A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Pathogenic variants in KANSL1 and 17q21.31 microdeletions are causative of Koolen-de Vries syndrome (KdVS), a neurodevelopmental syndrome with characteristic facial dysmorphia. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes have identifiable patterns of DNA methylation (DNAm) change: DNAm signatures or episignatures. Given the role of KANSL1 in histone acetylation, we tested whether variants underlying KdVS are associated with a DNAm signature. We profiled whole-blood DNAm for 13 individuals with KANSL1 variants, four individuals with 17q21.31 microdeletions, and 21 typically developing individuals, using Illumina's Infinium EPIC array. In this study, we identified a robust DNAm signature of 456 significant CpG sites in 8 individuals with KdVS, a pattern independently validated in an additional 7 individuals with KdVS. We also demonstrate the diagnostic utility of the signature and classify two KANSL1 VUS as well as four variants in individuals with atypical clinical presentation. Lastly, we investigated tissue-specific DNAm changes in fibroblast cells from individuals with KdVS. Collectively, our findings contribute to the understanding of the epigenetic landscape related to KdVS and aid in the diagnosis and classification of variants in this structurally complex genomic region.

Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies.

Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.

Experiencia de Mediktor(R): un nuevo evaluador de síntomas basado en inteligencia artificial para pacientes atendidos en el servicio de urgencias / A new artificial intelligence tool for assessing symptoms in patients seeking emergency department care: the Mediktor application

Objetivo. Analizar la concordancia entre los diagnósticos emitidos por MediktorR con el realizado por el médico responsable, así como valorar la utilidad de este dispositivo en pacientes que acuden a un servicio de urgencias (SU). Método. Estudio observacional prospectivo realizado en el SU de un hospital terciario universitario. A los pacientes con patologías médicas y quirúrgicas (cirugia y traumatologia) que no precisaban asistencia médica inmediata se les entrego una tableta digital para responder al interrogatorio de MediktorR. Según las respuestas, el software adjudicaba un listado de 10 prediagnosticos ordenados por probabilidad, que se ocultaban al paciente y al médico responsable, para no modificar el proceso habitual. Posteriormente se analizó el grado de coincidencia entre el diagnóstico médico y los diagnósticos ofrecidos por MediktorR. Resultados. 1.015 pacientes fueron incluidos, de los que 622 se consideraron casos válidos para el estudio. Se excluyeron los pacientes que no cumplían los criterios de inclusión, sin diagnostico al alta, con diagnostico final expresado como síntoma y aquellos con diagnósticos no incluidos en MediktorR. Las coincidencias entre el diagnostico medico (patrón oro) y los diez diagnósticos de MediktorR fueron de un 91,3%, en los tres primeros diagnósticos de un 75,4% y en el primer diagnóstico de un 42,9%. Según los grupos de diagnósticos más frecuentes, se objetivo una sensibilidad > 92% y una especificidad > 91% en la mayoría de ellos, con un índice kappa que oscilo entre el 0,24 y el 0,98. Conclusiones. MediktorR es una herramienta fiable para ayudar al diagnóstico de las enfermedades más prevalentes de un SU y fácil de utilizar por el público en general (AU)

Objectives. To analyze agreement between diagnoses issued by the Mediktor application and those of an attending physician, and to evaluate the usefulness of this application in patients who seek emergency care. Methods. Prospective observational study in a tertiary care university hospital emergency department. Patients with medical problems and surgical conditions (surgery and injuries) who did not require immediate emergency care responded to the Mediktor questions on a portable computer tablet. The software analyzed the answers and provided a list of 10 possible preliminary diagnoses in order of likelihood. The patient and the attending physician were blinded to the list to so that the usual care process would not be altered. The level of agreement between the physician's diagnosis and the Mediktor diagnosis was analyzed. Results. A total of 1015 patients were included; 622 cases were considered valid for study. Cases were excluded if the patients did not meet the inclusion criteria, they did not have a discharge diagnosis, they had a final diagnosis expressed as a symptom or their final diagnosis was not included in the Mediktor database. The physician's diagnosis (the gold standard) coincided with one of the 10 MEDIKTOR diagnoses in 91.3% of the cases, with one of the first 3 diagnoses in 75.4%, and with the first diagnosis in 42.9%. Sensitivity was over 92% and specificity over 91% in the majority of common diagnostic groups; the κ statistic ranged from 0.24 to 0.98. Conclusions. The Mediktor application is a reliable diagnostic aid for the most prevalent problems treated in a hospital emergency department. The general public finds it easy to use (AU)

Neumonía por Neisseria meningitidis: descripción de un caso / Pneumonia by Neisseria meningitidis: a case report

No disponible

Probióticos: más allá de la salud intestinal / Probiotics: beyond intestinal health

Objetivos: Revisar el efecto de los probióticos sobre parámetros relacionados no solo con la salud intestinal, sino con efectos sistémicos, especialmente sobre el sistema inmunitario y las infecciones. Resultados: Existen múltiples estudios y artículos publicados sobre probióticos en los que se evalúan efectos no exclusivamente intestinales, sino además más allá del intestino, sobre todo a nivel del sistema inmunitario y control de infecciones. Conclusiones: Aunque son necesarias más evidencias, todo apunta a que determinadas cepas probióticas ejercen efectos no solo a nivel local en el aparato digestivo, sino también a nivel sistémico, sobre todo a nivel de sistema inmune (AU)

Objectives: The aim of this article is to examine the effects of probiotics related to intestinal health as well as its systemic effects, principally on the immune system and infections. Results: There are multiple studies and articles published about probiotics in which not only are the effects on the intestinal tract investigated but also those outside the intestine, above all on the immune system and infections. Conclusions: Although more evidence is needed, it seems to be clear that some probiotic strains affect the digestive system not only at a local level, but also systemically, especially the immune system (AU)

Diagnóstico clínico y de laboratorio de la artritis gonocócica: a propósito de un caso / Clinical and laboratory diagnosis of gonococcal arthritis: presentation of a case

Introducción. La artritis gonocócica es una patología infrecuente en países de Europa occidental. Conseguir un diagnóstico temprano es vital para evitar una diseminación sistémica potencialmente fatal. Un caso en el trabajo rutinario de nuestro laboratorio, nos invita a realizar una breve revisión sobre la fisiopatología y el diagnóstico de la enfermedad. Observación clínica. Varón de 64 años, con fiebre, poliartralgias, e inflamación en tobillo derecho. Se procede a artrococentesis obteniendo muestra de líquido sinovial, con resultados analíticos sugerentes de artritis infecciosa, verificada mediante cultivo con aislamiento de N. gonorrhoeae, que el antibiograma muestra sensible a penicilina y ceftriaxona. Discusión. La infección diseminada de N. gonorrhoeae (DGI) incluye signos como poliartralgias, tenosinovitis y dermatitis. Ciertos casos pueden cursar además con artritis monoarticular, asociada a cultivos positivos de líquido sinovial, aunque hemocultivos negativos. Los elevados índices de resistencia a penicilina y tetraciclina, obligan a recomendar ceftriaxona i.v. como tratamiento de elección. Conclusión. La artritis gonocócica puede cursar en pacientes sin lesiones en la mucosa genitourinaria. Se asocia comúnmente a hemocultivos negativos. Solo el aislamiento del microorganismo en líquido sinovial permite un diagnóstico definitivo (AU)

Introduction. Gonococcal arthritis is an uncommon disease in western European countries. Obtaining an early diagnosis is essential to prevent potentially fatal dissemination. A case in the routine work of our laboratory led us to present a short review of the pathophysiology and diagnosis of the disease. Clinical observation. A 64 year-old male with, a fever, multiple joint pains, and inflammation in the right ankle. A sample of synovial fluid was obtained by arthrocentesis, with analytical results suggestive of infectious arthritis. This was confirmed by a culture, with the isolation of N. gonorrhoeae, which the antibiogram showed susceptibility to penicillin and ceftriaxone. Discussion. Disseminated N. gonorrhoeae infection includes signs such as, multiple joint pains, tenosynovitis and dermatitis. Certain cases can also present with, single joint arthritis, combined with positive synovial fluid cultures, although with negative blood cultures. The elevated rates of resistance to penicillin and tetracycline require recommending IV ceftriaxone as the treatment of choice. Conclusion. Gonococcal arthritis can occur in patients without lesions in the genitourinary mucosa. It is commonly associated with negative blood cultures. Only the isolation of the microorganism in synovial fluid enables a definitive diagnosis to be made (AU)

Piosalpingitis neumocócica: descripción de un caso inusual / Pneumococcal pyosalpinx: description of an unusual case

Objetivo. Analizar tanto las características clínicas así como las modalidades diagnósticas y el tratamiento adecuado de un caso de piosalpingitis neumocócica acontecido en el Hospital de Mérida. Paciente. Mujer aquejada de dolor abdominal, principalmente en hipogastrio, náuseas, vómitos y fiebre. Portadora de DIU. Resultados. La paciente es intervenida quirúrgicamente por la presencia de abscesos purulentos en ambas trompas. Se decide salpingectomía bilateral. Se identifica Streptococcus pneumoniae como agente causante de la infección. Se pauta tratamiento con cefotaxima. Conclusión. La piosalpingitis neumocócica es de difícil diagnóstico debido a su inespecificidad y baja frecuencia en la población. No obstante, es importante un reconocimiento temprano, mediante el análisis de muestras microbiológicas, para evitar la mortalidad y la morbilidad asociadas (AU)

Objective. To examine the clinical characteristics, diagnostic modalities, and appropriate treatment of a case of pneumococcal pyosalpinx managed in the Hospital of Mérida, Spain. Patient. A woman complained of abdominal pain, especially in the hypogastrium, nausea, vomiting and fever. The patient was an intrauterine device (IUD) carrier. Results. The patient underwent surgery due to the presence of purulent abscesses in both tubes. Bilateral salpingectomy was performed. Streptococcus pneumoniae was identified as the cause of the infection and cefotaxime was prescribed. Conclusions. Because of its lack of specificity and low frequency in the population, pneumococcal pyosalpinx is difficult to diagnose. However, early recognition, by analyzing microbiological samples, is important to prevent mortality and morbidity (AU)