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Herein we report a study on the sequential substitution of different nucleophiles on cyanuric chloride to obtain potential candidates for metal sensors (5a-c). The set of nucleophiles on the 1,3,5-triazine ring includes a phenolic BODIPY, an aminoalkyl pyridine and aminoalkyl phosphoramidates, each one designed to play a specific role in the final fluoroionophore. Three new triazine triads were synthesized in similar yields: 5a (45%), 5b (43%) and 5c (52%) after a methodical sequential combination of the nucleophiles via thermodependent nucleophilic aromatic substitution of the three chlorine atoms of cyanuric chloride. To ratify the synthetic results we simulated the reaction mechanisms for the different nucleophiles, aiming to address the distinctive orthogonality and temperature control inherent in this process, identifying and providing a sound rationale for any preferential sequence of nucleophiles inserted into the triazine core. According to our experimental and computational analysis (thermo- and kinetic preferences), we have identified the following preferential order for the sequential substitution: p-hydroxybenzaldehyde > 2-(pyridin-2-yl)ethanamine > aminoalkyl phosphoramidate, indicating that all steps follow a single-step process (concerted) in two stages, where nucleophilic addition precedes leaving group dissociation. The Meisenheimer σ-complex was identified as a transition state structure, with insufficient stability to exist as an intermediate. We observed a consistent and progressive increase in barrier height: 2-8 kcal mol-1 for the first step, 9-15 kcal mol-1 for the second step, and >15 kcal mol-1 for the third substitution. These findings align with the experimental observation of thermodependency in the sequential substitution.
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Signal processing is a very useful field of study in the interpretation of signals in many everyday applications. In the case of applications with time-varying signals, one possibility is to consider them as graphs, so graph theory arises, which extends classical methods to the non-Euclidean domain. In addition, machine learning techniques have been widely used in pattern recognition activities in a wide variety of tasks, including health sciences. The objective of this work is to identify and analyze the papers in the literature that address the use of machine learning applied to graph signal processing in health sciences. A search was performed in four databases (Science Direct, IEEE Xplore, ACM, and MDPI), using search strings to identify papers that are in the scope of this review. Finally, 45 papers were included in the analysis, the first being published in 2015, which indicates an emerging area. Among the gaps found, we can mention the need for better clinical interpretability of the results obtained in the papers, that is not to restrict the results or conclusions simply to performance metrics. In addition, a possible research direction is the use of new transforms. It is also important to make new public datasets available that can be used to train the models.
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[This corrects the article DOI: 10.3389/fpsyg.2024.1302657.].
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PURPOSE: To determine the effects of stratified primary care for low back pain (SPLIT program) in decreasing back-related disability for patients with low back pain (LBP) in primary care. METHODS: We conducted a before-and-after study. We compared health-related outcomes for 2 sequential, independent cohorts of patients with LBP recruited at 7 primary care units in Portugal. The first prospective cohort study characterized usual care (UC) and collected data from February to September 2018. The second was performed when the SPLIT program was implemented and collected data from November 2018 to October 2021. Between cohorts, physical therapists were trained in the implementation of the SPLIT program, which used the STarT Back Screening Tool to categorize patients for matched treatment. We compared back-related disability (Roland-Morris Disability Questionnaire, 0-24 points), pain (Numeric Pain Rating Scale, 0-10 points), perceived effect of treatment (Global Perceived Effect Scale, -5 to +5 points), and health-related quality of life (EuroQoL 5 dimensions 3 levels index, 0-1 points). RESULTS: We enrolled a total of 447 patients: 115 in the UC cohort (mostly treated with pharmacologic treatment) and 332 in the SPLIT cohort (all referred for a physical therapy intervention program). Over the study period of 6 months, patients in the SPLIT program showed significantly greater improvements in back-related disability (ß, -2.94; 95% CI, -3.63 to -2.24; P ≤ .001), pain (ß, -0.88; 95% CI, -1.18 to -0.57; P ≤ .001), perceived effect of treatment (ß, 1.40; 95% CI, 0.97 to 1.82; P ≤ .001), and health-related quality of life (ß, 0.11; 95% CI, 0.08 to 0.14; P ≤ .001) compared with UC. CONCLUSIONS: Patients in the SPLIT program for LBP showed greater benefits regarding health-related outcomes than those receiving UC.
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Dolor de la Región Lumbar , Atención Primaria de Salud , Calidad de Vida , Humanos , Dolor de la Región Lumbar/terapia , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Dimensión del Dolor , Evaluación de la Discapacidad , Portugal , Estudios Controlados Antes y Después , Modalidades de Fisioterapia , AncianoRESUMEN
Empathy is a crucial component to infer and understand others' emotions. However, a synthesis of studies regarding empathy and its neuronal correlates in perceptual tasks using event-related potentials (ERPs) has yet to occur. The current systematic review aimed to provide that overview. Upon bibliographic research, 30 studies featuring empathy assessments and at least one perceptual task measuring ERP components in healthy participants were included. Four main focus categories were identified, as follows: Affective Pictures, Facial Stimuli, Mental States, and Social Language. The Late Positive Potential was the most analyzed in Affective Pictures and was reported to be positively correlated with cognitive and affective empathy, along with other late components. In contrast, for Facial Stimuli, early components presented significant correlations with empathy scales. Particularly, the N170 presented negative correlations with cognitive and affective empathy. Finally, augmented N400 was suggested to be associated with higher empathy scores in the Mental States and Social Language categories. These findings highlight the relevance of early perceptual stages of empathic processing and how different EEG/ERP methodologies provide relevant information.
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From over-exploitation of resources to urban pollution, sustaining well-being requires solving social dilemmas of cooperation. Often such dilemmas are studied assuming that individuals occupy fixed positions in a network or lattice. In spatial settings, however, agents can move, and such movements involve costs. Here we investigate how mobility costs impact cooperation dynamics. To this end, we study cooperation dilemmas where individuals are located in a two-dimensional space and can be of two types: cooperators-or cleaners, who pay an individual cost to have a positive impact on their neighbours-and defectors-or polluters, free-riding on others' effort to sustain a clean environment. Importantly, agents can pay a cost to move to a cleaner site. Both analytically and through agent-based simulations we find that, in general, introducing mobility costs increases pollution felt in the limit of fast movement (equivalently slow strategy revision). The effect on cooperation of increasing mobility costs is non-monotonic when mobility co-occurs with strategy revision. In such scenarios, low (yet non-zero) mobility costs minimise cooperation in low density environments; whereas high costs can promote cooperation even when a minority of agents initially defect. Finally, we find that heterogeneity in mobility cost affects the final distribution of strategies, leading to differences in who supports the burden of having a clean environment.
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Conducta Cooperativa , Humanos , Teoría del Juego , Modelos Teóricos , Bienestar Social/economíaRESUMEN
Mismatch negativity (MMN) is an event-related potential component automatically elicited by events that violate predictions based on prior events. To elicit this component, researchers use stimulus repetition to induce predictions, and the MMN is obtained by subtracting the brain response to rare or unpredicted stimuli from that of frequent stimuli. Under the Predictive Processing framework, one increasingly popular interpretation of the mismatch response postulates that MMN represents a prediction error. In this context, the reduced MMN amplitude to auditory stimuli has been considered a potential biomarker of Schizophrenia, representing a reduced prediction error and the inability to update the mental model of the world based on the sensory signals. It is unclear, however, whether this amplitude reduction is specific for auditory events or if the visual MMN reveals a similar pattern in schizophrenia spectrum disorder. This review and meta-analysis aimed to summarise the available literature on the vMMN in schizophrenia. A systematic literature search resulted in 10 eligible studies that resulted in a combined effect size of g = -.63, CI [-.86, -.41], reflecting lower vMMN amplitudes in patients. These results are in line with the findings in the auditory domain. This component offers certain advantages, such as less susceptibility to overlap with components generated by attentional demands. Future studies should use vMMN to explore abnormalities in the Predictive Processing framework in different stages and groups of the SSD and increase the knowledge in the search for biomarkers in schizophrenia.
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Esquizofrenia , Humanos , Esquizofrenia/fisiopatología , Electroencefalografía/métodos , Potenciales Evocados Visuales/fisiología , Percepción Visual/fisiologíaRESUMEN
The widespread adoption of high-calorie, high-fat, high-sucrose diets (HFHSD) has become a global health concern, particularly due to their association with cardiovascular diseases and metabolic disorders. These comorbidities increase susceptibility to severe outcomes from viral infections and trauma, with trauma-related incidents significantly contributing to global mortality rates. This context underscores the critical need for a reliable blood supply. Recent research has focused on high molecular weight (MW) polymerized human hemoglobin (PolyhHb) as a promising alternative to red blood cells (RBCs), showing encouraging outcomes in previous studies. Given the overlap of metabolic disorders and trauma-related health issues, it is crucial to assess the potential toxicity of PolyhHb transfusions, particularly in models that represent these vulnerable populations. This study evaluated the effects of PolyhHb exchange transfusion in guinea pigs that had developed metabolic disorders due to a 12-week HFHSD regimen. The guinea pigs, underwent a 20â¯% blood volume exchange transfusion with either PolyhHb or the lower molecular weight polymerized bovine hemoglobin, Oxyglobin. Results revealed that both PolyhHb and Oxyglobin transfusions led to liver damage, with a more pronounced effect observed in HFHSD-fed animals. Additionally, markers of cardiac dysfunction indicated signs of cardiac injury in both the HFHSD and normal diet groups following the Oxyglobin transfusion. This study highlights how pre-existing metabolic disorders can exacerbate the potential side effects of hemoglobin-based oxygen carriers (HBOCs). Importantly, the newer generation of high MW PolyhHb showed lower cardiac toxicity compared to the earlier generation low MW PolyhHb, known as Oxyglobin, even in models with pre-existing endothelial and metabolic challenges.
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Enfermedades Cardiovasculares , Hemoglobinas , Enfermedades Metabólicas , Peso Molecular , Animales , Hemoglobinas/metabolismo , Hemoglobinas/farmacología , Cobayas , Masculino , Modelos Animales de Enfermedad , Dieta Alta en Grasa/efectos adversos , Humanos , Sustitutos Sanguíneos/farmacologíaRESUMEN
Background: The purpose of this study is to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. Methods: We conducted an observational, retrospective, multicentre study in NC patients who received IR cysteamine for at least 12 months, switched to ER cysteamine, and received it for at least 6 months before inclusion. Results: Data were collected from nine patients (four children, five adults) 36 months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. The estimated glomerular filtration rate (eGFR) remained stable in patients with preserved kidney function. No significant changes in white blood cell (WBC) cystine levels were observed after the switch. There was no significant difference in the cysteamine dose received. However, some patients were receiving <50% of the recommended dose of cysteamine before and after the switch and showed elevated levels of WBC cystine. Conclusions: Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population.
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Introduction: Models of attachment and information processing suggest that the attention infants allocate to social information might occur in a schema-driven processing manner according to their attachment pattern. A major source of social information for infants consists of facial expressions of emotion. We tested for differences in attention to facial expressions and emotional discrimination between infants classified as securely attached (B), insecure-avoidant (A), and insecure-resistant (C). Methods: Sixty-one 14-month-old infants participated in the Strange Situation Procedure and an experimental task of Visual Habituation and Visual Paired-Comparison Task (VPC). In the Habituation phase, a Low-Arousal Happy face (habituation face) was presented followed by a VPC task of 6 trials composed of two contrasting emotional faces always involving the same actress: the one used in habituation (trial old face) and a new one (trial new face) portraying changes in valence (Low-Arousal Angry face), arousal (High-Arousal Happy face), or valence + arousal (High-Arousal Angry face). Measures of fixation time (FT) and number of fixations (FC) were obtained for the habituation face, the trial old face, the trial new face, and the difference between the trial old face and the trial new face using an eye-tracking system. Results: We found a higher FT and FC for the trial new face when compared with the trial old face, regardless of the emotional condition (valence, arousal, valence + arousal contrasts), suggesting that 14-month-old infants were able to discriminate different emotional faces. However, this effect differed according to attachment pattern: resistant-attached infants (C) had significantly higher FT and FC for the new face than patterns B and A, indicating they may remain hypervigilant toward emotional change. On the contrary, avoidant infants (A) revealed significantly longer looking times to the trial old face, suggesting overall avoidance of novel expressions and thus less sensitivity to emotional change. Discussion: Overall, these findings corroborate that attachment is associated with infants' social information processing.
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Blood-level oxygenation-dependent (BOLD) functional magnetic resonance imaging (fMRI) is the most common modality to study functional connectivity in the human brain. Most research to date has focused on connectivity between pairs of brain regions. However, attention has recently turned towards connectivity involving more than two regions, that is, higher-order connectivity. It is not yet clear how higher-order connectivity can best be quantified. The measures that are currently in use cannot distinguish between pairwise (i.e., second-order) and higher-order connectivity. We show that genuine higher-order connectivity can be quantified by using multivariate cumulants. We explore the use of multivariate cumulants for quantifying higher-order connectivity and the performance of block bootstrapping for statistical inference. In particular, we formulate a generative model for fMRI signals exhibiting higher-order connectivity and use it to assess bias, standard errors, and detection probabilities. Application to resting-state fMRI data from the Human Connectome Project demonstrates that spontaneous fMRI signals are organized into higher-order networks that are distinct from second-order resting-state networks. Application to a clinical cohort of patients with multiple sclerosis further demonstrates that cumulants can be used to classify disease groups and explain behavioral variability. Hence, we present a novel framework to reliably estimate genuine higher-order connectivity in fMRI data which can be used for constructing hyperedges, and finally, which can readily be applied to fMRI data from populations with neuropsychiatric disease or cognitive neuroscientific experiments.
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Encéfalo , Conectoma , Humanos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Conectoma/métodos , Imagen por Resonancia Magnética/métodos , ProbabilidadRESUMEN
This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.
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Antirreumáticos , Espondiloartritis Axial , Espondilitis Anquilosante , Humanos , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adalimumab/uso terapéutico , Antirreumáticos/uso terapéutico , Factor de Necrosis Tumoral alfa , Resultado del TratamientoRESUMEN
This descriptive study aimed to investigate the current practices of Portuguese and Brazilian soccer coaches in the design and implementation of small-sided games (SSGs) in soccer. A total of 187 male coaches participated in the online survey, consisting of 82 Portuguese and 105 Brazilian individuals. These coaches held various positions within the technical staff, with 63 serving as head coaches, 38 as assistant coaches, 38 as physical trainers, and 48 in other roles related to the technical staff. Additionally, the participants represented both youth (n = 102) and adult competitive levels (n = 59), along with some who were not currently associated with a specific group. The survey consisted of 32 questions divided into three main sections: (i) the timing of SSG application, (ii) the methods used for applying SSGs, and (iii) the reasons for applying SSGs. The Chi-square test revealed a statistically significant association between nationality and the frequency of SSGs used in training sessions during the pre-season (p = 0.039) and in-season (p < 0.001). Moreover, significant association between nationality and the time allocated to employing SSGs for targeting aerobic training (p < 0.001) was found. There was a significant association between nationality and the weekly frequency of SSGs use for targeting sprint training (p = 0.019). The Chi-square test identified significant associations between nationality and the use of SSGs for targeting technical training (p = 0.002), as well as for tactical training (p = 0.002). In summary, this study underscores that SSGs are primarily employed to enhance aerobic fitness, change of direction, technical skills, and tactical behaviors. Coaches generally favor employing SSGs two to three times a week, with typical sessions lasting between 16 to 30 minutes. Notably, the major discrepancies between nationalities lie in the importance assigned to the use of SSGs. However, in practice, the formats and objectives for implementing SSGs remain relatively similar.
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The phytochemical investigation of the leaves and trunk bark of a specimen of Ocotea aciphylla collected in the southern portion of the Amazon forest led to the isolation of an oxabicyclo[3.2.2]nonane-type neolignan and 15 bicyclo[3.2.1]octanoid neolignans, 14 of which are unreported compounds (2-15), including one with an unusual oxidation pattern of the side chain at C-1' and two rare 7.1',8.3'-connected bicyclo[3.2.1]octanoid derivatives. Their structures and relative configurations were determined by extensive spectrometric analysis based on 1D- and 2D-NMR spectroscopy and HRESIMS data, while their absolute configurations were unambiguously assigned using electronic and vibrational circular dichroism data assisted by density functional theory calculations. Additionally, known sesquiterpenes, phenylpropanoids, and phytosterols were also isolated.
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Lignanos , Ocotea , Lignanos/química , Ocotea/química , Alcanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Dicroismo CircularRESUMEN
PURPOSE: Glioma is associated with pathologically high (peri)tumoral brain activity, which relates to faster progression. Functional connectivity is disturbed locally and throughout the entire brain, associating with symptomatology. We, therefore, investigated how local activity and network measures relate to better understand how the intricate relationship between the tumor and the rest of the brain may impact disease and symptom progression. METHODS: We obtained magnetoencephalography in 84 de novo glioma patients and 61 matched healthy controls. The offset of the power spectrum, a proxy of neuronal activity, was calculated for 210 cortical regions. We calculated patients' regional deviations in delta, theta and lower alpha network connectivity as compared to controls, using two network measures: clustering coefficient (local connectivity) and eigenvector centrality (integrative connectivity). We then tested group differences in activity and connectivity between (peri)tumoral, contralateral homologue regions, and the rest of the brain. We also correlated regional offset to connectivity. RESULTS: As expected, patients' (peri)tumoral activity was pathologically high, and patients showed higher clustering and lower centrality than controls. At the group-level, regionally high activity related to high clustering in controls and patients alike. However, within-patient analyses revealed negative associations between regional deviations in brain activity and clustering, such that pathologically high activity coincided with low network clustering, while regions with 'normal' activity levels showed high network clustering. CONCLUSION: Our results indicate that pathological activity and connectivity co-localize in a complex manner in glioma. This insight is relevant to our understanding of disease progression and cognitive symptomatology.
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Mapeo Encefálico , Glioma , Humanos , Mapeo Encefálico/métodos , Encéfalo/diagnóstico por imagen , Magnetoencefalografía , Glioma/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.
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Raquitismo Hipofosfatémico Familiar , Hipofosfatemia , Humanos , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/diagnóstico , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Hipercalciuria/diagnóstico , Hipercalciuria/tratamiento farmacológico , Hipercalciuria/genética , Riñón/metabolismo , Fosfatos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIc/metabolismoRESUMEN
BACKGROUND: Differences in short and long-latency Event-Related Potentials (ERPs) can help us infer abnormalities in brain processing, considering early and later stages of stimuli processing across tasks and conditions. In autism research, the adult population remains largely understudied compared to samples at early stages of development. In this context, this scoping review briefly summarises what has been described in community and subclinical adult samples of autism. METHOD: The current scoping review and meta-analysis includes 50 records (N = 1652) and comprehensively explores short and long-latency ERP amplitudes and their relationship with autistic traits in adult community samples. RESULTS: This meta-analysis identified, with small to medium effect sizes, distinctive patterns in late ERP amplitudes, indicating enhanced responses to visual stimuli and the opposite patterns to auditory tasks in the included sample. Additionally, a pattern of higher amplitudes was also found for the component P3b in autistic traits. DISCUSSION: Differential effects in visual and auditory domains are explored in light of the predictive processing framework for Autism. It remains possible that different brain mechanisms operate to explain symptoms related with different sensory modalities. P3b is discussed as a possible component of interest in future studies as it revealed a more robust effect for differentiating severity in the expression of autistic traits in adulthood.