Creating Expressive Social Robots That Convey Symbolic and Spontaneous Communication.

Robots are becoming an increasingly important part of our society and have started to be used in tasks that require communicating with humans. Communication can be decoupled in two dimensions: symbolic (information aimed to achieve a particular goal) and spontaneous (displaying the speaker's emotional and motivational state) communication. Thus, to enhance human-robot interactions, the expressions that are used have to convey both dimensions. This paper presents a method for modelling a robot's expressiveness as a combination of these two dimensions, where each of them can be generated independently. This is the first contribution of our work. The second contribution is the development of an expressiveness architecture that uses predefined multimodal expressions to convey the symbolic dimension and integrates a series of modulation strategies for conveying the robot's mood and emotions. In order to validate the performance of the proposed architecture, the last contribution is a series of experiments that aim to study the effect that the addition of the spontaneous dimension of communication and its fusion with the symbolic dimension has on how people perceive a social robot. Our results show that the modulation strategies improve the users' perception and can convey a recognizable affective state.

An integrated cellular and molecular model of gastric neuroendocrine cancer evolution highlights therapeutic targets.

Gastric neuroendocrine carcinomas (G-NEC) are aggressive malignancies with poorly understood biology and a lack of disease models. Here, we use genome sequencing to characterize the genomic landscapes of human G-NEC and its histologic variants. We identify global and subtype-specific alterations and expose hitherto unappreciated gains of MYC family members in a large part of cases. Genetic engineering and lineage tracing in mice delineate a model of G-NEC evolution, which defines MYC as a critical driver and positions the cancer cell of origin to the neuroendocrine compartment. MYC-driven tumors have pronounced metastatic competence and display defined signaling addictions, as revealed by large-scale genetic and pharmacologic screening of cell lines and organoid resources. We create global maps of G-NEC dependencies, highlight critical vulnerabilities, and validate therapeutic targets, including candidates for clinical drug repurposing. Our study gives comprehensive insights into G-NEC biology.

Schistosomiasis screening in non-endemic countries from a cost perspective: Knowledge gaps and research priorities. The case of African long-term residents in a Metropolitan Area, Spain.

BACKGROUND: Imported schistosomiasis is an emerging issue in European countries as a result of growing global migration from schistosomiasis-endemic countries, mainly in sub-Saharan Africa. Undetected infection may lead to serious long-term complications with an associated high cost for public healthcare systems especially among long-term migrants. OBJECTIVE: To evaluate from a health economics perspective the introduction of schistosomiasis screening programs in non-endemic countries with high prevalence of long-term migrants. METHODOLOGY: We calculated the costs associated with three approaches-presumptive treatment, test-and-treat and watchful waiting-under different scenarios of prevalence, treatment efficacy and the cost of care resulting from long-term morbidity. Costs were estimated for our study area, in which there are reported to reside 74,000 individuals who have been exposed to the infection. Additionally, we methodically reviewed the potential factors that could affect the cost/benefit ratio of a schistosomiasis screening program and need therefore to be ascertained. RESULTS: Assuming a 24% prevalence of schistosomiasis in the exposed population and 100% treatment efficacy, the estimated associated cost per infected person of a watchful waiting strategy would be €2,424, that of a presumptive treatment strategy would be €970 and that of a test-and-treat strategy would be €360. The difference in averted costs between test-and-treat and watchful waiting strategies ranges from nearly €60 million in scenarios of high prevalence and treatment efficacy, to a neutral costs ratio when these parameters are halved. However, there are important gaps in our understanding of issues such as the efficacy of treatment in infected long-term residents, the natural history of schistosomiasis in long-term migrants and the feasibility of screening programs. CONCLUSION: Our results support the roll-out of a schistosomiasis screening program based on a test-and-treat strategy from a health economics perspective under the most likely projected scenarios, but important knowledge gaps should be addressed for a more accurate estimations among long-term migrants.

Primary and Community Care Transformation in Post-COVID Era: Nationwide General Practitioner Survey.

Introduction: The health emergency caused by COVID-19 has led to substantial changes in the usual working system of primary healthcare centers and in relations with users. The Catalan Society of Family and Community Medicine designed a survey that aimed to collect the opinions and facilitate the participation of its partners on what the future work model of general practitioners (GPs) should look like post-COVID-19. Methodology: Online survey of Family and Community Medicine members consisting of filiation data, 22 Likert-type multiple-choice questions grouped in five thematic axes, and a free text question. Results: The number of respondents to the questionnaire was 1051 (22.6% of all members): 83.2% said they spent excessive time on bureaucratic tasks; 91.8% were against call center systems; 66% believed that home care is the responsibility of every family doctor; 77.5% supported continuity of care as a fundamental value of patient-centered care; and >90% defended the contracting of complementary tests and first hospital visits from primary healthcare (PHC). Conclusions: The survey responses describe a strong consensus on the identity and competencies of the GP and on the needs of and the threats to the PHC system. The demand for an increase in health resources, greater professional leadership, elimination of bureaucracy, an increase in the number of health professionals, and greater management autonomy, are the axes towards which a new era in PHC should be directed.

TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status.

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.

A Bio-Inspired Endogenous Attention-Based Architecture for a Social Robot.

A robust perception system is crucial for natural human-robot interaction. An essential capability of these systems is to provide a rich representation of the robot's environment, typically using multiple sensory sources. Moreover, this information allows the robot to react to both external stimuli and user responses. The novel contribution of this paper is the development of a perception architecture, which was based on the bio-inspired concept of endogenous attention being integrated into a real social robot. In this paper, the architecture is defined at a theoretical level to provide insights into the underlying bio-inspired mechanisms and at a practical level to integrate and test the architecture within the complete architecture of a robot. We also defined mechanisms to establish the most salient stimulus for the detection or task in question. Furthermore, the attention-based architecture uses information from the robot's decision-making system to produce user responses and robot decisions. Finally, this paper also presents the preliminary test results from the integration of this architecture into a real social robot.

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.

Safety of Whole-Body Abrogation of the TRF1 Shelterin Protein in Wild-Type and Cancer-Prone Mouse Models.

Telomeres are considered potential anti-cancer targets. Most studies have focused on telomerase inhibition, but this strategy has largely failed in clinical trials. Direct disruption of the shelterin complex through TRF1 inhibition can block tumorigenesis in cancer mouse models by a mechanism that involves DNA damage induction and reduction of proliferation and stemness. Any anti-cancer target, however, must fulfill the requisite of not showing deleterious effects in healthy tissues. Here, we show that Trf1 genetic deletion in wild-type and cancer-prone p53- and Ink4Arf-deficient mice does not affect organismal viability and only induces mild phenotypes like decreased body weight and hair graying or hair loss, the skin being the most affected tissue. Importantly, we found that Trf1 is essential for tumorigenesis in p53- and Ink4Arf-deficient mice, as we did not find a single tumor originating from Trf1-deleted cells. These findings indicate a therapeutic window for targeting Trf1 in cancer treatment.

Detecting and Classifying Human Touches in a Social Robot Through Acoustic Sensing and Machine Learning.

An important aspect in Human-Robot Interaction is responding to different kinds of touch stimuli. To date, several technologies have been explored to determine how a touch is perceived by a social robot, usually placing a large number of sensors throughout the robot's shell. In this work, we introduce a novel approach, where the audio acquired from contact microphones located in the robot's shell is processed using machine learning techniques to distinguish between different types of touches. The system is able to determine when the robot is touched (touch detection), and to ascertain the kind of touch performed among a set of possibilities: stroke, tap, slap, and tickle (touch classification). This proposal is cost-effective since just a few microphones are able to cover the whole robot's shell since a single microphone is enough to cover each solid part of the robot. Besides, it is easy to install and configure as it just requires a contact surface to attach the microphone to the robot's shell and plug it into the robot's computer. Results show the high accuracy scores in touch gesture recognition. The testing phase revealed that Logistic Model Trees achieved the best performance, with an F-score of 0.81. The dataset was built with information from 25 participants performing a total of 1981 touch gestures.

Telomeric RNAs are essential to maintain telomeres.

Telomeres are transcribed generating long non-coding RNAs known as TERRA. Deciphering the role of TERRA has been one of the unsolved issues of telomere biology in the past decade. This has been, in part, due to lack of knowledge on the TERRA loci, thus preventing functional genetic studies. Here, we describe that long non-coding RNAs with TERRA features are transcribed from the human 20q and Xp subtelomeres. Deletion of the 20q locus by using the CRISPR-Cas9 technology causes a dramatic decrease in TERRA levels, while deletion of the Xp locus does not result in decreased TERRA levels. Strikingly, 20q-TERRA ablation leads to dramatic loss of telomere sequences and the induction of a massive DNA damage response. These findings identify chromosome 20q as a main TERRA locus in human cells and represent the first demonstration in any organism of the essential role of TERRA in the maintenance of telomeres.

Asymptomatic peripheral arterial disease in type 2 diabetes patients: a 10-year follow-up study of the utility of the ankle brachial index as a prognostic marker of cardiovascular disease.

BACKGROUND: Our aim was to evaluate the relationship between asymptomatic peripheral arterial disease, diagnosed only by the ankle brachial index (ABI), and cardiovascular disease (CVD) after a 10-year follow-up period in patients with type 2 diabetes. METHODS: In 1996, the ankle brachial index was measured in 262 patients with type 2 diabetes. During the 10-year follow-up period (mean follow-up time, 7.7 years), all nonfatal cardiovascular events and mortality were recorded. RESULTS: A total of 52 patients died during the follow-up time. The mortality of the patients with normal (0.91-1.24) and abnormal ABI (≤0.90) at the beginning of the study was 16.8% and 52.8%, respectively (p < 0.05). The incidence rate of fatal and nonfatal CVD was 26.9 (95% confidence intervals [CI]: 20.7-37.3) for the patients with a normal baseline ABI and 81.9 (95% CI: 50.9-131.8) for those with an abnormal baseline ABI. An abnormal baseline ABI was associated with a greater risk of CVD (hazard ratio = 2.32; 95% CI: 1.27-4.22). CONCLUSION: ABI values ≤0.9 in patients with type 2 diabetes mellitus and no history of intermittent vascular claudication or rest pain were associated with a higher risk of coronary or cerebrovascular morbidity and mortality.

[Fragility non-spinal fractures in a cohort of 5,201 women aged 65 years and older during a 3-year follow-up]. / Incidencia de fractura no vertebral por fragilidad en una cohorte de 5,201 mujeres de 65 años o más durante 3 años de seguimiento.

BACKGROUND AND OBJECTIVE: Low-trauma non-spinal fractures are a growing source of morbidity and mortality in the elderly. We aimed to evaluate the overall incidence of low-trauma non-spinal fractures and of the main skeletal sites in a cohort of women from Spain. PATIENTS AND METHOD: A total of 5,201 women, aged 65 or older, were enrolled in a 3-year cohort study by non-probabilistic sampling of consecutive cases in 58 primary care centers in Spain, with 6-month visits. All radiological or surgically confirmed low trauma non-spinal fractures were collected. RESULTS: 311 women (6.0%) sustained a total of 363 fractures after a 3.01-year median follow-up, and 14,999 women-year. The incidence rate of overall non-spinal fractures was 2,420 cases per 100,000 women-year. The incidence rates of hip, forearm and humeral fractures were 887,369 and 333 cases/100,000 women-year respectively. CONCLUSIONS: Low-trauma non-spinal fractures are highly incident in Spain in women aged 65 years or older, similar to other western countries.

Incidencia de fractura no vertebral por fragilidad en una cohorte de 5.201 mujeres de 65 años o más durante 3 años de seguimiento / Fragility non-spinal fractures in a cohort of 5, 201 women aged 65 years and older during a 3-year follow-up

Fundamento y objetivo: Las fracturas no vertebrales por traumatismo leve son una causa creciente de morbimortalidad en los ancianos. Nuestro objetivo ha sido determinar la incidencia de fracturas no vertebrales por traumatismo leve, en conjunto y en las principales localizaciones anatómicas, en una muestra de mujeres españolas. Pacientes y método: Se incluyó a 5.201 mujeres de 65 años o más seleccionadas mediante un muestreo no probabilístico de casos consecutivos en las consultas de 58 centros de atención primaria de España. El estudio fue de carácter prospectivo y tuvo 3 años de duración, con visitas periódicas cada 6 meses. Se recogieron todas las fracturas no vertebrales por fragilidad confirmadas por radiología o por el informe quirúrgico. Resultados: Se recogieron 363 fracturas no vertebrales en 311 mujeres (6,0%), tras una mediana de seguimiento de 3,01 años y en un total de 14.999 mujeres/año. La tasa de incidencia de cualquier fractura no vertebral fue de 2.420 por 100.000 mujeres/año. Las tasas de incidencias de fracturas de cadera, antebrazo y húmero fueron de 887, 360 y 333 casos por 100.000 mujeres/año, respectivamente. Conclusiones: Las fracturas no vertebrales por traumatismo leve en mujeres de 65 años o más tienen una incidencia elevada en España, similar a la de otros países occidentales

Background and objective: Low-trauma non-spinal fractures are a growing source of morbidity and mortality in the elderly. We aimed to evaluate the overall incidence of low-trauma non-spinal fractures and of the main skeletal sites in a cohort of women from Spain. Patients and method: A total of 5,201 women, aged 65 or older, were enrolled in a 3-year cohort study by non-probabilistic sampling of consecutive cases in 58 primary care centers in Spain, with 6-month visits. All radiological or surgically confirmed low trauma non-spinal fractures were collected. Results: 311 women (6.0%) sustained a total of 363 fractures after a 3.01-year median follow-up, and 14,999 women-year. The incidence rate of overall non-spinal fractures was 2,420 cases per 100,000 women-year. The incidence rates of hip, forearm and humeral fractures were 887, 369 and 333 cases/100,000 women-year respectively. Conclusions: Low-trauma non-spinal fractures are highly incident in Spain in women aged 65 years or older, similar to other western countries