Assessing the impact of the awareness level on a co-operative game

Context: When playing a co-operative game, being aware of your collaborators (where they are playing, what they are doing, the abilities they have, etc.) is essential for achieving the game's goals. This led to the definition of Gamespace Awareness in order to guide in the identification of the awareness needs in the form of a compilation of the awareness elements that a co-operative game should feature. Objective: Gamespace Awareness does not establish how much awareness information players must be provided with. This constitutes the main motivation for this work: to assess the impact of different levels of Gamespace Awareness elements on a co-operative game. Method: A multiplayer action game was developed that supports three different awareness configurations, each one featuring different awareness levels (high, medium and low). The impact of these awareness levels was measured as regards game score, time, players’ happiness while playing, enjoyment and perceived usefulness. Several techniques such as subjective surveys and facial expression analysis were used to measure these factors. Results: The analysis of the results shows that the higher the awareness, the better the game score. However, the highest level of player happiness was not achieved with the most awareness-enabled configuration; we found that the players’ enjoyment depends not only on their awareness level but also on their expertise level. Finally, the awareness elements related to the present and the future were the most useful, as could be expected in a multiplayer action game. Conclusions: The results showed that the medium level awareness obtained the best results. We therefore concluded that a certain level of awareness is necessary, but that excessive awareness could negatively affect the game experience

THE OUTSTANDING UNIVERSAL VALUE OF THE HISTORIC COLONIAL CENTRE OF THE CITY OF GRACIAS (HONDURAS)

[EN] This paper analyses the outstanding universal values, integrity, and authenticity of the city of Gracias (Honduras), as well as its protection and heritage management tools. The main objective is to demonstrate that Gracias meets the UNESCO requirements to qualify as a candidate for inclusion in the International List of the World Heritage Convention (1971). Gracias is a colonial Spanish city, founded in 1536, in the region of Lempira. It had great productive, strategic and administrative importance in Central America, demonstrated in part by its hosting of the Audiencia de los Confines. The Audiencia was the highest court of the Spanish Crown with jurisdiction over the current republics of Guatemala, Belize, El Salvador, Honduras, Nicaragua, Costa Rica and the region of Chiapas. The aim of this court was to represent the interests of the indigenous people in these areas. An on-site analysis, diagnosis and assessment of the heritage elements was carried out from architectural, urban planning, historical, and intangible heritage perspectives. Additionally, other similar sites in Central America have been analysed for comparison. Results show that this city meets criterion iv of the World Heritage Convention: an outstanding example of a type of building, architectural or technological ensemble or landscape which illustrates (a) significant stage(s) in human history. Furthermore, the city's heritage assets are well-preserved and most of them remain functional; the indigenous culture is alive; and planning, conservation and managing tools are in use. Currently, Gracias maintains its harmony and life and its respect for the natural environment, creating a cultural landscape that has been maintained for almost 500 years.Viñals Blasco, MJ.; Teruel Serrano, MD.; Alonso-Monasterio Fernandez, P. (2020). THE OUTSTANDING UNIVERSAL VALUE OF THE HISTORIC COLONIAL CENTRE OF THE CITY OF GRACIAS (HONDURAS). International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences (Online). 44:565-572. https://doi.org/10.5194/isprs-archives-XLIV-M-1-2020-565-2020S5655724

Optimizing the timing of nephrology referral for patients with diabetic kidney disease

Diabetis mellitus; Malaltia renal diabètica; Atenció multidisciplinàriaDiabetes mellitus; Diabetic kidney disease; Multidisciplinary careDiabetes mellitus; Enfermedad renal diabética; Atención multidisciplinariaAge-standardized rates of diabetes mellitus (DM)-related complications, such as acute myocardial infarction, stroke or amputations, have decreased in recent years, but this was not associated with a clear reduction of the incidence of advanced chronic kidney disease (CKD) requiring renal replacement therapy. The early detection of diabetic kidney disease (DKD) is a key to reduce complications, morbidity and mortality. Consensus documents and clinical practice guidelines recommend referral of DM patients to nephrology when the estimated glomerular filtration rate falls below 30 mL/min/1.73 m2 or when albuminuria exceeds 300 mg/g urinary creatinine. Conceptually, it strikes as odd that patients with CKD are referred to the specialist caring for the prevention and treatment of CKD only when >70% of the functioning kidney mass has been lost. The increasing global health burden of CKD, driven in large part by DKD, the suboptimal impact of routine care on DKD outcomes as compared with other DM complications, the realization that successful therapy of CKD requires early diagnosis and intervention, the advances in earlier diagnosis of kidney injury and the recent availability of antidiabetic drugs with a renal mechanism of action and lack of hypoglycaemia risk, which additionally are cardio- and nephroprotective, all point towards a paradigm shift in the care for DM patients in which they should be referred earlier to nephrology as part of a coordinated and integrated care approach.Sources of support: FIS/Fondos FEDER PI18/01386, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM

Exploring Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors for Organ Protection in COVID-19

Hospital admissions and mortality from the Coronavirus disease 2019 (COVID-19) pandemic are spreading throughout the world, and second and third waves are thought to be likely. Risk factors for severe COVID-19 include diabetes, chronic kidney disease and cardiovascular disease. Currently, there is no vaccine and no approved therapy. Therapeutic approaches are aimed at preventing viral replication and spread, limiting the impact of the inflammatory overdrive (cytokine storm), preventing thromboembolic complications and replacing or supporting organ function. However, despite organ support, mortality is currently 65% for those receiving advanced respiratory support and 78% for those requiring renal replacement therapies. Thus, efforts should be made to provide adjuvant organ protection therapy. This may imply novel therapies in clinical development (e.g., the Fas ligand trap asunercept), but uptake of repurposed drugs already in clinical use may be faster. In this regard, sodium glucose co-transporter-2 (SGLT2) inhibitors were recently shown to protect the heart and kidney both within and outside of a diabetic milieu context. Further, preclinical data support a beneficial effect for the lung. We now discuss the potential benefits and risks of SGLT2 inhibitors in COVID-19 and an ongoing clinical trial testing the impact of dapagliflozin on outcomes in COVID-19 patients with respiratory failure

Prepulse inhibition predicts spatial working memory performance in the inbred Roman high- and low-avoidance rats and in genetically heterogeneous NIH-HS rats: relevance for studying pre-attentive and cognitive anomalies in schizophrenia

Animal models of schizophrenia-relevant symptoms are increasingly important for progress in our understanding of the neurobiological basis of the disorder and for discovering novel and more specific treatments. Prepulse inhibition (PPI) and working memory, which are impaired in schizophrenic patients, are among the symptoms/processes modeled in those animal analogues. We have evaluated whether a genetically-selected rat model, the Roman high-avoidance inbred strain (RHA-I), displays PPI deficits as compared with its Roman low-avoidance (RLA-I) counterpart and the genetically heterogeneous NIH-HS rat stock. We have investigated whether PPI deficits predict spatial working memory impairments (in the Morris water maze; MWM) in these three rat types (Experiment 1), as well as in a separate sample of NIH-HS rats stratified according to their extreme (High, Medium, Low) PPI scores (Experiment 2). The results from Exp. 1 show that RHA-I rats display PPI and spatial working memory deficits compared to both RLA-I and NIH-HS rats. Likewise, in Exp. 2, “Low-PPI” NIH-HS rats present significantly impaired working memory with respect to “Medium-PPI” and “High-PPI” NIH-HS subgroups. Further support to these results comes from correlational, factorial and multiple regression analyses, which reveal that PPI is positively associated with spatial working memory performance. Conversely, cued learning in the MWM was not associated with PPI.Thus, using genetically-selected and genetically heterogeneous rats, the present study shows, for the first time, that PPI is a positive predictor of performance in a spatial working memory task. These results may have translational value for schizophrenia symptom research in humans, as they suggest that either by psychogenetic selection or by focusing on extreme PPI scores from a genetically heterogeneous rat stock, it is possible to detect a useful (perhaps “at risk”) phenotype to study cognitive anomalies linked to schizophrenia

A spatial judgement task to determine background emotional state in laboratory rats (Rattus norvegicus)

Humans experiencing different background emotional states display contrasting cognitive (e.g. judgement) biases when responding to ambiguous stimuli. We have proposed that such biases may be used as indicators of animal emotional state. Here, we use a spatial judgement task, in which animals are trained to expect food in one location and not another, to determine whether rats in relatively positive or negative emotional states respond differently to ambiguous stimuli of intermediate spatial location. We housed 24 rats with environmental enrichment for seven weeks. Enrichment was removed for half the animals prior to the start of training (‘U’: unenriched) to induce a relatively negative emotional state, whilst being left in place for the remaining rats (‘E’: enriched). After six training days, the rats successfully discriminated between the rewarded and unrewarded locations in terms of an increased latency to arrive at the unrewarded location, with no housing treatment difference. The subjects then received three days of testing in which three ambiguous ‘probe’ locations, intermediate between the rewarded and unrewarded locations, were introduced. There was no difference between the treatments in the rats’ judgement of two out of the three probe locations, the exception being when the ambiguous probe was positioned closest to the unrewarded location. This result suggests that rats housed without enrichment, and in an assumed relatively negative emotional state, respond differently to an ambiguous stimulus compared to rats housed with enrichment, providing evidence that cognitive biases may be used to assess animal emotional state in a spatial judgement task

Effect of lurbinectedin on the QTc interval in patients with advanced solid tumors: an exposure–response analysis

Purpose: This study assessed the effect of lurbinectedin, a highly selective inhibitor of oncogenic transcription, on the change from baseline in Fridericia’s corrected QT interval (¿QTcF) and electrocardiography (ECG) morphological patterns, and lurbinectedin concentration–¿QTcF (C-¿QTcF) relationship, in patients with advanced solid tumors. Methods: Patients with QTcF = 500 ms, QRS < 110 ms, PR < 200 ms, and normal cardiac conduction and function received lurbinectedin 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks. ECGs were collected in triplicate via 12-lead digital recorder in treatment cycle 1 and 2 and analyzed centrally. ECG collection time-matched blood samples were drawn to measure lurbinectedin plasma concentration. No effect on QTc interval was concluded if the upper bound (UB) of the least square (LS) mean two-sided 90% confidence intervals (CI) for ¿QTcF at each time point was < 20 ms. C-¿QTcF was explored using linear mixed-effects analysis. Results: A total of 1707 ECGs were collected from 39 patients (females, 22; median age, 56 years). The largest UB of the 90% CI of ¿QTcF was 9.6 ms, thus lower than the more conservative 10 ms threshold established at the ICH E14 guideline for QT studies in healthy volunteers. C-¿QTcF was better fit by an effect compartment model, and the 90% CI of predicted ¿QTcF at Cmax was 7.81 ms, also below the 10 ms threshold of clinical concern. Conclusions: ECG parameters and C-¿QTcF modelling in this prospective study indicate that lurbinectedin was not associated with a clinically relevant effect on cardiac repolarization

Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing

Background: Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively. // Results: We systematically investigate both dominance—here representing any non-additive within-locus interaction—and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance. // Conclusions: Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality