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In line with the positive effects of personalized learning, personalized assessments are expected to maximize learner motivation and engagement, allowing learners to show what they truly know and can do. Considering the advances in Generative Artificial Intelligence (GenAI), in this perspective article, we elaborate on the opportunities of integrating GenAI into personalized educational assessments to maximize learner engagement, performance, and access. We also draw attention to the challenges of integrating GenAI into personalized educational assessments regarding its potential risks to the assessment's core values of validity, reliability, and fairness. Finally, we discuss possible solutions and future directions.
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Delithiation of layered oxide electrodes triggers irreversible oxygen loss, one of the primary degradation modes in lithium-ion batteries. However, the delithiation-dependent mechanisms of oxygen loss remain poorly understood. Here we investigate the oxygen non-stoichiometry in Li1.18-xNi0.21Mn0.53Co0.08O2-δ electrodes as a function of Li content by using cycling protocols with long open-circuit voltage steps at varying states of charge. Surprisingly, we observe substantial oxygen loss even at moderate delithiation, corresponding to 2.5, 4.0 and 7.6 ml O2 per gram of Li1.18-xNi0.21Mn0.53Co0.08O2-δ after resting at upper capacity cut-offs of 135, 200 and 265 mAh g-1 for 100 h. Our observations suggest an intrinsic oxygen instability consistent with predictions of high oxygen activity at intermediate potentials versus Li/Li+. In addition, we observe a large chemical expansion coefficient with respect to oxygen non-stoichiometry, which is about three times greater than those of classical oxygen-deficient materials such as fluorite and perovskite oxides. Our work challenges the conventional wisdom that deep delithiation is a necessary condition for oxygen loss in layered oxide electrodes and highlights the importance of calendar ageing for investigating oxygen stability.
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The time-resolved analysis of heart rate (HR) and heart rate variability (HRV) is crucial for the evaluation of the dynamic changes of autonomic activity under different clinical and behavioral conditions. Standard HRV analysis is performed in the frequency domain because the sympathetic activations tend to increase low-frequency HRV oscillations, while the parasympathetic ones increase high-frequency HRV oscillations. However, a strict separation of HRV in frequency bands may cause biased estimations, especially in the low frequency range. To overcome this limitation, we propose a robust estimator that combines HR and HRV dynamics, based on the correlation of the Poincaré plot descriptors of interbeat intervals from the electrocardiogram. To validate our method, we used electrocardiograms gathered from open databases where standardized paradigms were applied to elicit changes in autonomic activity. Our proposal outperforms the standard spectral approach for the estimation of low- and high-frequency fluctuations in HRV, and its performance is comparable to newer methods. Our method constitutes a valuable, robust, time-resolved, and cost-effective tool for a better understanding of autonomic activity through HR and HRV in healthy state and potentially for pathological conditions.
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In recent years, large language models (LLMs) have seen rapid advancement and adoption, and are increasingly being used in educational contexts. In this perspective article, we explore the open challenge of leveraging LLMs to create personalized learning environments that support the "whole learner" by modeling and adapting to both cognitive and non-cognitive characteristics. We identify three key challenges toward this vision: (1) improving the interpretability of LLMs' representations of whole learners, (2) implementing adaptive technologies that can leverage such representations to provide tailored pedagogical support, and (3) authoring and evaluating LLM-based educational agents. For interpretability, we discuss approaches for explaining LLM behaviors in terms of their internal representations of learners; for adaptation, we examine how LLMs can be used to provide context-aware feedback and scaffold non-cognitive skills through natural language interactions; and for authoring, we highlight the opportunities and challenges involved in using natural language instructions to specify behaviors of educational agents. Addressing these challenges will enable personalized AI tutors that can enhance learning by accounting for each student's unique background, abilities, motivations, and socioemotional needs.
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BACKGROUND: Hispanics are the largest growing ethnic minority group in the U.S. Despite significant progress in providing norms for this population, updated normative data are essential. OBJECTIVE: To present the methodology for a study generating normative neuropsychological test data for Spanish-speaking adults living in the U.S. using Bayesian inference as a novel approach. METHODS: The sample consisted of 253 healthy adults from eight U.S. regions, with individuals originating from a diverse array of Latin American countries. To participate, individuals must have met the following criteria: were between 18 and 80 years of age, had lived in the U.S. for at least 1 year, self-identified Spanish as their dominant language, had at least one year of formal education, were able to read and write in Spanish at the time of evaluation, scored≥23 on the Mini-Mental State Examination, <10 on the Patient Health Questionnaire- 9, and <10 on the Generalized Anxiety Disorder scale. Participants completed 12 neuropsychological tests. Reliability statistics and norms were calculated for all tests. CONCLUSION: This is the first normative study for Spanish-speaking adults in the U.S. that uses Bayesian linear or generalized linear regression models for generating norms in neuropsychology, implementing sociocultural measures as possible covariates.
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Teorema de Bayes , Hispânico ou Latino , Testes Neuropsicológicos , Humanos , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Estados Unidos , Idoso , Testes Neuropsicológicos/estatística & dados numéricos , Testes Neuropsicológicos/normas , Adulto Jovem , Valores de Referência , Adolescente , Idoso de 80 Anos ou mais , Idioma , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Hispanics are a significant demographic in the U.S., with diverse cultures and languages. Assessing cognition in this group is complex as cultural and linguistic factors have been found to affect test performance. OBJECTIVE: To generate normative data on the World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) in a sample of Spanish-speaking Hispanics residing in the U.S. METHODS: The sample included 245 Spanish-speaking individuals aged 18-80 across the U.S. (California, Connecticut, Florida, Indiana, New Jersey, Oregon, Virginia, and Wisconsin). Participants were administered the WHO-UCLA AVLT as part of a comprehensive neuropsychological battery. A Bayesian regression approach was used to estimate normative data, including covariates found to be important for predicting performances on measures of learning and memory. RESULTS: Bayesian models showed a logarithmic link between education and all WHO-UCLA AVLT trials, except recognition. For delayed recall, increased Spanish proficiency benefited women's performance exclusively. Time in the U.S. was a significant predictor for total recall, indicating worse performance with longer residency. CONCLUSION: Recognizing cultural factors like language proficiency and duration of U.S. residence is essential for accurately evaluating cognitive function among Spanish-speaking Hispanics. This research emphasizes the importance of accounting for cultural nuances in developing norms for neuropsychological assessments, thereby improving their relevance and effectiveness in diverse communities.
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Hispânico ou Latino , Aprendizagem Verbal , Humanos , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adolescente , Estados Unidos , Aprendizagem Verbal/fisiologia , Adulto Jovem , Idoso de 80 Anos ou mais , Teorema de Bayes , Testes Neuropsicológicos/normas , Testes Neuropsicológicos/estatística & dados numéricos , Valores de Referência , IdiomaRESUMO
BACKGROUND: The Rey-Osterrieth Complex Figure Test (ROCFT) and the Clock Drawing Test (CDT) are commonly used in clinical practice. The ROCFT measures constructional praxis, visual perception, and visuospatial learning and memory, and the CDT assesses for visuospatial, constructional, and executive difficulties. Several neurological disorders are associated with visuospatial and visuo-constructional impairments, yet reliable normative data accounting for sociodemographic and acculturative variables are scarce for Hispanics living in the U.S. OBJECTIVE: To generate normative data for the ROCFT and CDT in a Spanish-speaking adult population living in the U.S. METHODS: The sample consisted of 245 cognitively healthy adults recruited from several states in the U.S. Each participant was administered the ROCFT and CDT as part of a larger cognitive battery. The ROCFT and CDT were normed using a Bayesian approach. Age, age2, education, sex, acculturation, and language proficiency were included as predictors in the analyses. RESULTS: ROCFT performance was associated with education and age, particularly as they interacted with Spanish language proficiency and time spent in the U.S. Education was significantly associated with recall abilities and a lower memory recall on the ROCFT. Age was found to vary depending on a person's bilingual abilities. Sex did not emerge as a predictor of performance, and it did not interact significantly with other variables. CONCLUSION: This is the first study to include acculturation and language proficiency variables in the creation of norms for the assessment of visuo-constructional abilities. This study will have a large impact on the practice of neuropsychology in the U.S.
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Hispânico ou Latino , Testes Neuropsicológicos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estados Unidos , Idoso , Testes Neuropsicológicos/normas , Adulto Jovem , Valores de Referência , Percepção Visual/fisiologia , Memória/fisiologia , Percepção Espacial/fisiologiaRESUMO
BACKGROUND: Hispanics/Latinos are the largest racial/ethnic group among underrepresented populations in the U.S. and multiple sociodemographic, cultural, and linguistic factors have been found to impact their performances on cognitive testing. Despite this, few normative data are available for the heterogeneous Spanish-speaking population in the U.S. OBJECTIVE: To generate normative data on the Trail-Making Test (TMT), Bells Test, Symbol-Digit Modalities Test (SDMT), and the Brief Test of Attention (BTA) for Spanish speakers residing in the U.S. METHODS: The sample included 245 Spanish-speaking individuals aged 18- 80 from eight states across the U.S. (California, Connecticut, Florida, Indiana, New Jersey, Oregon, Virginia, and Wisconsin). Participants were administered attention and processing speed measures as part of a comprehensive neuropsychological battery. We used a Bayesian regression approach to estimate normative data, including covariates found to be important for predicting performances on measures of attention and processing speed. RESULTS: Sociodemographic factors including education, time in the U.S., acculturation, age, and/or sex had differential effects on the TMT-A, TMT-B, SDMT, and the BTA whereas the Bells Test was not influenced by any of these sociodemographic factors. CONCLUSION: Our findings indicate that while sex, age, and educational attainment are important factors to consider, language and acculturation can also influence attention and processing speed performances among Spanish speakers in the U.S.
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Atenção , Hispânico ou Latino , Testes Neuropsicológicos , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Idoso , Estados Unidos , Atenção/fisiologia , Testes Neuropsicológicos/estatística & dados numéricos , Testes Neuropsicológicos/normas , Idoso de 80 Anos ou mais , Valores de Referência , Idioma , Velocidade de ProcessamentoRESUMO
BACKGROUND: The Test of Memory Malingering (TOMM) is a widely used performance validity measure that is available in both English and Spanish. The Spanish version, however, has historically lacked normative data from samples that are representative of the U.S. Hispanic/Spanish speaking population. OBJECTIVE: The aim of the current study was to collect normative data on the update TOMM 2 for Hispanic individuals residing in the U.S. METHODS: Normative data on the TOMM 2 was collected across 9 sites from different regions of the U.S. The total sample consisted of nâ=â188 cognitively healthy adults aged 18 and over with no current or prior history of neurological or psychiatric disorder. Descriptive analyses were performed on total raw scores. RESULTS: Participants obtained a mean score of 48.15 (SDâ=â2.81) on trial 1 of the TOMM 2, 49.86 (SDâ=â0.487) on trial 2, and 49.84 (SDâ=â0.509) on the recognition trial. Scores are provided for traditional cutoff scores as well as some popular cutoffs reported in the literature. Item level analyses were conducted as well as evaluation of performance based on a variety of demographics. CONCLUSION: When compared to the English-speaking normative sample used for the original TOMM, this sample demonstrated better performance on the TOMM 2 indicating better cultural appropriateness of the items. This is the first study conducted that provides culturally appropriate descriptive norms for use with Spanish speakers living in the U.S.
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Hispânico ou Latino , Testes Neuropsicológicos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Testes Neuropsicológicos/normas , Valores de Referência , Estados UnidosRESUMO
BACKGROUND: Normative data for Spanish-speaking populations, particularly Hispanics in the U.S., is notably scarce. OBJECTIVE: This study aims to establish normative data for executive function tests (Modified Wisconsin Card Sorting Test and Stroop Color and Word Test) among Spanish-speaking Hispanics in the U.S. METHODS: We assessed 245 individuals aged 18-80 from eight U.S. states (California, Connecticut, Florida, Indiana, New Jersey, Oregon, Virginia, and Wisconsin) and employed Bayesian regression to estimate norms, considering various sociodemographic factors influencing performance. RESULTS: The posterior distribution suggests a high probability that age impacts SCWT performance, with older adults likely to show greater declines, particularly among those with high proficiency in Spanish. The posterior distribution suggests a stronger effect of age on M-WCST performance among individuals with longer U.S. residency. Educational attainment demonstrates a robust positive impact on M-WCST outcomes, with lower levels of education associated with a higher probability of increased errors. An interaction between education and Spanish proficiency was observed, influencing SCWT scores differently across proficiency levels. Sex and acculturation levels interact to affect SCWT performance, with distinct patterns observed between men and women. This suggests that the impact of acculturation on cognitive test performance may vary by gender. CONCLUSION: Establishing culturally sensitive normative data can enhance accurate identification of executive dysfunction and reduce misdiagnosis risks. This study underscores the importance of considering sociocultural factors including acculturation and language proficiency in neuropsychological assessments to better serve diverse populations.
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Função Executiva , Hispânico ou Latino , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Função Executiva/fisiologia , Idoso , Adolescente , Adulto Jovem , Estados Unidos , Idoso de 80 Anos ou mais , Valores de Referência , Testes Neuropsicológicos/normas , Teste de Classificação de Cartas de WisconsinRESUMO
Macrophage activation plays a central role in the development of atherosclerotic plaques. Interaction with oxidized low-density lipoprotein (oxLDL) leads to macrophage differentiation into foam cells and oxylipin production, contributing to plaque formation. 7-Ketocholesterol (7KC) is an oxidative byproduct of cholesterol found in oxLDL particles and is considered a factor contributing to plaque progression. During atherosclerotic lesion regression or stabilization, macrophages undergo a transformation from a pro-inflammatory phenotype to a reparative anti-inflammatory state. Interleukin-10 (IL-10) and PGE1 appear to be crucial in resolving both acute and chronic inflammatory processes. After coffee consumption, the gut microbiota processes non-absorbed chlorogenic acids producing various lower size phenolic acids. These colonic catabolites, including dihydroferulic acid (DHFA), may exert various local and systemic effects. We focused on DHFA's impact on inflammation and oxidative stress in THP-1 macrophages exposed to oxLDL, 7KC, and lipopolysaccharides (LPS). Our findings reveal that DHFA inhibits the release of several pro-inflammatory mediators induced by LPS in macrophages, such as CCL-2, CCL-3, CCL-5, TNF-α, IL-6, and IL-17. Furthermore, DHFA reduces IL-18 and IL-1ß secretion in an inflammasome-like model. DHFA demonstrated additional benefits: it decreased oxLDL uptake and CD36 expression induced by oxLDL, regulated reactive oxygen species (ROS) and 8-isoprostane secretion (indicating oxidative stress modulation), and selectively increased IL-10 and PGE1 levels in the presence of inflammatory stimuli (LPS and 7KC). Finally, our study highlights the pivotal role of PGE1 in foam cell inhibition and inflammation regulation within activated macrophages. This study highlights DHFA's potential as an antioxidant and anti-inflammatory agent, particularly due to its ability to induce PGE1 and IL-10.
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Ácidos Cumáricos , Cetocolesteróis , Lipopolissacarídeos , Lipoproteínas LDL , Macrófagos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Lipoproteínas LDL/metabolismo , Lipopolissacarídeos/farmacologia , Cetocolesteróis/farmacologia , Ácidos Cumáricos/farmacologia , Anti-Inflamatórios/farmacologia , Polifenóis/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Colo/metabolismo , Colo/efeitos dos fármacos , Interleucina-10/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Mediadores da Inflamação/metabolismoRESUMO
BACKGROUND: Linguistic deficits are common across neurological and neurodegenerative disorders. Currently there are limited neuropsychological norms available for Spanish-speaking adults residing in the U.S. OBJECTIVE: To generate norms for two verbal fluency tests and the Boston Naming Test (BNT) in a Spanish-speaking population in the U.S., with adjustments for demographic and cultural variables. METHODS: The sample consisted of 245 adults from the U.S. Participants completed phonological and semantic verbal fluency tests and the BNT. A standardized four-step statistical procedure was used. RESULTS: For the phoneme F, interactions between Spanish proficiency, age, and education arose. Better performance on phonemes A, S, and M was related to education. Spanish proficiency, acculturation, and time in the U.S. were associated with the phonemes S, A, P, M, and R. An age by education interaction was found for phonemes M and R. The FAS and PMR triads were related to age, sex, time in U.S., and Spanish proficiency. For the semantic verbal fluency tests, an interaction between education and Spanish proficiency arose. For the BNT, test scores were related to education, and significant interactions were also found based on education's interaction with Spanish proficiency and acculturation. CONCLUSION: This study highlights the importance of accounting for sociodemographic and acculturative factors when developing normative data for verbal fluency tests and the BNT for dominant Spanish-speaking adults in the U.S. These sociodemographically-adjusted norms will help improve accuracy of diagnosis and interpretation of linguistic test performance in Spanish speakers living in the U.S.
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Hispânico ou Latino , Testes Neuropsicológicos , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Estados Unidos , Idoso , Testes Neuropsicológicos/normas , Valores de Referência , Adulto Jovem , Testes de Linguagem , Idioma , Comportamento Verbal/fisiologia , Semântica , Adolescente , Escolaridade , Idoso de 80 Anos ou maisRESUMO
The interplay between the brain and interoceptive signals is key in maintaining internal balance and orchestrating neural dynamics, encompassing influences on perceptual and self-awareness. Central to this interplay is the differentiation between the external world, others and the self, a cornerstone in the construction of bodily self-awareness. This review synthesizes physiological and behavioral evidence illustrating how interoceptive signals can mediate or influence bodily self-awareness, by encompassing interactions with various sensory modalities. To deepen our understanding of the basis of bodily self-awareness, we propose a network physiology perspective. This approach explores complex neural computations across multiple nodes, shifting the focus from localized areas to large-scale neural networks. It examines how these networks operate in parallel with and adapt to changes in visceral activities. Within this framework, we propose to investigate physiological factors that disrupt bodily self-awareness, emphasizing the impact of interoceptive pathway disruptions, offering insights across several clinical contexts. This integrative perspective not only can enhance the accuracy of mental health assessments but also paves the way for targeted interventions.
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Conscientização , Interocepção , Autoimagem , Humanos , Interocepção/fisiologia , Conscientização/fisiologia , Rede Nervosa/fisiologia , Encéfalo/fisiologiaRESUMO
Objective: To generate normative data (ND) for executive functions tests in the Waranka minority population of Ecuador. Method: Four-hundred participants aged 6-17 completed the Symbol-Digit Modalities Test (SDMT), Trail-Making Test (TMT), Modified-Wisconsin Card Sorting Test (M-WCST), and Test of Colors-Words (STROOP). Scores were normed using multiple linear regressions, including age, age2, natural logarithm of mean parent education (MPE), sex, bilingualism, and two-way interactions as predictors. Results: Age by MPE and Age2 by MPE interactions arose for SDMT, so that children with illiterate parents scored lower than those with literate parents. Girls scored higher in SDMT. All TMT and M-WCST scores were influenced by age2. Age by MPE interaction was found for TMT-A, so that children with higher MPE went faster; and age by bilingualism interaction for TMT-B, so that more bilingual children needed less time. Stroop-Word and Color were influenced by age2 by MPE interaction, so that children, while older, scored higher, especially those with higher MPE. Also, age2 by sex interaction arose, so that girls increased scores curvilinearly while boys linearly. Word-Color was influenced by age, while Stroop-interference by age2. Age by MPE interaction was found for MCST-Categories and Perseveration, so that perseverations decreased to then increased, especially in those with illiterate parents. M-WCST-Category scores increased to then decrease later on age in children with illiterate parents. Z-scores calculated through indigenous ND were significantly lower than generated through non-indigenous norms. Conclusions: ND for minority populations are critical since Waranka sample performed worse when using non-indigenous norms for z-score calculation.
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In recent years, there has been an increasing interest in studying brain-heart interactions. Methodological advancements have been proposed to investigate how the brain and the heart communicate, leading to new insights into some neural functions. However, most frameworks look at the interaction of only one brain region with heartbeat dynamics, overlooking that the brain has functional networks that change dynamically in response to internal and external demands. We propose a new framework for assessing the functional interplay between cortical networks and cardiac dynamics from noninvasive electrophysiological recordings. We focused on fluctuating network metrics obtained from connectivity matrices of EEG data. Specifically, we quantified the coupling between cardiac sympathetic-vagal activity and brain network metrics of clustering, efficiency, assortativity, and modularity. We validate our proposal using open-source datasets: one that involves emotion elicitation in healthy individuals, and another with resting-state data from patients with Parkinson's disease. Our results suggest that the connection between cortical network segregation and cardiac dynamics may offer valuable insights into the affective state of healthy participants, and alterations in the network physiology of Parkinson's disease. By considering multiple network properties, this framework may offer a more comprehensive understanding of brain-heart interactions. Our findings hold promise in the development of biomarkers for diagnostic and cognitive/motor function evaluation.
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BACKGROUND: Hypoxic ischemic brain injury (HIBI) induced by cardiac arrest (CA) seems to predominate in cortical areas and to a lesser extent in the brainstem. These regions play key roles in modulating the activity of the autonomic nervous system (ANS), that can be assessed through analyses of heart rate variability (HRV). The objective was to evaluate the prognostic value of various HRV parameters to predict neurological outcome after CA. METHODS: Retrospective monocentric study assessing the prognostic value of HRV markers and their association with HIBI severity. Patients admitted for CA who underwent EEG for persistent coma after CA were included. HRV markers were computed from 5 min signal of the ECG lead of the EEG recording. HRV indices were calculated in the time-, frequency-, and non-linear domains. Frequency-domain analyses differentiated very low frequency (VLF 0.003-0.04 Hz), low frequency (LF 0.04-0.15 Hz), high frequency (HF 0.15-0.4 Hz), and LF/HF ratio. HRV indices were compared to other prognostic markers: pupillary light reflex, EEG, N20 on somatosensory evoked potentials (SSEP) and biomarkers (neuron specific enolase-NSE). Neurological outcome at 3 months was defined as unfavorable in case of best CPC 3-4-5. RESULTS: Between 2007 and 2021, 199 patients were included. Patients were predominantly male (64%), with a median age of 60 [48.9-71.7] years. 76% were out-of-hospital CA, and 30% had an initial shockable rhythm. Neurological outcome was unfavorable in 73%. Compared to poor outcome, patients with a good outcome had higher VLF (0.21 vs 0.09 ms2/Hz, p < 0.01), LF (0.07 vs 0.04 ms2/Hz, p = 0.003), and higher LF/HF ratio (2.01 vs 1.01, p = 0.008). Several non-linear domain indices were also higher in the good outcome group, such as SD2 (15.1 vs 10.2, p = 0.016) and DFA α1 (1.03 vs 0.78, p = 0.002). These indices also differed depending on the severity of EEG pattern and abolition of pupillary light reflex. These time-frequency and non-linear domains HRV parameters were predictive of poor neurological outcome, with high specificity despite a low sensitivity. CONCLUSION: In comatose patients after CA, some HRV markers appear to be associated with unfavorable outcome, EEG severity and PLR abolition, although the sensitivity of these HRV markers remains limited.
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Eletroencefalografia , Parada Cardíaca , Frequência Cardíaca , Sistema de Registros , Humanos , Masculino , Feminino , Estudos Retrospectivos , Prognóstico , Frequência Cardíaca/fisiologia , Pessoa de Meia-Idade , Eletroencefalografia/métodos , Parada Cardíaca/fisiopatologia , Idoso , Hipóxia-Isquemia Encefálica/fisiopatologia , Hipóxia-Isquemia Encefálica/diagnóstico , Hipóxia-Isquemia Encefálica/etiologia , Eletrocardiografia/métodos , Sistema Nervoso Autônomo/fisiopatologia , Paris/epidemiologia , Potenciais Somatossensoriais Evocados/fisiologia , Reflexo Pupilar/fisiologiaRESUMO
Mesenchymal stem cells (MSCs) are used in cell therapy; nonetheless, their application is limited by their poor survival after transplantation in a proinflammatory microenvironment. Macroautophagy/autophagy activation in MSCs constitutes a stress adaptation pathway, promoting cellular homeostasis. Our proteomics data indicate that RUBCNL/PACER (RUN and cysteine rich domain containing beclin 1 interacting protein like), a positive regulator of autophagy, is also involved in cell death. Hence, we screened MSC survival upon various cell death stimuli under loss or gain of function of RUBCNL. MSCs were protected from TNF (tumor necrosis factor)-induced regulated cell death when RUBCNL was expressed. TNF promotes inflammation by inducing RIPK1 kinase-dependent apoptosis or necroptosis. We determine that MSCs succumb to RIPK1 kinase-dependent apoptosis upon TNF sensing and necroptosis when caspases are inactivated. We show that RUBCNL is a negative regulator of both RIPK1-dependent apoptosis and necroptosis. Furthermore, RUBCNL mutants that lose the ability to regulate autophagy, retain their function in negatively regulating cell death. We also found that RUBCNL forms a complex with RIPK1, which disassembles in response to TNF. In line with this finding, RUBCNL expression limits assembly of RIPK1-TNFRSF1A/TNFR1 complex I, suggesting that complex formation between RUBCNL and RIPK1 represses TNF signaling. These results provide new insights into the crosstalk between the RIPK1-mediated cell death and autophagy machineries and suggest that RUBCNL, due to its functional duality in autophagy and apoptosis/necroptosis, could be targeted to improve the therapeutic efficacy of MSCs. Abbreviations: BAF: bafilomycin A1; CASP3: caspase 3; Caspases: cysteine-aspartic proteases; cCASP3: cleaved CASP3; CQ: chloroquine; CHX: cycloheximide; cPARP: cleaved poly (ADP-ribose) polymerase; DEPs: differential expressed proteins; ETO: etoposide; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain-like; MSC: mesenchymal stem cell; MTORC1: mechanistic target of rapamycin kinase complex 1; Nec1s: necrostatin 1s; NFKB/NF-kB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PLA: proximity ligation assay; RCD: regulated cell death; RIPK1: receptor (TNFRSF)-interacting serine-threonine kinase 1; RIPK3: receptor-interacting serine-threonine kinase 3; RUBCNL/PACER: RUN and cysteine rich domain containing beclin 1 interacting protein like; siCtrl: small interfering RNA nonsense; siRNA: small interfering RNA; TdT: terminal deoxynucleotidyl transferase; Tm: tunicamycin; TNF: tumor necrosis factor; TNFRSF1A/TNFR1: tumor necrosis factor receptor superfamily, member 1a.
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OBJECTIVE: To generate normative data for the Verbal Fluency Test (VFT) and the Boston Naming Test (BNT) in the Costa Rican population. METHOD: The sample consisted of 563 healthy older people (aged 59-90 years). Polynomial multiple regression analyses were run to evaluate the effects of the age, sex, and education variables on VFT and BNT scores. RESULTS: The results showed a significant linear effect of education on the four-letter VF scores and an effect of sex on the letter P score, with females performing better than males. The explained variance ranged from 20.9% to 28.3%. A linear effect of age and education was also found for the four semantic VF scores, with scores decreasing with increasing age and lower education. The sex variable was significant for all semantic categories, with females performing better than males except in the animal category. The explained variance ranged from 21.7% to 30.9%. In the BNT, a linear effect of education was found, so that the more education, the better the score. In addition, a sex effect was also found, with males having higher scores than females. The predictors of the model explained 9.6% of the variance. CONCLUSIONS: This is the first study that generates normative data for the VF and BNT in the Costa Rican population over 59 years of age based on demographic variables. The use of these normative data will help clinicians in Costa Rica to better understand language functioning in the elderly, allowing for better classification and diagnosis in the future.
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Magnetic resonance elastography (MRE) is a promising neuroimaging technique to probe tissue microstructure, which has revealed widespread softening with loss of structural integrity in the aging brain. Traditional MRE approaches assume mechanical isotropy. However, white matter is known to be anisotropic from aligned, myelinated axonal bundles, which can lead to uncertainty in mechanical property estimates in these areas when using isotropic MRE. Recent advances in anisotropic MRE now allow for estimation of shear and tensile anisotropy, along with substrate shear modulus, in white matter tracts. The objective of this study was to investigate age-related differences in anisotropic mechanical properties in human brain white matter tracts for the first time. Anisotropic mechanical properties in all tracts were found to be significantly lower in older adults compared to young adults, with average property differences ranging between 0.028-0.107 for shear anisotropy and between 0.139-0.347 for tensile anisotropy. Stiffness perpendicular to the axonal fiber direction was also significantly lower in older age, but only in certain tracts. When compared with fractional anisotropy measures from diffusion tensor imaging, we found that anisotropic MRE measures provided additional, complementary information in describing differences between the white matter integrity of young and older populations. Anisotropic MRE provides a new tool for studying white matter structural integrity in aging and neurodegeneration.