Targeting TLR4 with ApTOLL Improves Heart Function in Response to Coronary Ischemia Reperfusion in Pigs Undergoing Acute Myocardial Infarction.

Toll-like receptor 4 (TLR4) contributes to the pathogenesis of coronary ischemia/reperfusion (IR). To test whether the new TLR4 antagonist, ApTOLL, may prevent coronary IR damage, we administered 0.078 mg/kg ApTOLL or Placebo in pigs subjected to IR, analyzing the levels of cardiac troponins, matrix metalloproteinases, pro-, and anti-inflammatory cytokines, heart function, and tissue integrity over a period of 7 days after IR. Our results show that ApTOLL reduced cardiac troponin-1 24 h after administration, improving heart function, as detected by a significant recovery of the left ventricle ejection fraction (LVEF) and the shortening fraction (FS) cardiac parameters. The extension of necrotic and fibrotic areas was also reduced, as detected by Evans blue/2,3,5-triphenyltetrazolium chloride (TTC) staining, Hematoxylin/Eosine, and Masson Trichrome staining of heart sections, together with a significant reduction in the expression of the extracellular matrix-degrading, matrix metalloproteinase 9. Finally, the expression of the following cytokines, CCL1, CCL2, MIP1-A-B, CCL5, CD40L, C5/C5A, CXCL1, CXCL10, CXCL11, CXCL12, G-CSF, GM-CSF, ICAM-1, INF-g, IL1-a, ILI-b, IL-1Ra, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, IL16, IL17-A, IL17- E, IL18, IL21, IL27, IL32, MIF, SERPIN-E1, TNF-a, and TREM-1, were also assayed, detecting a pronounced decrease of pro-inflammatory cytokines after 7 days of treatment with ApTOLL. Altogether, our results show that ApTOLL is a promising new tool for the treatment of acute myocardial infarction (AMI).post-print3782 K

Emociones y salud en el trabajo: análisis del constructo “trabajo emocional” y propuesta de evaluación

El Trabajo Emocional (TE) es un constructo multidimensional que alude a la carga emocional, la valencia de la misma, su variedad y a su relación con el puesto de trabajo o con la cultura organizacional, así como con la efectividad del desempeño y el bienestar del trabajador. El objetivo de la presente investigación es el estudio y análisis del constructo de TE, así como la propuesta de un instrumento para su evaluación, recogiendo no sólo las dimensiones clásicas del constructo (i.e. disonancia emocional), sino también aquellos aspectos directamente vinculados con normas organizacionales del TE. Con una población española de cajeras (N=458), los análisis de fiabilidad, validez factorial y criterial, mostraron resultados psicométricos adecuados. Asimismo, dentro de la validez de criterio se refrendaron los estudios que señalan la relación entre el TE y el desgaste profesional

APRIL: A double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke

Inflammation; Neuroprotection; StrokeInflamació; Neuroprotecció; IctusInflamación; Neuroprotección; IctusIn the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a <6h window from symptoms onset to ApTOLL/placebo administration. The trial is currently being conducted and is divided into two parts: Phase Ib and Phase IIa. In Phase Ib, 32 patients will be allocated to four dose ascending levels to select, based on safety criteria, the best two doses to be administered in the following Phase IIa in which 119 patients will be randomized to three arms of treatment (dose A, dose B, and placebo).The study is supported by grants from the Spanish Ministry of Science, Innovation and Universities (RTC-2017-6651-1 and RTC2019-006795-1). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication

Videogame-related experiences among regular adolescent gamers

The objective of this study was to identify the videogame-related experiences expressed by regular adolescent gamers and to explore the socio-family factors related to these experiences. A cross-sectional observational and descriptive study was carried out with a convenience sample of regular Spanish videogamers between 16 and 18 years old. To measure the use of videogames for evasion and its negative consequences, the Questionnaire of Videogame-Related Experiences (Cuestionario de Experiencias Relacionadas con Videojuegos, CERV) was used and socio-family variables collected, evaluating their relationship with the results of the CERV. A total of 206 adolescents participated, 89.3% men [84.3-93.2] and 17.9% [12.9-23.9] allocating more than 35 hours a week to videogames. The CERV subscale related to the evasive use of videogames (max. = 24 points) obtained a mean value of 11.71 (SD = 3.52) and the mean value for the subscale related to the negative consequences (max. = 27 points) was 7.14 (SD = 3.33). A higher frequency of high values of evasive use (p = .038) and higher scores of this subscale (p = .02) were found in gamers without brothers or sisters. Higher scores and larger numbers of negative consequences were found in gamers who play more than 21 hours a week (p = .032). In conclusion, frequent use of videogames does not seem to be carried out with an evasive purpose, except in the case of absence of siblings. Frequent videogame use has only proven to carry a higher level of negative consequences when playing more than 21 hours a week. No other socio-family variables related to these subscales of the CERV have been identified

Nephroprotective effects of synthetic flavonoid hidrosmin in experimental diabetic nephropathy

Diabetes mellitus (DM) is a high‐impact disease commonly characterized by hyperglycemia, inflammation, and oxidative stress. Diabetic nephropathy (DN) is a common diabetic microvascular complication and the leading cause of chronic kidney disease worldwide. This study investigates the protective effects of the synthetic flavonoid hidrosmin (5‐O‐(beta-hydroxyethyl) diosmin) in experimental DN induced by streptozotocin injection in apolipoprotein E deficient mice. Oral administration of hidrosmin (300 mg/kg/day, n = 11) to diabetic mice for 7 weeks markedly reduced albuminuria (albumin‐to‐creatinine ratio: 47 ± 11% vs. control) and ameliorated renal pathological damage and expression of kidney injury markers. Kidneys of hidrosmin‐treated mice exhibited lower content of macrophages and T cells, reduced expression of cytokines and chemokines, and attenuated inflammatory signaling pathways. Hidrosmin treatment improved the redox balance by reducing prooxidant enzymes and enhancing antioxidant genes, and also decreased senescence markers in diabetic kidneys. In vitro, hidrosmin dose‐dependently reduced the expression of inflammatory and oxidative genes in tubuloepithelial cells exposed to either high‐glucose or cytokines, with no evidence of cytotoxicity at effective concentrations. In conclusion, the synthetic flavonoid hidrosmin exerts a beneficial effect against DN by reducing inflammation, oxidative stress, and senescence pathways. Hidrosmin could have a potential role as a coadjutant therapy for the chronic complications of DM.This work was supported by grants from the Spanish Ministry of Science and Innovation- FEDER funds (Retos Colaboración RTC2017-6089-1 and Retos Investigación RTI2018-098788-B-I00) and Instituto de Salud Carlos III (PI20/00487 and DTS 19/00093

Defective hippocampal neurogenesis underlies cognitive impairment by carotid stenosis-induced cerebral hypoperfusion in mice.

Chronic cerebral hypoperfusion due to carotid artery stenosis is a major cause of vascular cognitive impairment and dementia (VCID). Bilateral carotid artery stenosis (BCAS) in rodents is a well-established model of VCID where most studies have focused on white matter pathology and subsequent cognitive deficit. Therefore, our aim was to study the implication of adult hippocampal neurogenesis in hypoperfusion-induced VCID in mice, and its relationship with cognitive hippocampal deficits. Mice were subjected to BCAS; 1 and 3 months later, hippocampal memory and neurogenesis/cell death were assessed, respectively, by the novel object location (NOL) and spontaneous alternation performance (SAP) tests and by immunohistology. Hypoperfusion was assessed by arterial spin labeling-magnetic resonance imaging (ASL-MRI). Hypoperfused mice displayed spatial memory deficits with decreased NOL recognition index. Along with the cognitive deficit, a reduced number of newborn neurons and their aberrant morphology indicated a remarkable impairment of the hippocampal neurogenesis. Both increased cell death in the subgranular zone (SGZ) and reduced neuroblast proliferation rate may account for newborn neurons number reduction. Our data demonstrate quantitative and qualitative impairment of adult hippocampal neurogenesis disturbances associated with cerebral hypoperfusion-cognitive deficits in mice. These findings pave the way for novel diagnostic and therapeutic targets for VCID.This work was supported by grants from Spanish Ministry of Science and Innovation (MCIN) PID2019-106581RB-I00 (MM), from Leducq Foundation for Cardiovascular Research TNE-19CVD01 (MM) and TNE-21CVD04 (MM and IL), and from Instituto de Salud Carlos III (ISCIII) and co-financed by the European Development Regional Fund “A Way to Achieve Europe” PI20/00535 and RICORS-ICTUS RD21/0006/0001 (IL). CNIC was supported by ISCIII, MCIN, and ProCNIC Foundation, and is a Severo Ochoa Center of Excellence (CEX2020-001041-S). The microscopy experiments were performed in Unidad de Microscopía e Imagen Dinámica, CNIC, ICTS-ReDib, co-funded by MCIN/AEI/10.13039/501100011033 and FEDER “Una manera de hacer Europa” (#ICTS-2018- 04-CNIC-16). Part of the research work included in this publication has been carried out in the ReDIB ICTS infrastructure BioImaC, MCIN.S

APRIL: a double-blind, placebo-controlled, randomized, Phase Ib/IIa clinical study of ApTOLL for the treatment of acute ischemic stroke

In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a <6h window from symptoms onset to ApTOLL/placebo administration. The trial is currently being conducted and is divided into two parts: Phase Ib and Phase IIa. In Phase Ib, 32 patients will be allocated to four dose ascending levels to select, based on safety criteria, the best two doses to be administered in the following Phase IIa in which 119 patients will be randomized to three arms of treatment (dose A, dose B, and placebo).Peer ReviewedPostprint (published version

Pharmacotherapy negative outcomes resulting in Primary Care Emergency visits

Objetivo Analizar la prevalencia de los resultados negativos asociados a la medicación (RNM) que son causa de consulta en un servicio de urgencias de atención primaria (SUAP) en un entorno rural. Determinar la evitabilidad y la gravedad de los mismos. Diseño Estudio observacional descriptivo transversal. Emplazamiento SUAP de Mula. Murcia. Participantes Un total de 330 pacientes, en un periodo de 33 semanas. Mediciones principales Número y tipo de RNM: el farmacéutico, a través de los datos obtenidos de un cuestionario validado y la historia clínica, evaluó si existía relación entre los medicamentos que toma el paciente y el motivo de acudir a urgencias. En caso de sospecha de RNM se reevaluaba con el médico y se confirmaban o no los RNM identificados. Resultados De los 330 pacientes fueron evaluables 317. La media de edad de los pacientes era de 39,63 años y el 51,42% eran mujeres. La media de medicamentos que utilizaban fue de 1,38. Se detectaron un 26,50% (IC 95% 21,94-31,62) de pacientes con RNM como causa de visita a urgencias. El 53,57% de los RNM detectados fue de la categoría de efectividad y el 40,48% de necesidad. El 77,41% (IC-95% 67,35-85,01) de las visitas causadas por RNM fueron evitables. En cuanto a la gravedad, el 92,986% de los RNM eran leves. Conclusiones Una de cada 4 visitas al SUAP de Mula está causada por un RNM y, de ellas, el 77,41% son evitables.Objective Our aim was to estimate the prevalence of Pharmacotherapy negative outcomes in Primary Care Emergency visits in a rural environment, and to determine their preventability and severity. Design Descriptive study with an analytical component. Site Primary Care Emergency Service (SUAP), Mula. Murcia. Patients The study consisted of 330 patients over a 33 week period. Method Number and type of Pharmacotherapy negative outcomes: Pharmacist through the data, a validated questionnaire and medical history, assessing whether there was a relationship between the medications and the patient, and the reason for going to the Primary Care Emergency. In case of suspicion of Pharmacotherapy negative outcomes the patient is reassessed by the doctor, and the Pharmacotherapy negative outcomes confirmed or not identified. Results Of the 330 patients, 317 were evaluable. The mean age of patients was 39.63 years and 51.42% were women. The mean number of drugs used was 1.38, and 26.50% (95% CI, 21.94% -31.62%) patients were detected with Pharmacotherapy negative outcomes as a cause of visiting the Primary Care Emergency. 53.57% of the detected Pharmacotherapy negative outcomes detected as regards efficacy was 53.75%, 40.48% as regards need. More than three-quarters (77.41%; 95% CI, 67.35% -85.01%) of emergency visits caused by Pharmacotherapy negative outcomes were avoidable. In terms of severity, 92.86% of the Pharmacotherapy negative outcomes were mild. Conclusions One in four Mula SUAP visits are due to a Pharmacotherapy negative outcomes, and 77.41% of them are preventable

First-in-human phase I clinical trial of a TLR4-binding DNA aptamer, ApTOLL: Safety and pharmacokinetics in healthy volunteers.

ApTOLL is an aptamer that antagonizes Toll-like receptor 4 and improves functional outcomes in models of ischemic stroke and myocardial infarction. The aim of this study was to characterize the safety and pharmacokinetics of ApTOLL in healthy volunteers. A first-in-human dose-ascending, randomized, placebo-controlled phase I clinical trial to assess safety and pharmacokinetics of ApTOLL (30-min infusion intravenously) was performed in 46 healthy adult male volunteers. The study was divided into two parts: part A included seven single ascending dose levels, and part B had one multiple dose cohort. Safety and pharmacokinetic parameters were evaluated. No serious adverse events or biochemistry alterations were detected at any dose nor at any administration pattern studied. Maximum concentration was detected at the end of the infusion and mean half-life was 9.3 h. Interestingly, exposure increased in the first four levels receiving doses from 0.7 mg to 14 mg (AUC of 2,441.26 h∗ng/mL to 23,371.11 h∗ng/mL) but remained stable thereafter (mean of 23,184.61 h∗ng/mL after 70 mg). Consequently, the multiple dose study did not show any accumulation of ApTOLL. These results show an excellent safety and adequate pharmacokinetic profile that, together with the efficacy demonstrated in nonclinical studies, provide the basis to start clinical trials in patients.This study was sponsored by aptaTargets S.L. (Madrid, Spain) and was conducted at the Clinical Trials Unit (La Princesa Hospital, Madrid, Spain). The study was supported by a grant from the Spanish Ministry of Science, Innovation and Universities (RTC-2017-6651- 1). Authors acknowledge David Segarra and M. Eugenia Zarabozo (aptaTargets S.L.) for their contribution in the management and funding of the trial, and Alba Singla (Anagram; Barcelona, Spain) for her contribution in the monitoring of the trial.S