GABAergic neurotransmission and new strategies of neuromodulation to compensate synaptic dysfunction in early stages of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, brain atrophy due to neuronal and synapse loss, and formation of two pathological lesions: extracellular amyloid plaques, composed largely of amyloid-beta peptide (Aβ), and neurofibrillary tangles formed by intracellular aggregates of hyperphosphorylated tau protein. Lesions mainly accumulate in brain regions that modulate cognitive functions such as the hippocampus, septum or amygdala. These brain structures have dense reciprocal glutamatergic, cholinergic, and GABAergic connections and their relationships directly affect learning and memory processes, so they have been proposed as highly susceptible regions to suffer damage by Aβ during AD course. Last findings support the emerging concept that soluble Aβ peptides, inducing an initial stage of synaptic dysfunction which probably starts 20–30 years before the clinical onset of AD, can perturb the excitatory–inhibitory balance of neural circuitries. In turn, neurotransmission imbalance will result in altered network activity that might be responsible of cognitive deficits in AD. Therefore, Aβ interactions on neurotransmission systems in memory-related brain regions such as amygdaloid complex, medial septum or hippocampus are critical in cognitive functions and appear as a pivotal target for drug design to improve learning and dysfunctions that manifest with age. Since treatments based on glutamatergic and cholinergic pharmacology in AD have shown limited success, therapies combining modulators of different neurotransmission systems including recent findings regarding the GABAergic system, emerge as a more useful tool for the treatment, and overall prevention, of this dementia. In this review, focused on inhibitory systems, we will analyze pharmacological strategies to compensate neurotransmission imbalance that might be considered as potential therapeutic interventions in AD

Implementation of intelligent data acquisition system for ITER fast controllers using RIO devices.

A basic requirement of the data acquisition systems used in long pulse fusion experiments is the real time physical events detection in signals. Developing such applications is usually a complex task, so it is necessary to develop a set of hardware and software tools that simplify their implementation. This type of applications can be implemented in ITER using fast controllers. ITER is standardizing the architectures to be used for fast controller implementation. Until now the standards chosen are PXIe architectures (based on PCIe) for the hardware and EPICS middleware for the software. This work presents the methodology for implementing data acquisition and pre-processing using FPGA-based DAQ cards and how to integrate these in fast controllers using EPICS

ITER fast plant system controller prototype based on PXIe platform

The ITER CODAC design identifies slow and fast plant system controllers (PSC). The gast OSCs are based on embedded technologies, permit sampling rates greater than 1 KHz, meet stringent real-time requirements, and will be devoted to data acquisition tasks and control purposes. CIEMAT and UPM have implemented a prototype of a fast PSC based on commercial off-the-shelf (COTS) technologies with PXI hardware and software based on EPIC

Neurons of the Dentate Molecular Layer in the Rabbit Hippocampus

The molecular layer of the dentate gyrus appears as the main entrance gate for information into the hippocampus, i.e., where the perforant path axons from the entorhinal cortex synapse onto the spines and dendrites of granule cells. A few dispersed neuronal somata appear intermingled in between and probably control the flow of information in this area. In rabbits, the number of neurons in the molecular layer increases in the first week of postnatal life and then stabilizes to appear permanent and heterogeneous over the individuals’ life span, including old animals. By means of Golgi impregnations, NADPH histochemistry, immunocytochemical stainings and intracellular labelings (lucifer yellow and biocytin injections), eight neuronal morphological types have been detected in the molecular layer of developing adult and old rabbits. Six of them appear as interneurons displaying smooth dendrites and GABA immunoreactivity: those here called as globoid, vertical, small horizontal, large horizontal, inverted pyramidal and polymorphic. Additionally there are two GABA negative types: the sarmentous and ectopic granular neurons. The distribution of the somata and dendritic trees of these neurons shows preferences for a definite sublayer of the molecular layer: small horizontal, sarmentous and inverted pyramidal neurons are preferably found in the outer third of the molecular layer; vertical, globoid and polymorph neurons locate the intermediate third, while large horizontal and ectopic granular neurons occupy the inner third or the juxtagranular molecular layer. Our results reveal substantial differences in the morphology and electrophysiological behaviour between each neuronal archetype in the dentate molecular layer, allowing us to propose a new classification for this neural population

Associations between Screen Time and Physical Activity among Spanish Adolescents

Excessive time in front of a single or several screens could explain a displacement of physical activity. The present study aimed at determining whether screen-time is associated with a reduced level of moderate to vigorous physical activity (MVPA) in Spanish adolescents living in favorable environmental conditions. or more to total screen-time showed a 64% (OR = 0.61, 95% CI, 0.44–0.86) increased risk of failing to achieve the recommended adolescent MVPA level. Participation in organized physical activities and sports competitions were more strongly associated with MVPA than screen-related behaviors.No single screen-related behavior explained the reduction of MVPA in adolescents. However, the total time accumulated through several screen-related behaviors was negatively associated with MVPA level in boys. This association could be due to lower availability of time for exercise as the time devoted to sedentary screen-time activities increases. Participation in organized physical activities seems to counteract the negative impact of excessive time in front of screens on physical activity

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2015 and GOLD 2019 staging: a pooled analysis of individual patient data

In 2019, The Global Initiative for Chronic Obstructive Lung Disease (GOLD) modified the grading system for patients with COPD, creating 16 subgroups (1A–4D). As part of the COPD Cohorts Collaborative International Assessment (3CIA) initiative, we aim to compare the mortality prediction of the 2015 and 2019 COPD GOLD staging systems. We studied 17 139 COPD patients from the 3CIA study, selecting those with complete data. Patients were classified by the 2015 and 2019 GOLD ABCD systems, and we compared the predictive ability for 5-year mortality of both classifications. In total, 17 139 patients with COPD were enrolled in 22 cohorts from 11 countries between 2003 and 2017; 8823 of them had complete data and were analysed. Mean±sd age was 63.9±9.8 years and 62.9% were male. GOLD 2019 classified the patients in milder degrees of COPD. For both classifications, group D had higher mortality. 5-year mortality did not differ between groups B and C in GOLD 2015; in GOLD 2019, mortality was greater for group B than C. Patients classified as group A and B had better sensitivity and positive predictive value with the GOLD 2019 classification than GOLD 2015. GOLD 2015 had better sensitivity for group C and D than GOLD 2019. The area under the curve values for 5-year mortality were only 0.67 (95% CI 0.66–0.68) for GOLD 2015 and 0.65 (95% CI 0.63–0.66) for GOLD 2019

Feasibility of a walking virtual reality system for rehabilitation: objective and subjective parameters

[EN] Background: Even though virtual reality (VR) is increasingly used in rehabilitation, the implementation of walking navigation in VR still poses a technological challenge for current motion tracking systems. Different metaphors simulate locomotion without involving real gait kinematics, which can affect presence, orientation, spatial memory and cognition, and even performance. All these factors can dissuade their use in rehabilitation. We hypothesize that a marker-based head tracking solution would allow walking in VR with high sense of presence and without causing sickness. The objectives of this study were to determine the accuracy, the jitter, and the lag of the tracking system and its elicited sickness and presence in comparison of a CAVE system. Methods: The accuracy and the jitter around the working area at three different heights and the lag of the head tracking system were analyzed. In addition, 47 healthy subjects completed a search task that involved navigation in the walking VR system and in the CAVE system. Navigation was enabled by natural locomotion in the walking VR system and through a specific device in the CAVE system. An HMD was used as display in the walking VR system. After interacting with each system, subjects rated their sickness in a seven-point scale and their presence in the Slater-Usoh-Steed Questionnaire and a modified version of the Presence Questionnaire. Results: Better performance was registered at higher heights, where accuracy was less than 0.6 cm and the jitter was about 6 mm. The lag of the system was 120 ms. Participants reported that both systems caused similar low levels of sickness (about 2.4 over 7). However, ratings showed that the walking VR system elicited higher sense of presence than the CAVE system in both the Slater-Usoh-Steed Questionnaire (17.6 +/- 0.3 vs 14.6 +/- 0.6 over 21, respectively) and the modified Presence Questionnaire (107.4 +/- 2.0 vs 93.5 +/- 3.2 over 147, respectively). Conclusions: The marker-based solution provided accurate, robust, and fast head tracking to allow navigation in the VR system by walking without causing relevant sickness and promoting higher sense of presence than CAVE systems, thus enabling natural walking in full-scale environments, which can enhance the ecological validity of VR-based rehabilitation applications.The authors wish to thank the staff of LabHuman for their support in this project, especially José Miguel Martínez and José Roda for their assistance. This study was funded in part by Ministerio de Economia y Competitividad of Spain (Project NeuroVR, TIN2013-44741-R and Project REACT, TIN2014-61975-EXP), by Ministerio de Educacion y Ciencia of Spain (Project Consolider-C, SEJ2006-14301/PSIC), and by Universitat Politecnica de Valencia (Grant PAID-10-14).Borrego, A.; Latorre Grau, J.; Llorens Rodríguez, R.; Alcañiz Raya, ML.; Noé, E. (2016). Feasibility of a walking virtual reality system for rehabilitation: objective and subjective parameters. Journal of NeuroEngineering and Rehabilitation. 13:1-9. https://doi.org/10.1186/s12984-016-0174-1S1913Lee KM. Presence. Explicated Communication Theory. 2004;14(1):27–50.Riva G. Is presence a technology issue? Some insights from cognitive sciences. Virtual Reality. 2009;13(3):159–69.Banos RM, et al. Immersion and emotion: their impact on the sense of presence. Cyberpsychol Behav. 2004;7(6):734–41.Llorens R, et al. Tracking systems for virtual rehabilitation: objective performance vs. subjective experience. A practical scenario. Sensors (Basel). 2015;15(3):6586–606.Navarro MD, et al. Validation of a low-cost virtual reality system for training street-crossing. A comparative study in healthy, neglected and non-neglected stroke individuals. Neuropsychol Rehabil. 2013;23(4):597–618.Parsons TD. Virtual reality for enhanced ecological validity and experimental control in the clinical, affective and social neurosciences. Front Hum Neurosci. 2015;9:660.Cameirao MS, et al. Neurorehabilitation using the virtual reality based Rehabilitation Gaming System: methodology, design, psychometrics, usability and validation. J Neuroeng Rehabil. 2010;7:48.Llorens R, et al. Improvement in balance using a virtual reality-based stepping exercise: a randomized controlled trial involving individuals with chronic stroke. Clin Rehabil. 2015;29(3):261–8.Llorens R, et al. Videogame-based group therapy to improve self-awareness and social skills after traumatic brain injury. J Neuroeng Rehabil. 2015;12:37.Fong KN, et al. Usability of a virtual reality environment simulating an automated teller machine for assessing and training persons with acquired brain injury. J Neuroeng Rehabil. 2010;7:19.Levin MF, Weiss PL, Keshner EA. Emergence of virtual reality as a tool for upper limb rehabilitation: incorporation of motor control and motor learning principles. Phys Ther. 2015;95(3):415–25.Llorens R, et al. Effectiveness, usability, and cost-benefit of a virtual reality-based telerehabilitation program for balance recovery after stroke: a randomized controlled trial. Arch Phys Med Rehabil. 2015;96(3):418–25. e2.Cruz-Neira C, et al. Scientists in wonderland: A report on visualization applications in the CAVE virtual reality environment. In: 1993. Proceedings IEEE 1993 Symposium on Research Frontiers in Virtual Reality. 1993.Juan MC, Perez D. Comparison of the levels of presence and anxiety in an acrophobic environment viewed via HMD or CAVE. Presence. 2009;18(3):232–48.Yang YR, et al. Virtual reality-based training improves community ambulation in individuals with stroke: a randomized controlled trial. Gait Posture. 2008;28(2):201–6.Cho KH, Lee WH. Virtual walking training program using a real-world video recording for patients with chronic stroke: a pilot study. Am J Phys Med Rehabil. 2013;92(5):371–84.Darter BJ, Wilken JM. Gait training with virtual reality-based real-time feedback: improving gait performance following transfemoral amputation. Phys Ther. 2011;91(9):1385–94.Yang S, et al. Improving balance skills in patients who had stroke through virtual reality treadmill training. Am J Phys Med Rehabil. 2011;90(12):969–78.Walker ML, et al. Virtual reality-enhanced partial body weight-supported treadmill training poststroke: feasibility and effectiveness in 6 subjects. Arch Phys Med Rehabil. 2010;91(1):115–22.Riley PO, et al. A kinematic and kinetic comparison of overground and treadmill walking in healthy subjects. Gait Posture. 2007;26(1):17–24.Alton F, et al. A kinematic comparison of overground and treadmill walking. Clin Biomech. 1998;13(6):434–40.Lee SJ, Hidler J. Biomechanics of overground vs. treadmill walking in healthy individuals. J Appl Physiol. 2008;104(3).Slater M. Measuring presence: a response to the witmer and Singer presence questionnaire. Presence. 1999;8(5):560–5.Viau A, et al. Reaching in reality and virtual reality: a comparison of movement kinematics in healthy subjects and in adults with hemiparesis. J Neuroeng Rehabil. 2004;1(1):11.Parsons TD, et al. The potential of function-led virtual environments for ecologically valid measures of executive function in experimental and clinical neuropsychology. Neuropsychol Rehabil. 2015;11:1–31. doi: 10.1080/09602011.2015.1109524 .Aravind G, Lamontagne A. Perceptual and locomotor factors affect obstacle avoidance in persons with visuospatial neglect. J Neuroeng Rehabil. 2014;11:38.Darekar A, Lamontagne A, Fung J. Dynamic clearance measure to evaluate locomotor and perceptuo-motor strategies used for obstacle circumvention in a virtual environment. Hum Mov Sci. 2015;40:359–71.Whittle MW. Chapter 4 - Methods of gait analysis. In: Whittle MW, editor. Gait analysis. Edinburgh: Butterworth-Heinemann; 2007. p. 137–75.Hodgson E, et al. WeaVR: a self-contained and wearable immersive virtual environment simulation system. Behav Res Methods. 2015;47(1):296–307.Akizuki H, et al. Effects of immersion in virtual reality on postural control. Neurosci Lett. 2005;379(1):23–6.Thies SB, et al. Comparison of linear accelerations from three measurement systems during "reach & grasp". Med Eng Phys. 2007;29(9):967–72.Fiala M. Designing highly reliable fiducial markers. IEEE Trans Pattern Anal Mach Intell. 2010;32(7):1317–24.Garrido-Jurado S, et al. Automatic generation and detection of highly reliable fiducial markers under occlusion. Pattern Recognition. 2014;47(6):2280–92.Kim K, et al. Effects of virtual environment platforms on emotional responses. Comput Methods Programs Biomed. 2014;113(3):882–93.Slater M, Steed A. A virtual presence counter. Presence. 2000;9(5):413–34.Witmer BG, Singer MJ. Measuring presence in virtual environments: a presence questionnaire. Presence Teleop Virt. 1998;7(3):225–40.Martín-Gutiérrez J, et al. Design and validation of an augmented book for spatial abilities development in engineering students. Comput Graph. 2010;34(1):77–91.Lopez-Mir F, et al. Design and validation of an augmented reality system for laparoscopic surgery in a real environment. Biomed Res Int. 2013;2013:758491.Abawi DF, Bienwald J, Dorner R. Accuracy in optical tracking with fiducial markers: an accuracy function for ARToolKit. In: Third IEEE and ACM International symposium on mixed and augmented reality, ISMAR 2004. 2004.Malbezin P, Piekarski W, Thomas BH. Measuring ARTootKit accuracy in long distance tracking experiments. In: The first IEEE International workshop augmented reality toolkit. 2002.Paquette C, Paquet N, Fung J. Aging affects coordination of rapid head motions with trunk and pelvis movements during standing and walking. Gait Posture. 2006;24(1):62–9.Graham JE, et al. Walking speed threshold for classifying walking independence in hospitalized older adults. Phys Ther. 2010;90(11):1591–7.Gorea A. A refresher of the original Bloch’s Law paper (bloch, july 1885). i-Perception. 2015;6:4.Moss JD, Muth ER. Characteristics of head-mounted displays and their effects on Simulator sickness. Hum Factors. 2011;53(3):308–19.Draper MH, et al. Effects of image scale and system time delay on Simulator sickness within head-coupled virtual environments. Hum Factors. 2001;43(1):129–46.Fujisaki W. Effects of delayed visual feedback on grooved pegboard test performance. Front Psychol. 2012;3:61.Keshner EA, et al. Augmenting sensory-motor conflict promotes adaptation of postural behaviors in a virtual environment. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:1379–82.Slaboda JC, Keshner EA. Reorientation to vertical modulated by combined support surface tilt and virtual visual flow in healthy elders and adults with stroke. J Neurol. 2012;259(12):2664–72.Tossavainen T. Comparison of CAVE and HMD for visual stimulation in postural control research. Stud Health Technol Inform. 2004;98:385–7.Akiduki H, et al. Visual-vestibular conflict induced by virtual reality in humans. Neurosci Lett. 2003;340(3):197–200.Duh HBL, et al. Effects of field of view on balance in an immersive environment. In: Virtual Reality, 2001. Proceedings. IEEE. 2001.Krijn M, et al. Treatment of acrophobia in virtual reality: the role of immersion and presence. Behav Res Ther. 2004;42(2):229–39.Mania K, Chalmers A. The effects of levels of immersion on memory and presence in virtual environments: a reality centered approach. Cyberpsychol Behav. 2001;4(2):247–64.Gorini A, et al. The role of immersion and narrative in mediated presence: the virtual hospital experience. Cyberpsychol Behav Soc Netw. 2011;14(3):99–105.Fromberger P, et al. Virtual viewing time: the relationship between presence and sexual interest in androphilic and gynephilic Men. PLoS One. 2015;10(5), e0127156.Slater M, et al. Visual realism enhances realistic response in an immersive virtual environment. IEEE Comput Graph Appl. 2009;29(3):76–84.Nir-Hadad SY, et al. A virtual shopping task for the assessment of executive functions: Validity for people with stroke. Neuropsychol Rehabil. 2015;11:1–26. doi: 10.1080/09602011.2015.1109523 .Vasilyeva M, Lourenco SF. Development of spatial cognition. Wiley Interdiscip Rev Cogn Sci. 2012;3(3):349–62.Banakou D, Groten R, Slater M. Illusory ownership of a virtual child body causes overestimation of object sizes and implicit attitude changes. Proc Natl Acad Sci U S A. 2013;110(31):12846–51.Yee N, Bailenson JN, Ducheneaut N. The proteus effect: implications of transformed digital self-representation on online and offline behavior. Commun Res. 2009;36(2):285–312.Baylor AL. Promoting motivation with virtual agents and avatars: role of visual presence and appearance. Philos Trans R Soc Lond B Biol Sci. 2009;364(1535):3559–65.Clemente M, et al. Assessment of the influence of navigation control and screen size on the sense of presence in virtual reality using EEG. Expert Sys App. 2014;41(4, Part 2):1584–92.Clemente M, et al. An fMRI study to analyze neural correlates of presence during virtual reality experiences. 2013. Interacting with Computers

The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR''s