Multifunctionalized Carbon Dots as an Active Nanocarrier for Drug Delivery to the Glioblastoma Cell Line.

Nanoparticle-based nanocarriers represent a viable alternative to conventional direct administration in cancer cells. This advanced approach employs the use of nanotechnology to transport therapeutic agents directly to cancer cells, thereby reducing the risk of damage to healthy cells and enhancing the efficacy of treatment. By approving nanoparticle-based nanocarriers, the potential for targeted, effective treatment is greatly increased. The so-called carbon-based nanoparticles, or carbon dots, have been hydrothermally prepared and initiated by a polymerization process. We synthesized and characterized nanoparticles of 2-acrylamido-2-methylpropanesulfonic acid, which showed biocompatibility with glioblastoma cells, and further, we tested them as a carrier for the drug riluzole. The obtained nanoparticles have been extensively characterized by techniques to obtain the exact composition of their surface by using Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), and nuclear magnetic resonance (NMR) spectroscopy, as well as cryo-transmission electron microscopy. We found that the surface of the synthesized nanoparticles (NPs) is covered mainly by sulfonated, carboxylic, and substituted amide groups. These functional groups make them suitable as carriers for drug delivery in cancer cells. Specifically, we have successfully utilized the NPs as a delivery system for the drug riluzole, which has shown efficacy in treating glioblastoma cancer cells. The effect of nanoparticles as carriers for the riluzole system on glioblastoma cells was studied using live-cell synchrotron-based FTIR microspectroscopy to monitor in situ biochemical changes. After applying nanoparticles as nanocarriers, we have observed changes in all biomacromolecules, including the nucleic acids and protein conformation. These findings provide a strong foundation for further exploration into the development of targeted treatments for glioblastoma.

Efficient and scalable gene delivery method with easily generated cationic carbon dots.

Gene delivery is a complex process with several challenges when attempting to incorporate genetic material efficiently and safely into target cells. Some of the key challenges include not only efficient cellular uptake and endosomal escape to ensure that the genetic material can exert its effect but also minimizing the toxicity of the delivery system, which is vital for safe gene delivery. Of importance, if gene delivery systems are intended for biomedical applications or clinical use, they must be scalable and easy and affordable to manufacture to meet the demand. Here, we show an efficient gene delivery method using a combination of carbon dots coated by PEI through electrostatic binding to easily generate cationic carbon dots. We show a biofunctional approach to generate optimal cationic carbon dots (CCDs) that can be scaled up to meet specific transfection demands. CCDs improve cell viability and increase transfection efficiency four times over the standard of PEI polyplexes. Generated CCDs enabled the challenging transfection protocol to produce retroviral vectors via cell cotransfection of three different plasmids into packing cells, showing not only high efficiency but also functionality of the gene delivery, tested as the capacity to produce infective retroviral particles.

Non-pharmacological therapeutic needs in people with Dravet syndrome.

Dravet syndrome (DS) is a genetic rare disease, which is usually caused by a mutation in the SCN1A gene. DS is characterised by a drug-resistant epilepsy and by cognitive and behavioural disturbances. Thus, DS patients require both pharmacological and non-pharmacological treatments. However, there is a paucity of studies on non-pharmacological therapies and their potential benefits. The main aim of this study was to describe the non-pharmacological therapy modalities received by DS patients and their socio-economic impact on the family. Thus, we designed an online survey addressed to caregivers of DS patients. Our results indicated that up to 91.9% of the surveyed patients required non-pharmacological therapies, which were mainly directed to treat cognitive, sensory and motor impairments. In many cases, the economic costs of these therapies were borne entirely by the families. Nevertheless, patients required a deployment of resources not only at a health care level, but also at an educational level.

The Accuracy and Absolute Reliability of a Knee Surgery Assistance System Based on ArUco-Type Sensors.

Recent advances allow the use of Augmented Reality (AR) for many medical procedures. AR via optical navigators to aid various knee surgery techniques (e.g., femoral and tibial osteotomies, ligament reconstructions or menisci transplants) is becoming increasingly frequent. Accuracy in these procedures is essential, but evaluations of this technology still need to be made. Our study aimed to evaluate the system's accuracy using an in vitro protocol. We hypothesised that the system's accuracy was equal to or less than 1 mm and 1° for distance and angular measurements, respectively. Our research was an in vitro laboratory with a 316 L steel model. Absolute reliability was assessed according to the Hopkins criteria by seven independent evaluators. Each observer measured the thirty palpation points and the trademarks to acquire direct angular measurements on three occasions separated by at least two weeks. The system's accuracy in assessing distances had a mean error of 1.203 mm and an uncertainty of 2.062, and for the angular values, a mean error of 0.778° and an uncertainty of 1.438. The intraclass correlation coefficient was for all intra-observer and inter-observers, almost perfect or perfect. The mean error for the distance's determination was statistically larger than 1 mm (1.203 mm) but with a trivial effect size. The mean error assessing angular values was statistically less than 1°. Our results are similar to those published by other authors in accuracy analyses of AR systems.

External validation of the Melanoma Institute Australia Sentinel Node Metastasis Risk Prediction Tool using the National Cancer Database.

BACKGROUND: To improve patient selection for sentinel node (SN) biopsy, the Melanoma Institute of Australia (MIA) created a predictive model based on readily available clinicopathologic factors. OBJECTIVES: Validation of the MIA nomogram using the National Cancer Database (NCDB), a nationwide oncology outcomes database for >1500 Commission-accredited cancer programs in the United States. METHODS: A total of 60,165 patients were included in the validation. The probability of SN positivity was calculated for each patient. Using calculated probabilities, a receiver operating characteristic curve was generated to assess the model's discrimination ability. RESULTS: At baseline, the NCDB cohort had different clinicopathologic characteristics compared with the original MIA data set. Despite these differences, the MIA nomogram retained high-predictive accuracy within the NCDB dataset (C-statistic, 0.733 [95% CI, 0.726-0.739]), although calibration weakened for the highest risk decile. LIMITATIONS: The NCDB collects data from hospital registries accredited by the Commission on Cancer. CONCLUSIONS: In conclusion, this study validated the use of the MIA nomogram in a nationwide oncology outcomes database collected from >1500 Commission-accredited cancer programs in the United States, demonstrating the potential for this nomogram to predict SN positivity and reduce the number of negative SN biopsies.

Heat-induced seizures, premature mortality, and hyperactivity in a novel Scn1a nonsense model for Dravet syndrome.

Dravet syndrome (Dravet) is a severe congenital developmental genetic epilepsy caused by de novo mutations in the SCN1A gene. Nonsense mutations are found in ∼20% of the patients, and the R613X mutation was identified in multiple patients. Here we characterized the epileptic and non-epileptic phenotypes of a novel preclinical Dravet mouse model harboring the R613X nonsense Scn1a mutation. Scn1aWT/R613X mice, on a mixed C57BL/6J:129S1/SvImJ background, exhibited spontaneous seizures, susceptibility to heat-induced seizures, and premature mortality, recapitulating the core epileptic phenotypes of Dravet. In addition, these mice, available as an open-access model, demonstrated increased locomotor activity in the open-field test, modeling some non-epileptic Dravet-associated phenotypes. Conversely, Scn1aWT/R613X mice, on the pure 129S1/SvImJ background, had a normal life span and were easy to breed. Homozygous Scn1aR613X/R613X mice (pure 129S1/SvImJ background) died before P16. Our molecular analyses of hippocampal and cortical expression demonstrated that the premature stop codon induced by the R613X mutation reduced Scn1a mRNA and NaV1.1 protein levels to ∼50% in heterozygous Scn1aWT/R613X mice (on either genetic background), with marginal expression in homozygous Scn1aR613X/R613X mice. Together, we introduce a novel Dravet model carrying the R613X Scn1a nonsense mutation that can be used to study the molecular and neuronal basis of Dravet, as well as the development of new therapies associated with SCN1A nonsense mutations in Dravet.

Probing the Impact of Prematurity on Segmentation Abilities in the Context of Bilingualism.

Infants born prematurely are at a high risk of developing linguistic deficits. In the current study, we compare how full-term and healthy preterm infants without neuro-sensorial impairments segment words from fluent speech, an ability crucial for lexical acquisition. While early word segmentation abilities have been found in monolingual infants, we test here whether it is also the case for French-dominant bilingual infants with varying non-dominant languages. These bilingual infants were tested on their ability to segment monosyllabic French words from French sentences at 6 months of (postnatal) age, an age at which both full-term and preterm monolinguals are able to segment these words. Our results establish the existence of segmentation skills in these infants, with no significant difference in performance between the two maturation groups. Correlation analyses failed to find effects of gestational age in the preterm group, as well as effects of the language dominance within the bilingual groups. These findings indicate that monosyllabic word segmentation, which has been found to emerge by 4 months in monolingual French-learning infants, is a robust ability acquired at an early age even in the context of bilingualism and prematurity. Future studies should further probe segmentation abilities in more extreme conditions, such as in bilinguals tested in their non-dominant language, in preterm infants with medical issues, or testing the segmentation of more complex word structures.

Monitoring oocyte-based human pluripotency acquisition using synchrotron-based FTIR microspectroscopy reveals specific biomolecular trajectories.

The reprogramming of human somatic cells to induced pluripotent cells (iPSCs) has become a milestone and a paradigm shift in the field of regenerative medicine and human disease modeling including drug testing and genome editing. However, the molecular processes occurring during reprogramming and affecting the pluripotent state acquired remain largely unknown. Of interest, different pluripotent states have been described depending on the reprogramming factors used and the oocyte has emerged as a valuable source of information for candidate factors. The present study investigates the molecular changes occurring in somatic cells during reprogramming with either canonical (OSK) or oocyte-based (AOX15) combinations using synchrotron-radiation Fourier transform infrared (SR FTIR) spectroscopy. The data acquired by SR FTIR indicates different representation and conformation of biological relevant macromolecules (lipids, nucleic acids, carbohydrates and proteins) depending on the reprogramming combination used and at different stages during the reprogramming process. Association analysis based on cells spectra suggest that pluripotency acquisition trajectories converge at late intermediate stages while they diverge at early stages. Our results suggest that OSK and AOX15 reprogramming operates through differential mechanisms affecting nucleic acids reorganization and day 10 comes out as a candidate hinge point to further study the molecular pathways involved in the reprogramming process. This study indicates that SR FTIR approach contribute unpaired information to distinguish pluripotent states and to decipher pluripotency acquisition roadmaps and landmarks that will enable advanced biomedical applications of iPSCs.

Meaningful and experiential learning in a fascial approach in practice education in the degree of physiotherapy: A pilot study at a Spanish University.

BACKGROUND AND INTRODUCTION: A pilot experience of teaching innovation was developed in the masotherapy practice classes of the University of Seville's degree of physiotherapy using an active learning approach. OBJECTIVE: Significant experiential learning-specific teaching strategies were implemented to address learning style diversity and promote dynamic participation, active listening, and the creation of clinical simulation learning environments. METHODS: The strategies implemented included establishing an affective climate in the classroom that would encourage interaction among participants, facilitating the flow of information and the teaching-learning process, considering students' previous ideas, elaborating upon content maps and key questions to guide the teaching-learning process, establishing discussions favoring student brainstorming, using illustrations and videos ("visual thinking"), implementing experimental demonstrations and simulated clinical scenarios, and collaborative activities mediated by information and communication technology. RESULTS: The evaluation, which was developed using a questionnaire (pretest-posttest) that allowed the development of learning ladders and considered the complexity of the generated knowledge, revealed significant advances in student learning. CONCLUSION: The implementation of significant experiential learning-specific teaching strategies is useful for achieving the learning objectives of this subject. Further research is needed to conclude firmly in this regard.

Spanish National Registry of Major Osteoporotic Fractures (REFRA) seen at Fracture Liaison Services (FLS): objectives and quality standards.

REFRA-FLS is a new registry in Spain aimed at identifying individuals over 50 years of age with a fragility fracture. Using this registry, we found hip fracture is the most prevalent fracture. Treatment for osteoporosis was 87.7%, with 65.3% adherence. REFRA-FLS provides fundamental data in the study of fragility fractures. PURPOSE: Fragility fractures are a growing public health concern in modern-aged societies. Fracture Liaison Services (FLS) have been shown to successfully lower rates of secondary fractures. A new registry (REFRA-FLS) has been created to monitor quality indicators of FLS units in Spain and to explore the occurrence and characteristic of fragility fractures identified by these centers. METHODS: We conducted a prospective cohort study based on fragility fractures recorded in the REFRA-FLS registry. Participants were individuals 50 years or above who suffered a low energy fragility fracture identified by the 10 participating FLS units during the study period. The type of FLS unit, the characteristics of the individuals at baseline, along with patient outcomes as quality indicators among those who completed 1 year of follow-up were analyzed. RESULTS: A total of 2965 patients and 3067 fragility fractures were identified, and the most frequent locations were hip (n = 1709, 55.7%) and spine (n = 492, 16.0%). A total of 43 refractures (4.5%) and 46 deaths (4.9%) were observed among 948 individuals in the follow-up analyses. Time from fracture to evaluation was less than 3 months in 76.7% of individuals. Osteoporosis treatment was prescribed in 87.7%, and adherence was 65.3% in Morisky-Green test. CONCLUSION: Our results provide a comprehensive picture of fragility fractures identified in FLS units from Spain. Overall, quality indicators are satisfactory although a much higher use of DXA would be desirable. As the registry grows with the incorporation of new FLS units and longer follow-up, incoming analyses will provide valuable insight.

Quality of Life in Women after Deep Endometriosis Surgery: Comparison with Spanish Standardized Values.

The quality of life (QoL) of women who have been surgically treated for endometriosis may be severely impaired. Therefore, QoL can be a determining factor in the recovery of these patients. The aims of this study were to evaluate if the QoL of women surgically treated for deep endometriosis differs from a healthy age-matched population from Catalonia (Spain) and to analyze the QoL of these women considering concomitant events. This is an observational cross-sectional study, where 112 women (between 18 and 48 years old), with endometriosis treated by surgery at Hospital Universitario La Paz (Madrid, Spain), were enrolled to assess the QoL using the second version of the 12-item short form (SF-12) questionnaire. The QoL in these women were tested against a reference population of healthy women using a standardized one-sample comparison method. In addition, the QoL was compared according to the pathophysiology and type of surgery. In women with endometriosis, the physical health component, but not mental health component, was positively correlated with age (r = 0.19; p-Value = 0.048). In addition, physical (20.3 ± 29.2) and social functions (29.7 ± 38.3) and the overall physical health component (37.8 ± 19.4) were significantly lower than the reference population. On the contrary, the body pain (64.1 ± 41.2), emotional role (62.5 ± 42.2), mental health (54.4 ± 26.0), vitality (59.3 ± 31.2), and the overall mental health component (59.4 ± 26.6) had significantly higher scores than the reference. The anatomical compartment of endometriosis, reintervention, bowel nodule resection, and fertility preservation did not show statistical differences in QoL. Women with deep endometriosis had worse physical and social functions, and the overall physical health, compared to the norm in Spanish women. Bodily pain, emotional role, vitality, and the overall mental health improved. These areas could be considered protective factors in this disease. Considering the importance of QoL in adjustments in mental and physical health, it would be necessary to improve these areas of QoL in women surgically treated for deep endometriosis.

Evolution of Type D Personality Traits After Cochlear Implantation in Severely Hearing Impaired Adults 55 Years and Older: An Exploratory Prospective, Longitudinal, Controlled, Multicenter Study.

PURPOSE: To study the evolution of type D personality traits in older adults after cochlear implantation compared with a control group of severely hearing impaired older adults who did not receive a cochlear implant (CI). The influence of COVID-19 on this evolution was also explored. Type D personality combines a high degree of negative affectivity (NA) and social inhibition (SI). METHODS: In this prospective, longitudinal, controlled multicenter exploratory study, 76 older CI users and 21 severely hearing impaired controls without CI were included. The CI group and the control group did not differ significantly regarding age, formal education, residual hearing, Type D Scale-14 (DS14) total score, NA, and SI at baseline. Type D personality traits were assessed with the DS14 at baseline (T0) and 14 months later (T14). RESULTS: Type D personality traits differed significantly over time between the CI group and the control group (p < 0.001). In the CI group, the DS14 total score (mean delta T = -6.63; p < 0.001), NA (mean delta T = -3.26; p < 0.001), and SI (mean delta T = -3.37; p < 0.001) improved significantly over time (delta T = T14-T0), whereas no significant difference was found in the control group. Significantly fewer subjects were categorized as type D personalities in the CI group (delta T = -12; p = 0.023) at T14, whereas no significant change was found in the control group (delta T = 3; p = 0.250). COVID-19 did not influence the evolution of type D personality traits significantly in the CI group. CONCLUSION: Cochlear implantation has a positive effect on type D personality traits in older adults with a severe-to-profound hearing impairment.

The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis.

INTRODUCTION: Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and neurodevelopmental delay. Despite available antiseizure medications (ASMs), there is a need for new therapeutic options with greater efficacy in reducing seizure frequency and with adequate safety and tolerability profiles. Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. Fenfluramine decreases seizure frequency, prolongs periods of seizure freedom potentially helping to reduce risk of Sudden Unexpected Death in Epilepsy (SUDEP) and improves patient cognitive abilities positively impacting on patients' Quality of Life (QoL). Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. The aim of this study was to determine the relative value contribution of fenfluramine for the treatment of DS in Spain using MCDA. METHOD: A literature review was performed to populate an adapted a MCDA framework for orphan-drug evaluation in Spain. A panel of ten Spanish experts, including neurologists, hospital pharmacists, patient representatives and decision-makers, scored four comparative evidence matrices. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Dravet syndrome is considered a severe, rare disease with significant unmet needs. Fenfluramine is perceived to have a higher efficacy profile than all available alternatives, with a better safety profile than stiripentol and topiramate and to provide improved QoL versus studied alternatives. Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam. Participants perceived that fenfluramine could lead to indirect costs savings compared to available alternatives due to its efficacy in controlling seizures. Overall, fenfluramine's therapeutic impact on patients with DS is considered high and supported by high-quality evidence. CONCLUSIONS: Based on reflective MCDA, fenfluramine is considered to add greater benefit in terms of efficacy, safety and QoL when compared with available ASMs.

Guidance on Dravet syndrome from infant to adult care: Road map for treatment planning in Europe.

Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug-resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up-to-date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families.

Understanding menstrual blood-derived stromal/stem cells: Definition and properties. Are we rushing into their therapeutic applications?

Cells with mesenchymal stem cell properties have been identified in menstrual blood and termed menstrual blood-derived stem/stromal cells (MenSCs). MenSCs have been proposed as ideal candidates for cell-based therapy in regenerative medicine and immune-related diseases. However, MenSCs identity has been loosely defined so far and there is controversy regarding their cell markers and differentiation potential. In this review, we outline the origin of MenSCs in the context of regenerating human endometrium, with attention to endometrial eMSCs as reference cells to understand MenSCs. We summarize the cell identity markers analyzed and the immunomodulatory and reparative properties reported. We also address the recent use of MenSCs in cell reprogramming. The main goal of this review is to contribute to the understanding of the identity and properties of MenSCs as well as to identify potential caveats and new venues that deserve to be explored to strengthen their potential applications.

Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies.

With an expanding elderly population, an increasing number of older adults will experience spinal cord injury (SCI) and might be candidates for cell-based therapies, yet there is a paucity of research in this age group. The objective of the present study was to analyze how aged rats tolerate behavioral testing, surgical procedures, post-operative complications, intra-spinal cell transplantation and immunosuppression, and to examine the effectiveness of human iPSC-derived Neural Progenitor Cells (IMR90-hiPSC-NPCs) in a model of SCI. We performed behavioral tests in rats before and after inducing cervical hemi-contusions at C4 level with a fourth-generation Ohio State University Injury Device. Four weeks later, we injected IMR90-hiPSC-NPCs in animals that were immunosuppressed by daily cyclosporine injection. Four weeks after injection we analyzed locomotor behavior and mortality, and histologically assessed the survival of transplanted human NPCs. As rats aged, their success at completing behavioral tests decreased. In addition, we observed high mortality rates during behavioral training (41.2%), after cervical injury (63.2%) and after cell injection (50%). Histological analysis revealed that injected cells survived and remained at and around the grafted site and did not cause tumors. No locomotor improvement was observed in animals four weeks after IMR90-hiPSC-NPC transplantation. Our results show that elderly rats are highly vulnerable to interventions, and thus large groups of animals must be initially established to study the potential efficacy of cell-based therapies in age-related chronic myelopathies.

Literacy, power, and affective (dis)encounter: An ethnographic study on a low-income community in Spain.

In areas of social exclusion, there are greater risks of facing discrimination at school. The teaching-learning processes may contribute toward the perpetuation of this inequality. This research analyzes a literacy event that takes place in a low-income school in Southern Spain. The new literacy studies have come to examine how power relationships and affective bonds work in such literacy practices. An ethnographic method was followed to facilitate a deeper understanding of multimodal literacy. Further, a social semiotics multimodal approach was adopted to analyze the meaning-making social process that takes place in the classroom. The participants comprised two teachers and 17 children, whose ages range from 5 to 7 years. Data were collected in the form of reports, audio recordings, video recordings, and photographs over a two-years period. The results obtained have revealed that the children have been taught writing and reading through a dominant orthodox model that fails to consider the community's and families' cultural capitals. They also show that the literacy process does not grant any affective quality. Neither is there an authentic dialogic space created between the school and the community. This lack of dialogue generates an inequality in the actual acquisition of comprehensive reading and writing skills at school, with instances of groups exclusion, owing to the anti-hegemonic practices of knowledge acquisition.