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Despite the high efficiency of current SARS-CoV-2 mRNA vaccines in reducing COVID-19 morbidity and mortality, waning immunity and the emergence of resistant variants underscore the need for novel vaccination strategies. This study explores a heterologous mRNA/Modified Vaccinia virus Ankara (MVA) prime/boost regimen employing a trimeric form of the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein compared to a homologous MVA/MVA regimen. In C57BL/6 mice, the RBD was delivered during priming via an mRNA vector encapsulated in nanoemulsions (NE) or lipid nanoparticles (LNP), followed by a booster with a replication-deficient MVA-based recombinant virus (MVA-RBD). This heterologous mRNA/MVA regimen elicited strong anti-RBD binding and neutralizing antibodies (BAbs and NAbs) against both the ancestral SARS-CoV-2 strain and different variants of concern (VoCs). Additionally, this protocol induced robust and polyfunctional RBD-specific CD4 and CD8 T cell responses, particularly in animals primed with mLNP-RBD. In K18-hACE2 transgenic mice, the LNP-RBD/MVA combination provided complete protection from morbidity and mortality following a live SARS-CoV-2 challenge compared with the partial protection observed with mNE-RBD/MVA or MVA/MVA regimens. Although the mNE-RBD/MVA regimen only protects half of the animals, it was able to induce antibodies with Fc-mediated effector functions besides NAbs. Moreover, viral replication and viral load in the respiratory tract were markedly reduced and decreased pro-inflammatory cytokine levels were observed. These results support the efficacy of heterologous mRNA/MVA vaccine combinations over homologous MVA/MVA regimen, using alternative nanocarriers that circumvent intellectual property restrictions of current mRNA vaccine formulations.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Ratones Endogámicos C57BL , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Virus Vaccinia , Animales , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Ratones , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , COVID-19/prevención & control , COVID-19/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Neutralizantes/inmunología , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Humanos , Femenino , Nanopartículas/administración & dosificación , Vacunación , Vacunas de ARNm/administración & dosificación , Ratones Transgénicos , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Linfocitos T CD8-positivos/inmunología , Enzima Convertidora de Angiotensina 2/inmunología , Enzima Convertidora de Angiotensina 2/genética , LiposomasRESUMEN
BACKGROUND: NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated. OBJECTIVES: The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD. METHODS: This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers. RESULTS: Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging. CONCLUSION: This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.
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Hipotiroidismo Congénito , Factor Nuclear Tiroideo 1 , Humanos , Recién Nacido , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/diagnóstico , Hipotiroidismo Congénito/sangre , Tamizaje Neonatal/métodos , Pruebas de Función de la Tiroides , Glándula Tiroides/metabolismo , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/patología , Factor Nuclear Tiroideo 1/genética , Factor Nuclear Tiroideo 1/metabolismo , Tirotropina/sangreRESUMEN
Objectives: The association between anti-Ro/SSA antibodies and the appearance of cardiac rhythm disorders in adults is discussed. We aim to study this relationship, together with active treatments and comorbidities, and its impact on daily clinical practice in adults with systemic autoimmune diseases (SADs). Methods: This cross-sectional single-center study was conducted in a tertiary hospital between January 2021 and March 2022. A sample of adult patients followed up in the SAD Unit with a diagnosis of a SAD and previously tested for anti-Ro/SSA and anti-La/SSB were recruited. All of them underwent a 12-lead electrocardiogram. Results: 167 patients were included. 90 (53.9%) were positive for anti-Ro60, 101 (60.5%) for anti-Ro52, and 45 (26.9%) for anti-La/SSB; 52 (31.3%) were triple-negative. 84% were women, and the mean age was 59 years (standard deviation 12.8). The most common SAD was primary Sjögren's syndrome (34.8%), followed by systemic lupus erythematosus (24.6%) and rheumatoid arthritis (22.8%). A statistically significant relationship was found between anti-Ro52 positivity and cardiac rhythm disorders (relative risk = 2.007 [1.197-3.366]), specifically QTc prolongation (relative risk = 4.248 [1.553-11.615]). Multivariate regressions showed a significant association, with diabetes mellitus being the most related comorbidity. The association between anti-Ro52 antibodies and atrioventricular conduction disorders was not significant. Conclusions: The presence of anti-Ro52 antibodies in adult patients with SADs is associated with an increased risk of QTc prolongation. Electrocardiographic screening of patients with SAD, anti-Ro52 antibodies, and other risk factors, like diabetes mellitus or QT-prolonging drugs, seems advisable. Those with baseline electrocardiogram abnormalities or additional risk factors should undergo electrocardiographic monitoring.
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BACKGROUND: Although malnutrition is frequently observed in patients with heart failure (HF), this diagnosis should be performed carefully since HF itself is associated with increased inflammatory activity, which affects body weight, functionality, and some nutritional parameters; thus, its isolated interpretation can erroneously identify surrogate markers of severity as markers of malnutrition. In this context, we aimed to evaluate the prevalence of malnutrition using different classification systems and perform a comprehensive nutritional evaluation to determine the reliability of different diagnostic techniques. PATIENTS AND METHODS: Eighty-three patients with a recent hospital admission due to HF were evaluated. GLIM diagnosis criteria and subjective global assessment (SGA) were performed; a comprehensive anthropometric, functional, and biochemical nutritional evaluation was performed, in which bioelectrical impedance analysis (BIA), nutritional ultrasound, and dual-energy X-ray absorptiometry (DXA) were performed. Additionally, mortality and additional admissions due to HF were determined after a mean follow up of 18 months. RESULTS: Malnutrition according to the GLIM criteria (54%) accurately distinguished patients with impaired functionality, lower lean mass, skeletal mass index, and appendicular muscle mass (BIA), as well as lower trunk fat mass, trunk lean mass, fat-free mass (DXA), and decreased albumin and increased C-reactive protein serum levels. According to SGA, there were significant changes in body composition parameters determined by BIA, muscle ultrasound, and functional tests between well-nourished patients and patients with risk of malnutrition (53.7%) or who had malnutrition (7.1%), but not when the last two groups were compared. BIA and DXA showed strong correlations when evaluating muscle and fat mass in HF patients, but correlations with nutritional ultrasound were limited, as well as functional tests. A multivariate analysis showed that no significant association was observed between body composition and mortality, but preperitoneal fat was associated with an increased risk of new hospital admissions (OR: 0.73). CONCLUSIONS: GLIM criteria identified a lower percentage of patients with HF and malnutrition compared with SGA; thus, SGA could have a role in preventing malnutrition in HF patients. Nutritional evaluation with BIA and DXA in patients with HF showed reliable results of body composition parameters in HF, and both help with the diagnosis of malnutrition according to the GLIM or SGA criteria and could provide complementary information in some specific cases.
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Absorciometría de Fotón , Composición Corporal , Impedancia Eléctrica , Insuficiencia Cardíaca , Desnutrición , Evaluación Nutricional , Estado Nutricional , Ultrasonografía , Humanos , Desnutrición/diagnóstico , Masculino , Femenino , Anciano , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/fisiopatología , Ultrasonografía/métodos , Persona de Mediana Edad , Anciano de 80 o más Años , Reproducibilidad de los Resultados , PrevalenciaRESUMEN
The widespread presence of arsenic (As) and fluoride (F-) in groundwater poses substantial risks to human health on a global scale. These elements have been identified as the most prevalent geogenic contaminants in groundwater in northern Mexico. Consequently, this study aimed to evaluate the human health and ecological risks associated with the content of As and F- in the Meoqui-Delicias aquifer, which is in one of Mexico's most emblematic irrigation districts. Concentrations of As and F- were measured in 38 groundwater samples using ICP-MS and ion chromatography, respectively. Overall, these elements showed a similar trend across the aquifer, revealing a positive correlation between them and pH. The concentration of As and F- in the groundwater ranged from 5.3 µg/L to 303 µg/L and from 0.5 mg/L to 8.8 mg/L, respectively. Additionally, the levels of As and F- surpassed the established national standards for safe drinking water in 92% and 97% of samples, respectively. Given that groundwater is used for both agricultural purposes and human activities, this study also assessed the associated human health and ecological risks posed by these elements using Monte Carlo simulation and Species Sensitivity Distribution. The findings disclosed a significant noncarcinogenic health risk associated with exposure to As and F-, as well as an unacceptable carcinogenic health risk to As through water consumption for both adults and children. Furthermore, a high ecological risk to aquatic species was identified for F- and high to medium risks for As in the sampling sites. Therefore, the findings in this study provide valuable information for Mexican authorities and international organizations (e.g., WHO) about the adverse effects that any exposure without treatment to groundwater from this region represents for human health.
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Arsénico , Monitoreo del Ambiente , Fluoruros , Agua Subterránea , Método de Montecarlo , Contaminantes Químicos del Agua , Agua Subterránea/química , Fluoruros/análisis , Contaminantes Químicos del Agua/análisis , Arsénico/análisis , México , Humanos , Medición de Riesgo , Agua Potable/químicaRESUMEN
Buddleja cordata cell suspension cultures could be used as a tool for investigating the capabilities of this species to tolerate heavy metals (HMs) and for assessing the effects of HMs on the accumulation of phenolic compounds in this species. It grows in a wide range of habitats in Mexico, including ultramafic soils, and mobilizes some HMs in the soil. The mobilization of these HMs has been associated with phenolic substances. In addition, this species is used in Mexican traditional medicine. In the present study, a B. cordata cell suspension culture was grown for 18 days in a culture medium enriched with Cu (0.03-0.25 mM), Fe (0.25-1.5 mM), Mn (0.5-3.0 mM), or Zn (0.5-2.0 mM) to determine the effects of these HMs on growth and HM accumulation. We also assessed the effects of the HMs on phenolic compound accumulation after 1 and 18 days of HM exposure. Cells were able to grow at almost all tested HM concentrations and accumulated significant amounts of each HM. The highest accumulation levels were as follows: 1160 mg Cu kg-1, 6845 mg Fe kg-1, 3770 mg Mn kg-1, and 6581 mg Zn kg-1. Phenolic compound accumulation was affected by the HM exposure time and corresponded to each HM and its concentration. Future research should analyze whole plants to determine the capabilities of Buddleja cordata to accumulate abnormally high amounts of HM and to evaluate the physiological impact of changes in the accumulation of phenolic compounds.
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OBJECTIVE: To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients. METHODS: Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3). RESULTS: Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p<0.001). SCORE, mSCORE EULAR 2015/2016 and QRISK3 effectively differentiated between low and high CV risk patients, although the cumulative rate of CV events observed over 7.5 years was lower than expected based on the frequency predicted by these risk scales. Additionally, model improvement was observed when combining QRISK3 with any other scale, particularly the combination of QRISK3 and SCORE2, which yielded the lowest Akaike information criterion (411.15) and Bayesian information criterion (420.10), making it the best predictive model. CONCLUSIONS: Risk chart algorithms are very useful for discriminating PsA at low and high CV risk. An integrated model featuring QRISK3 and SCORE2 yielded the optimal synergy of QRISK3's discrimination ability and SCORE2's calibration accuracy.
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Artritis Psoriásica , Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/complicaciones , Estudios Prospectivos , Estudios Retrospectivos , Artritis Psoriásica/complicaciones , Teorema de Bayes , Estudios de Seguimiento , AlgoritmosRESUMEN
BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) recommends an upper limit of 10% for atypia of undetermined significance (AUS). Recent data suggest that this category might be overused when the rate of cases with molecular positive results is low. As a quality metric, the AUS and positive call rates for this facility's cytology laboratory and each cytopathologist (CP) were calculated. METHODS: A retrospective analysis of all thyroid cytology cases in a 4.5-year period was performed. Cases were stratified by TBSRTC, and molecular testing results were collected for indeterminate categories. The AUS rate was calculated for each CP and the laboratory. The molecular positive call rate (PCR) was calculated with and without the addition of currently negative to the positive results obtained from the ThyroSeq report. RESULTS: A total of 7535 cases were classified as nondiagnostic, 7.6%; benign, 69%; AUS, 17.5%; follicular neoplasm/suspicious for follicular neoplasm, 1.4%; suspicious for malignancy, 0.7%; and malignant, 3.8%. The AUS rate for each CP ranged from 9.9% to 36.8%. The overall PCR was 24% (range, 13%-35.6% per CP). When including cases with currently negative results, the PCR increased to 35.5% for the cytology laboratory (range, 13%-42.6% per CP). Comparison analysis indicates a combination of overcalling benign cases and, less frequently, undercalling of higher TBSRTC category cases. CONCLUSIONS: The AUS rate in the context of PCR is a useful metric to assess cytology laboratory and cytopathologists' performance. Continuous feedback on this metric could help improve the overall quality of reporting thyroid cytology.
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Control de Calidad , Neoplasias de la Tiroides , Humanos , Estudios Retrospectivos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/diagnóstico , Biopsia con Aguja Fina/normas , Citodiagnóstico/métodos , Citodiagnóstico/normas , Glándula Tiroides/patología , Nódulo Tiroideo/patología , Nódulo Tiroideo/genética , Nódulo Tiroideo/diagnóstico , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/diagnóstico , CitologíaRESUMEN
OBJECTIVE: To establish the predictive value of the QRESEARCH risk estimator version 3 (QRISK3) algorithm in identifying Spanish patients with ankylosing spondylitis (AS) at high risk of cardiovascular (CV) events and CV mortality. We also sought to determine whether to combine QRISK3 with another CV risk algorithm: the traditional SCORE, the modified SCORE (mSCORE) EULAR 2015/2016 or the SCORE2 may increase the identification of AS patients with high-risk CV disease. METHODS: Information of 684 patients with AS from the Spanish prospective CARdiovascular in ReuMAtology (CARMA) project who at the time of the initial visit had no history of CV events and were followed in rheumatology outpatient clinics of tertiary centers for 7.5 years was reviewed. The risk chart algorithms were retrospectively tested using baseline data. RESULTS: After 4,907 years of follow-up, 33 AS patients had experienced CV events. Linearized rate=6.73 per 1000 person-years (95 % CI: 4.63, 9.44). The four CV risk scales were strongly correlated. QRISK3 correctly discriminated between people with lower and higher CV risk, although the percentage of accumulated events over 7.5 years was clearly lower than expected according to the risk established by QRISK3. Also, mSCORE EULAR 2015/2016 showed the same discrimination ability as SCORE, although the percentage of predicted events was clearly higher than the percentage of actual events. SCORE2 also had a strong discrimination capacity according to CV risk. Combining QRISK3 with any other scale improved the model. This was especially true for the combination of QRISK3 and SCORE2 which achieved the lowest AIC (406.70) and BIC (415.66), so this combination would be the best predictive model. CONCLUSIONS: In patients from the Spanish CARMA project, the four algorithms tested accurately discriminated those AS patients with higher CV risk and those with lower CV risk. Moreover, a model that includes QRISK3 and SCORE2 combined the best discrimination ability of QRISK3 with the best calibration of SCORE2.
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Algoritmos , Enfermedades Cardiovasculares , Espondilitis Anquilosante , Humanos , Masculino , Femenino , Enfermedades Cardiovasculares/epidemiología , Persona de Mediana Edad , Adulto , Medición de Riesgo/métodos , Estudios de Seguimiento , España/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Estudios Retrospectivos , Estudios Prospectivos , Factores de RiesgoRESUMEN
PURPOSE: External validation of existing risk calculators (RC) to assess the individualized risk of detecting prostate cancer (PCa) in prostate biopsies is needed to determine their clinical usefulness. The objective was to externally validate the Rotterdam Prostate Cancer RCs 3 and 4 (RPCRC-3/4) and that incorporating PHI (RPCRC-PHI) in a contemporary Spanish cohort. METHODS: Multicenter prospective study that included patients suspicious of harboring PCa. Men who attended the urology consultation were tested for PHI before prostate biopsy. To evaluate the performance of the prediction models: discrimination (receiver operating characteristic (ROC) curves), calibration and net benefit [decision curve analysis (DCA)] were calculated. These analyses were carried out for detection of any PCa and clinically significant (cs)PCa, defined as ISUP grade ≥ 2. RESULTS: Among the 559 men included, 337 (60.28%) and 194 (34.7%) were diagnosed of PCa and csPCa, respectively. RPCRC-PHI had the best discrimination ability for detection of PCa and csPCa with AUCs of 0.85 (95%CI 0.82-0.88) and 0.82 (95%CI 0.78-0.85), respectively. Calibration plots showed that RPCRC-3/4 underestimates the risk of detecting PCa showing the need for recalibration. In DCA, RPCRC-PHI shows the highest net benefit compared to biopsy all men. CONCLUSIONS: The RPCRC-PHI performed properly in a contemporary clinical setting, especially for prediction of csPCa.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Estudios Prospectivos , Clasificación del Tumor , Medición de Riesgo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Biopsia , Toma de DecisionesRESUMEN
Nb-based catalysts supported on porous silica with different textural properties have been synthesized, characterized, and tested in the one-pot reaction of furfural to obtain valuable chemicals. The catalytic results reveal that the presence of fluoride in the synthesis, which limits the growing of the porous silica, limits diffusional problems of the porous silica, obtaining higher conversion values at shorter reaction times. On the other hand, the incorporation of NbOx species in the porous silica provides Lewis acid sites and a small proportion of Brönsted acid sites, in such a way that the main products are alkyl furfuryl ethers, which can be used as fuel additives.
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Furaldehído , Niobio , Furaldehído/química , Hidrogenación , Dióxido de Silicio/química , CatálisisRESUMEN
Vaccines based on mRNA technology have revolutionized the field. In fact, lipid nanoparticles (LNP) formulated with mRNA are the preferential vaccine platform used in the fight against SARS-CoV-2 infection, with wider application against other diseases. The high demand and property right protection of the most potent cationic/ionizable lipids used for LNP formulation of COVID-19 mRNA vaccines have promoted the design of alternative nanocarriers for nucleic acid delivery. In this study we have evaluated the immunogenicity and efficacy of different rationally designed lipid and polymeric-based nanoparticle prototypes against SARS-CoV-2 infection. An mRNA coding for a trimeric soluble form of the receptor binding domain (RBD) of the spike (S) protein from SARS-CoV-2 was encapsulated using different components to form nanoemulsions (NE), nanocapsules (NC) and lipid nanoparticles (LNP). The toxicity and biological activity of these prototypes were evaluated in cultured cells after transfection and in mice following homologous prime/boost immunization. Our findings reveal good levels of RBD protein expression with most of the formulations. In C57BL/6 mice immunized intramuscularly with two doses of formulated RBD-mRNA, the modified lipid nanoparticle (mLNP) and the classical lipid nanoparticle (LNP-1) were the most effective delivery nanocarriers at inducing binding and neutralizing antibodies against SARS-CoV-2. Both prototypes fully protected susceptible K18-hACE2 transgenic mice from morbidity and mortality following a SARS-CoV-2 challenge. These results highlight that modulation of mRNAs immunogenicity can be achieved by using alternative nanocarriers and support further assessment of mLNP and LNP-1 prototypes as delivery vehicles for mRNA vaccines.
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The Interferon Stimulated Gene 15 (ISG15), a unique Ubiquitin-like (Ubl) modifier exclusive to vertebrates, plays a crucial role in the immune system. Primarily induced by interferon (IFN) type I, ISG15 functions through diverse mechanisms: (i) covalent protein modification (ISGylation); (ii) non-covalent intracellular action; and (iii) exerting extracellular cytokine activity. These various roles highlight its versatility in influencing numerous cellular pathways, encompassing DNA damage response, autophagy, antiviral response, and cancer-related processes, among others. The well-established antiviral effects of ISGylation contrast with its intriguing dual role in cancer, exhibiting both suppressive and promoting effects depending on the tumour type. The multifaceted functions of ISG15 extend beyond intracellular processes to extracellular cytokine signalling, influencing immune response, chemotaxis, and anti-tumour effects. Moreover, ISG15 emerges as a promising adjuvant in vaccine development, enhancing immune responses against viral antigens and demonstrating efficacy in cancer models. As a therapeutic target in cancer treatment, ISG15 exhibits a double-edged nature, promoting or suppressing oncogenesis depending on the tumour context. This review aims to contribute to future studies exploring the role of ISG15 in immune modulation and cancer therapy, potentially paving the way for the development of novel therapeutic interventions, vaccine development, and precision medicine.
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El sinhogarismo supone un problema sociosanitario emergente relacionado principalmente con el desarrollo de patologías mentales y con diversas adicciones. La película El solista, dirigida por Joe Wright, representa un instrumento de gran utilidad para entender esta cuestión dado que revela el caso real de un músico que padece esquizofrenia y que vive en la calle, el señor Nathaniel Anthony Ayers Junior. Al mismo tiempo, la película permite analizar las circunstancias que le llevaron a esa situación y los factores que influyen en el proceso de inclusión social. Por lo tanto, se defiende el empleo de esta película como recurso pedagógico para la formación de estudiantes y profesionales.(AU)
Homelessness is an emerging socio-sanitary problem principally related to the development of mental pathologies and various addictions. The film The Soloist, directed by Joe Wright, represents a very useful resource to understand this issue since it reveals the real case of a musician who suffers from schizophrenia and who is homeless, Mr. Nathaniel Anthony Ayers Junior. At the same time, the film allows to analyze the circumstances that led him to this situation and the factors involved in the social inclusion process. Hence, the use of this film as a pedagogical resource for the training of students and professionals is defended.(AU)
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Humanos , Películas Cinematográficas , Medicina , Aislamiento Social , Esquizofrenia , Respeto , Medicina en las Artes , Salud Mental , Resiliencia PsicológicaRESUMEN
Introduction: The generation of an HIV-1 vaccine able to induce long-lasting protective immunity remains a main challenge. Here, we aimed to modify next-generation soluble, prefusion-stabilized, close-to-native, glycan-engineered clade C gp140 envelope (Env) trimers (sC23v4 KIKO and ConCv5 KIKO) for optimal display on the cell surface following homologous or heterologous vector delivery. Methods: A combination of the following modifications scored best regarding the preservation of closed, native-like Env trimer conformation and antigenicity when using a panel of selected broadly neutralizing (bnAb) and non-neutralizing (nnAb) monoclonal antibodies for flow cytometry: i) replacing the natural cleavage site with a native flexible linker and introducing a single amino acid substitution to prevent CD4 binding (*), ii) fusing a heterologous VSV-G-derived transmembrane moiety to the gp140 C-terminus, and iii) deleting six residues proximal to the membrane. Results: When delivering membrane-tethered sC23v4 KIKO* and ConCv5 KIKO* via DNA, VSV-GP, and NYVAC vectors, the two native-like Env trimers provide differential antigenicity profiles. Whereas such patterns were largely consistent among the different vectors for either Env trimer, the membrane-tethered ConCv5 KIKO* trimer adopted a more closed and native-like structure than sC23v4 KIKO*. In immunized mice, VSV-GP and NYVAC vectors expressing the membrane-tethered ConCv5 KIKO* administered in prime/boost combination were the most effective regimens for the priming of Env-specific CD4 T cells among all tested combinations. The subsequent booster administration of trimeric ConCv5 KIKO* Env protein preserved the T cell activation levels between groups. The evaluation of the HIV-1-specific humoral responses induced in the different immunization groups after protein boosts showed that the various prime/boost protocols elicited broad and potent antibody responses, preferentially of a Th1-associated IgG2a subclass, and that the obtained antibody levels remained high at the memory phase. Discussion: In summary, we provide a feasible strategy to display multiple copies of native-like Env trimers on the cell surface, which translates into efficient priming of sustained CD4+ T cell responses after vector delivery as well as broad, potent, and sustained antibody responses following booster immunizations with the homologous, prefusion-stabilized, close-to-native ConCv5 KIKO* gp140 Env trimer.
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Vacunas contra el SIDA , Seropositividad para VIH , VIH-1 , Animales , Ratones , Anticuerpos Anti-VIH , VIH-1/genética , Proteínas de la Membrana , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Anticuerpos Neutralizantes , Vacunas contra el SIDA/genética , InmunidadRESUMEN
Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches were developed for single cell analysis but are often biased, manually curated and yet unproven in spatial omics. Here we apply a stemness model for assessing oncogenic states to single cell and spatial omic cancer datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic features from non-transformed stem cells to identify dedifferentiated cell states in tumors. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. This machine learning model identified stem-like cell populations not identified in single cell or spatial transcriptomic analysis using existing methods. For the first time, we demonstrate the application of a ML tool across five emerging spatial transcriptomic and proteomic technologies to identify oncogenic stem-like cell types in the tumor microenvironment.
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Proteómica , Transcriptoma , Modelos Logísticos , Perfilación de la Expresión Génica , Aprendizaje AutomáticoRESUMEN
Background: Atrial fibrillation (AF), which is associated with cryptogenic stroke, is the most common sustained arrhythmia in the general population. Because AF is asymptomatic and intermittent, its detection rate increases with the duration of monitoring. The objective of this study is to review the available evidence on the safety, efficacy, effectiveness and cost-effectiveness of AF diagnosis by prolonged monitoring with an implantable Holter monitor in adult patients with idiopathic or cryptogenic stroke of suspected cardioembolic origin, compared to conventional monitoring. Methods: Two independent reviewers performed a systematic review of the literature, identifying relevant studies through a structured search of Medline (Ovid), EMBASE, Web of Science and Cochrane Library and the databases of national and international health technology assessment agencies. The quality of the included studies was assessed with AGREE-II, AMSTAR-2 and CHEC. GRADE criteria were used to summarise the evidence. Results: Four of the 211 papers identified were included: 1 clinical practice guideline, 2 systematic reviews, and 1 economic evaluation. The quality of the evidence reviewed was low. An implantable Holter monitor might be more effective in detecting AF than conventional monitoring. Serious adverse events were similar in both groups. The economic evaluation suggests that the technology is cost-effective. Conclusions: The available evidence suggests the diagnostic superiority of the implantable Holter monitor over the traditional Holter monitor. Due to the low quality of the evidence, further and higher quality studies on these technologies are needed before solid conclusions can be drawn.
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BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.