Polymorphisms indicating risk of inflammatory bowel disease or antigenicity to anti-TNF drugs as biomarkers of response in children

Crohn’s disease; Polymorphism; PediatricEnfermedad de Crohn; Polimorfismo; PediátricoMalaltia de Crohn; Polimorfisme; PediatriaFew genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.This research was funded by Instituto de Salud Carlos III, grant number PI19/00792 and PI22/00584 (L.L-F.), both cofunded by the European Union, by Instituto de Investigación Sanitaria Gregorio Marañón, grant number 2021-II-postdoc-01 (S.S-M.), and by Consejería de Educación, Universidades, Ciencia y Portavocía Comunidad de Madrid, grant number PEJ-2021-AI/BMD-21866 (P.Z-C.)

Association between HLA DNA Variants and Long-Term Response to Anti-TNF Drugs in a Spanish Pediatric Inflammatory Bowel Disease Cohort

Adalimumab; Infliximab; PharmacogeneticsAdalimumab; Infliximab; FarmacogenèticaAdalimumab; Infliximab; FarmacogenéticaThe genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.This research was funded by Instituto de Salud Carlos III, grant number PI19/00792 (L.A.L.-F.) and Juan Rodes program JR19/00005 (E.L.-M.), by Instituto de Investigación Sanitaria Gregorio Marañón, grant number 2021-II-postdoc-01 (S.S.-M.), and by Consejería de Educación, Universidades, Ciencia y Portavocía Comunidad de Madrid, grant number PEJ-2021-AI/BMD-21866 (P.Z.-C.). The study was co-funded by the European Union

Whole transcription profile of responders to anti-tnf drugs in pediatric inflammatory bowel disease

Background: Up to 30% of patients with pediatric inflammatory bowel disease (IBD) do not respond to anti-Tumor Necrosis Factor (anti-TNF) therapy. The aim of this study was to identify pharmacogenomic markers that predict early response to anti-TNF drugs in pediatric patients with IBD. Methods: An observational, longitudinal, prospective cohort study was conducted. The study population comprised 38 patients with IBD aged 0.6 or <−0.6 and p value < 0.05). After validation, FCGR1A, FCGR1B, and GBP1 were overexpressed in non-responders two weeks after initiation of anti-TNF treatment (Log2FC 1.05, 1.21, and 1.08, respectively, p value < 0.05). Conclusion: Expression of the FCGR1A, FCGR1B, and GBP1 genes is a pharmacogenomic biomarker of early response to anti-TNF agents in pediatric IBDInstituto de Salud Carlos III número de becas PI16 / 00559 y PI19 / 00792Consejería de Educación y Deporte de la Comunidad de Madrid PEJ16 / MED / AI-1260Instituto de Investigaciones Sanitarias Gregorio Marañón PRE2018-2Fondos Europeos de Desarrollo Regional (FEDER) del Comisión Europe

Evaluation of Compliance with the Guidelines for the Safe Use of Potassium Chloride

RESUMEN Objetivo: Analizar el grado de cumplimiento del “Protocolo de Utilización de Cloruro potásico” implantado en nuestro hospital, mediante la realización de auditorías periódicas presenciales, durante el periodo 2013-2016. Métodos: Estudio descriptivo de las auditorías realizadas a los 6 meses post-implantación (principios de 2013), y después cada año (2014-2016). Los indicadores de evaluación se establecen siguiendo las recomendaciones recogidas en el Protocolo y se refieren al almacenamiento, prescripción, preparación y administración de soluciones de potasio. Las unidades asistenciales evaluadas son: unidades autorizadas (almacenamiento y doble chequeo en la preparación y antes de la administración) y en todas las unidades de críticos y urgencias clínicas (prescripción y etiquetado correcto para su administración). Resultados: Se audita un total de 55 unidades asistenciales, que han mostrado un 100% de cumplimiento para los indicadores referentes a prescripción y etiquetado correcto. De dichas unidades, 12 (críticos y urgencias) están autorizadas para disponer de ampollas de cloruro potásico 1M. En estas 12, no se obtuvo un cumplimiento correcto de los otros dos indicadores, debido a que una no realizó su almacenamiento de forma adecuada (2014) y, en otras tampoco se cumplimentó el registro de doble chequeo (3 en 2013, 1 en 2014 y 2015). Conclusión: Las auditorías mostraron el correcto seguimiento de dicho Protocolo para la mayoría de los criterios evaluados, si bien, ponen de manifiesto la necesidad de realizar estrategias periódicas de intensificación y recuerdo para garantizar el adecuado cumplimiento de todas las recomendaciones establecidas.ABSTRACT Objective: To analyze the degree of compliance with the “Guidelines for the safe use of potassium chloride” implemented in our hospital, using periodic audits, during the period 2013-2016. Methods: Descriptive study of the audits carried out at 6 months post-implementation (beginning of 2013) and then every year (2014-2016). The evaluation indicators were developed following the recommendations included in the Guidelines and referred to storage, prescription, preparation and administration of potassium solutions. The patient care units evaluated are: critical care authorized units (storage and independent double checks during preparation of solutions and before its administration) and all patient care units (prescription and correct labeling for its correct administration). Results: There were audited 55 patient care units, which showed a compliance of 100% for the prescription and correct labeling indicators. Of those units, 12 (critical and emergency units) are authorized to have concentrated potassium chloride ampoules 1M. These 12 units did not have a correct compliance with the other two indicators, because one unit did not show a correct storage (in 2014) and the double check required was not verified by 3 units in 2013, one in 2014 and 2015. Conclusion: The audits showed the correct follow-up with the Guidelines for most of the evaluated criteria, however demonstrated the need to carry out periodic strategies of intensification and remembrance to guarantee the correct compliance of all the established recommendations

Evaluación del cumplimiento del protocolo de utilización de cloruro potásico

Objective: To analyze the degree of compliance with the “Guidelines for the safe use of potassium chloride” implemented in our hospital, using periodic audits, during the period 2013-2016. Methods: Descriptive study of the audits carried out at 6 months post-implementation (beginning of 2013) and then every year (2014-2016). The evaluation indicators were developed following the recommendations included in the Guidelines and referred to storage, prescription, preparation and administration of potassium solutions. The patient care units evaluated are: critical care authorized units (storage and independent double checks during preparation of solutions and before its administration) and all patient care units (prescription and correct labeling for its correct administration). Results: There were audited 55 patient care units, which showed a compliance of 100% for the prescription and correct labeling indicators. Of those units, 12 (critical and emergency units) are authorized to have concentrated potassium chloride ampoules 1M. These 12 units did not have a correct compliance with the other two indicators, because one unit did not show a correct storage (in 2014) and the double check required was not verified by 3 units in 2013, one in 2014 and 2015. Conclusion: The audits showed the correct follow-up with the Guidelines for most of the evaluated criteria, however demonstrated the need to carry out periodic strategies of intensification and remembrance to guarantee the correct compliance of all the established recommendations.Objetivo: Analizar el grado de cumplimiento del “Protocolo de Utilización de Cloruro potásico” implantado en nuestro hospital, mediante la realización de auditorías periódicas presenciales, durante el periodo 2013-2016. Métodos: Estudio descriptivo de las auditorías realizadas a los 6 meses post-implantación (principios de 2013), y después cada año (2014-2016). Los indicadores de evaluación se establecen siguiendo las recomendaciones recogidas en el Protocolo y se refieren al almacenamiento, prescripción, preparación y administración de soluciones de potasio. Las unidades asistenciales evaluadas son: unidades autorizadas (almacenamiento y doble chequeo en la preparación y antes de la administración) y en todas las unidades de críticos y urgencias clínicas (prescripción y etiquetado correcto para su administración). Resultados: Se audita un total de 55 unidades asistenciales, que han mostrado un 100% de cumplimiento para los indicadores referentes a prescripción y etiquetado correcto. De dichas unidades, 12 (críticos y urgencias) están autorizadas para disponer de ampollas de cloruro potásico 1M. En estas 12, no se obtuvo un cumplimiento correcto de los otros dos indicadores, debido a que una no realizó su almacenamiento de forma adecuada (2014) y, en otras tampoco se cumplimentó el registro de doble chequeo (3 en 2013, 1 en 2014 y 2015). Conclusión: Las auditorías mostraron el correcto seguimiento de dicho Protocolo para la mayoría de los criterios evaluados, si bien, ponen de manifiesto la necesidad de realizar estrategias periódicas de intensificación y recuerdo para garantizar el adecuado cumplimiento de todas las recomendaciones establecidas

Inhibition of Biogenic Amines Formation in Fermented Foods by the Addition of Cava Lees

Food safety can be compromised by some bioactive compounds such as biogenic amines that can be specially found in fermented foods due to the bacterial decarboxylation of some amino acids by fermentative or spoilage bacteria. Cava lees are a winery by-product rich in fiber and phenolic compounds and previous works have raised their revalorization from a food safety point of view. The aim of the current work was to investigate whether the use of cava lees can help to control biogenic amine formation in bread and fermented sausages. In bread, only very low levels of biogenic amines (putrescine, cadaverine, and/or spermidine) were found, whose content did not vary with the addition of different amounts of lees. However, the addition of lees in fermented sausages significantly reduced the formation of tyramine and cadaverine. In sausages spontaneously fermented and inoculated with Salmonella spp., the presence of cadaverine and putrescine diminished by 62 and 78%, respectively, due to the addition of cava lees. The addition of cava lees phenolic extract also showed an anti aminogenic effect (21% for cadaverine and 40% for putrescine), although in a lesser extent than cava lees. Cava lees and their phenolic extract were shown to be an effective strategy to control the undesirable accumulation of high levels of biogenic amines during the production of fermented products

Phase I study of plitidepsin in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma

Previous studies showed antitumor activity for plitidepsin plus dexamethasone (DXM) in relapsed/refractory multiple myeloma (r/r MM), and in vitro synergism with bortezomib (BTZ) or DXM against MM cells. This phase I trial evaluated plitidepsin (3-h intravenous infusion Day 1 and 15), BTZ (subcutaneous bolus Day 1, 4, 8, and 11), and DXM (orally Day 1, 8, 15, and 22), every 4 weeks in 36 r/r MM patients. Twenty-two patients were treated using a standard dose escalation design (10 at the recommended dose [RD] cohort), and 14 additional patients were treated to expand the RD cohort. No dose-limiting toxicities (DLTs) occurred during dose escalation. The highest dose level evaluated (plitidepsin 5.0 mg/m2 , BTZ 1.3 mg/m2 , DXM 40.0 mg) was the RD for phase II studies. Results shown herein are focused on this RD. Two patients had DLTs (grade 3 diarrhea, and grade 3 nausea/vomiting refractory to antiemetic therapy). Grade ? 3 hematological toxicity (thrombocytopenia 46%, anemia 33%, and neutropenia 17%) was manageable and did not result in treatment discontinuation. Transient and manageable grade 3 ALT increase (26%) was the most common biochemical abnormality. At the RD cohort, overall response rate was 22.2% (95%CI, 6.4%-47.6%), including one stringent complete response, one very good partial response, and two partial responses in r/r patients to BTZ and/or lenalidomide. The clinical benefit rate was 77.8% (95%CI, 52.4-93.6%). No major pharmacokinetic drug-drug interaction was found. In conclusion, the triple combination of plitidepsin, BTZ, and DXM showed an acceptable safety profile and had moderate activity in adult patients with r/r MM.FUNDING: The study was funded by Pharma Mar, S.A. ACKNOWLEDGMENTS: The authors thank the patients, their families, and investigators teams for their participation in this phase I clinical trial

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD

El estudio de los incendios forestales como contribución al conocimiento de la arqueología del paisaje de montaña

El estudio de los incendios forestales del pasado ha permitido poner de relieve la importancia del fuego en la configuración de los paisajes de las zonas de montaña desde el inicio del Holoceno. Las formaciones vegetales asociadas a las quemas regulares y las perturbaciones provocadas en el paisaje han evolucionado a la vez que las actividades humanas se transformaban y se adaptaban a los cambios ambientales. En los últimos años, distintas técnicas paleobotánicas enmarcadas en la geohistoria ambiental han resaltado la importancia de los trabajos pluridisciplinarios. Concretamente, se ha visto la necesidad de complementar y contrastar los indicadores relativos a las plantas leñosas, tales como el polen y los palinomorfos no polínicos. Por ejemplo, las condiciones sedimentarias de los lagos y las turberas han permitido el estudio de macrocarbones (> 150 μm) y microcarbones sedimentarios ( 400 μm) ha aportado información espacial local y relativa a la composición de especies leñosas. Asimismo, las marcas de fuego en los anillos de crecimiento de los árboles son una opción para ajustar algunas cronologías. Este trabajo tiene como objetivo valorar qué aportaciones se pueden realizar desde la geografía histórica ambiental que sean útiles para la arqueología del paisaje de montaña. Para ello se han revisado las principales técnicas paleobotánicas para el estudio de los incendios del pasado en las zonas de montaña, se debate acerca de la precisión espacial y temporal de los carbones según su tamaño y la técnica de muestreo empleada y se discute cómo distinguir las señales climáticas y humanas en los incendios forestales. Los principales resultados apuntan a que los incendios naturales han quemado todo tipo de paisajes con independencia de la formación vegetal. La cantidad de biomasa disponible en cada momento se ha demostrado que ha sido un factor determinante de la intensidad de los incendios. Finalmente, la combinación de carbones sedimentarios e indicadores polínicos sugieren que han existido fuegos provocados por la acción humana desde el inicio del Neolítico, mientras que aún no queda claro si los incendios que hubo en tiempos pretéritos tuvieron influencia antrópica o no