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Abstract Background Kilohertz high-frequency alternating current (KHFAC) stimulation has demonstrated to induce rapid and reversible nerve blocks without causing nerve damage. Previous studies have explored frequency-dependent effects using a transcutaneous approach in humans from 5 to 20 kHz. Nevertheless, its application in humans is limited by the lack of stimulators approved for frequencies above 20 kHz. Therefore, this study aimed to assess the effects and safety of transcutaneous KHFAC stimulation using a novel prototype stimulator, comparing interventions at 30, 40, and 50 kHz to sham stimulation on experimental pain, sensory, motor, and neurophysiological outcomes. Methods A randomized, double-blind, sham-controlled crossover study involving 34 healthy participants was conducted. Four interventions (30, 40, 50 kHz, and sham) were administered, and stimulation was applied for 20 min to the median nerve of the non-dominant hand. A prototype stimulator capable of delivering frequencies between 1 and 50 kHz, with a maximum peak-to-peak output current intensity of 400 mA was designed. The intensity applied during the stimulation was below motor threshold, evoking a ‘strong but comfortable’ tingling sensation. Primary outcomes included heat pain threshold (HPT), pressure pain threshold (PPT), and adverse effects. The secondary outcomes included static two-point discrimination sensitivity, isometric pinch strength, and median sensory nerve action potential (SNAP). Results Compared with the sham stimulation, all the active interventions exhibited a significantly greater increase in the PPT during and immediately after the stimulation, while only a significant increase was observed at 40 kHz (4.1 N/cm2; 95%CI 0.3 to 7.9) at 15 min post-intervention. Compared to sham stimulation, the 40 kHz intervention had a significantly greater effect on the HPT at all time points, with the greatest difference (1.4 °C; 0.6 to 2.1) occurring immediately post-intervention. Adverse effects during active interventions included petechiae, erythema, and itching, which resolved at 24 h post-intervention. For secondary outcomes, only a significant reduction in the median SNAP velocity was observed in the sham stimulation group compared to the 50 kHz group. Conclusions Active KHFAC stimulation, particularly at 40 kHz, delivered through a novel stimulator, effectively increased the PPT and HPT without affecting tactile or motor outcomes, inducing mild skin-related adverse effects. These findings have potential implications for people with pain-related pathologies. Trial registration NCT05230836.

Abstract The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.

Abstract A 16-year-old man presented with short VA supraventricular tachycardia and 2:1 atrioventricular ratio. The correct maneuvers allowed us to guide not only the mechanism but also the probable location of the atrioventricular block.

Reseña del libro La trinchera universal. Los voluntarios internacionales y la Guerra Civil española (Granada, Comares, 2021), de Javier Sánchez Zapatero (ed.). En este libro se estudia la producción testimonial y literaria producida por los brigadistas extranjeros que participaron en la contienda, con capítulos dedicados a voluntarios de diferente procedencia y abriendo el estudio a otros nombres que no son los míticos Hemingway, Malraux u Orwell, cuyo análisis ha dejado en un segundo plano a una variedad de autores y de testigos sobre nuestra contienda bélica nacional. El libro contiene tres grandes apartados redactados por especialistas de universidades españolas y extranjeras: "Panoramas", con estados de la cuestión sobre las literaturas anglosajonas, francófonas, germánicas e iberoamericanas y su relación con la Guerra Civil; "Semblanzas", en el que se esbozan descripciones biográficas y literarias de importantes voluntarios que combatieron en España; y "Representaciones", con dos investigaciones que analizan la figura del brigadista internacional en las literaturas inglesa y española desde 1936 hasta la actualidad.

Abstract Background Significant consequences of COVID-19 within academic/professional life are, at the psychological level, related to worry, tension, stress; coping strategies and lifestyle changes. This study describes the process of design and validation of an inventory (QPIC), which aims to assess the psychological impact that a situation of confinement can produce among university students and teachers. Methods Design of the instrument and psychometric tests. A sample of 862 students and 229 professors affiliated to Spanish and Colombian universities was used. Data were collected in April 2020 with the request of the favourable Bioethics Committee IR/2020. Results Six experts carried out the content validation. A confirmatory factor analysis of the theoretical dimensions proposed for the scales was performed and the internal consistency of each of the three initial scales was confirmed (0.866, 0.813 and 0.834). Conclusion A rigorous and reliable instrument is achieved, consisting of two final scales: (a) Worry, tension and stress scale (b) Coping scale, which helps to measure individual psychological effects in housebound situations. It is an instrument designed, constructed ad hoc to assess the impact of confinement and subjected to validation. The factor structure and reliability of the instrument are examined and good psychometric properties are obtained. The application of this inventory will make it possible to assess the impact on people’s mental health during a period of confinement.

Abstract Background Motor impairments are very common in neurological diseases such as multiple sclerosis. Noninvasive brain stimulation could influence the motor function of patients. Objective The aim of this meta-analysis was to evaluate the effectiveness of transcranial direct current stimulation (tDCS) on balance and gait ability in patients with multiple sclerosis. Additionally, a secondary aim was to compare the influence of the stimulation location of tDCS on current effectiveness. Methods A search was conducted for randomized controlled trials published up to May 2023 comparing the application of tDCS versus a sham or control group. The primary outcome variables were balance and gait ability. Results Eleven studies were included in the qualitative analysis, and ten were included in the quantitative analysis, which included 230 patients with multiple sclerosis. The average effect of tDCS on gait functionality was superior to that of the control group (SMD = -0.71; 95% CI, -1.05 to -0.37). However, the overall results of the tDCS vs. sham effect on static balance did not show significant differences between groups (MD = 1.26, 95% CI, -1.31 to 3.82). No significant differences were found when different locations of tDCS were compared. Conclusions These results reveal that tDCS is an effective treatment for improving gait ability with a low quality of evidence. However, the application of tDCS has no effect on static balance in patients with multiple sclerosis with very low quality of evidence. Similarly, there seems to be no difference regarding the stimulation area with tDCS.

Purpose: The aim was to analyze the accuracy of digital models and 3D-printed casts from full-arch digital impressions using two intraoral scanners (iTeroTM and PrimescanTM). Materials and methods: A crossover reliability study was designed, scanning children and teenagers with iTeroTM and PrimescanTM. Accuracy was evaluated by measuring intercanine, intermolar, and ipsilateral canine–molar distances intraorally and comparing these measurements with those from plaster casts, digital models obtained with intraoral scanners, and 3D-printed casts. A paired comparison and a general linear model with a one-way repeated measures ANOVA procedure were carried out with a confidence level of 95% (p ≤ 0.05). Results: A total of 51 subjects were analyzed (mean age 12.35 ± 2.57). Statistical differences (p < 0.05) were found in the upper and lower arch regarding accuracy in comparison to intraoral measurements, except for the iTeroTM-printed cast and canine–molar upper right and intercanine lower distances (p > 0.05 for all comparisons). Regarding a comparison between reproduction methods, the plaster cast oversized the intercanine upper distance in comparison with both intraoral scanners’ digital models and the PrimescanTM-printed cast (p = 0.001), but there were no differences in the lower arch (p > 0.05 for all comparisons). Conclusion: Intraoral scanners reproduce tooth structures with similar accuracy to conventional methods.

Soil invertebrates are key to decomposition, a central ecosystem process related to soil health. In many temperate areas climate change will decrease soil water content, which strongly modulates biological activity. However, data are lacking on how shifts in rainfall patterns affect soil biota and the ecosystem processes they provide. Here, we used the bait-lamina test to experimentally assess how a severe drought event influenced detritivore feeding activity, during a wheat growing season, in soils under long-term organic or conventional farming. Additionally, biotic and abiotic soil parameters were measured. Feeding activity was reduced under extreme drought and conventional management, although no climate-management synergies were found. Vertical migrations of Collembola and Oribatida partially explained the unexpectedly higher bait consumption at shallower depths in response to drought. Exploratory mixed-effects longitudinal random forests (a novel machine learning technique) were used to explore whether the relative abundances of meso‑, microfauna and microbes of the decomposer food web, or abiotic soil parameters, affected the feeding activity of detritivores. The model including meso‑ and microfauna selected four Nematoda taxa and explained higher variance than the model with only microbiota, indicating that detritivore feeding is closely associated with nematodes but not with microbes. Additionally, the model combining fauna and microbiota explained less variance than the faunal model, suggesting that microbe-fauna synergies barely affected detritivore feeding. Moreover, soil water and mineral nitrogen contents were found to strongly determine detritivore feeding, in a positive and negative way, respectively. Hence, our results suggest that severe drought and conventional farming impair the feeding activity of soil detritivores and thus, probably, decomposition and nutrient mineralization in soils. Furthermore, machine learning algorithms arise as a powerful technique to explore the identity of potential key drivers relating biodiversity to ecosystem functioning.

The aim of this study was to evaluate the comfort of children and adolescents with conventional full-arch dental impression methods compared to two intraoral scanners (iTeroTM and PrimescanTM). Methods: A monocentric, analytical, controlled crossover study was designed to compare conventional impression and digital impression with two intraoral scanners (iTeroTM and PrimescanTM) in children and teenagers. Patient comfort was evaluated using a 100 mm VAS scale adapted to Spanish and for children. A descriptive and analytical statistical method was conducted with a confidence level of 95% (p ≤ 0.05) and asymptotic or bilateral significance. Results: A total of 51 subjects were enrolled in the study (mean age = 12.35 years). Although the group of 10–14-year-olds was the most numerous, gender was equally distributed among the age groups. None of the variables on the VAS scale showed differences between the gender categories (p > 0.05). There were differences (p < 0.05) with respect to the age categories, as the middle adolescent group showed the worst general perception and total comfort during the conventional impression. Statistically significant differences were found between all VAS scale items and the three impression methods (p < 0.05). Conclusions: The digital impression technique is superior in terms of total comfort to the conventional alginate impression in children and adolescents.

The exploration of patterns of health beliefs about COVID-19 among nursing students may be beneficial to identify behaviors, attitudes and knowledge about contagion risk. We sought to analyze the variables of risk perception, perceived risk factors, coping style, sense of coherence and knowledge of preventive measures as possible predictors of having suffered from COVID-19. Participants were nursing students from 13 universities in Spain. Sociodemographic and health variables were collected. To test the independent variables, the Perception Risk Coping Knowledge (PRCK-COVID-19) scale was created and validated because there was no specific survey for young people adapted to the pandemic situation of COVID-19. It was validated with adequate psychometric properties. A total of 1562 students (87.5% female, mean age 21.5 ± 5.7 years) responded. The high perception of the risk of contagion, the high level of knowledge and a coping style focused on the situation were notable. Significant differences by gender were found in the coping styles, problem-focused, avoidance and knowledge scales, with women scoring higher in all categories. The multiple regression analysis was significant (F = 3.68; p < 0.001). The predictor variables were the coping styles subscale search for support and the intrinsic and extrinsic perceived risk factors. Our model predicts that nursing students with a social support-based coping style are at a higher risk of becoming infected with COVID-19, based on their own health belief model.

La récurrence de la post-mémoire chez des descendants de personnes ayant subi des événements tragiques a engendré un courant narratif dans lequel Lydie Salvayre, pour le cas français de descendants d’exilés républicains espagnols, se distingue avec son œuvre Pas pleurer. L’écrivaine a ressenti l’obligation morale de restaurer le passé dans le but de sortir de l’oubli des hommes, des femmes, des événements historiques et sociaux, des tendances idéologiques… sans tomber dans le manichéisme auquel celles-ci peuvent conduire. Le mélange de fiction, d’autobiographie et d’intertextualité en tant que mécanisme de remémoration et la défense du métissage linguistique et de l’interculturalité sont autant d’éléments clés de l’analyse.

PurposeThe aim of this systematic review is to evaluate the perception of the patient, the chairside time, and the reliability and/or reproducibility of intraoral scanners for full arch in pediatric patients.MethodsA data search was performed in four databases (Medline-Pubmed, Scopus, ProQuest and Web of Science) in accordance with the PRISMA 2020 statements. Studies were classified in three categories (patient perception, scanning or impression time and reliability and/or reproducibility). The resources, the data extraction and the quality assessment were carried out independently by two operators. The variables recorded were population characteristics, material and methods aspects and included country, study design and main conclusion. A quality assessment of the selected studies was performed with QUADAS-2 tool, and Kappa-Cohen Index was calculated to analyze examiner agreement.ResultsThe initial search obtained 681 publications, and finally four studies matching inclusion criteria were selected. The distribution of the studies in the categories was three for the analysis of the patient's perception and scanning or impression time; and two items to assess the reliability and/or reproducibility of intraoral scans. All included studies have a repeated measures–transversal design. The sample size ranged between 26 and 59 children with a mean age. The intraoral scanners evaluated were Lava C.O.S, Cerec Omnicam, TRIOS Classic, TRIOS 3-Cart and TRIOS Ortho. The quality assessment of the studies using QUADAS-2 tool revealed a low risk of bias while evaluating patient perception, but an unclear risk of bias in the analysis of accuracy or chairside time. In relation to the applicability concerns, the patient selection was of high risk of bias. All studies agreed that the patient perception and comfort is better with intraoral scanners in comparison with the conventional method. The accuracy or reliability of the digital procedure is not clear, being clinically acceptable. In relation with the chairside time, it depends on the intraoral scanner, with contradictory data in the different analyzed studies.ConclusionThe use of intraoral scanners in children is a favorable option, finding a significantly higher patient perception and comfort with intraoral scanners compared to the conventional impression method. The evidence for reliability or reproducibility is not strong to date, however, the differences between the intraoral measurements and the digital models would be clinically acceptable.

BackgroundUnmodulated high-frequency alternating currents (HFAC) are employed for producing peripheral nerves block. HFAC have been applied in humans with frequencies up to 20 kHz, whether transcutaneously, percutaneously, or via surgically-implanted electrodes. The aim of this study was to assess the effect of percutaneous HFAC, applied with ultrasound-guided needles at 30 kHz, on the sensory-motor nerve conduction of healthy volunteers.MethodsA parallel, double-blind, randomized clinical trial with a placebo control was conducted. Percutaneous HFAC at 30 kHz or sham stimulation was applied via ultrasound-guided needles in 48 healthy volunteers (n = 24 in each group) for 20 min. The assessed outcome variables were pressure pain threshold (PPT), mechanical detection threshold (MDT), maximal finger flexion strength (MFFS), antidromic sensory nerve action potential (SNAP), hand temperature, and subjective sensations by the participants. The measurements were recorded pre-intervention, during the stimulation (at 15 min), immediately post-intervention (at 20 min), and 15 min after the end of treatment.ResultsThe PPT increased in the active group compared with sham stimulation, both during the intervention [14.7%; 95% confidence interval (CI): 4.4–25.0], immediately post-intervention (16.9%; 95% CI: −7.2–26.5), and 15 min after the end of the stimulation (14.3%; 95% CI: 4.4–24.3) (p < 0.01). The proportion of participants who reported feelings of numbness and heaviness was significantly higher in the active group (46 and 50%, respectively) than in the sham group (8 and 18%, respectively) (p < 0.05). No intergroup differences were observed in the remaining outcome variables. No unexpected adverse effects derived from the electrical stimulation were reported.ConclusionPercutaneous stimulation with HFAC at 30 kHz applied to the median nerve increased the PPT and subjective perception of numbness and heaviness. Future research should evaluate its potential therapeutic effect in people with pain.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04884932, identifier NCT04884932.

Abstract Soil biodiversity constitutes the biological pillars of ecosystem services provided by soils worldwide. Soil life is threatened by intense agricultural management and shifts in climatic conditions as two important global change drivers which are not often jointly studied under field conditions. We addressed the effects of experimental short-term drought over the wheat growing season on soil organisms and ecosystem functions under organic and conventional farming in a Swiss long term trial. Our results suggest that activity and community metrics are suitable indicators for drought stress while microbial communities primarily responded to agricultural practices. Importantly, we found a significant loss of multiple pairwise positive and negative relationships between soil biota and process-related variables in response to conventional farming, but not in response to experimental drought. These results suggest a considerable weakening of the contribution of soil biota to ecosystem functions under long-term conventional agriculture. Independent of the farming system, experimental and seasonal (ambient) drought conditions directly affected soil biota and activity. A higher soil water content during early and intermediate stages of the growing season and a high number of significant relationships between soil biota to ecosystem functions suggest that organic farming provides a buffer against drought effects.

Abstract The number of Web APIs for accessing information and services is continuously increasing, and yet, no tools exist to automate the time-consuming and error-prone process of invoking those APIs and composing their responses. The recent emergence of widely-adopted, standardized, Web-API description formats and the development of Linked Data technologies for data integration have motivated our work on the LRA (Linked REST APIs) methodology [1, 2]. LRA relies on RDF service specifications to automate the development process around the usage of Web APIs. This automation represents a great opportunity to systematize and improve the quality of service-oriented application development. However, LRA’s reliance on SPARQL as the user-interaction model may hinder its adoption, because it requires developers to learn the intricacies of the unconventional graph data model and its associated datasets. In this paper we have developed the LRA Workbench ( $$LRA_{Wbench}$$ L R A Wbench ), which takes advantage of the emergent schema of Web-API specifications, in order to simplify the formulation of LRA-compliant SPARQL queries. Our empirical evaluation of the $$LRA_{Wbench}$$ L R A Wbench usability demonstrates that our tool significantly improves the performance of developers formulating SPARQL queries for LRA. A subsequent study on the effectiveness of the $$LRA_{Wbench}$$ L R A Wbench demonstrated that developers using LRA tend to produce code with considerable better structural complexity, in less time, than developers manually composing APIs.

Abstract Background Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method able to modulate neuronal activity after stroke. The aim of this systematic review was to determine if tDCS combined with robotic therapy (RT) improves limb function after stroke when compared to RT alone. Methods A search for randomized controlled trials (RCTs) published prior to July 15, 2021 was performed. The main outcome was function assessed with the Fugl-Meyer motor assessment for upper extremities (FM/ue) and 10-m walking test (10MWT) for the lower limbs. As secondary outcomes, strength was assessed with the Motricity Index (MI) or Medical Research Council scale (MRC), spasticity with the modified Ashworth scale (MAS), functional independence with the Barthel Index (BI), and kinematic parameters. Results Ten studies were included for analysis (n = 368 enrolled participants). The results showed a non-significant effect for tDCS combined with RT to improve upper limb function [standardized mean difference (SMD) = − 0.12; 95% confidence interval (CI): − 0.35–0.11)]. However, a positive effect of the combined therapy was observed in the lower limb function (SMD = 0.48; 95% CI: − 0.15–1.12). Significant results favouring tDCS combined with RT were not found in strength (SMD = − 0.15; 95% CI: − 0.4–0.1), spasticity [mean difference (MD) = − 0.15; 95% CI: − 0.8–0.5)], functional independence (MD = 2.5; 95% CI: − 1.9–6.9) or velocity of movement (SMD = 0.06; 95% CI: − 0.3–0.5) with a “moderate” or “low” recommendation level according to the GRADE guidelines. Conclusions Current findings suggest that tDCS combined with RT does not improve upper limb function, strength, spasticity, functional independence or velocity of movement after stroke. However, tDCS may enhance the effects of RT alone for lower limb function. tDCS parameters and the stage or type of stroke injury could be crucial factors that determine the effectiveness of this therapy.

Background One of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by the tumor cells. We have generated a CAR specific for the splice variant extra domain A (EDA) of fibronectin, which is highly expressed in the tumor stroma of many types of tumors but not in healthy tissues.Methods EDA expression was explored in RNA-seq data from different human tumor types and by immunohistochemistry in paraffin-embedded tumor biopsies. Murine and human anti-EDA CAR-T cells were prepared using recombinant retro/lentiviruses, respectively. The functionality of EDA CAR-T cells was measured in vitro in response to antigen stimulation. The antitumor activity of EDA CAR-T cells was measured in vivo in C57BL/6 mice challenged with PM299L-EDA hepatocarcinoma cell line, in 129Sv mice-bearing F9 teratocarcinoma and in NSG mice injected with the human hepatocarcinoma cell line PLC.Results EDA CAR-T cells recognized and killed EDA-expressing tumor cell lines in vitro and rejected EDA-expressing tumors in immunocompetent mice. Notably, EDA CAR-T cells showed an antitumor effect in mice injected with EDA-negative tumor cells lines when the tumor stroma or the basement membrane of tumor endothelial cells express EDA. Thus, EDA CAR-T administration delayed tumor growth in immunocompetent 129Sv mice challenged with teratocarcinoma cell line F9. EDA CAR-T treatment exerted an antiangiogenic effect and significantly reduced gene signatures associated with epithelial-mesenchymal transition, collagen synthesis, extracellular matrix organization as well as IL-6-STAT5 and KRAS pathways. Importantly, the human version of EDA CAR, that includes the human 41BB and CD3ζ endodomains, exerted strong antitumor activity in NSG mice challenged with the human hepatocarcinoma cell line PLC, which expresses EDA in the tumor stroma and the endothelial vasculature. EDA CAR-T cells exhibited a tropism for EDA-expressing tumor tissue and no toxicity was observed in tumor bearing or in healthy mice.Conclusions These results suggest that targeting the tumor-specific fibronectin splice variant EDA with CAR-T cells is feasible and offers a therapeutic option that is applicable to different types of cancer.

This article shows the use of a high-frequency Full-Bridge inverter to design an alternating magnetic field generator for experimental studies on anti-cancer treatment with magnetic nanoparticles. In magnetic hyperthermia, nanoparticles are used to raise the pathological cancerous cell’s temperature high enough to induce their death by apoptosis, but not as high as to destroy them by thermal ablation of the whole tissue volume, consequently leaving healthy cells alive. Conventionally, sinusoidal alternating magnetic fields are used to heat the nanoparticles, which can be more easily produced than other waveforms. However, there are no theoretical nor experimental reasons to choose the sinusoidal waveform. This work aims to develop an improved power system to study the effect of different waveforms of the magnetic field on heat production when exciting magnetic nanoparticles, aiming at demonstrating that other waveforms can be much more efficient in producing heat than conventional sinusoids. To prove our hypothesis, we designed an inverter able to generate four waveforms at high frequencies and a fifth sinusoidal signal derived by a resonant capacitor, in the range of 100 kHz to 1 MHz and up to 10 mT of peak intensity. Also, we used SiC devices to process high currents at high switching frequencies efficiently. Additionally, to enhance the system efficiency, Zero-Voltage Switching is used to reduce switching losses and minimize electromagnetic noise and interference. The experimental results obtained with non-sinusoidal waveforms have shown a remarkable performance improvement compared to classical sine wave excitation. The nanoparticles’ heat dissipation depends on the applied alternating magnetic field’s signal slope, signal frequency, and peak field intensity. We conclude that further work deserves to be done to find the optimum work conditions in function of the used particle and biological environment to test if this type of magnetic field generator could overcome the conventional system’s performance.

Abstract Background High frequency alternating current (HFAC) stimulation have been shown to produce a peripheral nerve conduction block. Currently, all the studies applying HFAC stimulation in clinical studies, have employed frequencies below 10 kHz. The main aim of this work was to investigate the neuromodulatory effect of transcutaneous 20 kHz stimulation on somatosensory and pain thresholds, and maximal handgrip strength. Methods A randomized, crossover, single-blinded, placebo-controlled trial was conducted following recruitment of fourteen healthy volunteers. Transcutaneous stimulation at 20 kHz and sham stimulation were applied over the ulnar and median nerves of fourteen healthy volunteers for 20 min. Maximal handgrip strength (MHS), mechanical detection threshold (MDT) and pressure pain threshold (PPT) were registered prior to, during (15 min), immediately after the end (20 min), and 10 min following stimulation. Results The 20 kHz stimulation showed a lower MHS during the stimulation at the 15 min (30.1 kgs SE 2.8) and at 20 min (31.8 kgs, SE 2.8) when compared to sham stimulation (35.1 kgs, SE 3.4; p

Over the last few years, the financial sector has undergone a digital revolution that has had a severe impact on different related areas such as, the entities, the cybersecurity of systems, regulations and, of course, customers. SOTER project takes the challenge providing a complete set of tools to enhance the cybersecurity levels by implementing, in addition to non-technological tools, an innovative onboarding process has been implemented with the goals of increasing security, improving the user experience and integrity in the sector, and facilitating the customer entry into the digital marketplace by combining a set of breakthrough technologies. The cybersecurity research plays a crucial role in the conception and implementation of the onboarding process and for this kind of processes it has to be studied as an individual area by itself, as it is necessary to analyze the possible threats that can affect them, their origin and the solution(s) that can be taken to address them. Therefore, the SOTER project presents a fully digital onboarding process, innovative, adaptable to both current and future market needs and to possible changes in regulation, based on the most advanced technologies available today, and above all guaranteeing the cybersecurity of both entities and end users.

There is a paucity of adequate mouse models and cell lines available to study lung squamous cell carcinoma (LUSC). We have generated and characterized two models of phenotypically different transplantable LUSC cell lines, i.e. UN-SCC679 and UN-SCC680, derived from A/J mice that had been chemically induced with N-nitroso-tris-chloroethylurea (NTCU). Furthermore, we genetically characterized and compared both LUSC cell lines by performing whole-exome and RNA sequencing. These experiments revealed similar genetic and transcriptomic patterns that may correspond to the classic LUSC human subtype. In addition, we compared the immune landscape generated by both tumor cells lines in vivo and assessed their response to immune checkpoint inhibition. The differences between the two cell lines are a good model for the remarkable heterogeneity of human squamous cell carcinoma. Study of the metastatic potential of these models revealed that both cell lines represent the organotropism of LUSC in humans, i.e. affinity to the brain, bones, liver and adrenal glands. In summary, we have generated valuable cell line tools for LUSC research, which recapitulates the complexity of the human disease.

Abstract Background Transcranial direct-current stimulation (tDCS) is an easy-to-apply, cheap, and safe technique capable of affecting cortical brain activity. However, its effectiveness has not been proven for many clinical applications. Objective The aim of this systematic review was to determine whether the effect of different strategies for gait training in patients with neurological disorders can be enhanced by the combined application of tDCS compared to sham stimulation. Additionally, we attempted to record and analyze tDCS parameters to optimize its efficacy. Methods A search in Pubmed, PEDro, and Cochrane databases was performed to find randomized clinical trials that combined tDCS with gait training. A chronological filter from 2010 to 2018 was applied and only studies with variables that quantified the gait function were included. Results A total of 274 studies were found, of which 25 met the inclusion criteria. Of them, 17 were rejected based on exclusion criteria. Finally, 8 trials were evaluated that included 91 subjects with stroke, 57 suffering from Parkinson’s disease, and 39 with spinal cord injury. Four of the eight assessed studies did not report improved outcomes for any of its variables compared to the placebo treatment. Conclusions There are no conclusive results that confirm that tDCS can enhance the effect of the different strategies for gait training. Further research for specific pathologies, with larger sample sizes and adequate follow-up periods, are required to optimize the existing protocols for applying tDCS.

Resumen: Objetivo: Determinar si la estimulación eléctrica nerviosa transcutánea (TENS) tiene un efecto analgésico superior al placebo o a otros tratamientos en pacientes con fibromialgia. Además, se pretendía analizar los parámetros de aplicación óptimos para conseguir una mayor reducción del dolor. Diseño: Revisión sistemática. Fuentes de datos: Ensayos clínicos aleatorizados sobre el efecto del TENS en la fibromialgia en las bases de datos Pubmed, Cochrane y PEDro hasta noviembre de 2016. Selección de estudios: Se seleccionaron 8 estudios de un total de 62. Se incluyeron ensayos clínicos controlados en los que se aplicase TENS a personas con fibromialgia. Extracción de datos: Se analizó el dolor como variable principal, aunque también se incluyeron otras variables como fatiga, calidad de vida e impacto de la enfermedad, recorrido articular y depresión. Resultados: Seis de 8 trabajos obtuvieron una disminución significativa del dolor. En 2 estudios se aplicó el TENS como tratamiento complementario al ejercicio terapéutico con resultados evidenciando una disminución del dolor. El resto de variables estudiadas presentaron gran variabilidad y no se pudieron establecer resultados concluyentes. Conclusiones: El tratamiento con TENS resulta efectivo para la disminución del dolor en personas con fibromialgia. Además, la inclusión del TENS en programas de ejercicio terapéutico parece tener un efecto superior a la realización del ejercicio terapéutico de forma aislada. Sin embargo, no se ha demostrado eficacia en otras variables diferentes al dolor. Son necesarios más estudios que indaguen en la optimización de los parámetros del TENS y un mayor consenso entre las variables utilizadas. Abstract: Objective: To determine whether transcutaneous electrical nerve stimulation (TENS) has an analgesic effect greater than placebo or other treatments in patients with fibromyalgia. Furthermore, it was intended to analyze the optimal application parameters to achieve a greater reduction of pain. Design: A systematic review. Data source: Randomized clinical trials on the effect of TENS on fibromyalgia in the databases Pubmed, Cochrane and PEDro until November 2016. Selection of studies: 8 studies out of a total of 62 were selected. Controlled clinical trials in which TENS was applied in patients with fibromyalgia were included. Data extraction: Pain was analyzed as the main variable, although other variables such as fatigue, quality of life and impact, range of motion and depression were also included. Results: 6 out of 8 studies obtained a significant decrease of pain. In 2 studies, TENS was applied as complementary treatment to therapeutic exercise with results evidencing a decrease in pain. The rest of the variables studied presented a great variability and conclusive results could not be established. Conclusions: Treatment with TENS is effective for reducing pain in people with fibromyalgia. In addition, the inclusion of TENS in therapeutic exercise programs seems to have a greater effect than practicing therapeutic exercise in isolation. However, no efficacy has been demonstrated in other variables different to pain. Further studies are needed to investigate the optimization of the parameters of the TENS and a greater consensus among the variables used. Palabras clave: Fibromialgia, Estimulación eléctrica nerviosa transcutánea, Sensibilización central, Dolor crónico, Keywords: Fibromyalgia, Transcutaneous electric nerve stimulation, Central sensitization, Chronic pain

Toll-like receptors (TLRs) are natural initial triggers of innate and adaptive immune responses. With the advent of cancer immunotherapy, nucleic acids engineered as ligands of endosomal TLRs have been investigated for the treatment of solid tumors. Despite promising results, their systemic administration, similarly to other immunotherapies, raises safety issues. To overcome these problems, recent studies have applied the direct injection of endosomal TLR agonists in the tumor and/or draining lymph nodes, achieving high local drug exposure and strong antitumor response. Importantly, intratumoral delivery of TLR agonists showed powerful effects not only against the injected tumors but also often against uninjected lesions (abscopal effects), resulting in some cases in cure and antitumoral immunological memory. Herein, we describe the structure and function of TLRs and their role in the tumor microenvironment. Then, we provide our vision on the potential of intratumor versus systemic delivery or vaccination approaches using TLR agonists, also considering the use of nanoparticles to improve their targeting properties. Finally, we collect the preclinical and clinical studies applying intratumoral injection of TLR agonists as monotherapies or in combination with: (a) other TLR or STING agonists; (b) other immunotherapies; (c) radiotherapy or chemotherapy; (d) targeted therapies.

Introduction The use of immune-checkpoint inhibitors has drastically improved the management of patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory drugs that can reinvigorate the immune cytotoxic activity, in combination with antiprogrammed cell death 1 (PD-1) antibody, are a great promise to overcome resistance. We evaluated the impact of the SRC family kinases (SFKs) on NSCLC prognosis, and the immunomodulatory effect of the SFK inhibitor dasatinib, in combination with anti-PD-1, in clinically relevant mouse models of NSCLC.Methods A cohort of patients from University Clinic of Navarra (n=116) was used to study immune infiltrates by multiplex immunofluorescence (mIF) and YES1 protein expression in tumor samples. Publicly available resources (TCGA, Km Plotter, and CIBERSORT) were used to study patient’s survival based on expression of SFKs and tumor infiltrates. Syngeneic NSCLC mouse models 393P and UNSCC680AJ were used for in vivo drug testing.Results Among the SFK members, YES1 expression showed the highest association with poor prognosis. Patients with high YES1 tumor levels also showed high infiltration of CD4+/FOXP3+ cells (regulatory T cells (Tregs)), suggesting an immunosuppressive phenotype. After testing for YES1 expression in a panel of murine cell lines, 393P and UNSCC680AJ were selected for in vivo studies. In the 393P model, dasatinib+anti-PD-1 treatment resulted in synergistic activity, with 87% tumor regressions and development of immunological memory that impeded tumor growth when mice were rechallenged. In vivo depletion experiments further showed that CD8+ and CD4+ cells are necessary for the therapeutic effect of the combination. The antitumor activity was accompanied by a very significant decrease in the number of Tregs, which was validated by mIF in tumor sections. In the UNSCC680AJ model, the antitumor effects of dasatinib+anti-PD-1 were milder but similar to the 393P model. In in vitro assays, we demonstrated that dasatinib blocks proliferation and transforming growth factor beta-driven conversion of effector CD4+ cells into Tregs through targeting of phospholymphocyte-specific protein tyrosine kinase and downstream effectors pSTAT5 and pSMAD3.Conclusions YES1 protein expression is associated with increased numbers of Tregs in patients with NSCLC. Dasatinib synergizes with anti-PD-1 to impair tumor growth in NSCLC experimental models. This study provides the preclinical rationale for the combined use of dasatinib and PD-1/programmed death-ligand 1 blockade to improve outcomes of patients with NSCLC.

Abstract Background High-frequency alternating currents of greater than 1 kHz applied on peripheral nerves has been used in animal studies to produce a motor nerve block. It has been evidenced that frequencies higher than 5 kHz are necessary to produce a complete peripheral nerve block in primates, whose nerve thickness is more similar to humans. The aim of the study was to determine the effect on muscle strength after the application of a high-frequency stimulation at 5 and 10 kHz compared to sham stimulation in healthy volunteers. Findings Transcutaneous stimulation at 5 kHz, 10 kHz and sham stimulation were applied to eleven healthy volunteers over the ulnar and median nerves for 20 min. Maximal handgrip strength was measured before, during, immediately after the intervention, and 10 min after the end of intervention. The 10 kHz stimulation showed a lower handgrip strength during the intervention (28.1 N, SEM 3.9) when compared to 5 kHz (31.1 N, SEM 3.6; p

Cell-cycle checkpoints are essential feedback mechanisms that promote genome integrity. However, in the face of unrepairable DNA lesions, bypass mechanisms can suppress checkpoint activity and allow cells to resume proliferation. The molecular mechanisms underlying this biological response are currently not understood. Taking advantage of unique separation-of-function mutants, we show that the Polo-like kinase (PLK) Cdc5 uses a phosphopriming-based interaction mechanism to suppress G2/M checkpoint arrest by targeting Polo kinase activity to centrosomes. We also show that key subunits of the evolutionarily conserved RSC complex are critical downstream effectors of Cdc5 activity in checkpoint suppression. Importantly, the lethality and checkpoint defects associated with loss of Cdc5 Polo box activity can be fully rescued by artificially anchoring Cdc5 kinase domain to yeast centrosomes. Collectively, our results highlight a previously unappreciated role for centrosomes as key signaling centers for the suppression of cell-cycle arrest induced by persistent or unrepairable DNA damage.

The intensity used during transcutaneous electrical nerve stimulation (TENS) in both, clinical practice and research studies, is often based on subjective commands such as "strong but comfortable sensation". There is no consensus regarding the effectiveness dose of TENS. The objective was to determine the difference in the effect of spinal TENS on soleus H-reflex modulation when applied by two therapists instructed to apply the stimulation at a "strong but comfortable" intensity. Twenty healthy volunteers divided into two groups: Therapist 1 (n = 10) and Therapist 2 (n = 10). Both therapist applied spinal TENS and sham stimulation at the T10-12 spinal level for 40min in random order to each subject, at an intensity designed to produce a "strong but comfortable" sensation. To avoid habituation, the intensity was adjusted every 2min. Soleus H-reflex was recorded before, during, and 10min after TENS by an observer blinded to the stimulus applied. Despite the instruction to apply TENS at a "strong comfortable" level, a significant difference in current density was identified: Therapist 1 (0.67mA/cm2, SD 0.54) applied more than Therapist 2 (0.53mA/cm2, SD 0.57; p

In modern aircraft designs, following the More Electrical Aircraft (MEA) philosophy, there is a growing need for new high-power converters. In this context, innovative solutions to provide high efficiency and power density are required. This paper proposes an unregulated LLC full-bridge operating at resonant frequency to obtain a constant gain at all loads. The first harmonic approximation (FHA) model is not accurate enough to estimate the voltage gain in converters with high parasitic resistance. A modified FHA model is proposed for voltage gain analysis, and time-based models are used to calculate the instantaneous current required for the ZVS transition analysis. A method using charge instead of current is proposed and used for this ZVS analysis. Using this method, an auxiliary circuit is proposed to achieve complete ZVS within the whole load range, avoiding a gapped transformer design and increasing the efficiency and power density. A 28 Vdc output voltage prototype, with 10 kW peak output power, has been developed to validate the theoretical analysis and the proposed auxiliary circuit. The maximum efficiency (96.3%) is achieved at the nominal power of 5 kW.