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Ankle and foot deformity is one of the most common musculoskeletal disorders in children and a leading cause of functional impairment and diminished quality of life when not treated. A spectrum of conditions may produce foot and ankle deformities, with congenital disorders the most frequent cause, followed by acquired conditions. Congenital disorders include congenital talipes equinovarus or congenital clubfoot, metatarsus adductus, skewfoot, congenital vertical talus, and tarsal coalition.Some of these deformities are frequent and easily diagnosed based on clinical features, but clinical overlap between pathologies can be challenging. Thus imaging plays a paramount role in evaluating these patients. Radiographs are the first imaging modality of choice, but they may not be sufficient in infants due to the lack of ossification of the tarsal bones. Ultrasonography allows not only a detailed visualization of the cartilaginous structures but also permits a dynamic study of the foot and ankle. Computed tomography may be necessary in certain conditions such as tarsal coalitions.

Explainable artificial intelligence has become a vitally important research field aiming, among other tasks, to justify predictions made by intelligent classifiers automatically learned from data. Importantly, efficiency of automated explanations may be undermined if the end user does not have sufficient domain knowledge or lacks information about the data used for training. To address the issue of effective explanation communication, we propose a novel information-seeking explanatory dialogue game following the most recent requirements to automatically generated explanations. Further, we generalise our dialogue model in form of an explanatory dialogue grammar which makes it applicable to interpretable rule-based classifiers that are enhanced with the capability to provide textual explanations. Finally, we carry out an exploratory user study to validate the corresponding dialogue protocol and analyse the experimental results using insights from process mining and argument analytics. A high number of requests for alternative explanations testifies the need for ensuring diversity in the context of automated explanations.

Objective: Dental caries is one of the most common chronic diseases affecting millions of people globally. Some studies revealed the presence of bidirectional relationship between allergic rhinitis (AR) and oral diseases, with each disease having a potential impact on the other. In this study we aimed to systematically review the literature and analyze the available evidence regarding whether AR contributes to the development of dental caries. Methods: Three authors, members of the YO-IFOS rhinology study group, independently analyzed the data sources (Pubmed, the Cochrane Library, EMBASE, SciELO) for papers assessing the relationship between rhinitis and caries, in adult and pediatric patients. Results: Eight studies met the inclusion criteria (87612 participants). Six studies were performed in children. A total of three studies found an association between AR and dental caries. Only two studies had adjusted the measure of effect for potentially confounding variables. Regarding the quality of the selected studies according to the NICE classification, the most observed methodological limitations detected were: (1) the cross-sectional design of the included studies which could have introduced a simultaneity bias, and (2) not clearly reporting the inclusion and exclusion criteria. Conclusion: This systematic review can neither confirm nor deny the presence of an association between AR and caries. Despite the evidence is very scarce to conclude a relationship between AR and caries, the option for examining patients with repetitive caries by an otolaryngologist and those with AR by odontologist should be considered, as these examinations do not possess any risk for the patient.

Increased exercise is a marker of health in fibromyalgia (FM). However, patients frequently avoid physical activity as a way of minimizing the pain they feel. This deprives them of opportunities to obtain positive reinforcement, increasing functional impact.This study examines the mediating role of depressive symptoms between walking (as physical exercise), functional impact, and pain, at different levels of positive affect (PA) among women with fibromyalgia.Cross-sectional correlational study.Mutual aid associations for fibromyalgia in Spain.231 women diagnosed with FM.Moderate mediation analyses were conducted using PROCESS.First, a simple mediation model showed that depression mediated the effect of walking on functional impact, but not on pain. Additionally, the moderated mediated model showed that this effect was significant at medium and high levels of PA, but not when levels of PA were low.Provision of resources focused on positive affect seem to increase the positive effects of walking on functional impact through the reduction of depressive symptoms. Nurses can improve adherence of patients with FM to walking behavior through increasing positive affect.

Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

The explanatory capacity of interpretable fuzzy rule-based classifiers is usually limited to offering explanations for the predicted class only. A lack of potentially useful explanations for non-predicted alternatives can be overcome by designing methods for the so-called counterfactual reasoning. Nevertheless, state-of-the-art methods for counterfactual explanation generation require special attention to human evaluation aspects, as the final decision upon the classification under consideration is left for the end user. In this paper, we first introduce novel methods for qualitative and quantitative counterfactual explanation generation. Then, we carry out a comparative analysis of qualitative explanation generation methods operating on (combinations of) linguistic terms as well as a quantitative method suggesting precise changes in feature values. Then, we propose a new metric for assessing the perceived complexity of the generated explanations. Further, we design and carry out two human evaluation experiments to assess the explanatory power of the aforementioned methods. As a major result, we show that the estimated explanation complexity correlates well with the informativeness, relevance, and readability of explanations perceived by the targeted study participants. This fact opens the door to using the new automatic complexity metric for guiding multi-objective evolutionary explainable fuzzy modeling in the near future Ilia Stepin is an FPI researcher (grant PRE2019-090153). Jose M. Alonso-Moral is a Ramon y Cajal researcher (grant RYC-2016–19802). This work was supported by the Spanish Ministry of Science and Innovation (grants RTI2018-099646-B-I00, PID2021-123152OB-C21, and TED2021-130295B-C33) and the Galician Ministry of Culture, Education, Professional Training and University (grants ED431F2018/02, ED431G2019/04, and ED431C2022/19). All the grants were co-funded by the European Regional Development Fund (ERDF/FEDER program). SI

Fuel poverty is a serious condition in New Zealand, caused by the inability to afford sufficient energy services and resulting in detriment to health and wellbeing. Inconsistent ways of describing and measuring fuel poverty affect the perception and depth of the issue and the proposed interventions. This article analyses the proposed definition and indicators of energy hardship developed by the Ministry of Business, Innovation and Employment, in addition to the literature and the perspectives of five New Zealand experts. Findings suggest that the proposed energy hardship description and measures are well-aligned with the recommendations given by the interviewed experts and the literature findings on fuel poverty, which bodes well for effective interventions to minimise the issue.

We describe a case of a patient who experienced recurrent COVID-19 pneumonia over a period of 123 days. Neither remdesivir nor convalescent plasma were temporally associated with viral clearance or increased plasma neutralization capacity. Antibody levels remained low until day 151 and cellular immunity increased overtime with no viral evolution.

Tongue base and hypopharynx are the major sites of obstruction in OSA patients with failed palatal surgery. In recent years, several minimally invasive procedures have been developed to address tongue base obstruction. However, the research focus has consistently been on the effectiveness of surgery in reducing obstructive sleep apnoea rather than on postoperative complications. In this systematic review and metanalysis we aim to review the complication rate of minimally invasive base of tongue procedures for OSAS in adults.PubMed (Medline), the Cochrane Library, EMBASE, Scopus, SciELO and Trip Database.Data sources were checked by three authors of the YO-IFOS sleep apnoea study group. Three authors extracted the data. Main outcome was expressed as the complication rate and 95% confidence interval for each surgical technique.20 studies (542 patients) met the inclusion criteria. The mean complication rate is 12.79%; 4.65% for minor complications, 6.42% if they are moderate, and 1.77% if severe. The most reported complication overall is infection, in 1.95% of cases, followed by transient swallowing disorder, occurring in 1.30% of the total sample.The heterogeneity amongst the included studies prevents us from obtaining solid conclusions. The available evidence suggests that minimally invasive base of tongue procedures may present a wide spectrum of complication rates, ranging from 4.4% in tongue base radiofrequency to up to 42.42% in tongue base ablation.

To examine the mediating role of pain acceptance (PAcc) between fear of negative evaluation (FNE) and activity avoidance (AV) at different levels of positive affect (PA) (moderator) among women diagnosed with fibromyalgia (FM) (moderate mediation model). This study was cross-sectional in design. A convenience sample of women with FM ( n = 231) completed measures of pain severity, FNE, PAcc, AV, and PA. A simple mediation model and a moderate mediation model was constructed and analyzed using the SPSS macro-PROCESS. First, PAcc mediated the effect of FNE on AV (β = .02, SE = 0.008; [95% CI [0.0075, 0.0394]). Second, a mediated effect of PAcc between FNE and AV moderated by PA at medium and high levels of PA were found ( m: 0.23; β = −.22, p = .0006; h: 9.59; β = −.34, p = .0002. Future work should seek to validate study findings in diverse samples of FM patients. Additionally, future work should explore how FM self-management interventions that include PAcc can promote increased activity among women suffering from FM with medium to high levels of PA.

Fundoscopy is the standard method for diagnosis and follow-up of intraocular retinoblastoma, but it is sometimes insufficient to discern whether tumors are inactivated following treatments. In this work, we hypothesized that the amount of conserved nuclear DNA sequences in the cell-free DNA (cfDNA) fraction of the aqueous humor (AH) might complement fundoscopy for retinoblastoma follow-up. To address our hypothesis, we developed highly sensitive droplet digital polymerase chain reaction (ddPCR) methods to quantify highly conserved DNA sequences of nucleus-encoded genes (GAPDH and B4GALNT1) and of a mitochondrial gene, MT-ATP6. We obtained AH samples during intravitreal treatments. We analyzed 42 AH samples from 25 patients with intraocular retinoblastoma and 11 AH from controls (non-cancer patients). According to clinical criteria, we grouped patients as having progression-free or progressive retinoblastoma. cfDNA concentration in the AH was similar in both retinoblastoma groups. Copy counts for nucleus-derived sequences of GAPDH and B4GALNT1 were significantly higher in the AH from patients with progressive disease, compared to the AH from progression-free patients and control non-cancer patients. The presence of mitochondrial DNA in the AH explained that both retinoblastoma groups had similar cfDNA concentration in AH. The optimal cut-off point for discriminating between progressive and progression-free retinoblastomas was 108 GAPDH copies per reaction. Among patients having serial AH samples analyzed during their intravitreal chemotherapy, GAPDH copies were high and decreased below the cut-off point in those patients responding to chemotherapy. In contrast, one non-responder patient remained with values above the cut-off during follow-up, until enucleation. We conclude that the measurement of conserved nuclear gene sequences in AH allows follow-up of intraocular retinoblastoma during intravitreal treatment. The method is applicable to all patients and could be relevant for those in which fundoscopy evaluation is inconclusive.

En la actualidad, las calificaciones energéticas de los edificios son uno de los factores clave a la hora de caminar hacia una sociedad más sostenible. Este enfoque tiene el objetivo de mejorar la eficiencia energética y la sostenibilidad en el sector de la construcción, reduciendo significativamente el consumo energético y las emisiones de gases de efecto invernadero. Este Trabajo de Fin de Grado propone una metodología para la determinación de la calificación energética del consumo de energía primaria no renovable de los edificios en Cataluña, mediante el uso de un modelo de aprendizaje autónomo basado en redes neuronales. El modelo está elaborado con el lenguaje de programación Python y una serie de sus librerías como TensorFlow y sklearn. El modelo es evaluado con una base de datos que contiene información básica de las edificaciones, obviando los elementos más técnicos como las instalaciones o un desglose detallado y numérico de la envolvente térmica de la edificación. Finalmente, se obtiene una precisión máxima del 47.62% utilizando dicha base de datos con información básica de las edificaciones que podría ser fácilmente obtenida por el público no especializado en el área Actualment, les qualificacions energètiques dels edificis són un dels factors clau a l'hora de caminar cap a una societat més sostenible. Aquest enfocament té l'objectiu de millorar l'eficiència energètica i la sostenibilitat al sector de la construcció, reduint significativament el consum energètic i les emissions de gasos d'efecte hivernacle. Aquest Treball de Fi de Grau proposa una metodologia per a la determinació de la qualificació energètica del consum d’energia primària no renovable dels edificis a Catalunya, mitjançant l’ús d’un model d’aprenentatge autònom basat en xarxes neuronals. El model està elaborat amb el llenguatge de programació Python i una sèrie de les seves llibreries com ara TensorFlow i sklearn. El model és avaluat amb una base de dades que conté informació bàsica de les edificacions, obviant els elements més tècnics com les instal·lacions o un desglossament detallat i numèric de l'envolupant tèrmica de l'edificació. Finalment, s'obté una precisió màxima del 47,62% utilitzant aquesta base de dades amb informació bàsica de les edificacions que podria ser fàcilment obtinguda pel públic no especialitzat en l'àrea Today, energy ratings of buildings are one of the key factors in moving towards a more sustainable society. This approach aims to improve energy efficiency and sustainability in the building sector, significantly reducing energy consumption and greenhouse gas emissions. This Final Degree Project proposes a methodology for determining the energy rating of the non-renewable primary energy consumption of buildings in Catalonia, by using an autonomous learning model based on neural networks. The model is developed using the Python programming language and a series of its libraries such as TensorFlow and sklearn. The model is evaluated with a database that contains basic information about the buildings, ignoring the more technical elements such as the installations or a detailed and numerical breakdown of the building's thermal envelope. Finally, a maximum accuracy of 47.62% is obtained by using such a database with basic building information that could be easily obtained by the non-specialist public

Biological therapeutics represent an increasing and critical component of newly approved drugs; however, the inability to deliver biologics intracellularly in a controlled manner remains a major limitation. We have developed a semi-synthetic, tunable phage-like particle (PLP) platform derived from bacteriophage λ. The shell surface can be decorated with small-molecule, biological and synthetic moieties, alone or in combination and in defined ratios. Here, we demonstrate that the platform can be used to deliver biological macromolecules intracellularly and in a controlled manner. Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that has been widely recognized as an ideal target for the treatment of a variety of cancers. Recently, UbV.7.2, a novel biologic derived from the ubiquitin scaffold, was developed for inhibition of USP7, but issues remain in achieving efficient and controlled intracellular delivery of the biologic. We have shown that decoration of PLPs with trastuzumab (Trz), a HER2-targeted therapeutic used in the treatment of various cancers, results in specific targeting and uptake of Trz-PLPs into HER2-overexpressing breast cancer cells. By simultaneously decorating PLPs with Trz and UbV.7.2, we now show that these particles are also internalized by HER2-positive cells, thus providing a means for intracellular delivery of the biologic in a controlled fashion. Internalized particles retain USP7 inhibition activity of UbV.7.2 and alter the metabolic and proteomic landscapes of these cells. This study demonstrates that the λ "designer nanoparticles" represent a powerful system for the intracellular delivery of biologics in a defined dose.

Gastroesophageal reflux disease (GERD) leads to the accumulation of bile-induced reactive oxygen species and oxidative stress in esophageal tissues, causing inflammation and DNA damage. The progression sequence from healthy esophagus to GERD and eventually cancer is associated with a microbiome shift. Lactobacillus species are commensal organisms known for their probiotic and antioxidant characteristics in the healthy esophagus. This prompted us to investigate how Lactobacilli survive in a bile-rich environment during GERD, and to identify their interaction with the bile-injured esophageal cells. To model human reflux conditions, we exposed three Lactobacillus species (L. acidophilus, L. plantarum, and L. fermentum) to bile. All species were tolerant to bile possibly enabling them to colonize the esophageal epithelium under GERD conditions. Next, we assessed the antioxidant potential of Lactobacilli and role in bile injury repair: we measured bile-induced DNA damage using the ROS marker 8-oxo guanine and COMET assay. Lactobacillus addition after bile injury accelerated repair of bile-induced DNA damage through recruitment of pH2AX/RAD51 and reduced NFκB-associated inflammation in esophageal cells. This study demonstrated anti-genotoxic and anti-inflammatory effects of Lactobacilli, making them of significant interest in the prevention of Barrett’s esophagus and esophageal adenocarcinoma in patients with GERD.

Vegetarian and vegan diets are increasingly being adopted in Spain, a trend mainly driven by ethical concerns for animal welfare and the environment. This has resulted in a growing market for plant-based substitutes of meat products. However, available data on the nutritional value of such meat analogues in Mediterranean countries are still limited. In this study, the labelling information of four categories of plant-based meat analogues (n = 100) and the corresponding conventional meat products (n = 48) available on the Spanish market was surveyed and compared. The nutrient content of plant-based meat analogues varied significantly, due to the wide range of ingredients used in their formulation. Some of these products were found to have a low protein content, which in others was enhanced by the addition of cereals and legumes. Compared to the meat products, the plant-based analogues contained lower levels of total fat as well as saturated fat, which ranged from 30% of total fat in burgers to less than 15% in meatballs, sausages, and nuggets; in contrast, they contained higher amounts of fiber and complex carbohydrates. Overall, the meat analogues cannot be considered as nutritionally equivalent substitutes to conventional meat products due to a high variability of protein content and other nutrients.

International audience; Background The identification of patients at high risk of a disabling disease course would be invaluable in guiding initial therapy in Crohn’s disease (CD). Our objective was to evaluate a combination of clinical, serological, and genetic factors to predict complicated disease course in pediatric-onset CD. Methods Data for pediatric-onset CD patients, diagnosed before 17 years of age between 1988 and 2004 and followed more than 5 years, were extracted from the population-based EPIMAD registry. The main outcome was defined by the occurrence of complicated behavior (stricturing or penetrating) and/or intestinal resection within the 5 years following diagnosis. Lasso logistic regression models were used to build a predictive model based on clinical data at diagnosis, serological data (ASCA, pANCA, anti-OmpC, anti-Cbir1, anti-Fla2, anti-Flax), and 369 candidate single nucleotide polymorphisms. Results In total, 156 children with an inflammatory (B1) disease at diagnosis were included. Among them, 35% (n = 54) progressed to a complicated behavior or an intestinal resection within the 5 years following diagnosis. The best predictive model (PREDICT-EPIMAD) included the location at diagnosis, pANCA, and 6 single nucleotide polymorphisms. This model showed good discrimination and good calibration, with an area under the curve of 0.80 after correction for optimism bias (sensitivity, 79%, specificity, 74%, positive predictive value, 61%, negative predictive value, 87%). Decision curve analysis confirmed the clinical utility of the model. Conclusions A combination of clinical, serotypic, and genotypic variables can predict disease progression in this population-based pediatric-onset CD cohort. Independent validation is needed before it can be used in clinical practice.

A les pàgines 11-31 està el text en anglès i a les pàgines 117-138 el text en castellà The contemporary essay film is situated within the deep transformations of cinema that led to post-cinema, just as it arises from the revolution experienced by the classic documentary, now transformed into the post-documentary, whose main axes are subjectivity and thought. Following the ideas of Deleuze and Guattari, the essay film can be considered as a sign of a new image of thought derived from cinema but more complex. The essay mode in general, as a way of thinking, adapts to the complexities of the contemporary world through its fluid, rhizomatic and multidimensional condition. Likewise, based on the hypothesis that the essay form corresponds to a certain mentality anthropologically understood, it results in the existence of a post-subject that is especially evident with the essay film and that confronts the crisis of transcendental subjectivity that has characterized the twentieth-century thought. El film-ensayo contemporáneo se sitúa en el seno de las profundas transformaciones del cinematógrafo que desembocan en el poscine, así como surge de la revolución que ha experimentado el documental clásico, transformado ahora en un posdocumental, cuyos ejes principales son la subjetividad y el pensamiento. Acudiendo a las ideas de Deleuze y Guattari, se puede considerar que el film-ensayo es un indicio de una nueva imagen del pensamiento derivada del cine, pero más compleja. El modo ensayo en general, como forma de pensamiento, se adecúa a las complejidades del mundo contemporáneo, a través de su condición fluida, rizomática y multidimensional. Asimismo, a partir de la hipótesis de que la forma ensayo corresponde a una determinada mentalidad entendida antropológicamente, se deriva la existencia de un postsujeto que se evidencia especialmente con el film-ensayo y que confronta la crisis de la subjetividad trascendental que ha caracterizado el pensamiento del siglo XX.

Many sweat-based wearable monitoring systems have been recently proposed, but the data provided by those systems often lack a reliable and meaningful relation to standardized blood values. One clear example is lactate, a relevant biomarker for both sports and health sectors, with a complex sweat–blood bioequivalence. This limitation decreases its individual significance as a sweat-based biomarker. Taking into account the insights of previous studies, a multiparametric methodology has been proposed to predict blood lactate from non-invasive independent sensors: sweat lactate, sweat rate, and heart rate. The bioequivalence study was performed with a large set of volunteers (>30 subjects) in collaboration with sports institutions (Institut Nacional d’Educació Física de Catalunya, INEFC, and Centre d’Alt Rendiment, CAR, located in Spain). A neural network algorithm was used to predict blood lactate values from the sensor data and subject metadata. The developed methodology reliably and accurately predicted blood lactate absolute values, only adding 0.3 mM of accumulated error when compared to portable blood lactate meters, the current gold standard for sports clinicians. The approach proposed in this work, along with an integrated platform for sweat monitoring, will have a strong impact on the sports and health fields as an autonomous, real-time, and continuous monitoring tool The authors kindly acknowledge the support from the Spanish Ministerio de Indústria, Energía y Turismo (AEI Clusters Program, AEI2009L1CA011), Ministerio de Ciencia y Innovació n (PID2020-114070RB-I00), Agencia Estatal de Investigación (RED2018-102829-T and CPP2021-009021), and AGAUR (2019 DI 18 and 2021PROD00064)

The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell–specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5′-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R–targeting therapeutics.

CONSORT Diagram (PP = Per Protocol Population).

Related adverse events in the vaccine arm. Number of adverse events.

Overview of all adverse events in the safety evaluable population.

Explainable Artificial Intelligence (XAI) focuses on research and technology that can explain an AI system’s functioning and its underlying methods, and also on making these explanations better through personalization. Our research study investigates a natural language personalization method called lexical alignment in understanding an explanation provided by a conversational agent. The study setup was online and navigated the participants through an interaction with a conversational agent. Participants faced either an agent designed to align its responses to those of the participants, a misaligned agent, or a control condition that did not involve any dialogue. The dialogue delivered an explanation based on a pre-defined set of causes and effects. The recall and understanding of the explanations was evaluated using a combination of Yes-No questions, a Cloze test (fill-in-the-blanks), and What-style questions. The analysis of the test scores revealed a significant advantage in information recall for those who interacted with an aligning agent against the participants who either interacted with a non-aligning agent or did not go through any dialogue. The Yes-No type questions that included probes on higher-order inferences (understanding) also reflected an advantage for the participants who had an aligned dialogue against both non-aligned and no dialogue conditions. The results overall suggest a positive effect of lexical alignment on understanding of explanations.

Heterotrophic prokaryotes (HP) contribute largely to dissolved organic matter (DOM) processing in the ocean, but they also release diverse organic substances. The bioavailability of DOM released by HP under varying environmental conditions are not fully elucidated. In this study, we investigated the effect of P-limitation on the bioavailability of DOM released by a single bacterial strain and 2 natural HP communities. These HP were grown under P-replete and P-limited conditions, and their DOM (HP-DOM) was used as a substrate for natural prokaryotic communities from a coastal site in the Northwestern Mediterranean Sea. We followed changes in prokaryotic growth, enzymatic activity, diversity and community composition together with the consumption of HP-DOM fluorescence (FDOM). HP-DOM produced under P-replete and P-limited conditions promoted both significant and similar prokaryotic growth. The humic-like fluorescence, commonly considered recalcitrant, was consumed during the incubations when this peak was initially dominating the FDOM pool, and this consumption coincided with higher alkaline phosphatase activity. HP-DOM supported growth of diverse prokaryotic communities and P-driven differences in HP-DOM quality selected for different indicator taxa in the degrading communities. Taken together, our findings emphasize that HP-DOM lability is dependent on both the DOM quality, shaped by P availability, and the composition of the consumers community.

Chemical synthesis of RNA conjugates has opened new strategies to study enzymatic mechanisms in RNA biology. To gain insights into poorly understood RNA nucleotide methylation processes, we developed a new method to synthesize RNA-conjugates for the study of RNA recognition and methyl-transfer mechanisms of SAM-dependent m6A RNA methyltransferases. These RNA conjugates contain a SAM cofactor analogue connected at the N6-atom of an adenosine within dinucleotides, a trinucleotide or a 13mer RNA. Our chemical route is chemo- and regio-selective and allows flexible modification of the RNA length and sequence. These compounds were used in crystallization assays with RlmJ, a bacterial m6A rRNA methyltransferase. Two crystal structures of RlmJ in complex with RNA–SAM conjugates were solved and revealed the RNA-specific recognition elements used by RlmJ to clamp the RNA substrate in its active site. From these structures, a model of a trinucleotide bound in the RlmJ active site could be built and validated by methyltransferase assays on RlmJ mutants. The methyl transfer by RlmJ could also be deduced. This study therefore shows that RNA-cofactor conjugates are potent molecular tools to explore the active site of RNA modification enzymes.

One of the most effective ways to improve quality of life in dementia is by exposing people to meaningful activities. The study of engagement is crucial to identify which activities are significant for persons with dementia and customize them. Previous work has mainly focused on developing assessment tools and the only available model of engagement for people with dementia focused on factors influencing engagement or influenced by engagement. This article focuses on the internal functioning of engagement and presents the development and testing of a model specifying the components of engagement, their measures, and the relationships they entertain. We collected behavioral and physiological data while participants with dementia (N = 14) were involved in six sessions of play, three of game-based cognitive stimulation and three of robot-based free play. We tested the concurrent validity of the measures employed to gauge engagement and ran factorial analysis and Structural Equation Modeling to determine whether the components of engagement and their relationships were those hypothesized. The model we constructed, which we call the ENGAGE-DEM, achieved excellent goodness of fit and can be considered a scaffold to the development of affective computing frameworks for measuring engagement online and offline, especially in HCI and HRI.

A abordagem sistematizada de problemas é um dos aspectos mais importantes de um programa da qualidade. Diversas ferramentas foram desenvolvidas para auxiliar o profissional a compreender os problemas que ocorrem em seu dia a dia, achar a causa raiz e encontrar soluções adequadas para eles. O trabalho proposto teve por objetivo aplicar ferramentas da área de gestão da qualidade, trabalhando todos os seus aspectos de resolução de problemas, para encontrar a causa raiz da avaliação ruim realizada pelo cliente acerca do atendimento, com o intuito de melhorar a nota de satisfação (avaliação realizada pelo cliente) de atendimento de uma campanha de atendimento ao cliente. Dentre as ferramentas que foram utilizadas, estão: gráfico de Pareto, diagrama de causa e efeito, Matriz GUT e 5W2H. Os resultados encontrados foram ações de melhorias contínuas que contribuirão para melhora do indicador da operação, confirmando o objetivo da gestão da qualidade, a satisfação total dos clientes.

Collin McKinney and David F. Richter, eds, Spanish Graphic Narratives: Recent Developments in Sequential Art (Cham, Switzerland: Palgrave Macmillan 2020). 315 pp. ISBN: 9783030568221 (£59.99)Jan Baetens, Hugo Frey and Stephen E. Tabachnick, eds, The Cambridge History of the Graphic Novel (Cambridge: Cambridge University Press, 2018). 677 pp. ISBN: 9781107171411 (hardback, £125)Renaud Chavanne, ed., with Adam Rusek, Wojciech Birek, Jerzy Szyłak, and Piotr Machłajewski, Histoire de la bande dessinée polonaise. Translated by Anna Morawska. (Montrouge: PLG, 2019). 186 pp. ISBN: 9782917837344 (€15.00)Mark McKinney, Postcolonialism and Migration in French Comics (Leuven: Leuven University Press, 2021). 400 pp. ISBN: 9789462702417. (€65.00)

INTRODUCTION: Capnocytophaga canimorsus is a commensal bacterium found in the saliva of dogs and cats. In most cases C. canimorsus causes local infection resulting from bite-wounds, scratches or licks but severe forms can occur. The following case describes a severe and rapidly fatal sepsis and disseminated intravascular coagulation with no evidence of bite in a patient without obvious cause of immunosuppression, diagnosed by polymerase chain reaction and 16S rRNA gene sequencing. CASE REPORT: Herein we present a rare case of a 39-year-old man who was taken care of by the emergency medical service for faintness, fever and chills associated with generalized mottling. Despite critical care management and broad-spectrum antibiotherapy, the patient presented an irrepressible shock with disseminated intravascular coagulation and multiple organ failure. He died during the night. The initial etiological assessment was negative but rod-shaped inclusions could be observed in his blood. A pan-bacterial polymerase chain reaction targeting part of the gene encoding 16S ribosomal ribonucleic acid (rRNA) was carried out directly on blood cultures; the sequencing identified Capnocytophaga canimorsus. CONCLUSIONS: This observation illustrates the potential severity of C. canimorsus infection even in a patient without neither obvious causes of immunosuppression nor evidence of bite. The presence of intracellular bacillary forms on the blood smear is an important information which should lead to performing a polymerase chain reaction and 16S rRNA gene sequencing.

L’entrée en guerre des États-Unis le 6 avril 1917 marque un tournant dans l’histoire du conflit. L’arrivée des premières troupes américaines à Saint-Nazaire le 26 juin est le prélude au transfert en Europe de plus de deux millions de soldats, accompagnés de nombreux civils. Au-delà du poids politique et militaire de cette intervention, toujours discuté, ses apports culturels ont provoqué des bouleversements profonds qui ont durablement affecté les sociétés européennes. Quels sont l’ampleur de ce phénomène, sa temporalité, ses modalités, ses acteurs, sa place dans le processus d’américanisation de l’Europe au xxe siècle ? Les différentes échelles d’analyse, continentale, nationale et locale (Nantes et Saint-Nazaire) permettent de rendre compte des diverses formes d’échanges et de transferts, y compris lors de la conférence de la Paix. Une image très positive de l’Amérique se déploie alors dans toute l’Europe, symbolisant l’espoir d’un monde nouveau. Cependant, au-delà de l’émotion populaire bien réelle qu’elle suscite, la présence américaine, massive mais finalement brève et souvent superficielle, provoque également des rejets et laisse, dans la région de l’Ouest, des traces éphémères. Elle renforce toutefois incontestablement l’intensité des relations transatlantiques et marque une nouvelle phase dans l’émergence d’un monde globalisé.

En este trabajo se realiza un análisis de una posible nueva modalidad de sucesión de empresa, cual es, la sucesión por transmisión de clientela. Para ello, se realiza una breve configuración de la sucesión de empresa, y de los diferentes tipos que existen, analizando la doctrina judicial y jurisprudencial, tanto nacional como comunitaria, que han ido modulando esta institución jurídica. En el caso de la sucesión por transmisión de clientela, el elemento que da lugar a la aplicación del art. 44 ET es simplemente que existe una transmisión de los clientes, sin que sea necesario que tenga lugar también una transmisión de elementos patrimoniales, materiales o inmateriales In this work, it is carried out an analysis of a possible new type of company succession, which is, the succession by transfer of customers. For this, it is realized a brief configuration of the succession of the company, and of the different types that exist, analyzing the judicial and jurisprudential doctrine, both national and community, that have been modulating this legal institution. In the case of succession by transmissionof customers, the element that gives rise to the application of art. 44 ET issimply that there is a transmissionof customers, without it being necessary for a transmissionof assets, tangible or intangible, to also take place. Universidad Pablo de Olavide

[EN] Massive DNA testing requires novel technologies to support a sustainable health system. In recent years, DNA superstructures have emerged as alternative probes and transducers. We, herein, report a multiplexed and highly sensitive approach based on an allele-specific hybridization chain reaction (AS-HCR) in the array format to detect single-nucleotide variants. Fast isothermal amplification was developed before activating the HCR process on a chip to work with genomic DNA. The assay principle was demonstrated, and the variables for integrating the AS-HCR process and smartphone-based detection were also studied. The results were compared to a conventional polymerase reaction chain (PCR)-based test. The developed multiplex method enabled higher selectivity against single-base mismatch sequences at concentrations as low as 103 copies with a limit of detection of 0.7% of the mutant DNA percentage and good reproducibility (relative error: 5% for intra-assay and 17% for interassay). As proof of concept, the AS-HCR method was applied to clinical samples, including human cell cultures and biopsied tissues of cancer patients. Accurate identification of single-nucleotide mutations in KRAS and NRAS genes was validated, considering those obtained from the reference sequencing method. To conclude, AS-HCR is a rapid, simple, accurate, and cost-effective isothermal method that detects clinically relevant genetic variants and has a high potential for point-of-care demands., The authors acknowledge the financial support received from EU FEDER, the Spanish Ministry of Economy and Competitiveness (PID2019-110713RB-I00), and the Generalitat Valenciana (PROMETEO/2020/094 and GVA-FPI-2017 Ph.D. grant).

Childbirth expectations during pregnancy are important factors related to birth satisfaction. The aim of this study is to validate the Childbirth Expectation Questionnaire (CEQ) in a sample of Spanish pregnant women; 231 women responded to the CEQ during their first trimester of pregnancy and 106 of them completed a re-test at the third trimester. Exploratory analyses with 1-to-6 factor solutions were carried out to investigate the internal structure of the CEQ. The three-factor solution (spousal support and control, medical support and environment, and labor pain and distress) showed the best properties in terms of model fit, number of items per factor, and item loadings. The internal consistency of scales was also good (.79 ≥ α ≤ .93). Test-retest analyses showed significant intercorrelations between expectations from the first to the third trimester of pregnancy. There is a need to assess childbirth expectations, and our results suggest that the CEQ is a valid and useful instrument to be used among Spanish pregnant women.

[EN] A biosensing system was developed to accurately detect a single nucleotide change in the target organism genome, integrating a selective isothermal amplification and a sensitive dendron-mediated DNA hybridization assay in the array format. The novelty arises from the coupling reactions of the dendron and its use as a crosslinker. The allele-specific probes were oligonucleotide-dendron conjugates prepared by fast and clean click-chemistry (thiol-yne reaction) and coupled onto the photo-activated surface of polycarbonate substrates (carbodiimide reaction). The output was forest-array chips with multipoint-site crosslinkers and compatible with current microarray fabrication technologies. The products of blocked recombinase polymerase amplification (blocked RPA), formed at 37 degrees C, were hybridized with attached probes for specific nucleotide genotyping. The developed approach exhibited sensitive recognition of DNA variants compared to chips based on linear crosslinkers (10-100 fold), showing excellent analytical performances for planar chip and fluidic formats. The methodology was successfully applied to detect the H1047R mutation in the PIK3CA gene (c.3140A > G) from clinical samples of human cancer tissues, the results being consistent with sequencing techniques. The colorimetric biosensing method was reliable, versatile, low cost, sensitive (detection limit genomic DNA: 0.02 ng mu L-1), and specific (accuracy >95%)., The MINECO Project PID2019-110713RB-I00 and Generalitat Valenciana PROMETEO/2020/094 are acknowledged.

[EN] We present the first synthesis of beta-lactam-derived haptens, leveraging the principles of diversity-oriented synthesis to discover compounds for drug allergy in vitro testing. We designed, synthesised, and performed in vitro immunological evaluation on 18 structurally diverse haptens derived from beta-lactam antibiotics. The antigens obtained with the synthesised haptens allow for the detection of specific anti-beta-lactam immunoglobulins G and E. Excellent diagnostic sensitivity (83%) and specificity (100%) were achieved when the panel of antigens was tested against a cohort of 31 human serum samples using a multiplexed compact disc-based in vitro testing tool. We posit that adopting this strategy could aid beta-lactam delabeling initiatives., This work was supported by the H2020 program (project COBIOPHAD, grant agreement No. 688448), Agencia Estatal de Investigacion (PID2019-110713RB-I00, FEDER awarded to S.M.); Generalitat Valenciana (PROMETEO/2020/094 awarded S.M.); and the National Institute of General Medical Sciences (GM- 1R35GM127045 awarded to S.L.S.). E.P.M. was supported by an FPU fellowship from the Ministerio de Educacio¿n, Cultura y Deporte (FPU15/01738 and EST18/00360). B.K.H. was supported by a fellowship from the National Science Foundation (DGE1144152 and DGE1745303).

The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression and modulate several biological processes, functioning as biomarkers for many diseases. Here, we identify and validate a unique miRNA signature during PR in pediatric patients with T1D by employing small RNA sequencing and RT-qPCR. These miRNAs were mainly related to the immune system, metabolism, stress, and apoptosis pathways. The implication in autoimmunity of the most dysregulated miRNA, miR-30d-5p, was evaluated in vivo in the non-obese diabetic mouse. MiR-30d-5p inhibition resulted in increased regulatory T cell percentages in the pancreatic lymph nodes together with a higher expression of CD200. In the spleen, a decrease in PD-1+ T lymphocytes and reduced PDCD1 expression were observed. Moreover, miR-30d-5p inhibition led to an increased islet leukocytic infiltrate and changes in both effector and memory T lymphocytes. In conclusion, the miRNA signature found during PR shows new putative biomarkers and highlights the immunomodulatory role of miR-30d-5p, elucidating the processes driving this phase.

Activation of voltage-gated calcium channels at presynaptic terminals leads to local increases in calcium and the fusion of synaptic vesicles containing neurotransmitter. Presynaptic output is a function of the density of calcium channels, the dynamic properties of the channel, the distance to docked vesicles, and the release probability at the docking site. We demonstrate that at Caenorhabditis elegans neuromuscular junctions two different classes of voltage-gated calcium channels, CaV2 and CaV1, mediate the release of distinct pools of synaptic vesicles. CaV2 channels are concentrated in densely packed clusters ~250 nm in diameter with the active zone proteins Neurexin, α-Liprin, SYDE, ELKS/CAST, RIM-BP, α-Catulin, and MAGI1. CaV2 channels are colocalized with the priming protein UNC-13L and mediate the fusion of vesicles docked within 33 nm of the dense projection. CaV2 activity is amplified by ryanodine receptor release of calcium from internal stores, triggering fusion up to 165 nm from the dense projection. By contrast, CaV1 channels are dispersed in the synaptic varicosity, and are colocalized with UNC-13S. CaV1 and ryanodine receptors are separated by just 40 nm, and vesicle fusion mediated by CaV1 is completely dependent on the ryanodine receptor. Distinct synaptic vesicle pools, released by different calcium channels, could be used to tune the speed, voltage-dependence, and quantal content of neurotransmitter release.

In yeast, most ribosomal proteins are produced from duplicated genes. These nearly identical protein pairs are expressed at varying levels, with one ‘major paralog’ usually predominating. The minor paralog is highly transcribed but held in check through reduced intron removal, but the mechanism and purpose of this copy-specific repression remains unclear. In this study, we searched for proteins that achieve copy-specific expression by acting through the intron of the minor paralog of the model duplicated small ribosomal subunit protein S9 genes. By mass spectrometry and gene deletion we demonstrate that the transcription factors Rim101 and Taf14 bind to the intron and inhibit the splicing of the minor RPS9 paralog. RPS9A is then specifically de-repressed during meiosis to ensure optimal expression of meiotic genes and efficient sporulation. Our results reveal a new regulatory paradigm where transcriptional factors can also modulate splicing rates to optimize the expression of duplicated ribosomal protein genes.

The literature on Organizational Socialization and Onboarding has assumed traditional work relationships located on-site in the company. Due to the Corona pandemic, remote work has gained tremendous importance. However, we do not yet know how the lack of physical presence affects organizational socialization. The research interest is to assess papers analyzing virtual organizational socialization systematically. The method used was a Systematic Literature Review (SLR). A protocol was made. In this, the search parameters were recorded. Literature relevant to the research question was identified and evaluated. This was examined and put into context. Key Findings: virtual organizational socialization represents a research gap. The literature is scattered; we only found a small number of relevant articles from different disciplines focusing on impediments of virtual organizational socialization. Research on onboarding practices that help overcome obstacles imposed by a higher degree of virtual work is needed.