Time-varying effective connectivity during visual object naming as a function of semantic demands

Accumulating evidence suggests that visual object understanding involves a rapid feedforward sweep, after which subsequent recurrent interactions are necessary. The extent to which recurrence plays a critical role in object processing remains to be determined. Recent studies have demonstrated that recurrent processing is modulated by increasing semantic demands. Differentially from previous studies, we used dynamic causal modeling to model neural activity recorded with magnetoencephalography while 14 healthy humans named two sets of visual objects that differed in the degree of semantic accessing demands, operationalized in terms of the values of basic psycholinguistic variables associated with the presented objects (age of acquisition, frequency, and familiarity). This approach allowed us to estimate the directionality of the causal interactions among brain regions and their associated connectivity strengths. Furthermore, to understand the dynamic nature of connectivity (i.e., the chronnectome; Calhoun et al., 2014) we explored the time-dependent changes of effective connectivity during a period (200–400 ms) where adding semantic-feature information improves modeling and classifying visual objects, at 50 ms increments. First, we observed a graded involvement of backward connections, that became active beyond 200 ms. Second, we found that semantic demands caused a suppressive effect in the backward connection from inferior frontal cortex (IFC) to occipitotemporal cortex over time. These results complement those from previous studies underscoring the role of IFC as a common source of top-down modulation, which drives recurrent interactions with more posterior regions during visual object recognition. Crucially, our study revealed the inhibitory modulation of this interaction in situations that place greater demands on the conceptual system

Machine Learning and Virtual Reality on Body Movements¿ Behaviors to Classify Children with Autism Spectrum Disorder

[EN] Autism spectrum disorder (ASD) is mostly diagnosed according to behavioral symptoms in sensory, social, and motor domains. Improper motor functioning, during diagnosis, involves the qualitative evaluation of stereotyped and repetitive behaviors, while quantitative methods that classify body movements' frequencies of children with ASD are less addressed. Recent advances in neuroscience, technology, and data analysis techniques are improving the quantitative and ecological validity methods to measure specific functioning in ASD children. On one side, cutting-edge technologies, such as cameras, sensors, and virtual reality can accurately detect and classify behavioral biomarkers, as body movements in real-life simulations. On the other, machine-learning techniques are showing the potential for identifying and classifying patients' subgroups. Starting from these premises, three real-simulated imitation tasks have been implemented in a virtual reality system whose aim is to investigate if machine-learning methods on movement features and frequency could be useful in discriminating ASD children from children with typical neurodevelopment. In this experiment, 24 children with ASD and 25 children with typical neurodevelopment participated in a multimodal virtual reality experience, and changes in their body movements were tracked by a depth sensor camera during the presentation of visual, auditive, and olfactive stimuli. The main results showed that ASD children presented larger body movements than TD children, and that head, trunk, and feet represent the maximum classification with an accuracy of 82.98%. Regarding stimuli, visual condition showed the highest accuracy (89.36%), followed by the visual-auditive stimuli (74.47%), and visual-auditive-olfactory stimuli (70.21%). Finally, the head showed the most consistent performance along with the stimuli, from 80.85% in visual to 89.36% in visual-auditive-olfactory condition. The findings showed the feasibility of applying machine learning and virtual reality to identify body movements' biomarkers that could contribute to improving ASD diagnosis.This work was supported by the Spanish Ministry of Economy, Industry, and Competitiveness funded project "Immersive virtual environment for the evaluation and training of children with autism spectrum disorder: T Room" (IDI-20170912) and by the Generalitat Valenciana funded project REBRAND (PROMETEO/2019/105). Furthermore, this work was co-founded by the European Union through the Operational Program of the European Regional development Fund (ERDF) of the Valencian Community 2014-2020 (IDIFEDER/2018/029).Alcañiz Raya, ML.; Marín-Morales, J.; Minissi, ME.; Teruel Garcia, G.; Abad, L.; Chicchi-Giglioli, IA. (2020). 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Información de medicamentos a la población desde el Servicio de Farmacia a través de Internet

Objectives: To describe and discuss the work of a Pharmacy Department for the health-care portal www.viatusalud.com. Methods: Using a web portal, a Pharmacy Department develops and updates a vademecum on drugs, and answers enquiries by end-users. Results: On December 31, 2002 more than 750 records on drugs were available, and 3030 enquiries had been answered. Conclusions: With this drug information and online enquiry service, our Pharmacy Department helps meet the demand of health-care information posed by the community and by patients previously seen at Clínica Universitaria. In addition, it allows areas of improvement to be detected in the information to be offered to patients fron a Pharmacy Department, and represents a tertiary source of information for health-care professionals

Incidence and characteristics of adverse drug reactions in a cohort of patients treated with PD-1/PD-L1 inhibitors in real-world practice

Adverse reaction; Immunotherapy; PharmacovigilanceReacción adversa; Inmunoterapia; FarmacovigilanciaReacció adversa; Immunoteràpia; FarmacovigilànciaBackground: Data related to adverse drug reactions (ADRs), specifically immune-related adverse events (irAEs), in long-term treatment with immunotherapy in real-world practice is scarce, as is general information regarding the management of ADRs. Objectives: To characterize and describe the incidence of ADRs in patients who began immunotherapy treatment in clinical practice. Methods: In a prospective observational study cancer patients ≥18 years of age who were treated with a monotherapy regime of PD-1/PD-L1 inhibitors were evaluated. The study period was from November 2017 to June 2019 and patients were followed up until June 2021. Patients were contacted monthly by telephone and their electronic health records were reviewed. Each ADR was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Results: Out of 99 patients, 86 met the inclusion criteria. Most were male (67.4%), with a median age of 66 (interquartile range, IQR: 59–76). The most frequent cancer was non-small cellular lung cancer (46 cases, 53.5%), followed by melanoma (22, 25.6%). A total of 74 patients (86%) were treated with anti-PD-1 drugs and 12 (14%) were treated with anti-PD-L1 drugs. The median treatment durations were 4.9 (IQR: 1.9–17.0) and 5.9 months (IQR: 1.2–12.3), respectively. Sixty-three patients (73%) developed from a total of 156 (44% of the total number of ADR) irADRs, wherein the most frequent were skin disorders (50 cases, 32%, incidence = 30.5 irADRs/100 patients per year [p-y]), gastrointestinal disorders (29, 19%, 17.7 irADRs/100 p-y), musculoskeletal disorders (17, 11%, 10.4 irADRs/100 p-y), and endocrine disorders (14, 9%, 8.6 irADRs/100 p-y). A total of 22 irADRs (14%) had a latency period of ≥12 months. Twelve irADRs (7.7%) were categorized as grade 3–4, and while 2 (1.3%) were categorized as grade 5 (death). Sixty-one irADRs (39.1%) in 36 patients required pharmacological treatment and 47 irADRs (30.1%) in 22 patients required treatment with corticosteriods. Conclusion: The majority of patients treated with anti-PD1/PDL1-based immunotherapy experienced adverse reactions. Although most of these reactions were mild, 11.5% were categorized as grade 3 or above. A high percentage of the reactions were immune-related and occurred throughout the treatment, thereby indicating that early identification and close monitoring is essential

Role of personal aptitudes as determinants of incident morbidity, lifestyles, quality of life, use of the health services and mortality (DESVELA cohort): qualitative study protocol for a prospective cohort study in a hybrid analysis

IntroductionMaintaining or acquiring healthier health-oriented behaviours and promoting physical and mental health amongst the Spanish population is a significant challenge for Primary Health Care. Although the role of personal aptitudes (characteristics of each individual) in influencing health behaviours is not yet clear, these factors, in conjunction with social determinants such as gender and social class, can create axes of social inequity that affect individuals’ opportunities to engage in health-oriented behaviours. Additionally, lack of access to health-related resources and opportunities can further exacerbate the issue for individuals with healthy personal aptitudes. Therefore, it is crucial to investigate the relationship between personal aptitudes and health behaviours, as well as their impact on health equity.ObjectivesThis paper outlines the development, design and rationale of a descriptive qualitative study that explores in a novel way the views and experiences on the relationship between personal aptitudes (activation, health literacy and personality traits) and their perception of health, health-oriented behaviours, quality of life and current health status.Method and analysisThis qualitative research is carried out from a phenomenological perspective. Participants will be between 35 and 74 years of age, will be recruited in Primary Health Care Centres throughout Spain from a more extensive study called DESVELA Cohort. Theoretical sampling will be carried out. Data will be collected through video and audio recording of 16 focus groups in total, which are planned to be held in 8 different Autonomous Communities, and finally transcribed for a triangulated thematic analysis supported by the Atlas-ti program.DiscussionWe consider it essential to understand the interaction between health-related behaviours as predictors of lifestyles in the population, so this study will delve into a subset of issues related to personality traits, activation and health literacy.Clinical trial registration: ClinicalTrials.gov, identifier NCT04386135

Risk factors and outcome of COVID-19 in patients with hematological malignancies

Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defned. Patients and methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confrmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n=58) or allogeneic stem cell transplantation (allo-SCT) (n=65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p=0.02). Prognostic factors identifed for day 45 overall mortality (OM) by logistic regression multivariate analysis included age>70 years [odds ratio (OR) 2.1, 95% con‑ fdence interval (CI) 1.2-3.8, p=0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p<0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p=0.02) whereas the use of hidroxycloroquine did not show signifcant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P=0.1). Conclusions: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of infammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19

Altered brain rhythms and functional network disruptions involved in patients with generalized fixation-off epilepsy

Fixation-off sensitivity (FOS) denotes the forms of epilepsy elicited by elimination of fixation. FOS-IGE patients are rare cases [1]. In a previous work [2] we showed that two FOS-IGE patients had different altered EEG rhythms when closing eyes; only beta band was altered in patient 1 while theta, alpha and beta were altered in patient 2. In the present work, we explain the relationship between the altered brain rhythms in these patients and the disruption in functional brain networks

Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

BACKGROUND: Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. CONCLUSIONS/SIGNIFICANCE: All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI

WW Domains of the Yes-Kinase-Associated-Protein (YAP) Transcriptional Regulator Behave as Independent Units with Different Binding Preferences for PPxY Motif-Containing Ligands

YAP is a WW domain-containing effector of the Hippo tumor suppressor pathway, and the object of heightened interest as a potent oncogene and stemness factor. YAP has two major isoforms that differ in the number of WW domains they harbor. Elucidating the degree of co-operation between these WW domains is important for a full understanding of the molecular function of YAP. We present here a detailed biophysical study of the structural stability and binding properties of the two YAP WW domains aimed at investigating the relationship between both domains in terms of structural stability and partner recognition. We have carried out a calorimetric study of the structural stability of the two YAP WW domains, both isolated and in a tandem configuration, and their interaction with a set of functionally relevant ligands derived from PTCH1 and LATS kinases. We find that the two YAP WW domains behave as independent units with different binding preferences, suggesting that the presence of the second WW domain might contribute to modulate target recognition between the two YAP isoforms. Analysis of structural models and phage-display studies indicate that electrostatic interactions play a critical role in binding specificity. Together, these results are relevant to understand of YAP function and open the door to the design of highly specific ligands of interest to delineate the functional role of each WW domain in YAP signaling.This work was supported by the Spanish Ministry of Education and Science [grant BIO2009-13261-CO2], the Spanish Ministry of Economy and Competitivity [grant BIO2012-39922-CO2] including FEDER (European Funds for Regional Development) funds and the Governement of Andalusia [grant CVI-5915]. Marius Sudol was supported by PA Breast Cancer Coalition Grants (#60707 and #920093) plus the Geisinger Clinic