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INTRODUCTION: The occiput-posterior (OP) fetal position is the most frequent form of labor dystocia. This position has been associated with delaying the second stage of labor and adverse outcomes. OBJECTIVES: This project aimed to improve the quality of intrapartum care provided by midwives for OP fetal positions during the second stage of labor. METHODS: This best practice implementation project was conducted at the Río Hortega University Hospital in Valladolid, Spain. The project followed the JBI Evidence Implementation Framework, which is based on an audit, feedback, and re-audit process. Current practices were compared against best practices in a baseline audit using 13 audit criteria. Barriers to compliance with best practices were identified and improvement strategies were implemented. An initial follow-up audit was carried out after 4 months to avoid secondary bias. After another 4 months, a second follow-up audit was conducted. Data were collected and compared using the JBI Practical Application of Clinical Evidence System (JBI PACES). RESULTS: The results revealed an improvement in all structure criteria (1-3), five of the process criteria (4-6, 8, 10), and all results criteria (11-13). One process criterion (8) reached maximum compliance in all audits. A key finding was the inadequate recording of upright positions (criterion 7) and the interpretation of cardiotocography (criterion 9). CONCLUSIONS: Evidence-based interventions for managing OP labor improved the quality of care and underlined the importance of ongoing training for midwives. Additional studies are required on positions and fetal monitoring during labor. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A279.
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WEMAC is a unique open multi-modal dataset that comprises physiological, speech, and self-reported emotional data records of 100 women, targeting Gender-based Violence detection. Emotions were elicited through visualizing a validated video set using an immersive virtual reality headset. The physiological signals captured during the experiment include blood volume pulse, galvanic skin response, and skin temperature. The speech was acquired right after the stimuli visualization to capture the final traces of the perceived emotion. Subjects were asked to annotate among 12 categorical emotions, several dimensional emotions with a modified version of the Self-Assessment Manikin, and liking and familiarity labels. The technical validation proves that all the targeted categorical emotions show a strong statistically significant positive correlation with their corresponding reported ones. That means that the videos elicit the desired emotions in the users in most cases. Specifically, a negative correlation is found when comparing fear and not-fear emotions, indicating that this is a well-portrayed emotional dimension, a specific, though not exclusive, purpose of WEMAC towards detecting gender violence.
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Emociones , Humanos , Femenino , Violencia de Género , Respuesta Galvánica de la Piel , AdultoRESUMEN
Staphylococcus hyicus is a significant pathogen in swine, primarily causing exudative epidermitis. Addressing S. hyicus infections requires both the characterization of virulence and antimicrobial resistance (AMR) in farm-recovered isolates. This study aimed to characterize the virulence, AMR, and biofilm formation of S. hyicus isolates from Spanish swine farms. A total of 49 isolates were analyzed, originating from animals with cutaneous, reproductive, and systemic clinical signs. Half of the isolates (49.0%) were positive for at least one virulence factor (VF) gene, with SHETA being the most frequent (28.6%). A high frequency of multidrug resistant (MDR) isolates was observed (83.7%), with significant resistance to commonly used antimicrobials, including lincosamides (83.7%), pleuromutilins (81.6%), penicillins (75.5%), and tetracyclines (73.5%). All isolates exhibited robust in vitro biofilm formation capacity (DC = 15.6 ± 7.0). Significant associations were found between VFs, biofilm formation, and AMR patterns, highlighting the link between the resistance to lincosamides and pleuromutilins (p < 0.001; Φ = 0.57) and macrolides (p < 0.001; Φ = 0.48), and the association of AMR with the ExhC and ExhD VF genes. These findings underscore the need for targeted diagnostics to improve management and therapeutic strategies to mitigate the impact of S. hyicus on swine production.
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Aim: This first-in-human study evaluated safety and efficacy of CD40 agonist MEDI5083 with durvalumab in patients with advanced solid tumors.Methods: Patients received MEDI5083 (3-7.5 mg subcutaneously every 2 weeks × 4 doses) and durvalumab (1500 mg every 4 weeks) either sequentially (N = 29) or concurrently (N = 9). Primary end point was safety; secondary end points included efficacy.Results: Thirty-eight patients received treatment. Most common adverse events (AEs) were injection-site reaction (ISR; sequential: 86%; concurrent: 100%), fatigue (41%; 33%), nausea (20.7%; 55.6%) and decreased appetite (24.1%; 33.3%). Nine patients had MEDI5083-related grade ≥3 AEs with ISR being the most common. Two patients experienced dose limiting toxicities (ISR). One death occurred due to a MEDI5083-related AE. MEDI5083 maximum tolerated dose was 5 mg. Objective response rate was 2.8% (1 partial response and 11 stable disease).Conclusion: MEDI5083 toxicity profile limits its further development.
MEDI5083 is a molecule that was designed as a potential anticancer medication. Once inside the body, MEDI5083 connects to specific proteins found on the surface of immune cells and cancer cells. It can boost the immune system of the body in multiple ways to help kill cancer cells. In this clinical study, 38 patients with various types of cancers (bladder, breast, colon, head and neck, kidney, lung, and pancreas) were treated with MEDI5083 together with another anticancer medicine called durvalumab. MEDI5083 was given to patients as an injection under the skin once every 2 weeks. Durvalumab was given to patients as an infusion once every 4 weeks. The study monitored whether treatment caused unwanted side effects and whether MEDI5083 was able to shrink the size of tumors.A total of 34 of 38 patients who received treatment experienced unwanted reactions at the site of MEDI5083 treatment injection. These symptoms were long lasting and did not go away with an applied steroid treatment. A total of 5 of 38 patients experienced extreme tiredness and 4 of 38 patients experienced fever. Of 38 patients enrolled, 6 discontinued treatment because of a MEDI5083-related side effect. Only one patient had a decrease in the size of their cancer mass with treatment. Because of safety concerns, this study was not completed. The injectable form of MEDI5083 is not being further tested in patients with cancer.
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Anticuerpos Monoclonales , Antígenos CD40 , Neoplasias , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Antígenos CD40/agonistas , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dosis Máxima Tolerada , Resultado del TratamientoRESUMEN
mRNA-4157 (V940) is an individualized neoantigen therapy targeting up to 34 patient-specific tumor neoantigens to induce T-cell responses and potentiate antitumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T-cell responses to neoantigens from the first-in-human, phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1-mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1-mg mRNA-4157 + 200-mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event; there were no grade 4/5 adverse events or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA individualized neoantigen therapy approach in oncology. Significance: The safety and immunogenicity results from this phase 1 study of mRNA-4157 as adjuvant monotherapy or combination therapy with pembrolizumab show generation of de novo and enhancement of existing neoantigen-specific T-cell responses and provide mechanistic proof of concept to support further development of mRNA-4157 for patients with resected solid tumors. See related commentary by Berraondo et al., p. 2021.
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Anticuerpos Monoclonales Humanizados , Antígenos de Neoplasias , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Melanoma , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos de Neoplasias/inmunología , Persona de Mediana Edad , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Masculino , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Linfocitos T/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inmunología , Medicina de Precisión/métodos , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
Glaesserella (Haemophilus) parasuis, the causative agent of Glässer's disease, is present in most pig farms as an early colonizer of the upper respiratory tract. It exhibits remarkable variability in virulence and antimicrobial resistance (AMR), with virulent strains capable of inducing respiratory or systemic disease. This study aimed to characterize the virulence and the AMR profiles in 65 G. parasuis isolates recovered from Spanish swine farms. Virulence was assessed using multiplex leader sequence (LS)-PCR targeting vtaA genes, with all isolates identified as clinical (presumed virulent). Pathotyping based on ten pangenome genes revealed the virulent HPS_22970 as the most frequent (83.1%). Diverse pathotype profiles were observed, with 29 unique gene combinations and two isolates carrying only potentially non-virulent pangenome genes. AMR phenotyping showed widespread resistance, with 63.3% classified as multidrug resistant, and high resistance to clindamycin (98.3%) and tylosin (93.3%). A very strong association was found between certain pathotype genes and AMR phenotypes, notably between the virulent HPS_22970 and tetracycline resistance (p < 0.001; Φ = 0.58). This study reveals the wide diversity and complexity of G. parasuis pathogenicity and AMR phenotype, emphasizing the need for the targeted characterization of clinical isolates to ensure appropriate antimicrobial treatments and the implementation of prophylactic measures against virulent strains.
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Sensors used in precision agriculture for the detection of heavy metals in irrigation water are generally expensive and sometimes their deployment and maintenance represent a permanent investment to keep them in operation, leaving a lasting polluting footprint in the environment at the end of their lifespan. This represents an area of opportunity to design new biological devices that can replace part, or all of the sensors currently used. In this article, a novel workflow is proposed to fully carry out the complete process of design, modeling, and simulation of reprogrammable microorganisms in silico. As a proof-of-concept, the workflow has been used to design three whole-cell biosensors for the detection of heavy metals in irrigation water, namely arsenic, mercury and lead. These biosensors are in compliance with the concentration limits established by the World Health Organization (WHO). The proposed workflow allows the design of a wide variety of completely in silico biodevices, which aids in solving problems that cannot be easily addressed with classical computing. The workflow is based on two technologies typical of synthetic biology: the design of synthetic genetic circuits, and in silico synthetic engineering, which allows us to address the design of reprogrammable microorganisms using software and hardware to develop theoretical models. These models enable the behavior prediction of complex biological systems. The output of the workflow is then exported in the form of complete genomes in SBOL, GenBank and FASTA formats, enabling their subsequent in vivo implementation in a laboratory. The present proposal enables professionals in the area of computer science to collaborate in biotechnological processes from a theoretical perspective previously or complementary to a design process carried out directly in the laboratory by molecular biologists. Therefore, key results pertaining to this work include the fully in silico workflow that leads to designs that can be tested in the lab in vitro or in vivo, and a proof-of-concept of how the workflow generates synthetic circuits in the form of three whole-cell heavy metal biosensors that were designed, modeled and simulated using the workflow. The simulations carried out show realistic spatial distributions of biosensors reacting to different concentrations (zero, low and threshold level) of heavy metal presence and at different growth phases (stationary and exponential) that are backed up by the whole design and modeling phases of the workflow.
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Aims: Our aims were to describe the clinical characteristics, adverse clinical events, healthcare resource utilization (HCRU) and costs of patients with major bleeding during direct Factor Xa inhibitor (FXai) use. Methods: This is a retrospective cohort study that included secondary data from computerized health records of seven Spanish Autonomous Communities. Patients with a first major bleeding during treatment with a direct FXai were analyzed during a 3-year period. Results: Of 8972 patients taking a direct FXai, 470 (5.24%) had major bleeding (mean age (SD) 77.93 (9.71) years, 61.06% women). The most frequent indications for using FXais were atrial fibrillation (78.09%) and venous thromboembolism (17.66%). Among those with major bleeding, 88.94% presented with gastrointestinal bleeding, 6.81% intracranial bleeding, 2.13% trauma-related bleeding and 4.26% other major bleeding. Prothrombin complex concentrates were used in 63.19%, followed by transfusion of blood products (20.21%) and Factor VIIa (7.66%). In total, 4.26% of patients died in the hospital due to the first major bleeding. At the study end (after 3-year follow-up), 28.94% of the patients had died, 12.34% had a myocardial infarction and 9.15% an ischemic stroke. At year 3, overall bleeding cost was EUR 5,816,930.5, of which 79.74% accounted for in-hospital costs to treat the bleeding episode. Conclusions: Despite the use of replacement agents being high, major events were common, with a 29% mortality at the end of the follow up, and HCRU and costs were high, evidencing the need for new reversal treatment strategies.
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Globally, the main molecular trials being developed to study the genetic determinants responsible for conferring resistance to bacterial organisms are amplification-based methods, hybridization-based methods, and sequence-based methods. In the specific case of Streptococcus suis, polymerase chain reaction is the only test tuned up until now for detecting resistant clinical isolates to macrolides and/or tetracyclines, the two main groups of antibiotics being ineffective against this human and animal pathogen.
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Antibacterianos , Macrólidos , Reacción en Cadena de la Polimerasa , Macrólidos/farmacología , Reacción en Cadena de la Polimerasa/métodos , Humanos , Antibacterianos/farmacología , Tetraciclina/farmacología , Farmacorresistencia Bacteriana/genética , Animales , ADN Bacteriano/genética , Pruebas de Sensibilidad Microbiana/métodosRESUMEN
Here were described the main three methods being used for analysis of antibiotic susceptibility or resistance of Streptococcus suis clinical isolates to antimicrobial agents: the Kirby-Bauer disk diffusion, the epsilometer test (E test), and the broth microdilution test. In each case, procedures, results, and interpretation are described, as well as their advantages or limitations when proceeds.
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Farmacorresistencia Bacteriana , Pruebas de Sensibilidad Microbiana , Pruebas de Sensibilidad Microbiana/métodos , Humanos , Antibacterianos/farmacología , Streptococcus suis/efectos de los fármacos , Pruebas Antimicrobianas de Difusión por DiscoRESUMEN
Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood.
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Proteínas de Unión al ADN , Proteína Potenciadora del Homólogo Zeste 2 , Mutación , Factores de Transcripción , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Ratones , Factores de Transcripción/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Femenino , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Línea Celular Tumoral , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismoRESUMEN
BACKGROUND: Isavuconazole (ISA) and voriconazole (VORI) are recommended as the first-line treatment for invasive aspergillosis (IA). Despite theoretical advantages of ISA, both triazole agents have not been compared in solid organ transplant recipients. METHODS: We performed a post hoc analysis of 2 retrospective multicenter cohorts of solid organ transplant recipients with invasive fungal disease (the SOTIS [Solid Organ Transplantation and ISavuconazole] and DiasperSOT [DIagnosis of ASPERgillosis in Solid Organ Transplantation] studies). We selected adult patients with proven/probable IA that were treated for ≥48 h with ISA (nâ =â 57) or VORI (nâ =â 77) as first-line therapy, either in monotherapy or combination regimen. The primary outcome was the rate of clinical response at 12 wk from the initiation of therapy. Secondary outcomes comprised 12-wk all-cause and IA-attributable mortality and the rates of treatment-emergent adverse events and premature treatment discontinuation. RESULTS: Both groups were comparable in their demographics and major clinical and treatment-related variables. There were no differences in the rate of 12-wk clinical response between the ISA and VORI groups (59.6% versus 59.7%, respectively; odds ratio [OR], 0.99; 95% confidence interval [CI], 0.49-2.00). This result was confirmed after propensity score adjustment (OR, 0.81; 95% CI, 0.32-2.05) and matching (OR, 0.79; 95% CI, 0.31-2.04). All-cause and IA-attributable mortality were also similar. Patients in the ISA group were less likely to experience treatment-emergent adverse events (17.5% versus 37.7%; P = 0.011) and premature treatment discontinuation (8.8% versus 23.4%; P = 0.027). CONCLUSIONS: Front-line treatment with ISA for posttransplant IA led to similar clinical outcomes than VORI, with better tolerability and higher treatment completion.
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Antifúngicos , Aspergilosis , Nitrilos , Trasplante de Órganos , Piridinas , Triazoles , Voriconazol , Humanos , Antifúngicos/uso terapéutico , Antifúngicos/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Voriconazol/uso terapéutico , Voriconazol/efectos adversos , Nitrilos/uso terapéutico , Nitrilos/efectos adversos , Estudios Retrospectivos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Trasplante de Órganos/efectos adversos , Resultado del Tratamiento , Anciano , Aspergilosis/tratamiento farmacológico , Aspergilosis/mortalidad , Aspergilosis/diagnóstico , Adulto , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/mortalidad , Infecciones Fúngicas Invasoras/diagnóstico , Receptores de TrasplantesRESUMEN
This work is devoted to evaluating the relationship between the oxygen content and catalytic activity in the CO oxidation process of the 6H-type BaFeO3-δ system. Strong evidence is provided about the improvement of catalytic performance with increasing Fe average oxidation state, thus suggesting the involvement of lattice oxygen in the catalytic process. The compositional and structural changes taking place in both the anionic and cationic sublattices of the catalysts during redox cycles have been determined by temperature-resolved neutron diffraction. The obtained results evidence a structural transition from hexagonal (P63/mmc) to orthorhombic (Cmcm) symmetry. This transition is linked to octahedra distortion when the Fe3+ concentration exceeds 40% (δ values higher than 0.2). The topotactical character of the redox process is maintained in the δ range 0 < δ < 0.4. This suggests that the cationic framework is only subjected to slight structural modifications during the oxygen exchange process occurring during the catalytic cycle.
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Lung diseases, including lung cancer, are rising causes of global mortality. Despite novel imaging technologies and the development of biomarker assays, the detection of lung cancer remains a significant challenge. However, the lung communicates directly with the external environment and releases aerosolized droplets during normal tidal respiration, which can be collected, stored and analzsed as exhaled breath condensate (EBC). A few studies have suggested that EBC contains extracellular vesicles (EVs) whose microRNA (miRNA) cargos may be useful for evaluating different lung conditions, but the cellular origin of these EVs remains unknown. In this study, we used nanoparticle tracking, transmission electron microscopy, Western blot analyses and super resolution nanoimaging (ONi) to detect and validate the identity of exhaled EVs (exh-EVs). Using our customizable antibody-purification assay, EV-CATCHER, we initially determined that exh-EVs can be selectively enriched from EBC using antibodies against three tetraspanins (CD9, CD63 and CD81). Using ONi we also revealed that some exh-EVs harbour lung-specific proteins expressed in bronchiolar Clara cells (Clara Cell Secretory Protein [CCSP]) and Alveolar Type II cells (Surfactant protein C [SFTPC]). When conducting miRNA next generation sequencing (NGS) of airway samples collected at five different anatomic levels (i.e., mouth rinse, mouth wash, bronchial brush, bronchoalveolar lavage [BAL] and EBC) from 18 subjects, we determined that miRNA profiles of exh-EVs clustered closely to those of BAL EVs but not to those of other airway samples. When comparing the miRNA profiles of EVs purified from matched BAL and EBC samples with our three tetraspanins EV-CATCHER assay, we captured significant miRNA expression differences associated with smoking, asthma and lung tumor status of our subjects, which were also reproducibly detected in EVs selectively purified with our anti-CCSP/SFTPC EV-CATCHER assay from the same samples, but that confirmed their lung tissue origin. Our findings underscore that enriching exh-EV subpopulations from EBC allows non-invasive sampling of EVs produced by lung tissues.
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Pruebas Respiratorias , Vesículas Extracelulares , Pulmón , MicroARNs , Humanos , MicroARNs/metabolismo , MicroARNs/genética , Vesículas Extracelulares/metabolismo , Pulmón/metabolismo , Pruebas Respiratorias/métodos , Femenino , Masculino , Espiración , Persona de Mediana Edad , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Biomarcadores/metabolismo , AdultoRESUMEN
MEK inhibitors have immunomodulatory activity and potential for synergistic activity when combined with PD-1 inhibitors. We evaluated selumetinib (inhibitor of MEK1/2) plus pembrolizumab (antiâPD-1 antibody) in patients with advanced/metastatic solid tumors. In this phase 1b study, adults with previously treated advanced/metastatic solid tumors received pembrolizumab 200 mg intravenously every 3 weeks plus selumetinib on days 1â14 per 3-week cycle (2 weeks on/1 week off); selumetinib dosing began at 50 mg orally twice daily with escalation in 25 mg increments for ≤ 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. Thirty-two patients were enrolled. Dose escalation was completed up to selumetinib 125 mg twice daily. The target DLT rate of 30% was not reached at any dose level. In the selumetinib 100 mg group, 2/11 patients (18.2%) experienced DLTs (n = 1 grade 3 diarrhea, n = 1 grade 3 fatigue). In the selumetinib 125 mg group, 3/14 (21.4%) experienced DLTs (n = 1 grade 2 retinal detachment, n = 1 grade 3 retinopathy, n = 1 grade 3 stomatitis). Dose-related changes in pharmacokinetic exposures were observed for selumetinib and N-desmethyl selumetinib up to 100 mg (saturation at 125 mg). Two patients achieved partial responses (1 each with selumetinib 75 mg and 125 mg) for an objective response rate of 6%. The study was stopped early because of insufficient efficacy. Although the target DLT rate was not reached at any dose level and no new safety signals were identified, selumetinib plus pembrolizumab had limited antitumor activity in this population. Trial registration: ClinicalTrials.gov , NCT03833427.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bencimidazoles , Neoplasias , Humanos , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Anciano , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Adulto , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Dosis Máxima Tolerada , Relación Dosis-Respuesta a Droga , Anciano de 80 o más AñosRESUMEN
Objective. To analyze the clinical characteristics of patients taking Factor Xa inhibitors (FXai), either direct FXai or enoxaparin (only in active cancer patients), and to estimate the incidence of and risk factors for major bleeding during FXai use. Methods. A retrospective cohort study, which included secondary data from computerized health records of primary care centers and hospitals in seven Spanish Autonomous Communities. Results. 9374 patients were analyzed, with 8972 taking direct FXai and 402 enoxaparin. At baseline, the mean age (SD) was 71.8 (9.4) years, 56.0% were women, 76.3% had hypertension, 33.6% had type 2 diabetes, and 25.5% had heart failure. The most common indication for FXai use was atrial fibrillation (72.3%), followed by venous thromboembolism (22.2%) and non-mechanical cardiac-valve replacement (5.6%). At the end of the follow-up period, the incidence rates of major bleeding overall, gastrointestinal, and intracranial were 10.2, 9.0, and 0.8 per 100 person-years, respectively. The total incidence of fatal major bleeding was 0.5 per 100 person-years. Incidence rates of all bleedings progressively decreased over time, with 62.5% of the first events occurring in the initial three months and reaching 76.8% within six months following initiation of treatment. Only 4.8% of the 1st major bleedings led to death, 2.3% in the case of major gastrointestinal bleeding, and 30.8% after an intracranial bleeding. 65.9% of patients discontinued anticoagulation after experiencing major bleeding. Conclusions. In Spain, patients taking FXai were old and had many comorbidities. Despite incidence rates of major bleeding were high, incidence rates of intracranial and fatal bleedings were low, but more efforts are required due to their relevant clinical impact.
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Background: To assess the anterior scleral thickness (AST), Schlemm's canal diameter (SCD), trabecular meshwork diameter (TMD) and conjunctiva tenon capsule thickness (CTT) in high myopic (HM) subjects and HM subjects with glaucoma (HMG) compared to control eyes. Methods: One hundred and twenty eyes were included, and AST at 0, 1, 2 and 3 mm from the scleral spur, SCD, TMD and CTT were measured. Results: Mean age was 64.2 ± 11.0 years, and the temporal SCD and temporal TMD were significantly longer in the HMG subjects compared to the controls (380.0 ± 62 µm vs. 316.7 ± 72 µm, p = 0.001) and (637.6 ± 113 µm vs. 512.1 ± 97 µm, p = 0.000), respectively. There were no significant differences between the HM and HMG subjects in SCD and TMD (all p > 0.025). Compared to the HM subjects, the temporal AST0 (432.5 ± 79 µm vs. 532.8 ± 99 µm, p = 0.000), temporal AST1 (383.9 ± 64 µm vs. 460.5 ± 80 µm, p = 0.000), temporal AST2 (404.0 ± 68 µm vs. 464.0 ± 88 µm, p = 0.006) and temporal AST3 (403.0 ± 80 µm vs. 458.1 ± 91 µm, p = 0.014) were significantly thinner in the HMG group. No differences were found between the CTT in the three groups (all p > 0.025). Conclusions: Our data indicate a thinner AST in HMG subjects and no differences in SCD and TMD between HM and HMG subjects.
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Purpose: The main aim of our study was to explore the utility of artificial intelligence (AI) in diagnosing autism spectrum disorder (ASD). The study primarily focused on using machine learning (ML) and deep learning (DL) models to detect ASD potential cases by analyzing text inputs, especially from social media platforms like Twitter. This is to overcome the ongoing challenges in ASD diagnosis, such as the requirement for specialized professionals and extensive resources. Timely identification, particularly in children, is essential to provide immediate intervention and support, thereby improving the quality of life for affected individuals. Methods: We employed natural language processing (NLP) techniques along with ML models like decision trees, extreme gradient boosting (XGB), k-nearest neighbors algorithm (KNN), and DL models such as recurrent neural networks (RNN), long short-term memory (LSTM), bidirectional long short-term memory (Bi-LSTM), bidirectional encoder representations from transformers (BERT and BERTweet). We extracted a dataset of 404,627 tweets from Twitter users using the platform's API and classified them based on whether they were written by individuals claiming to have ASD (ASD users) or by those without ASD (non-ASD users). From this dataset, we used a subset of 90,000 tweets (45,000 from each classification group) for the training and testing of these models. Results: The application of our AI models yielded promising results, with the predictive model reaching an accuracy of almost 88% when classifying texts that potentially originated from individuals with ASD. Conclusion: Our research demonstrated the potential of using AI, particularly DL models, in enhancing the accuracy of ASD detection and diagnosis. This innovative approach signifies the critical role AI can play in advancing early diagnostic techniques, enabling better patient outcomes and underlining the importance of early identification of ASD, especially in children.
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This study aimed to update the Streptococcus suis serotype distribution in Spain by analysing 302 clinical isolates recovered from diseased pigs between 2020 and 2022. The main objectives were to identify prevalent serotypes, differentiate specific serotypes 1, 14, 2, and 1/2, investigate specific genotypic and phenotypic antimicrobial resistance features, and explore associations between resistance genes and phenotypic resistances. Serotypes 9 (21.2%), 1 (16.2%), 2 (15.6%), 3 (6%), and 7 (5.6%) were the most prevalent, whereas serotypes 14 and 1/2 corresponded with 4.3% and 0.7% of all isolates. Antimicrobial resistance genes, including tet(O), erm(B), lnu(B), lsa(E), tet(M), and mef(A/E), were analysed, which were present in 85.8%, 65.2%, 7%, 7%, 6.3%, and 1% of the samples, respectively. Susceptibility testing for 18 antimicrobials revealed high resistance levels, particularly for clindamycin (88.4%), chlortetracycline (89.4%), and sulfadimethoxine (94.4%). Notably, seven significant associations (p < 0.0001) were detected, correlating specific antimicrobial resistance genes to the observed phenotypic resistance. These findings contribute to understanding the S. suis serotype distribution and its antibiotic resistance profiles in Spain, offering valuable insights for veterinary and public health efforts in managing S. suis-associated infections.
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Water is becoming an increasingly scarce resource due to growing multi-sector demand and the effects of climate change. During droughts, the proportional rule is the most widespread water allocation method applied in irrigation systems. However, this method fails to guarantee efficient water allocation or to provide a fair method of water allocation. This paper aims to verify whether by replacing the water allocation methods based on a proportional rule with methods based on a priority rule could improve the allocation of water resources and minimize the negative economic impacts of water shortages. The ultimate objective of this research is to design a water pricing scheme capable of guaranteeing efficient water reallocation during drought conditions. Therefore, an experiment was carried out for the largest irrigated area in southern Italy, covered by the Capitanata Reclamation and Irrigation board (CBC). A positive mathematical programming model was implemented in order to simulate the effects of the proposed mechanism. The findings show that priority mechanisms have the potential to improve overall economic efficiency in the event of water shortages. However, results also point to the need for optimal design of a differentiated water pricing scheme.