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Showing papers by "University of Alcalá published in 2021"


Journal ArticleDOI
TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.
Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

1,129 citations


Journal ArticleDOI
27 Apr 2021-JAMA
TL;DR: In this paper, the authors evaluated the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU).
Abstract: Importance Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count Results Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, −6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48];P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, −∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (Pfor noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%];P = .01). Conclusions and Relevance Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration ClinicalTrials.gov Identifier:NCT04486508

447 citations


Journal ArticleDOI
TL;DR: In this paper, the authors determined factors associated with COVID-19-related death in people with rheumatic diseases, including age, sex, smoking status, comorbidities, diagnosis, disease activity and medications.
Abstract: OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

405 citations


Journal ArticleDOI
01 Mar 2021-Chest
TL;DR: A systematic review and meta-analysis of 15 standard and COVID-19 specific sources found the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT and subsegmental PE, in critically ill patients, and in prospective studies.

347 citations


Journal ArticleDOI
01 Jan 2021-Nature
TL;DR: Using mouse models of skin squamous cell carcinoma and lung tumours, it is found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype.
Abstract: FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2-CD44-SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

191 citations


Journal ArticleDOI
TL;DR: The increased risk of hospitalisation due to COVID-19 in patients with asthma is largely associated with age and related comorbidities, and ICS and biologics may be associated with a protective effect against the most severe manifestations of CO VID-19.
Abstract: Background An association between the severity of COVID-19 and the presence of certain chronic conditions has been suggested. However, unlike influenza and other viruses, the disease burden in patients with asthma has been less evident. Objective To understand the impact of COVID-19 in patients with asthma. Methods Using big data analytics and artificial intelligence through the SAVANA Manager® clinical platform, we analysed clinical data from patients with asthma from January 1st to May 10th, 2020. Results Out of 71 182 patients with asthma, 1006 (1.41%) suffered from COVID-19. Compared to asthmatic individuals without COVID-19, patients with asthma and COVID-19 were significantly older (55 versus 42 years), predominantly female (66% versus 59%), smoked more frequently, and had higher prevalence of hypertension, dyslipidemias, diabetes, and obesity. Allergy-related factors such as rhinitis and eczema were less common in asthmatic patients with COVID-19 (p Conclusion Patients with asthma and COVID-19 were older and at increased risk due to comorbidity-related factors. ICS and biologics are generally safe and may be associated with a protective effect against severe COVID-19 infection.

143 citations


Journal ArticleDOI
TL;DR: In this paper, a variety of antithrombotic agents, doses, and durations of therapy are assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19.

126 citations


Journal ArticleDOI
Jonel Trebicka1, Javier Romaní Fernández2, Mária Papp3, Paolo Caraceni4, Wim Laleman5, Carmine Gambino6, Ilaria Giovo, Frank Erhard Uschner1, Christian Jansen7, Cesar Jimenez8, Rajeshwar P. Mookerjee9, Thierry Gustot, Agustín Albillos10, Rafael Bañares11, Peter Jarcuska12, Christian J. Steib13, Thomas Reiberger14, Juan Acevedo, Pietro Gatti, Debbie L. Shawcross15, Stefan Zeuzem1, Alexander Zipprich16, Salvatore Piano6, Thomas Berg17, Tony Bruns18, Karen Vagner Danielsen19, Minneke J. Coenraad20, Manuela Merli, Rudolf E. Stauber21, Heinz Zoller22, Jose Presa Ramos, Cristina Solé2, Germán Soriano, Andrea De Gottardi23, Henning Grønbæk24, Faouzi Saliba25, Christian Trautwein18, Haluk Tarik Kani26, Sven Francque, Stephen D. Ryder27, Pierre Nahon28, Pierre Nahon29, Manuel Romero-Gómez, Hans Van Vlierberghe30, Claire Francoz28, Michael Manns31, Elisabet Garcia-Lopez, Manuel Tufoni4, Alex Amoros, Marco Pavesi, Cristina Sanchez, Michael Praktiknjo7, Anna Curto, Carla Pitarch, Antonella Putignano, Esau Moreno, William Bernal15, Ferran Aguilar, Joan Clària2, Paola Ponzo, Zsuzsanna Vitális3, Giacomo Zaccherini4, Boglarka Balogh3, Alexander L. Gerbes13, Victor Vargas8, Carlo Alessandria, Mauro Bernardi4, Pere Ginès2, Richard Moreau28, Paolo Angeli6, Rajiv Jalan9, Vicente Arroyo, Miriam Maschmeier32, David Semela33, Laure Elkrief, Ahmed Elsharkawy34, Tamas Tornai34, István Tornai3, István Altorjay3, Agnese Antognoli4, Maurizio Baldassarre4, Martina Gagliardi4, Eleonora Bertoli6, Sara Mareso6, Alessandra Brocca6, Daniela Campion, Giorgio Maria Saracco, Martina Rizzo, Jennifer Lehmann7, Alessandra Pohlmann7, Maximilian J. Brol7, Johannes Chang7, Robert Schierwagen1, Elsa Solà, Nesrine Amari, Miguel Á. Rodríguez10, Frederik Nevens5, Ana Clemente11, Martin Janicko12, Daniel Markwardt13, Mattias Mandorfer14, Christoph Welsch1, T.M. Welzel1, Emanuela Ciraci, Vish Patel15, Cristina Ripoll16, Adam Herber17, Paul Horn, Flemming Bendtsen19, Lise Lotte Gluud19, Jelte J Schaapman20, Oliviero Riggio, Florian Rainer21, Joerg Tobiasch Moritz22, Monica Mesquita, Edilmar Alvarado-Tapias, Osagie Akpata9, Luise Aamann24, Didier Samuel25, Sylvie Tresson25, Pavel Strnad18, Roland Amathieu29, Roland Amathieu28, Macarena Simón-Talero8, Francois Smits, Natalie Van den Ende5, Javier Martínez10, Rita Garcia11, Harald Rupprechter14, Cornelius Engelmann17, Osman Ozdogan26 
TL;DR: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD and specific preventive and therapeutic strategies targeting these events may improve outcome in decompensated cirrhosis.

125 citations


Journal ArticleDOI
TL;DR: In this article, the regulatory role of nutritional components of WD and MD in the gut microbiota and immune system interplay, in order to understand, and create awareness of, the influence of diet over both key components.
Abstract: The most prevalent diseases of our time, non-communicable diseases (NCDs) (including obesity, type 2 diabetes, cardiovascular diseases and some types of cancer) are rising worldwide. All of them share the condition of an “inflammatory disorder”, with impaired immune functions frequently caused or accompanied by alterations in gut microbiota. These multifactorial maladies also have in common malnutrition related to physiopathology. In this context, diet is the greatest modulator of immune system–microbiota crosstalk, and much interest, and new challenges, are arising in the area of precision nutrition as a way towards treatment and prevention. It is a fact that the westernized diet (WD) is partly responsible for the increased prevalence of NCDs, negatively affecting both gut microbiota and the immune system. Conversely, other nutritional approaches, such as Mediterranean diet (MD), positively influence immune system and gut microbiota, and is proposed not only as a potential tool in the clinical management of different disease conditions, but also for prevention and health promotion globally. Thus, the purpose of this review is to determine the regulatory role of nutritional components of WD and MD in the gut microbiota and immune system interplay, in order to understand, and create awareness of, the influence of diet over both key components.

123 citations


Journal ArticleDOI
15 Apr 2021-Cell
TL;DR: This paper investigated the extent to which the rates and targets of horizontal gene transfer vary across thousands of bacterial strains from 15 human populations spanning a range of industrialization and found that industrialized lifestyles are associated with higher HGT rates and the functions of HGTs are related to the level of host industrialization.

119 citations


Journal ArticleDOI
TL;DR: In this article, a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) was generated to determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis.
Abstract: Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.

Journal ArticleDOI
TL;DR: The authors used experimentally-derived estimates of thermal tolerance limits for over 2000 terrestrial and aquatic species, and found that most of the variation in thermal tolerance can be attributed to a combination of adaptation to current climatic extremes, and the existence of evolutionary 'attractors' that reflect either boundaries or optima in temperature limits.
Abstract: Understanding how species' thermal limits have evolved across the tree of life is central to predicting species' responses to climate change. Here, using experimentally-derived estimates of thermal tolerance limits for over 2000 terrestrial and aquatic species, we show that most of the variation in thermal tolerance can be attributed to a combination of adaptation to current climatic extremes, and the existence of evolutionary 'attractors' that reflect either boundaries or optima in thermal tolerance limits. Our results also reveal deep-time climate legacies in ectotherms, whereby orders that originated in cold paleoclimates have presently lower cold tolerance limits than those with warm thermal ancestry. Conversely, heat tolerance appears unrelated to climate ancestry. Cold tolerance has evolved more quickly than heat tolerance in endotherms and ectotherms. If the past tempo of evolution for upper thermal limits continues, adaptive responses in thermal limits will have limited potential to rescue the large majority of species given the unprecedented rate of contemporary climate change.

Journal ArticleDOI
TL;DR: In this paper, the relevance of small fires was estimated by comparing a BA product generated from Sentinel-2 MSI images (20m spatial resolution) with a widely used global BA product based on MODIS images (500 m) focusing on sub-Saharan Africa.
Abstract: Fires are a major contributor to atmospheric budgets of greenhouse gases and aerosols, affect soils and vegetation properties, and are a key driver of land use change. Since the 1990s, global burned area (BA) estimates based on satellite observations have provided critical insights into patterns and trends of fire occurrence. However, these global BA products are based on coarse spatial-resolution sensors, which are unsuitable for detecting small fires that burn only a fraction of a satellite pixel. We estimated the relevance of those small fires by comparing a BA product generated from Sentinel-2 MSI (Multispectral Instrument) images (20-m spatial resolution) with a widely used global BA product based on Moderate Resolution Imaging Spectroradiometer (MODIS) images (500 m) focusing on sub-Saharan Africa. For the year 2016, we detected 80% more BA with Sentinel-2 images than with the MODIS product. This difference was predominately related to small fires: we observed that 2.02 Mkm2 (out of a total of 4.89 Mkm2) was burned by fires smaller than 100 ha, whereas the MODIS product only detected 0.13 million km2 BA in that fire-size class. This increase in BA subsequently resulted in increased estimates of fire emissions; we computed 31 to 101% more fire carbon emissions than current estimates based on MODIS products. We conclude that small fires are a critical driver of BA in sub-Saharan Africa and that including those small fires in emission estimates raises the contribution of biomass burning to global burdens of (greenhouse) gases and aerosols.

Journal ArticleDOI
TL;DR: Strong evidence supports the benefits of regular physical activity and exercise for the prevention and management of hypertension, and the Dietary Approaches to Stop Hypertension diet is the most effective dietary approach to prevent hypertension and to reduce blood pressure in individuals with pre-hypertension or hypertension.
Abstract: Hypertension affects approximately one third of the world's adult population and is a major cause of premature death despite considerable advances in pharmacological treatments. Growing evidence supports the use of lifestyle interventions for the prevention and adjuvant treatment of hypertension. In this Review, we provide a summary of the epidemiological research supporting the preventive and antihypertensive effects of major lifestyle interventions (regular physical exercise, body weight management and healthy dietary patterns), as well as other less traditional recommendations such as stress management and the promotion of adequate sleep patterns coupled with circadian entrainment. We also discuss the physiological mechanisms underlying the beneficial effects of these lifestyle interventions on hypertension, which include not only the prevention of traditional risk factors (such as obesity and insulin resistance) and improvements in vascular health through an improved redox and inflammatory status, but also reduced sympathetic overactivation and non-traditional mechanisms such as increased secretion of myokines.

Journal ArticleDOI
TL;DR: COPD remains prevalent in Spain and frequently underdiagnosed, with significant social and clinical differences including living alone, previous respiratory diagnoses, more comorbidities measured with the Charlson index, greater BODE and COTE scores, cognitive impairment, and depression.
Abstract: Background: Two previous national epidemiological studies, IBERPOC in 1997 and EPISCAN in 2007, determined the COPD burden in Spain. Changes in demographics and exposure to risk factors demand the periodic update of COPD prevalence and its determinants. Methods: EPISCAN II aimed to estimate the prevalence of COPD in the general population aged 40 years or older in all 17 regions of Spain. A random population screening sample, requiring 600 participants per region performed a questionnaire plus post-bronchodilator (post-BD) spirometry. Results: A total of 12,825 subjects were initially contacted, and 9433 (73.6%) agreed to participate, of whom 9092 performed a valid spirometry. Baseline characteristics were: 52.6% women, mean ± SD age 60 ± 11 years, 19.8% current- and 34.2% former-smokers. The prevalence of COPD measured by post-BD fixed ratio FEV1/FVC < 0.7 was 11.8% (95% C.I. 11.2–12.5) with a high variability by region (2.4-fold). Prevalence was 14.6% (95% C.I. 13.5–15.7) in males and 9.4% (95% C.I. 8.6–10.2) in females; according to the lower limit of normal (LLN) was 6.0% (95% C.I. 5.5–6.5) overall, by sex being 7.1% (95% C.I. 6.4–8.0) in males and 4.9% (95% C.I. 4.3–5.6) in females. Underdiagnosis of COPD was 74.7%. Cases with COPD were a mean of seven years older, more frequently male, of lower attained education, and with more smokers than the non-COPD population (p < 0.001). However, the number of cigarettes and pack-years in non-COPD participants was substantial, as it was the reported use of e-cigarettes (7.0% vs. 5.5%) (p = 0.045). There were also significant social and clinical differences including living alone, previous respiratory diagnoses, more comorbidities measured with the Charlson index, greater BODE and COTE scores, cognitive impairment, and depression (all p < 0.001). Conclusions: COPD remains prevalent in Spain and frequently underdiagnosed.

Journal ArticleDOI
TL;DR: In this article, the authors investigated the tracking control problem of marine surface vessels (MSVs) in the presence of uncertain dynamics and external disturbances, and proposed a novel event-triggered indirect neuroadaptive fault-tolerant control scheme.
Abstract: This paper investigates the tracking control problem of marine surface vessels (MSVs) in the presence of uncertain dynamics and external disturbances. The facts that actuators are subject to undesirable faults and input saturation are taken into account. Benefiting from the smoothness of the Gaussian error function, a novel saturation function is introduced to replace each nonsmooth actuator saturation nonlinearity. Applying the hand position approach, the original motion dynamics of underactuated MSVs are transformed into a standard integral cascade form so that the vector design method can be used to solve the control problem for underactuated MSVs. By combining the neural network technique and virtual parameter learning algorithm with the vector design method, and introducing an event triggering mechanism, a novel event-triggered indirect neuroadaptive fault-tolerant control scheme is proposed, which has several notable characteristics compared with most existing strategies: 1) it is not only robust and adaptive to uncertain dynamics and external disturbances but is also tolerant to undesirable actuator faults and saturation; 2) it reduces the acting frequency of actuators, thereby decreasing the mechanical wear of the MSV actuators, via the event-triggered control (ETC) technique; 3) it guarantees stable tracking without the a priori knowledge of the dynamics of the MSVs, external disturbances or actuator faults; and 4) it only involves two parameter adaptations--a virtual parameter and a lower bound on the uncertain gains of the actuators--and is thus more affordable to implement. On the basis of the Lyapunov theorem, it is verified that all signals in the tracking control system of the underactuated MSVs are bounded. Finally, the effectiveness of the proposed control scheme is demonstrated by simulations and comparative results.

Journal ArticleDOI
TL;DR: An event-triggering communication scheme is proposed to enhance the efficiency of network resource utilization while counteracting the impact of aperiodic DoS attacks on the USV control system performance and simulation results verify the effectiveness of the proposed co-design method.
Abstract: This paper addresses the co-design problem of a fault detection filter and controller for a networked-based unmanned surface vehicle (USV) system subject to communication delays, external disturbance, faults, and aperiodic denial-of-service (DoS) jamming attacks. First, an event-triggering communication scheme is proposed to enhance the efficiency of network resource utilization while counteracting the impact of aperiodic DoS attacks on the USV control system performance. Second, an event-based switched USV control system is presented to account for the simultaneous presence of communication delays, disturbance, faults, and DoS jamming attacks. Third, by using the piecewise Lyapunov functional (PLF) approach, criteria for exponential stability analysis and co-design of a desired observer-based fault detection filter and an event-triggered controller are derived and expressed in terms of linear matrix inequalities (LMIs). Finally, the simulation results verify the effectiveness of the proposed co-design method. The results show that this method not only ensures the safe and stable operation of the USV but also reduces the amount of data transmissions.

Journal ArticleDOI
01 Jan 2021
TL;DR: In this paper, the authors investigate the current status and future evolution of the workplace within the COVID-19 pandemic context and present a survey on the evolution of workplace culture.
Abstract: The purpose is to investigate the current status and future evolution of the workplace within the COVID-19 pandemic context. Documents, publications and surveys from numerous sources have been anal...

Journal ArticleDOI
TL;DR: Determining the risk-benefit profile of treating these ocular pathologies is a public health issue of supreme priority, even though many patients benefiting from therapeutic treatments are elderly, who are more vulnerable to COVID-19.
Abstract: The recent outbreak of coronavirus disease 2019 (COVID-19) has been declared a public health emergency worldwide. The scientific community has put in much effort and published studies that described COVID-19's biology, transmission, clinical diagnosis, candidate therapeutics, and vaccines. However, to date, only a few data are available on the impact of COVID-19 pandemic on ophthalmological care in different health care systems, its future consequences in terms of disability, and access to sight-saving cures for many patients. To reduce human-to-human transmission of the virus and also ensure supply of infrastructures, human resources, and disposable medical devices to many regions, it is crucial to assess risks and postpone non-essential outpatient visits and elective surgical procedures, especially in older patients and those with comorbidities. This delay or suspension in essential eye procedures may cause significant and rapid vision impairment to irreversible blindness. Determining the risk-benefit profile of treating these ocular pathologies is a public health issue of supreme priority, even though many patients benefiting from therapeutic treatments are elderly, who are more vulnerable to COVID-19. If not reversible, this process could lead to a dramatic increase in disability and unsustainable social costs for many Governments.

Journal ArticleDOI
TL;DR: A literature review on the main academic contributions in this area of AI-based CRMs in B2B digital marketing is developed and the results are analyzed using a statistical approach known as Multiple Correspondence Analysis (MCA) under the homogeneity analysis of variance by means of alternating least squares (HOMALS) framework programmed in the R language.

Journal ArticleDOI
TL;DR: A smoothly-convergent DRL (SCDRL) method is proposed based on the deep Q network (DQN) and reinforcement learning that converges more smoothly than the traditional deep Q learning while the path following error of the SCDRL is comparable to existing methods.
Abstract: This paper aims to solve the path following problem for an underactuated unmanned-surface-vessel (USV) based on deep reinforcement learning (DRL). A smoothly-convergent DRL (SCDRL) method is proposed based on the deep Q network (DQN) and reinforcement learning. In this new method, an improved DQN structure was developed as a decision-making network to reduce the complexity of the control law for the path following of a three-degree of freedom USV model. An exploring function was proposed based on the adaptive gradient descent to extract the training knowledge for the DQN from the empirical data. In addition, a new reward function was designed to evaluate the output decisions of the DQN, and hence, to reinforce the decision-making network in controlling the USV path following. Numerical simulations were conducted to evaluate the performance of the proposed method. The analysis results demonstrate that the proposed SCDRL converges more smoothly than the traditional deep Q learning while the path following error of the SCDRL is comparable to existing methods. Thanks to good usability and generality of the proposed method for USV path following, it can be applied to practical applications.

Journal ArticleDOI
TL;DR: A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported, forging a new stereogenic center α to the N atom.
Abstract: A nickel-catalyzed asymmetric reductive hydroarylation of vinyl amides to produce enantioenriched α-arylbenzamides is reported. The use of a chiral bisimidazoline (BIm) ligand, in combination with diethoxymethylsilane and aryl halides, enables the regioselective introduction of aryl groups to the internal position of the olefin, forging a new stereogenic center α to the N atom. The use of neutral reagents and mild reaction conditions provides simple access to pharmacologically relevant motifs present in anticancer, SARS-CoV PLpro inhibitors, and KCNQ channel openers.

Journal ArticleDOI
TL;DR: In this article, a cross-sectional study was conducted between March 27 and May 6, 2020, using an online questionnaire to measure changes in exposure to nature (including private green space and other greenery, views of nature from home and public natural spaces); sociodemographic, housing and lockdown-related characteristics; stress levels (visual stress scale); psychological distress (General Health Questionnaire − 12 items) and somatization (somatization scale).

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Oana Nicoară-Farcău1, Oana Nicoară-Farcău2, Guohong Han3, Marika Rudler4, Debora Angrisani1, Alberto Monescillo5, Ferran Torres6, Georgina Casanovas, Jaime Bosch1, Jaime Bosch7, Yong Lv3, Dominique Thabut4, Daiming Fan3, Virginia Hernández-Gea1, Juan Carlos García-Pagán1, Christophe Bureau, Juan G. Abraldes1, Frederik Nevens8, Karel Caca, Wim Laleman8, Beate Appenrodt9, Angelo Luca10, Jean-Pierre Vinel, Joachim Mössner, Marco Di Pascoli1, Alexander Zipprich11, Tilman Sauerbruch9, Francisco Martinez-Lagares, Luis Ruiz-del-Arbol, Angel Sierra5, Clemencia Guevara5, Elena Jimenez5, Jose Miguel Marrero5, Enrique Buceta, Juan Francisco Sanchez, Ana Castellot5, Monica Penate5, Ana Cruz5, Elena Peña, Bogdan Procopeț2, Álvaro Giráldez, Lucio Amitrano, Càndid Villanueva, Luis Ibáñez-Samaniego12, Gilberto Silva-Junior1, Javier Martínez13, Joan Genescà6, Jonel Trebicka, Elba Llop14, José María Palazón, José Castellote1, Susana G. Rodrigues7, Lise Lotte Gluud15, Carlos Noronha Ferreira, Rafael Ramis Barceló, Nuria Cañete6, Manuel Rodríguez, Arnulf Ferlitsch16, Jose Luis Mundi, Henning Grønbæk17, Manuel Hernández-Guerra, Romano Sassatelli, Alessandra Dell'Era, Marco Senzolo18, Manuel Romero-Gómez, Meritxell Casas6, Helena Masnou, Massimo Primignani, Aleksander Krag19, Jose Luis Calleja14, Christian Jansen9, Marie Angèle Robic, Irene Conejo6, María-Vega Catalina12, Agustín Albillos13, Edilmar Alvarado, Maria Anna Guardascione, Marcel Tanțău2, Luo Zuo4, Xuan Zhu20, Jianbo Zhao21, Hui Xue22, Zaibo Jiang23, Yuzheng Zhuge24, Chunqing Zhang25, Junhui Sun26, Pengxu Ding27, Weixin Ren28, Yingchun Li29, Kewei Zhang, Wenguang Zhang27, Chuangye He4, Jiawei Zhong21, Qifeng Peng22, Fuquan Ma23, Junyang Luo24, Ming Zhang25, Guangchuan Wang26, Minhuang Sun, Junjiao Dong27, Wei Bai3, Wengang Guo3, Qiuhe Wang3, Xulong Yuan3, Zhengyu Wang3, Tianlei Yu3, Bohan Luo3, Xiaomei Li3, Jie Yuan3, Na Han3, Ying Zhu3, Jing Niu3, Kai Li3, Zhanxin Yin3, Yongzhan Nie3, P Fischer2, Horia Ștefănescu2, Andreea Pop2, Stig Borbjerg Laursen19, Fanny Turon1, Anna Baiges1, José Ferrusquía-Acosta1, Marta Magaz1, Eira Cerda1, Luis Téllez1, Giulia Allegretti1, Guilherme Macedo, David Haldrup17, Patricia M. Santos, Miguel Moura, Daniela Reis, Liliane Meireles, Patricia Sousa, Paula Alexandrino, Carmen A. Navascués, Salvador Augustin6, Vincenzo La Mura, Rafael Bañares12, Raquel Diaz12, Marta Gómez14, Cristina Ripoll11 
TL;DR: A meta-analysis of data from 1327 patients with cirrhosis, acute variceal bleeding, and Child-Pugh score between 10-13 points or CP-B+AB found that preemptive TIPS increased the proportion who survived for 1 year, in both subgroups separately, compared with drugs plus endoscopy.

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TL;DR: This work presents a systematic review of the literature on researches that have been done in recent years to improve energy management systems for smart building using artificial intelligence techniques, and identified that many types of researches are in the domain of decision-making.
Abstract: Buildings are one of the main consumers of energy in cities, which is why a lot of research has been generated around this problem. Especially, the buildings energy management systems must improve in the next years. Artificial intelligence techniques are playing and will play a fundamental role in these improvements. This work presents a systematic review of the literature on researches that have been done in recent years to improve energy management systems for smart building using artificial intelligence techniques. An originality of the work is that they are grouped according to the concept of “Autonomous Cycles of Data Analysis Tasks”, which defines that an autonomous management system requires specialized tasks, such as monitoring, analysis, and decision-making tasks for reaching objectives in the environment, like improve the energy efficiency. This organization of the work allows us to establish not only the positioning of the researches, but also, the visualization of the current challenges and opportunities in each domain. We have identified that many types of researches are in the domain of decision-making (a large majority on optimization and control tasks), and defined potential projects related to the development of autonomous cycles of data analysis tasks, feature engineering, or multi-agent systems, among others.

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TL;DR: In this large observational study, tocilizumab was associated with a lower risk of death or ICU or death in patients with higher CRP levels, and this findings have implications for the design of future clinical trials.

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TL;DR: The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease as discussed by the authors, which is referred to as systemic inflammation and immune deficiency.
Abstract: The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.

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J. A. Rodriguez-Manfredi1, M. de la Torre Juarez2, A. Alonso3, V. Apestigue4, Ignacio Arruego4, T. Atienza5, Don Banfield6, J. Boland2, M. A. Carrera, Luis Castañer5, J. Ceballos1, H. Chen-Chen7, A. Cobos3, Pamela G. Conrad8, E. Cordoba2, T. del Río-Gaztelurrutia7, A. De Vicente-Retortillo1, Manuel Dominguez-Pumar5, Servando Espejo1, Alberto G. Fairén1, A. Fernández-Palma, R. Ferrandiz1, Francesca Ferri9, E. Fischer10, A. García-Manchado3, Miriam García-Villadangos1, Maria Genzer11, S. Gimenez1, Javier Gómez-Elvira4, Felipe Gómez1, Scott D. Guzewich12, Ari-Matti Harri11, Christina Hernandez2, M. Hieta11, Ricardo Hueso7, Iina Jaakonaho11, J. J. Jiménez4, V. Jiménez5, A. Larman, R. Leiter2, A. Lepinette1, Mark T. Lemmon13, G. López5, Soren N. Madsen2, T. Mäkinen11, M. Marin1, J. Martín-Soler1, German Martinez14, Antonio Molina1, Luis Mora-Sotomayor1, J. F. Moreno-Álvarez3, Sara Navarro1, Claire E. Newman, C. Ortega, M. C. Parrondo4, V. Peinado1, A. Peña3, I. Pérez-Grande15, Santiago Pérez-Hoyos7, Jorge Pla-Garcia1, Jouni Polkko11, M. Postigo1, Olga Prieto-Ballesteros1, S. C. R. Rafkin16, Miguel Ramos17, Mark I. Richardson, J. Romeral1, C. Romero1, Kirby Runyon18, Alfonso Saiz-Lopez1, Agustín Sánchez-Lavega7, Iñigo Sard, John T. Schofield2, Eduardo Sebastián1, M. D. Smith12, Robert Sullivan6, L. K. Tamppari2, A. D. Thompson2, Daniel Toledo4, F. Torrero3, J. Torres1, R. Urquí1, T. Velasco3, Daniel Viúdez-Moreiras1, S. Zurita1, Meda team 
TL;DR: The MEDA package and its scientific purpose are described as well as how it responded to the calibration tests and how it helps prepare for the human exploration of Mars.
Abstract: NASA’s Mars 2020 (M2020) rover mission includes a suite of sensors to monitor current environmental conditions near the surface of Mars and to constrain bulk aerosol properties from changes in atmospheric radiation at the surface. The Mars Environmental Dynamics Analyzer (MEDA) consists of a set of meteorological sensors including wind sensor, a barometer, a relative humidity sensor, a set of 5 thermocouples to measure atmospheric temperature at ∼1.5 m and ∼0.5 m above the surface, a set of thermopiles to characterize the thermal IR brightness temperatures of the surface and the lower atmosphere. MEDA adds a radiation and dust sensor to monitor the optical atmospheric properties that can be used to infer bulk aerosol physical properties such as particle size distribution, non-sphericity, and concentration. The MEDA package and its scientific purpose are described in this document as well as how it responded to the calibration tests and how it helps prepare for the human exploration of Mars. A comparison is also presented to previous environmental monitoring payloads landed on Mars on the Viking, Pathfinder, Phoenix, MSL, and InSight spacecraft.