez terminada la fase aguda de la enfermedad. El gran espectro del daño al miocardio en esta enfermedad puede variar desde una elevación asintomática de los niveles de troponinas cardíacas, hasta la aparición de una miocarditis fulminante y/o shock circulatorio, lo que puede dejar secuelas significativas. A pesar de que no existe una estrategia clara para abordar los eventos cardíacos que aparecen durante la COVID-19, y teniendo en cuenta que el manejo se hace principalmente para controlar los síntomas del paciente a medida que surgen, el objetivo de este trabajo fue conocer y recopilar la evidencia actual en esta temática, de tal manera que se pueda ofrecer al lector una guía de consulta en español que contribuya al desarrollo de su profesión sanitaria. La metodología utilizada fue una búsqueda de literatura en bases de datos como Medline, Scopus, Science Direct, con una ventana de tiempo entre 2019 y 2022. Los principales resultados revelaron que dentro de los mecanismos moleculares y fisiopatológicos implicados en este síndrome pos-COVID, se encuentra la afectación del sistema renina-angiotensina-aldosterona, al estar ligado el tropismo del SARS-Cov-2 a la enzima convertidora de angiotensina 2. Esto ocasiona una alteración de la respuesta neuro-humoral del sistema cardiovascular, renal y digestivo, lo que genera déficit en las vías de señalización y ocasiona lesión directa sobre corazón, pulmones y otros órganos. El síndrome pos-COVID-19, en general, se define como la aparición o persistencia de los síntomas posteriores a 3 o 4 semanas de aparecida la fase aguda de la enfermedad. Entonces, esta podría considerarse como una ventana de tiempo de riesgo y seguimiento estricto, para valorar de forma personalizada el riesgo entre los distintos grupos de pacientes, sobre todo de aquellos con antecedentes personales de enfermedad cardiovascular. Los principales resultados revelaron la presencia de trastornos como la insuficiencia cardiaca, las arritmias, la pericarditis y la miocarditis, que requieren de detección precoz y que se presentan días e incluso semanas posteriores a la fase aguda de la COVID-19.

Cardiovascular risk and diseases among patients recovered from COVID-19 is a recent field of study in the world medical literature and is also of vital importance because a large number of patients develop complications once the acute phase of the disease is over. The broad spectrum of myocardial injury in cardiovascular diseases can range from the asymptomatic elevation of cardiac troponin levels to the development of fulminant myocarditis and/or circulatory shock, which can leave significant sequelae. Despite the fact that there is no clear strategy to treat cardiac events that occur during COVID-19 infection and taking into account that treatment is mainly aimed at relieving patients' symptoms as they arise, the objective of this work was to find out and collect current evidence on this subject, so that readers can be offered a reference guide in Spanish that contributes to the development of their health profession. The methodology used was a literature search in databases including Medline, Scopus and ScienceDirect within a time window between 2019 and 2022. The main results revealed that the molecular and pathophysiological mechanisms involved in post-COVID-19 syndrome include the renin-angiotensin-aldosterone system since SARS-CoV-2 tropism is linked to angiotensin-converting enzyme 2. This causes an alteration of the neurohumoral response of the cardiovascular, renal and digestive systems, generating deficits in the signaling pathways and causing direct damage to the heart, lungs and other organs. PostCOVID-19 syndrome, in general, is defined as the occurrence or persistence of symptoms three or four weeks after the acute phase of the disease. This could then be considered as a time window of risk and strict follow-up to assess in a personalized way the risk among the different groups of patients, especially those with a past history of cardiovascular disease. The main results revealed disorders such as heart failure, arrhythmias, pericarditis and myocarditis, which require early detection and occur days or even weeks after the acute phase of COVID-19.

Riesgo de accidente cerebrovascular en pacientes con aterosclerosis carotídea asintomática: ¿se debe tratar médicamente o quirúrgicamente?

Los desórdenes cerebrovasculares siguen siendo la primera causa de morbilidad y mortalidad neurológica en el mundo, representando una de las entidades patológicas que genera mayor carga de enfermedad a nivel global. La aterosclerosis, o estenosis carotídea, es un potencial factor de riesgo para el ictus isquémico. La identificación y seguimiento estricto de esta condición son esenciales en la prevención secundaria de complicaciones a través de la atención primaria y el manejo especializado del riesgo cardiometabólico. No obstante, dependiendo de este riesgo y/o la presencia de sintomatología, es necesario realizar un manejo definitivo. Actualmente, existe controversia sobre si es mejor tratar la estenosis carotídea asintomática, ya sea médica o quirúrgicamente. Teniendo en cuenta la relevancia de esta entidad, el objetivo de esta revisión consiste en analizar la evidencia reciente sobre el riesgo de ictus isquémico en la aterosclerosis carotídea asintomática en adultos, y el potencial beneficio del manejo quirúrgico vs. farmacológico de esta condición. Para esto, se llevó a cabo una búsqueda bibliográfica en las bases de datos PubMed, ScienceDirect, Web of Science y MEDLINE, hasta el año 2023. Se evidenció que el riesgo de ictus asociado a estenosis carotídea asintomática es significativo (>10 %, aproximadamente), incluso en aquellos con terapia antiplaquetaria e hipolipemiante activa. En aquellos con manejo médico, la supervivencia a cinco años es alrededor del 80 %. Sin embargo, la progresión de la estenosis sucede en promedio en más del 60 % de los casos, y es significativa. Por el contrario, el stent carotídeo y la endarterectomía son intervenciones resolutivas. Pero existe un riesgo mayor comparado con la terapia médica, el cual se atribuye al periodo periy posoperatorio, así como a 30 días de aparición o recurrencia del ictus, infarto agudo de miocardio o muerte por cualquier causa; aunque el uso de la endarterectomía ha demostrado beneficios superiores a largo plazo en cuanto a estos mismos desenlaces. Entonces, la evidencia es heterogénea en cuanto a la superioridad del tratamiento quirúrgico comparado con la terapia farmacológica en el manejo de la aterosclerosis o estenosis carotídea asintomática. Sin embargo, parece ser que el manejo quirúrgico, específicamente la endarterectomía, podría impactar significativamente sobre la aparición o recurrencia del ictus ipsilateral y muerte a largo plazo, pero con resultados controversiales periy postoperatorios.

Cerebrovascular disorders remain the leading cause of neurological morbidity and mortality in the world, representing one of the pathological entities responsible for the greatest burden of disease worldwide. Carotid atherosclerosis or stenosis is a potential risk factor for ischemic stroke. The identification and strict follow-up of this condition are essential in the secondary prevention of complications through primary care and the specialized treatment of cardiometabolic risk. However, depending on this risk and/or presence of symptoms, definitive treatment is necessary. Currently, there is controversy as to whether asymptomatic carotid stenosis is better to be treated medically or surgically. Considering the significance of such entity, this review aims to analyze recent evidence on the risk of ischemic stroke in the case of asymptomatic carotid atherosclerosis among adults, as well as the potential benefit of the surgical vs. pharmacological treatment for this condition. For this purpose, a literature search for publications up to 2023 was carried out in PubMed, ScienceDirect, Web of Science and MEDLINE databases. It was shown that there is a significant risk of stroke associated with asymptomatic carotid stenosis (> 10 % approximately), even in patients with active antiplatelet and lipid-lowering therapy. Out of all those who receive medical treatment, around 80 % had a five-year survival rate. However, stenosis progression occurs on average in more than 60 % of the cases and is significant. On the other hand, carotid stenting and endarterectomy are curative interventions. Nevertheless, these procedures involve a higher risk compared to the medical therapy during the periand postoperative period, as well as 30 days afterwards, due to the occurrence or recurrence of stroke, acute myocardial infarction or death from any cause. Despite this, the use of endarterectomy has shown superior long-term benefits concerning these same outcomes. Thus, evidence regarding the superiority of surgical treatment compared to pharmacological treatment for asymptomatic carotid atherosclerosis or stenosis is heterogeneous. However, it seems that surgical treatment, specifically endarterectomy, could have a significant impact on the occurrence or recurrence of ipsilateral stroke and death in the long term but with controversial periand postoperative outcomes.

Consideraciones clínicas y desenlaces quirúrgicos del cáncer asociado a implante mamario: una enfermedad emergente de interés

El cáncer de mama sigue siendo una de las principales prioridades en salud global y salud pública y permanece como la neoplasia maligna más frecuente y mortal en mujeres en el mundo. El linfoma anaplásico de células grandes asociado a implante mamario (LACG-AIM) consiste en un linfoma no-Hodgkin de tipo raro, del cual se desconoce mucho sobre su patogenia y fisiopatología, pero que se ve cada vez con mayor frecuencia, debido al aumento de procedimientos estéticos. A la fecha, existen limitaciones en cuanto al conocimiento sobre el comportamiento clínico y se manifiesta de muchas formas, con un tiempo de evolución variable, y desenlaces quirúrgicos inciertos a mediano y largo plazo. Con base en lo anterior, el objetivo de esta revisión consiste en resumir evidencia sobre las consideraciones clínicas y desenlaces quirúrgicos del cáncer asociado a implante mamario, que faciliten la identificación y abordaje de esta condición. Se realizó una búsqueda bibliográfica en los motores de búsqueda y bases de datos PubMed, ScienceDirect, Embase, EBSCO y MEDLINE. Dentro de las consideraciones clínicas y quirúrgicas, se debe tener en cuenta el tipo de implante utilizado (texturizado), el tiempo del antecedente del implante, la severidad de las manifestaciones y la estadificación, para poder determinar la oportunidad de intervención quirúrgica y terapia neoadyuvante e intentar garantizar la supervivencia y evitar recurrencia. Aquellos pacientes sometidos a capsulectomía completa acompañado de radioterapia tienen mejores desenlaces.

Breast cancer continues to be one of the main priorities in global health and public health, and remains the most frequent and deadly malignant neoplasm in women worldwide. Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare type of Non-Hodgkin's lymphoma, whose pathogenesis and pathophysiology are not well known, but which is seen with increasing frequency due to the increase in cosmetic procedures. To date, there are limitations in terms of knowledge about the clinical behavior of the disease, which can manifest itself in many forms, with a variable evolution time and uncertain surgical outcomes in the medium- and long-term. Based on the above, the aim of this review is to summarize evidence on the clinical considerations and surgical outcomes of breast implant-associated cancer to facilitate the identification and management of this condition. A bibliographic search was performed in the search engines and databases pubmed, sciencedirect, embase, ebsco and medline. Within the clinical and surgical considerations, the type of implant used (textured), the time of the implant history, the severity of the manifestations, and the staging, must be taken into account in order to determine the opportunity for surgical intervention and neoadjuvant therapy, and to try to guarantee survival and avoid recurrence. Patients who undergo complete capsulectomy with radiotherapy have better outcomes.

Use of stem cell-enriched fat grafts in facial reconstruction: have they demonstrated superiority over autologous fat grafting? / Uso de injertos de grasa enriquecidos con células madre en la reconstrución facial: ¿han demostrado superioridad sobre los injertos de grasa autólogos?

Since the 1990s, big strides have been made in plastic and reconstructive surgery, thanks to the implementation of new techniques and resources for its execution. In cases where restoration is sought for small defects, biosurgery, involving the utilization of stem cells, biomaterials, chemical engineering, and tissue engineering, can be employed. The potential to stimulate the innate regenerative capacity of tissue and generate a persistent response over time, minimizing surgical trauma and re-interventions, lies in stem cell transplantation. However, the evidence published on this matter is very scarce, leading to divergence of opinions, suggestions, and recommendations. The aim of this review is to analyze the most recent evidence concerning the outcomes of using fat grafts enriched with stem cells in facial reconstruction, as compared to autologous fat grafts. The review of the literature demonstrates a marked trend suggesting that fat grafts enriched with stem cells may be superior to autologous grafts in facial reconstruction, with potential benefits in medium-term volume retention and faster attainment of results. (AU)

La cirugía plástica y reconstructiva, ha dado pasos agigantados desde la década de los años 90, con la implementación de nuevas técnicas y recursos para su realización. En los casos de defectos pequeños donde se busca la restauración, se puede hacer uso de la biocirugía, que involucra el uso de células madre, biomateriales, ingeniería química y de tejidos. El trasplante de células madre, tiene el potencial de estimular la capacidad innata regenerativa del tejido, así como de generar una respuesta persistente a lo largo del tiempo, minimizando el trauma quirúrgico y la reintervención. A pesar, de la ventaja plausible, la calidad y cantidad de la evidencia publicada al respecto es muy escasa, ocasionando divergencia de opiniones, sugerencias y recomendaciones. Con base en lo anterior, el objetivo de esta revisión consiste en realizar un análisis de la evidencia más reciente sobre los resultados en el uso de injertos de grasa enriquecidos con células madre en la reconstrucción facial, comparado a los injertos de grasa autólogos. A través de la revisión de la literatura, se pudo evidenciar que, aunque la evidencia es heterogénea a la fecha, existe una tendencia marcada en que el uso de injertos de grasa enriquecidos con células madre, podría ser superior a los injertos autólogos en la reconstrucción facial, con potenciales beneficios en la retención de volumen a mediano plazo y mayor celeridad en la obtención de resultados. (AU)

Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.

The peroxisome proliferator activated receptors PPARalpha, PPARgamma, and PPARdelta are ligand-activated transcription factors that play a key role in lipid homeostasis. The fibrates raise circulating levels of high-density lipoprotein cholesterol and lower levels of triglycerides in part through their activity as PPARalpha agonists; however, the low potency and restricted selectivity of the fibrates may limit their efficacy, and it would be desirable to develop more potent and selective PPARalpha agonists. Modification of the selective PPARdelta agonist 1 (GW501516) so as to incorporate the 2-aryl-2-methylpropionic acid group of the fibrates led to a marked shift in potency and selectivity toward PPARalpha agonism. Optimization of the series gave 25a, which shows EC50 = 4 nM on PPARalpha and at least 500-fold selectivity versus PPARdelta and PPARgamma. Compound 25a (GW590735) has been progressed to clinical trials for the treatment of diseases of lipid imbalance.