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Exudate absorption is a key parameter for proper wound dressing performance. Unlike standardized tests that consider exudate viscosity close to that of water, patients' exudates vary greatly in composition and, therefore, viscosity. This work aimed to investigate the effects of exudate viscosity and pore size of hydrogel-like dressings on the exudate absorption rate to establish rational criteria for the design of dressings that can meet the personalized needs of wound treatment. Computer-aided design (CAD) was used for Digital Light Processing (DLP) 3D printing of hydrogels with 0%, 30% and 60% porosity. The hydrogels were characterized in detail, and the absorption of two simulated exudate fluids (SEFs) was video-recorded. The same CAD files were used to develop in silico models to simulate exudate uptake rate. Both in vitro data and in silico modeling revealed that low-viscosity SEF penetrates faster through relatively small hydrogel pores (approx. 400 μm) compared to larger pores (approx. 1100 μm) due to capillary forces. However, in vitro vertical uptake took longer than when simulated using CAD design due to lateral fluid absorption through the pore walls in the hydrogel bulk. Distortions of hydrogel channels (micro-CT images) and lateral fluid absorption should be both considered for in silico simulation of SEF penetration. Overall, the results evidenced that porous hydrogel dressings allow rapid penetration (within a few seconds) and hosting of exudates, especially for pore size

The aim of this research is to analyse children's inter-age relationships in rural schools, given that the low number of pupils can limit the possibilities of socialising with children of the same age, encouraging relationships with older or younger classmates, both in the classroom and in the playgrounds. The research carried out was a mixed research, using a questionnaire sent to rural schools all over the country, and ethnographic fieldwork during four months in a rural school. The results show the good inter-age relationships that are generated in these environments and the good influence that multi-grade education has on the education and integral development of children. The study concludes by highlighting the value of children's inter-age relationships in rural schools and calling for further studies to increase knowledge on the subject.

ObjectiveNext-generation sequencing (NGS) panels are increasingly used for the diagnosis of monogenic systemic autoinflammatory diseases (SAIDs). However, their role in patients with adult-onset Still’s disease (AOSD) remains unknown. This study aims to assess the usefulness of NGS panels in AOSD patients to improve diagnosis and management of the disease.MethodsThis observational, multicenter study included all patients with AOSD diagnosis who underwent NGS panel testing in northern Spain. Clinical manifestations, laboratory parameters, complications, and therapeutic responses were recorded.ResultsA total of 24 patients (16 men, 8 women) with an average age of 42.2 ± 17.9 (mean ± SD) years, in whom NGS was performed, fulfilled the Yamaguchi and/or Fautrel criteria for AOSD. The most common symptoms, apart from fever, were skin rash (75%), asthenia (91.7%), and articular manifestations (91.7%). All patients had elevated acute-phase reactant levels and hyperferritinemia. Almost all patients received oral glucocorticoids as initial therapy. Conventional disease-modifying antirheumatic drugs (cDMARDs) were used in 17 (70.8%) patients and biologic therapy in 13 (54.1%) patients. Genetic variants were observed in 5 (20.8%) patients. None of them were classified as pathogenic. Variants of uncertain significance (VUS) were identified in NOD2 (c.2104C>T and c.2251G>A), TNFRSF1A (c.224C>T), TNFAIP3 (c.1939A>C), and SCN9A (c.2617G>A). Atypical manifestations and/or therapeutic refractoriness were observed in patients carrying genetic variants, except for one patient with the TNFAIP3 VUS. Four out of five patients with VUS had a severe and refractory course of the disease and required biologic therapy.ConclusionNGS was useful to rule out the presence of pathogenic genetic variants related to other SAIDs and to detect VUS that may help identify patients at risk for atypical and severe manifestations and poor response to conventional therapy.

Biodegradable and eco-sustainable medical devices represent an urgent need to face up to the increasing pollution associated to plastic device wastes. The present study aimed to develop semisolid extruded 3D (SSE-3D)-printed medical devices using mixtures of Xanthan gum (XG) and Guar gum (GG) as a green alternative to non-biodegradable synthetic polymers. The final purpose is to prepare biocompatible, biodegradable, and sterilizable implantable scaffolds with pro-regenerative and wound-healing properties. Inks prepared with 12 % w/v XG/GG (50:50) and blended with citric (CA), succinic (SA), or tartaric acid (TA) possessed suitable rheological profiles and allowed the 3D printing of porous scaffolds with high precision and structural control. Steam-heat sterilization triggered the cross-linking through ester bond formation (confirmed by ATR-FTIR and CP/MAS 13C-NMR). The scaffold crosslinked with SA had reproducible porosity (SEM and pycnometer), maintained the initial shape after 7 days swelling in PBS pH 7.4 and subjected to compression cycles (texturometer analysis), showed good cytocompatibility and hemocompatibility, and promoted angiogenesis in ovo in a chorioallantoic membrane model, evidencing tissue integration without toxicity. Furthermore, these scaffolds attenuated collagenase activity by trapping divalent ions (Ca2+ and Zn2+). Hence, by coupling angiogenic and anticollagenase activity, XG/GG scaffolds are promising candidates for wound healing and pro-regenerative applications.

Abstract This paper presents a new procedure for vaccine design against highly variable viruses such as Hepatitis C. The procedure uses an optimization algorithm to design vaccines that maximize the coverage of epitopes across different virus variants. Weighted epitopes based on the success ratio of immunological assays are used to prioritize the selection of epitopes for vaccine design. The procedure was successfully applied to design DC vaccines loaded with two HCV peptides, STG and DYP, which were shown to be safe, immunogenic, and able to induce significant levels of anti-viral cytokines, peptide-specific cellular immune responses and IgG antibodies. The procedure could potentially be applied to other highly variable viruses that currently lack effective vaccines.

Objective: To describe a variation in the final osteosynthesis technique for total ankle replacement (TAR) implantation through lateral approach. Methods: We retrospectively reviewed a series of cases dated between January 2022 and May 2023 in which intramedullary nailing was used as the osteosynthesis technique for the fibula during TAR implantation via lateral approach. Results: In all cases, skin scarring and soft tissue recovery to baseline were achieved in one and a half month to three months. Consolidation of the fibula occurred at an average of three months. No material was removed in any of the cases to date. Finally, patients were satisfied, resuming their previous activities. Conclusion: To our knowledge, this study is the first to investigate a modification of the osteosynthesis technique in the lateral approach to TAR. We believe the intramedullary nail for the fibula may be a useful tool to prevent soft tissue complications, requiring prospective and comparative studies to evaluate its efficacy. Level of Evidence IV; Therapeutic Studies; Case Series.

En este artículo se estudia la novela El entenado (1983), de Juan José Saer, una obra singular que se incluye dentro del género de la nueva novela histórica pero que se aleja de sus convenciones. El entenado no reflexiona sobre un hecho central de la historia de Argentina ni acude a testimonios colectivos, sino que desplaza su mirada al testimonio individual y a la narración de un acontecimiento histórico casi olvidado, marginal: la fallida expedición de Juan Díaz de Solís (1515) y el testimonio del único superviviente de la antropofagia ritual de los indios colastiné, el grumete Francisco del Puerto. Las herramientas teóricas de este artículo corresponden a los postulados de la novela histórica de Georg Lukács y a las premisas de María Cristina Pons sobre la nueva novela histórica de mediados del siglo XX en Latinoamérica; todo esto en diálogo con la poética del autor vertida en ensayos y entrevistas. El centro de este estudio, sin embargo, no es una reflexión genérica, sino el análisis detallado de los diversos desplazamientos que propone Saer: el genérico, el espacial y el temporal. Se subraya, principalmente, el movimiento que va de la fragmentación, de los cuerpos, o del discurso parcial de la historia, a la construcción de un sentido simbólico. Las conclusiones reflexionan sobre cómo integrar los elementos excluidos (históricos, sociales e individuales) en los grandes discursos y cómo dotarlos de sentido. Así, esta novela propone abandonar la infructuosa búsqueda de una verdad histórica y sustituirla por una verdad simbólica, más crítica e incluyente.

Dry powder inhalers (DPIs) have gained increasing clinical acceptance in the local treatment of lung diseases due to their ability to meet the evolving needs of patients while avoiding environmental concerns. However, some formulations for DPIs still encounter performance limitations in terms of aerodynamic properties and achievement of therapeutic doses. Innovative aerogel powder formulations for DPIs processed using combined supercritical CO2 (scCO2)-based technologies can overcome these limitations, especially in the case of poorly water-soluble drugs. The loading of hydrophobic drugs into aerogels can be optimized through a thorough understanding of the physicochemical properties of the formulation and the scCO2 processing conditions. In this study, drug-loaded alginate aerogel particles were prepared by combining gelation-emulsification techniques and scCO2-based technologies. Beclomethasone dipropionate (BDP), a hydrophobic corticosteroid, was incorporated into the aerogel matrix by scCO2 impregnation. The influence of contact time, initial amount of drug, and use of co-solvents on the efficiency of scCO2 impregnation were studied. The kinetics of the BDP adsorption process was modelled to elucidate the time required for the drug to attain equilibrium concentration under specific operating conditions. Nitrogen adsorption-desorption and helium pycnometry revealed particles with large surface area (>200 m2/g) and porosity (ca. 90%). The resulting aerogels had excellent aerodynamic properties at relevant BDP doses, as confirmed by in vitro lung deposition tests. Ex vivo permeability tests with porcine lung tissues evidenced that BDP released from the inhaled formulation could penetrate the bronchial tissue.

Abstract Originally considered to act as a transcriptional co-factor, Pirin has recently been reported to play a role in tumorigenesis and the malignant progression of many tumors. Here, we have analyzed the diagnostic and prognostic value of Pirin expression in the early stages of melanoma, and its role in the biology of melanocytic cells. Pirin expression was analyzed in a total of 314 melanoma biopsies, correlating this feature with the patient’s clinical course. Moreover, PIR downregulated primary melanocytes were analyzed by RNA sequencing, and the data obtained were validated in human melanoma cell lines overexpressing PIR by functional assays. The immunohistochemistry multivariate analysis revealed that early melanomas with stronger Pirin expression were more than twice as likely to develop metastases during the follow-up. Transcriptome analysis of PIR downregulated melanocytes showed a dampening of genes involved in the G1/S transition, cell proliferation, and cell migration. In addition, an in silico approach predicted that JARID1B as a potential transcriptional regulator that lies between PIR and its downstream modulated genes, which was corroborated by co-transfection experiments and functional analysis. Together, the data obtained indicated that Pirin could be a useful marker for the metastatic progression of melanoma and that it participates in the proliferation of melanoma cells by regulating the slow-cycling JARID1B gene.

The worldwide increase in diabetes entails a rise in associated diseases, with diabetic retinopathy on the forefront of the ocular complications. To overcome the challenges posed by ocular barriers, self-assembled nanocarriers have gathered increasing attention in recent years, with niosomes revealing themselves to be suitable for the delivery of a variety of drugs. This study investigated the mechanical properties of Langmuir monolayers comprising cholesterol, Tween 60, and 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), both individually and in binary and ternary systems. The cholesterol monolayer was characterized by an L-shaped isotherm, reflecting two surface aggregation states. Tween 60 exhibited expanded conformation and progressive aggregation, transitioning through a phase change. The addition of cholesterol to Tween 60 resulted in a subtle reduction in surface compressional modulus. The compression isotherms highlighted the stabilizing effect of cholesterol on the monolayer, affecting the film's resistance to compression. The introduction of DOTMA in Tween 60 monolayers revealed concentration-dependent effects, where the compression resistance of the film was proportional to DOTMA concentration. Ternary systems of cholesterol, DOTMA and Tween 60 exhibited unique behavior, with DOTMA enhancing film stability and cholesterol modulating this effect. Temperature and subphase ionic strength variations further exacerbated the effects of DOTMA concentration. Brewster Angle Microscopy confirmed the absence of microdomains in the compressed monolayer, supporting the hypothesis of a monolayer collapse. Overall, the research provided valuable insights into the intricate interactions and mechanical behavior of these surfactant systems and the feasibility of obtaining cationic niosome-based drug delivery.

BackgroundGrowing evidence suggests that Latina immigrant survivors of adverse childhood experiences (ACEs) are at increased risk for developing and remaining with either depression or anxiety or both symptoms. This study examined the feasibility and acceptability of a telehealth intervention—Cuidándome (quee-DAN-doh-meh, “taking care of myself”). Cuidándome is a 10-week, patient-centered, trauma-informed intervention delivered by a trained facilitator that promotes self-management of depression and anxiety symptoms through improved problem-solving skills and strategies. ObjectiveThe aim of this study was to examine the feasibility and acceptability of Cuidándome delivered remotely (via Zoom) with Latina immigrant ACE survivors with either depression or anxiety or both symptoms. We also estimated the effect sizes associated with the intervention on decreasing depression and anxiety symptoms and improving social problem–solving styles. MethodsWe evaluated Cuidándome using a randomized controlled trial design. Latina immigrants (N=47) who had experienced at least 1 ACE and had at least mild depression or anxiety symptoms were randomized to Cuidándome or a comparison group delivered by trained facilitators. We assessed for changes in depression and anxiety symptoms as well as social problem–solving styles at baseline, post intervention, and 3- and 6-month follow-up. ResultsAnalyses indicated significant decreases over time within both Cuidándome and comparison groups for depression and anxiety symptoms and maladaptive problem-solving. The intervention effect was largest for anxiety; at 6-month follow-up, Cuidándome participants had significantly lower anxiety scores than the comparison group. In addition, we observed a greater average point reduction in depression symptoms at 6 months among Cuidándome participants (5.7 points) than in the comparison group (3.7 points). ConclusionsA mental health program delivered via Zoom by a trained facilitator was feasible and acceptable to Latina immigrant women and can be beneficial for reducing anxiety and depression symptoms. More research is needed to assess the effectiveness of Cuidándome among a powered sample size of Latina immigrants. Trial RegistrationISRCTN Registry ISRCTN16668518; https://www.isrctn.com/ISRCTN16668518

3D printing is driving a shift in patient care away from a generalised model and towards personalised treatments. To complement fast-paced clinical environments, 3D printing technologies must provide sufficiently high throughputs for them to be feasibly implemented. Volumetric printing is an emerging 3D printing technology that affords such speeds, being capable of producing entire objects within seconds. In this study, for the first time, rotatory volumetric printing was used to simultaneously produce two torus- or cylinder-shaped paracetamol-loaded Printlets (3D printed tablets). Six resin formulations comprising paracetamol as the model drug, poly(ethylene glycol) diacrylate (PEGDA) 575 or 700 as photoreactive monomers, water and PEG 300 as non-reactive diluents, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as the photoinitiator were investigated. Two printlets were successfully printed in 12 to 32 s and exhibited sustained drug release profiles. These results support the use of rotary volumetric printing for efficient and effective manufacturing of various personalised medicines at the same time. With the speed and precision it affords, rotatory volumetric printing has the potential to become one of the most promising alternative manufacturing technologies in the pharmaceutical industry.

Inkjet printing has been extensively explored in recent years to produce personalised medicines due to its low cost and versatility. Pharmaceutical applications have ranged from orodispersible films to complex polydrug implants. However, the multi-factorial nature of the inkjet printing process makes formulation (e.g., composition, surface tension, and viscosity) and printing parameter optimization (e.g., nozzle diameter, peak voltage, and drop spacing) an empirical and time-consuming endeavour. Instead, given the wealth of publicly available data on pharmaceutical inkjet printing, there is potential for a predictive model for inkjet printing outcomes to be developed. In this study, machine learning (ML) models (random forest, multilayer perceptron, and support vector machine) to predict printability and drug dose were developed using a dataset of 687 formulations, consolidated from in-house and literature-mined data on inkjet-printed formulations. The optimized ML models predicted the printability of formulations with an accuracy of 97.22%, and predicted the quality of the prints with an accuracy of 97.14%. This study demonstrates that ML models can feasibly provide predictive insights to inkjet printing outcomes prior to formulation preparation, affording resource- and time-savings.

Objetivo. En este artículo presentamos un análisis de Planes Lectores de diversos centros educativos de Educación Secundaria en España para identificar cómo son y cómo deberían ser los mismos. Método. Se definieron trece variables de observación: presentación, marco teórico, contexto, trayectoria lectora del centro, cultura del centro, propuestas para promover la lectura (a nivel de aula, centro, biblioteca, familias y otras instituciones), competencias, implicación departamental, relación con otros planes, recursos, evaluación, actualización y elementos diferenciadores. Resultados. Los resultados muestran una amplia diversidad de prácticas, que, en conjunto, son claves para la mejora de la competencia lectora entre el alumnado. Conclusiones. Es posible concluir que esta indispensable herramienta de planificación podría ser mejor aprovechada por parte de los centros para racionalizar y visibilizar los esfuerzos que se hacen en los centros para desarrollar la competencia lectora del alumnado.

In this paper, we propose a novel hybrid network solution using optical code-division multiple-access and free-space optics (OCDMA-FSO) to support multiple data rates and quality-of-service according to user requirements. The proposed OCDMA-FSO network classifies users into diverse classes based on their requirements and allows for signal transmission in a fully asynchronous manner. The new hybrid network employs 2-D OCDMA codes as well as a variable aperture FSO receiver together with an equal gain combining (EGC) technique. We derive completely new analytical formalisms to evaluate the network performance in terms of average bit error rate (ABER), outage probability, effective data rate during outages, and ergodic capacity. The derived ABER expressions are validated via Monte-Carlo simulations. These new analytical formalisms are derived considering several atmospheric turbulence conditions such as uncorrelated, totally correlated, and partially correlated turbulence. To model this atmospheric turbulence, we derive the gamma-gamma (GG) distribution, which allows us to consider both the scintillation effect and the EGC technique. Finally, we carry out a comprehensive performance evaluation of the proposed hybrid network. Analytical results show that as the number of FSO receiver apertures increases, there is an improvement in overall performance levels. However, the ergodic capacity exhibits minimal improvement even as the number of FSO receiver apertures increases, regardless of the user requirements and turbulence conditions. The proposed network is a potential solution for scenarios that demand flexibility in bandwidth and data rate allocation.

The imbalance between life expectancy and quality of life is increasing due to the raising prevalence of chronic diseases. Musculoskeletal disorders and chronic wounds affect a growing percentage of people and demand more efficient tools for regenerative medicine. Scaffolds that can better mimic the natural physical stimuli that tissues receive under healthy conditions and during healing may significantly aid the regeneration process. Shape, mechanical properties, pore size and interconnectivity have already been demonstrated to be relevant scaffold features that can determine cell adhesion and differentiation. Much less attention has been paid to scaffolds that can deliver more dynamic physical stimuli, such as electrical signals. Recent developments in the precise measurement of electrical fields in vivo have revealed their key role in cell movement (galvanotaxis), growth, activation of secondary cascades, and differentiation to different lineages in a variety of tissues, not just neural. Piezoelectric scaffolds can mimic the natural bioelectric potentials and gradients in an autonomous way by generating the electric stimuli themselves when subjected to mechanical loads or, if the patient or the tissue lacks mobility, ultrasound irradiation. This review provides an analysis on endogenous bioelectrical signals, recent developments on piezoelectric scaffolds for bone, cartilage, tendon and nerve regeneration, and their main outcomes in vivo. Wound healing with piezoelectric dressings is addressed in the last section with relevant examples of performance in animal models. Results evidence that a fine adjustment of material composition and processing (electrospinning, corona poling, 3D printing, annealing) provides scaffolds that act as true emitters of electrical stimuli that activate endogenous signaling pathways for more efficient and long-term tissue repair.

A pesar de que la interacción en los procesos de enseñanza-aprendizaje es un fenómeno muy investigado, en el ámbito universitario no existen instrumentos para medirla. Teniendo esto en cuenta, este artículo tiene como objetivo validar el cuestionario "Instrumento de Medición de la Interacción en la Educación Superior (cuestionario IMIES)", que consta de 35 ítems tipo Likert. La validación se ha realizado con una muestra de 2.170 estudiantes universitarios de diferentes Grados y Másteres Oficiales de todos los cursos académicos en una Universidad del norte de España Según nuestros resultados, el cuestionario ha mostrado buenas propiedades y buenas medidas de fiabilidad en siete factores clave. Se puede concluir que el IMIES es una herramienta que contribuye a iniciar y mejorar la evaluación de los procesos de interacción en la enseñanza universitaria. Consideramos que es un instrumento útil tanto para el profesorado, como herramienta de autoevaluación, como para las universidades en su conjunto como herramienta de diagnóstico general para fomentar la interacción en sus aulas.

Pancreatic cancer (PC) is an aggressive cancer subtype presenting unmet clinical challenges. Conventional chemotherapy, which includes antimetabolite gemcitabine (GEM), is seriously undermined by a short half-life, its lack of targeting ability, and systemic toxicity. GEM incorporation in self-assembled nanosystems is still underexplored due to GEM’s hydrophilicity which hinders efficient encapsulation. We hypothesized that vitamin E succinate–GEM prodrug (VES-GEM conjugate) combines hydrophobicity and multifunctionalities that can facilitate the development of Pluronic® F68 and Pluronic® F127 micelle-based nanocarriers, improving the therapeutic potential of GEM. Pluronic® F68/VES-GEM and Pluronic® F127/VES-GEM micelles covering a wide range of molar ratios were prepared by solvent evaporation applying different purification methods, and characterized regarding size, charge, polydispersity index, morphology, and encapsulation. Moreover, the effect of sonication and ultrasonication and the influence of a co-surfactant were explored together with drug release, stability, blood compatibility, efficacy against tumour cells, and cell uptake. The VES-GEM conjugate-loaded micelles showed acceptable size and high encapsulation efficiency (>95%) following an excipient reduction rationale. Pluronic® F127/VES-GEM micelles evidenced a superior VES-GEM release profile (cumulative release > 50%, pH = 7.4), stability, cell growth inhibition (

Abstract Coronavirus disease 2019 (COVID-19) is the greatest threat to global health at the present time, and considerable public and private effort is being devoted to fighting this recently emerged disease. Despite the undoubted advances in the development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, uncertainty remains about their future efficacy and the duration of the immunity induced. It is therefore prudent to continue designing and testing vaccines against this pathogen. In this article we computationally designed two candidate vaccines, one monopeptide and one multipeptide, using a technique involving optimizing lambda-superstrings, which was introduced and developed by our research group. We tested the monopeptide vaccine, thus establishing a proof of concept for the validity of the technique. We synthesized a peptide of 22 amino acids in length, corresponding to one of the candidate vaccines, and prepared a dendritic cell (DC) vaccine vector loaded with the 22 amino acids SARS-CoV-2 peptide (positions 50-71) contained in the NTD domain (DC-CoVPSA) of the Spike protein. Next, we tested the immunogenicity, the type of immune response elicited, and the cytokine profile induced by the vaccine, using a non-related bacterial peptide as negative control. Our results indicated that the CoVPSA peptide of the Spike protein elicits noticeable immunogenicity in vivo using a DC vaccine vector and remarkable cellular and humoral immune responses. This DC vaccine vector loaded with the NTD peptide of the Spike protein elicited a predominant Th1-Th17 cytokine profile, indicative of an effective anti-viral response. Finally, we performed a proof of concept experiment in humans that included the following groups: asymptomatic non-active COVID-19 patients, vaccinated volunteers, and control donors that tested negative for SARS-CoV-2. The positive control was the current receptor binding domain epitope of COVID-19 RNA-vaccines. We successfully developed a vaccine candidate technique involving optimizing lambda-superstrings and provided proof of concept in human subjects. We conclude that it is a valid method to decipher the best epitopes of the Spike protein of SARS-CoV-2 to prepare peptide-based vaccines for different vector platforms, including DC vaccines.

ABSTRACT: Viral hepatitis is among the top four causes of mortality globally, causing 1.4 million deaths each year, exceeding tuberculosis, malaria and human immunodeficiency virus. Hepatitis B and C are responsible for 90% of hepatitis deaths, and the remaining 10% are caused by other hepatitis viruses. The annual number of deaths from hepatitis C is declining, whereas the numbers of deaths from hepatitis B and D are increasing. Hepatitis B alone represents the seven highest cause of mortality worldwide. Spurred on by development of curative antivirals for hepatitis C and expanding access to hepatitis B virus (HBV) vaccination, the World Health Organization has committed to eliminating viral hepatitis as a public health threat by 2030.Like the majority of current antivirals, those available for HBV are virostatic. They are capable of suppressing viral replication but cannot eliminate the virus from infected patients. Therefore, treatment is lifelong. Long-term adherence to medication continues to represent a major challenge. Importantly, HBV often reactivates, leading to potential life-threatening events in immunosuppressed patients. Therapeutic options are limited for hepatitis D; however, promising new, effective antivirals are on the horizon.Recent advances have emerged in medicinal chemistry and drug delivery approaches to produce ultra-long-acting (XLA) antivirals. These can extend antiviral activity from months to 1 year or even longer. These new formulations can overcome the challenges of daily dosing and maximize drug exposure. The development of XLA antivirals targeting viral hepatitis may also facilitate cure strategies.

This work aimed to develop water-based formulations for onychomycosis topical treatment using micelles of small pegylated surfactants associated with α-cyclodextrin (αCD) to deliver terbinafine to the nail. Kolliphor® RH40 (RH40) and Gelucire® 48/16 (GEL) single and mixed micelles (RH40:GEL 1:1) were prepared. αCD was added to the surfactants dispersions to form poly(pseudo)rotaxanes (PPR). Formulations were characterized in terms of drug solubilization (3 to 34-fold increase), particle size (9–11 nm) and Z-potential (+0.3 − +1.96 mV), blood compatibility (non-hemolytic), rheological behavior (solid-like viscoelastic properties after 5–10% αCD addition), drug release and interaction with the nail plate. GEL micelles and surfactant-10% αCD PPRs notably hydrated the nail plate. The high viscosity of PPR led to a slower drug release, except for RH40:GEL +10% αCD that surprisingly released terbinafine faster. The RH40:GEL +10% αCD formulation delivered twice more amount of terbinafine to deeper regions of nail plate compared to other formulations. The results evidenced the potential of PPR formed by small pegylated surfactants as a water-based formulation for nail drug delivery.

Semi-solid extrusion (SSE) is a three-dimensional printing (3DP) process that involves the extrusion of a gel or paste-like material via a syringe-based printhead to create the desired object. In pharmaceuticals, SSE 3DP has already been used to manufacture formulations for human clinical studies. To further support its clinical adoption, the use of a pressure sensor may provide information on the printability of the feedstock material in situ and under the exact printing conditions for quality control purposes. This study aimed to integrate a pressure sensor in an SSE pharmaceutical 3D printer for both material characterization and as a process analytical technology (PAT) to monitor the printing process. In this study, three materials of different consistency were tested (soft vaseline, gel-like mass and paste-like mass) under 12 different conditions, by changing flow rate, temperature, or nozzle diameter. The use of a pressure sensor allowed, for the first time, the characterization of rheological properties of the inks, which exhibited temperature-dependent, plastic and viscoelastic behaviours. Controlling critical material attributes and 3D printing process parameters may allow a quality by design (QbD) approach to facilitate a high-fidelity 3D printing process critical for the future of personalized medicine.

Uncontrolled hypertension remains a serious public health problem. Despite the long-term negative effects of adverse childhood experiences (ACEs) on health and health behaviors, few studies have explored how to support ACE survivors with uncontrolled hypertension. We conducted semi-structured individual interviews with 24 diverse patients to understand how ACE survivors may manage their hypertension compared to those who had not experienced ACEs. Using qualitative descriptive methods we categorized participants based on ACE experience: non ACEs, ACEs with sexual abuse, and ACEs without sexual abuse. Our thematic analysis revealed 5 themes: stress, childhood experiences, social support, experiences with health care, and attitudes about self-care. These themes revealed more about antecedents to health behaviors than about actual management of hypertension. Although all participants experienced challenges with healthy lifestyle changes, comments from those who did not experience ACEs reflected a more positive attitude about self-care, and adaptive strategies for overcoming challenges related to hypertension management. ACE survivors reported more depressive symptoms, maladaptive strategies, and negative experiences with health care which negatively impacted their disease management. ACE survivors may need additional resources for depression management and coping strategies for self-care—all of which may improve health behavior and blood pressure control.

Con la entrada en vigor de la LOMLOE se ha aprobado una nueva normativa que regula la promoción y evaluación del alumnado de Educación Secundaria en España, introduciendo importantes cambios sobre los criterios de repetición. En este trabajo, se presentan los hallazgos más reseñables por la literatura académica en términos de no promoción, destacando sus evidencias empíricas y sus alternativas, así como aspectos relacionados con la dirección de centros. El presente estudio se ha realizado en Cantabria, mediante un cuestionario abierto a directores de centros de Educación Secundaria y la conducción de entrevistas semiestructuradas a inspectores de la Consejería de Educación, para evaluar el estado y los efectos que tiene la repetición escolar en la región sobre el alumnado. Los resultados cualitativos obtenidos muestran una retirada paulatina por parte de los centros escolares de esta medida, motivada principalmente por el cambio de legislación y de mentalidad en los docentes ahora más orientada hacia una educación competencial.

Background: The advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has been associated with a significant decline in coronavirus disease 2019 (COVID-19) hospitalizations and deaths. However, little is known about the benefits experienced by different population groups and/or using distinct vaccines. Methods: The Spanish public registry was analyzed to examine associations between weekly vaccination scale-up and the incidence of COVID-19 hospitalizations by age, sex, and vaccine modality. The study period extended from January 2020 to June 2021. Results: A total of 363 960 COVID-19 hospitalizations were recorded in Spain during the study period, with three peaks in March 2020, November 2020, and January 2021. The incidence of COVID-19 hospitalizations per 100 000 population increased exponentially with age, on average 71.5% for each decade older. Overall, individuals older than 60 years of age accounted for 65% of all COVID-19 hospitalizations. The speedy vaccination rollout since the end of 2020, with prioritization of the elderly groups, resulted in a rapid fall in COVID-19 hospitalizations starting in February 2021. The benefit was already noticed 3–4 weeks after the first dose, regardless of the vaccine modality. Conclusions: COVID-19 hospitalizations increased exponentially with age in all three peaks of SARS-CoV-2 infection in Spain. Early mass vaccination of people over 60 years of age prevented a fourth wave of COVID-19 hospitalizations during the spring of 2021.

IntroductionThe COVID-19 pandemic created new and exacerbated existing stressors for frontline healthcare workers. Despite being disproportionately affected by COVID-19, little is known about the experiences of frontline healthcare workers serving marginalized populations in community settings.DesignWe used qualitative descriptive methods to understand the experiences of 12 frontline healthcare workers (HCWs) supporting primarily underserved populations in outpatient settings during COVID-19. Interviews were conducted from March to April 2021.MethodsInterviews were held virtually via Zoom using a semi-structured interview guide. Interviews were audio-recorded, transcribed verbatim, and uploaded into NVivo 12 qualitative data analysis software. The transcripts were dually coded by members of the research team and a thematic analysis was conducted.ResultsFour major themes from the interviews were identified: stressors and burnout, coping strategies, organizational support, and recommendations. HCWs described how the early adjustment period to the pandemic created new challenges as they attempted to navigate changes in the workplace and altered responsibilities at home. HCWs felt largely unsupported by their organizations as they attempted to cope with stressors. Organizational support programs and resources often did not meet frontline workers' needs, and sentiments of unappreciation from leadership contributed to feelings of burnout and frustration as pandemic-related challenges persisted and evolved.ConclusionDespite encountering numerous stressors at work and home, resulting from pandemic-related disruptions, frontline HCWs continued to provide care for their clients while navigating emerging challenges. Health organizations should include HCWs in decision-making processes when implementing support systems for workers during times of crisis.

The Fossil Forest of the Aragoncillo Range is one of several paleontological sites of exceptional scientific value in the Sierra de Selas (Province of Guadalajara, central Spain). This shows an accumulation of silicified tree trunks along with well-preserved macro- and microflora of lower Permian age. This ancient forest, dominated by tree ferns and conifers, was destroyed by volcanic eruptions that took place in many continental areas at this time. This site is in the Molina-Alto Tajo UNESCO Global Geopark, but it is highly vulnerable and has suffered continued impact from plundering. The lack of implementation of legislation that guarantees its conservation does not allow interested visitors to enjoy the site and understand the characteristics of life and climate of such a unique ecosystem from this time in Earth history.

Nanotechnology application in cancer treatment is promising and is likely to quickly spread worldwide in the near future. To date, most scientific studies on nanomaterial development have focused on deepening the attitudes of end users and experts, leaving clinical practice implications unexplored. Neuro-oncology might be a promising field for the application of nanotechnologies, especially for malignant brain tumors with a low-survival rate such as glioblastoma (GBM). As to improving patients’ quality of life and life expectancy, innovative treatments are worth being explored. Indeed, it is important to explore clinicians’ intention to use experimental technologies in clinical practice. In the present study, we conducted an exploratory review of the literature about healthcare workers’ knowledge and personal opinions toward nanomedicine. Our search (i) gives evidence for disagreement between self-reported and factual knowledge about nanomedicine and (ii) suggests the internet and television as main sources of information about current trends in nanomedicine applications, over scientific journals and formal education. Current models of risk assessment suggest time-saving cognitive and affective shortcuts, i.e., heuristics support both laypeople and experts in the decision-making process under uncertainty, whereas they might be a source of error. Whether the knowledge is poor, heuristics are more likely to occur and thus clinicians’ opinions and perspectives toward new technologies might be biased.

Immunotherapy with T cells genetically modified with chimeric antigen receptors (CARs) has shown significant clinical efficacy in patients with relapsed/refractory B-cell lymphoma. Nevertheless, more than 50% of treated patients do not benefit from such therapy due to either absence of response or further relapse. Elucidation of clinical and biological features that would predict clinical response to CART19 therapy is of paramount importance and eventually may allow for selection of those patients with greater chances of response. In the last 5 years, significant clinical experience has been obtained in the treatment of diffuse large B-cell lymphoma (DLBCL) patients with CAR19 T cells, and major advances have been made on the understanding of CART19 efficacy mechanisms. In this review, we discuss clinical and tumor features associated with response to CART19 in DLBCL patients as well as the impact of biological features of the infusion CART19 product on the clinical response. Prognosis of DLBCL patients that fail CART19 is poor and therapeutic approaches with new drugs are also discussed.

Introduction: Anal intraepithelial neoplasia (AIN) is the most likely precursor of squamous cells cancer which represents 90% of anal cancers. The use of biomolecular tests as a screening method has been extended by gynecology. Given the similarities that exist between the HPV disease in the lower genital tract and anorectal sectors, it is expected that HPV tests can provide information for the diagnosis, treatment and follow-up for AIN-affected patients. Objectives: Comparing the performance of anal cytology, PAP and HPV tests (Hybrid Capture and Papillocheck) against the histology of the diagnosis of low- and high-grade AIN in risk groups. Material and methods: A cross-sectional study was carried out to evaluate diagnostic methods for low- and high-grade AIN in 73 patients. Samples for anal PAP, Papillocheck and Hybrid Capture were taken from all patients who then, regardless of the results, underwent magnifying chromoendoscopy (MCE) along with biopsy. Diagnostic test performances and their 95% confidence intervals (CI: 95%) were calculated as well as the likelihood ratio for each test. Results: Of the 73 patients, 49 (67%) were women. The average age of the patients was 38 years. In 38 patients (52%), the histology was positive with 10 (14%) grade II AIN or higher. There were no statistically significant differences in sensitivity nor in specificity for low- and high-grade AINs between any of the tests. Conclusion: Anal PAP, the Hybrid Capture test (HC2, Qiagen) and PapilloCheck (Greiner Bio One) were highly sensitive but not specific for low- and high-grade AINs. Therefore, a biopsy should be conducted against a positive result of any of the tests to confirm AIN and the degree of dysplasia. The screening method selection depend on the availability but also costs of the test should be considered, since all the diagnostic tests have similar performance. Resumo: Introdução: A neoplasia intraepitelial anal é o precursor mais provável do câncer de células escamosas, que representa 90% dos tumores anais. O uso de exames biomoleculares como método de triagem foi ampliado pela ginecologia. Considerando-se as semelhanças entre as apresentações de HPV no trato genital inferior e anorretal, espera-se que os exames de HPV possam fornecer informações para o diagnóstico, tratamento e acompanhamento dos pacientes com neoplasia intraepitelial anal. Objetivo: Comparar o desempenho da citologia anal, Papanicolau, exames para HPV (teste de captura híbrida e Papillocheck) e histologia no diagnóstico de neoplasia intraepitelial anal de baixo e alto grau em grupos de risco. Material e métodos: Foi realizado um estudo transversal para avaliar métodos de diagnóstico de neoplasia intraepitelial anal de baixo e alto grau em 73 pacientes. Amostras para Papanicolau anal, Papillocheck e captura híbrida foram coletadas de todos os pacientes; independentemente dos resultados desses exames, todos foram submetidos a cromoendoscopia de ampliação (CEA) e biópsia. O desempenho dos exames e seus intervalos de confiança de 95% (95% CI) foram calculados, bem como a razão de verossimilhança para cada teste. Resultados: Dos 73 pacientes, 49 (67%) eram mulheres. A idade média dos pacientes foi de 38 anos. A histologia foi positiva em 38 pacientes (52%), dos quais dez (14%) apresentaram neoplasia intraepitelial anal grau II ou superior. Não foram observadas diferenças estatisticamente significativas na sensibilidade ou especificidade para as neoplasias intraepiteliais anal de baixo e alto grau entre qualquer um dos exames. Conclusão: O Papanicolau anal, o teste de captura híbrida (HC2, Qiagen) e o Papillocheck (Greiner Bio One) foram altamente sensíveis, mas não específicos para neoplasia intraepitelial anal de baixo e alto grau. Portanto, uma biópsia deve ser realizada após um resultado positivo em qualquer um dos testes para confirmar o diagnóstico de neoplasia intraepitelial anal e seu grau. A seleção do método de triagem depende da disponibilidade, mas os custos devem ser considerados, uma vez que todos os testes apresentam desempenho semelhante.

The aim of this work was to develop niosomes for the ocular delivery of epalrestat, a drug that inhibits the polyol pathway and protects diabetic eyes from damage linked to sorbitol production and accumulation. Cationic niosomes were made using polysorbate 60, cholesterol, and 1,2-di-O-octadecenyl-3-trimethylammonium propane. The niosomes were characterized using dynamic light scattering, zeta-potential, and transmission electron microscopy to determine their size (80 nm; polydispersity index 0.3 to 0.5), charge (−23 to +40 mV), and shape (spherical). The encapsulation efficiency (99.76%) and the release (75% drug release over 20 days) were measured with dialysis. The ocular irritability potential (non-irritating) was measured using the Hen’s Egg Test on the Chorioallantoic Membrane model, and the blood glucose levels (on par with positive control) were measured using the gluc-HET model. The toxicity of the niosomes (non-toxic) was monitored using a zebrafish embryo model. Finally, corneal and scleral permeation was assessed with the help of Franz diffusion cells and confirmed with Raman spectroscopy. Niosomal permeation was higher than an unencapsulated drug in the sclera, and accumulation in tissues was confirmed with Raman. The prepared niosomes show promise to encapsulate and carry epalrestat through the eye to meet the need for controlled drug systems to treat the diabetic eye.

The need for online educational tools has increased significantly since the COVID-19 pandemic forced many students to embrace distance learning as a classroom alternative. While many instructors have used "Edpuzzle" to enhance distance learning, there has been little research that assesses and compares the views of teachers and students on the tool's advantages and disadvantages. To examine the perceived advantages and disadvantages of using "Edpuzzle" for classroom learning, we surveyed a sample of 152 professors and their students on their experience with the tool. The results reveal numerous advantages, including that "Edpuzzle" is a motivating, dynamic, and novel self-learning tool for students. Likewise, the professors point out that it is easy to use, focuses the attention of students, and is versatile. The disadvantages of the tool mostly had to do with technological challenges and potential boredom. Based on this evaluation, it was concluded that students have a preference for graphic and visual material to complement other learning tools to help them better understand the lessons. When weighing the advantages and disadvantages posed by the professors and their students, it was found that the unique combination of interactive teaching that "Edpuzzle" provides is promising for the future.

Pulmonary drug delivery has recognized benefits for both local and systemic treatments. Dry powder inhalers (DPIs) are convenient, portable and environmentally friendly devices, becoming an optimal choice for patients. The tailoring of novel formulations for DPIs, namely in the form of porous particles, is stimulating in the pharmaceutical research area to improve delivery efficiency. Suitable powder technological approaches are being sought to design such formulations. Namely, aerogel powders are nanostructured porous particles with particularly attractive properties (large surface area, excellent aerodynamic properties and high fluid uptake capacity) for these purposes. In this review, the most recent development on powder technologies used for the processing of particulate porous carriers are described via updated examples and critically discussed. A special focus will be devoted to the most recent advances and uses of aerogel technology to obtain porous particles with advanced performance in pulmonary delivery.

Cross-reactive vaccines recognize common molecular patterns in pathogens and are able to confer broad spectrum protection against different infections. Antigens common to pathogenic bacteria that induce broad immune responses, such as the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of the genera Listeria, Mycobacterium, or Streptococcus, whose sequences present more than 95% homology at the N-terminal GAPDH1−22 peptide, are putative candidates for universal vaccines. Here, we explore vaccine formulations based on dendritic cells (DC) loaded with two molecular forms of Listeria monocytogenes GAPDH (LM-GAPDH), such as mRNA carriers or recombinant proteins, and compare them with the same molecular forms of three other antigens used in experimental vaccines, listeriolysin O of Listeria monocytogeness, Ag85A of Mycobacterium marinum, and pneumolysin of Streptococcus pneumoniae. DC loaded with LM-GAPDH recombinant proteins proved to be the safest and most immunogenic vaccine vectors, followed by mRNA encoding LM-GAPDH conjugated to lipid carriers. In addition, macrophages lacked sufficient safety as vaccines for all LM-GAPDH molecular forms. The ability of DC loaded with LM-GAPDH recombinant proteins to induce non-specific DC activation explains their adjuvant potency and their capacity to trigger strong CD4+ and CD8+ T cell responses explains their high immunogenicity. Moreover, their capacity to confer protection in vaccinated mice against challenges with L. monocytogenes, M. marinum, or S. pneumoniae validated their efficiency as cross-reactive vaccines. Cross-protection appears to involve the induction of high percentages of GAPDH1−22 specific CD4+ and CD8+ T cells stained for intracellular IFN-γ, and significant levels of peptide-specific antibodies in vaccinated mice. We concluded that DC vaccines loaded with L. monocytogenes GAPDH recombinant proteins are cross-reactive vaccines that seem to be valuable tools in adult vaccination against Listeria, Mycobacterium, and Streptococcus taxonomic groups.

AbstractIntroduction Soft contact lenses (SCLs) constitute a promising vehicle for ocular drug delivery due to their biocompatibility, prolonged contact with the eye and general acceptance. Soaking in the drug solution is the simplest method to load the drug into the SCLs. However, it usually does not ensure a controlled drug release, compatible with the therapeutic needs. Thus, additional approaches, such as the application of coatings on the SCLs that constitute a barrier to the drug release, have been tried to achieve that purpose [1]. The main goal of this work is to investigate the possibility of using a layer-by-layer (LbL) coating strategy, with alginate, chitosan and hyaluronic acid (ALG/CHI/HA) to get a controlled release of diclofenac from silicon based hydrogels.Materials and methods A lab-made silicon-based hydrogel intended for SCLs was loaded by soaking with the anti-inflammatory (diclofenac, DCF) and coated layer-by-layer (LbL) by immersion in solutions of alginate, chitosan and hyaluronic acid. Material properties such as transmittance, wettability, ionic permeability and swelling were studied. Drug release experiments were carried out under sink conditions (3 mL NaCl aqueous solution 130 mM, 36 °C, 180 rpm stirring). The coating stability and lysozyme-coating interaction was evaluated by quartz crystal microbalance with dissipation (QCM-D). A mathematical model was applied to predict the in vivo efficacy of the coated lenses. Chorioallantoic membrane (HET-CAM) tests were carried out to predict potential ocular irritation.Results The coating did not impair the studied physico-chemical properties, relevant for the application of the material in SCLs. HET-CAM tests did not suggest any potential for ocular irritation of both uncoated and coated samples. QCM-D data revealed the stability of the deposited layers and no adsorption of the protein. DCF release kinetics was controlled by the presence of the coating. The DCF concentration profile in the tear fluid estimated from the mathematical model predicts values above the half maximal inhibitory concentrations (IC50) for cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) during more than 2 weeks, for the coated hydrogels, while for the uncoated such levels are only expected in the first day of release.Discussion and conclusions ALG/CHI/HA LBL coated silicon hydrogels present adequate properties to be used in DCF releasing SCLs. They reveal an antifouling behaviour against lysozyme, one of the most abundant protein in lacrimal fluid. In vitro studies suggest that such system has potential to be used in the production of efficient therapeutic SCLs.

In the last decade, nanomedicine has arisen as an emergent area of medicine, which studies nanometric systems, namely polymeric micelles (PMs), that increase the solubility and the stability of the encapsulated drugs. Furthermore, their application in dermal drug delivery is also relevant. PMs present unique characteristics because of their unique core-shell architecture. They are colloidal dispersions of amphiphilic compounds, which self-assemble in an aqueous medium, giving a structure-type core-shell, with a hydrophobic core (that can encapsulate hydrophobic drugs), and a hydrophilic shell, which works as a stabilizing agent. These features offer PMs adequate steric protection and determine their hydrophilicity, charge, length, and surface density properties. Furthermore, due to their small size, PMs can be absorbed by the intestinal mucosa with the drug, and they transport the drug in the bloodstream until the therapeutic target. Moreover, PMs improve the pharmacokinetic profile of the encapsulated drug, present high load capacity, and are synthesized by a reproducible, easy, and low-cost method. In silico approaches have been explored to improve the physicochemical properties of PMs. Based on this, a computer-aided strategy was developed and validated to enable the delivery of poorly soluble drugs and established critical physicochemical parameters to maximize drug loading, formulation stability, and tumor exposure. Poly(2-oxazoline) (POx)-based PMs display unprecedented high loading concerning water-insoluble drugs and over 60 drugs have been incorporated in POx PMs. Among various stimuli, pH and temperature are the most widely studied for enhanced drug release at the site of action. Researchers are focusing on dual (pH and temperature) responsive PMs for controlled and improved drug release at the site of action. These dual responsive systems are mainly evaluated for cancer therapy as certain malignancies can cause a slight increase in temperature and a decrease in the extracellular pH around the tumor site. This review is a compilation of updated therapeutic applications of PMs, such as PMs that are based on Pluronics®, micelleplexes and Pox-based PMs in several biomedical applications.

Since their introduction, chewable dosage forms have gained traction due to their ability to facilitate swallowing, especially in paediatric, geriatric and dysphagia patients. Their benefits stretch beyond human use to also include veterinary applications, improving administration and palatability in different animal species. Despite their advantages, current chewable formulations do not account for individualised dosing and palatability preferences. In light of this, three-dimensional (3D) printing, and in particular the semi-solid extrusion technology, has been suggested as a novel manufacturing method for producing customised chewable dosage forms. This advanced approach offers flexibility for selecting patient-specific doses, excipients, and organoleptic properties, which are critical for ensuring efficacy, safety and adherence to the treatment. This review provides an overview of the latest advancements in chewable dosage forms for human and veterinary use, highlighting the motivations behind their use and covering formulation considerations, as well as regulatory aspects.

Abstract Objectives Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B‐cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30‐chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30‐CAR T to improve efficacy of CD30‐CAR therapy, using a targeting epitope within the non‐cleavable part of CD30 receptor, and memory stem T cells (TSCM) to improve engraftment, persistence and antitumor activity. Methods TSCM‐like cultures were generated and expanded ex vivo and transduced at day 1 or 2 with a lentiviral vector encoding the CD30‐CAR. Therapeutic in vivo experiments were performed using NSG mice injected with L540 (sc) or L428 (iv) and treated with CD30‐CAR T cells when the tumor was established. Results CD30‐CAR TSCM‐like cells generated and expanded ex vivo, despite CD30 expression and fratricide killing of CD30+ CAR T cells, were not impaired by soluble CD30 and completely eradicated Hodgkin lymphoma in vivo, showing high persistence and long‐lasting immunity. In addition, highly enriched CD30‐CAR TSCM‐like products confer a survival advantage in vivo, in contrast to more differentiated CAR T cells, with higher tumor infiltration and enhanced antitumor effect. Conclusion This study supports the use of a refined CD30‐CAR T cells with highly enriched TSCM‐like products to improve clinical efficacy of CAR T for Hodgkin lymphoma.

The glycolytic enzyme and bacterial virulence factor of Listeria monocytogenes, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Lmo2459), ADP-ribosylated the small GTPase, Rab5a, and blocked phagosome maturation. This inhibitory activity localized within the NAD binding domain of GAPDH at the N-terminal 1–22 peptides, also conferred listeriosis protection when used in dendritic cell-based vaccines. In this study, we explore GAPDH of Listeria, Mycobacterium, and Streptococcus spp. taxonomic groups to search for epitopes that confer broad protection against pathogenic strains of these bacteria. GAPDH multivalent epitopes are selected if they induce inhibitory actions and wide-ranging immune responses. Proteomic isolation of GAPDH from dendritic cells infected with Listeria, Mycobacterium, or Streptococcus confirmed similar enzymatic, Rab5a inhibitory and immune stimulation abilities. We identified by bioinformatics and functional analyses GAPDH N-terminal 1–22 peptides from Listeria, Mycobacterium, and Streptococcus that shared 95% sequence homology, enzymatic activity, and B and T cell immune domains. Sera obtained from patients or mice infected with hypervirulent pathogenic Listeria, Mycobacterium, or Streptococcus presented high levels of anti-GAPDH 1–22 antibodies and Th2 cytokines. Monocyte derived dendritic cells from healthy donors loaded with GAPDH 1–22 peptides from Listeria, Mycobacterium, or Streptococcus showed activation patterns that correspond to cross-immunity abilities. In summary, GAPDH 1–22 peptides appeared as putative candidates to include in multivalent dendritic based vaccine platforms for Listeria, Mycobacterium, or Streptococcus.

(1) Background: The purpose of this study was to synthesize melatonin-eluting contact lenses (CLs) and evaluate both the ocular kinetics of the released melatonin and its effect on tear volume and intraocular pressure. (2) Methods: In vitro, melatonin-eluting CLs were synthesized by using non-functionalized (HEMA) and functionalized (HEMA/APMA) monomers. In vivo, a short-term prospective and randomized study was performed on 15 rabbits divided into two groups: 12 rabbits wearing functionalized CLs and 3 rabbits without CLs as a control. The melatonin levels in tears, aqueous humor, vitreous body and retina, tear volume, and intraocular pressure were measured for 8 h. (3) Results: In vitro, both monomers did not show differences in terms of melatonin loading and release (p ≥ 0.05). In vivo, the melatonin concentration was elevated in tears and aqueous humor after 2 and 4 h of wearing CLs, respectively (p < 0.05). Additionally, the CLs increased tear volume for 2 h (p < 0.05). (4) Conclusions: The melatonin-eluting CLs released their content over the ocular surface for at least 2 h, which was associated with a secretagogue effect on tear volume. However, the increased amount of melatonin found in the aqueous humor had no effect on intraocular pressure.

Small-diameter synthetic vascular grafts are required for surgical bypass grafting when there is a lack of suitable autologous vessels due to different reasons, such as previous operations. Thrombosis is the main cause of failure of small-diameter synthetic vascular grafts when used for this revascularization technique. Therefore, the development of biodegradable vascular grafts capable of providing a localized and sustained antithrombotic drug release mark a major step forward in the fight against cardiovascular diseases, which are the leading cause of death globally. The present paper describes the use of an extrusion-based 3D printing technology for the production of biodegradable antiplatelet tubular grafts for cardiovascular applications. For this purpose, acetylsalicylic acid (ASA) was chosen as a model molecule due to its antiplatelet activity. Poly(caprolactone) and ASA were combined for the fabrication and characterization of ASA-loaded tubular grafts. Moreover, rifampicin (RIF) was added to the formulation containing the higher ASA loading, as a model molecule that can be used to prevent vascular prosthesis infections. The produced tubular grafts were fully characterized through multiple techniques and the last step was to evaluate their drug release, antiplatelet and antimicrobial activity and cytocompatibility. The results suggested that these materials were capable of providing a sustained ASA release for periods of up to 2 weeks. Tubular grafts containing 10% (w/w) of ASA showed lower platelet adhesion onto the surface than the blank and grafts containing 5% (w/w) of ASA. Moreover, tubular grafts scaffolds containing 1% (w/w) of RIF were capable of inhibiting the growth of Staphylococcus aureus. Finally, the evaluation of the cytocompatibility of the scaffold samples revealed that the incorporation of ASA or RIF into the composition did not compromise cell viability and proliferation at short incubation periods (24 h).

Dry eye disease is a common ocular disorder that is characterised by tear deficiency or excessive tear evaporation. Current treatment involves the use of eye drops; however, therapeutic efficacy is limited because of poor ocular bioavailability of topically applied formulations. In this study, digital light processing (DLP) 3D printing was employed to develop dexamethasone-loaded punctal plugs. Punctal plugs with different drug loadings were fabricated using polyethylene glycol diacrylate (PEGDA) and polyethylene glycol 400 (PEG 400) to create a semi-interpenetrating network (semi-IPN). Drug-loaded punctal plugs were characterised in terms of physical characteristics (XRD and DSC), potential drug-photopolymer interactions (FTIR), drug release profile, and cytocompatibility. In vitro release kinetics of the punctal plugs were evaluated using an in-house flow rig model that mimics the subconjunctival space. The results showed sustained release of dexamethasone for up to 7 days from punctal plugs made with 20% w/w PEG 400 and 80% w/w PEGDA, while punctal plugs made with 100% PEGDA exhibited prolonged releases for more than 21 days. Herein, our study demonstrates that DLP 3D printing represents a potential manufacturing platform for fabricating personalised drug-loaded punctal plugs with extended release characteristics for ocular administration.

Abstract Background Invariant natural killer T (iNKT) cells are a small population of lymphocytes with unique specificity for glycolipid antigens presented by non-polymorphic CD1d receptor on dendritic cells (DCs). iNKT cells play a central role in tumor immunology since they are implicated in the coordination of innate and adaptive immune responses. These cells can be activated with the prototypic lipid α-galactosylceramide (α-GalCer), stimulating interferon gamma (IFN-γ) production and cytokine secretion, which contribute to the enhancement of T cell activation. Methods We evaluated the antitumor effect of a combination of dendritic cells (DCs) and tumor cells with the iNKT cell agonist α-GalCer in a therapeutic model of B cell lymphoma. iNKT, NK and T cell phenotype was determined by flow cytometry. Serum cytokines were analyzed by Luminex technology. Significant differences between survival curves were assessed by the log-rank test. For all other data, Mann–Whitney test was used to analyze the differences between groups. Results This vaccine induced a potent (100% survival), long-lasting and tumor-specific antitumor immune response, that was associated with an increase of both Th1 cytokines and IFN-γ secreting iNKT cells (4.59 ± 0.41% vs. 0.92 ± 0.12% in control group; p = 0.01) and T cells (CD4 IFN-γ+: 3.75 ± 0.59% vs. 0.66 ± 0.18% p = 0.02; CD8 IFN-γ+: 10.61 ± 0.84% vs. 0.47 ± 0.03% p = 0.002). Importantly, natural killer (NK) cells played a critical role in the antitumor effect observed after vaccination. Conclusions This study provides clinically relevant data for the development of iNKT-cell based immunotherapy treatments for patients with B cell malignancies.

Despite the tremendous progress made in the field of cancer therapy in recent years, certain solid tumors still cannot be successfully treated. Alongside classical treatments in the form of chemotherapy and/or radiotherapy, targeted treatments such as immunotherapy that cause fewer side effects emerge as new options in the clinics. However, these alternative treatments may not be useful for treating all types of cancers, especially for killing infiltrative and circulating tumor cells (CTCs). Recent advances pursue the trapping of these cancer cells within a confined area to facilitate their removal for therapeutic and diagnostic purposes. A good understanding of the mechanisms behind tumor cell migration may drive the design of traps that mimic natural tumor niches and guide the movement of the cancer cells. To bring this trapping idea into reality, strong efforts are being made to create structured materials that imitate myelinated fibers, blood vessels, or pre-metastatic niches and incorporate chemical cues such as chemoattractants or adhesive proteins. In this review, the different strategies used (or could be used) to trap tumor cells are described, and relevant examples of their performance are analyzed.

Pseudophakic cystoid macular edema (PCME), caused by chronic inflammation, is the most common cause of visual impairment in the medium-term after cataract surgery. Therefore, the prophylactic topical administration of combined steroidal and non-steroidal anti-inflammatory drugs is commonly done. Drug-eluting intraocular lenses (IOLs) gained interest as an efficient way to overcome the compliance issues related to the use of ocular drops without the need for additional surgical steps. The incorporation of functional monomers and molecular imprinting were herein applied to design hydrogels suitable as IOLs and able to co-deliver steroidal (dexamethasone sodium phosphate) and non-steroidal (bromfenac sodium) drugs. The incorporation of N-(2-aminopropyl) methacrylamide (APMA) increased the drug uptake and improved the in vitro release kinetics. Imprinting with bromfenac resulted in a decreased drug release due to permanent drug bonding, while imprinting with dexamethasone increased the amount of dexamethasone released after dual-drug loading. The application of a mathematical model to predict the in vivo drug release behavior suggests the feasibility of achieving therapeutic drug concentrations of bromfenac and dexamethasone in the aqueous humor for about 2 and 8 weeks, respectively, which is compatible with the current topical prophylaxis after cataract surgery.

The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.

Vaccines are the most effective medical intervention due to their continual success in preventing infections and improving mortality worldwide. Early vaccines were developed empirically however, rational design of vaccines can allow us to optimise their efficacy, by tailoring the immune response. Establishing the immune correlates of protection greatly informs the rational design of vaccines. This facilitates the selection of the best vaccine antigens and the most appropriate vaccine adjuvant to generate optimal memory immune T cell and B cell responses. This review outlines the range of vaccine types that are currently authorised and those under development. We outline the optimal immunological correlates of protection that can be targeted. Finally we review approaches to rational antigen selection and rational vaccine adjuvant design. Harnessing current knowledge on protective immune responses in combination with critical vaccine components is imperative to the prevention of future life-threatening diseases.

Contact lenses (CLs) are prone to biofilm formation, which may cause severe ocular infections. Since the use of antibiotics is associated with resistance concerns, here, two alternative strategies were evaluated to endow CLs with antibiofilm features: copolymerization with the antifouling monomer 2-methacryloyloxyethyl phosphorylcholine (MPC) and loading of the antioxidant resveratrol with known antibacterial activity. MPC has, so far, been used to increase water retention on the CL surface (Proclear® 1 day CLs). Both poly(hydroxyethyl methacrylate) (HEMA) and silicone hydrogels were prepared with MPC covering a wide range of concentrations (from 0 to 101 mM). All hydrogels showed physical properties adequate for CLs and successfully passed the hen’s egg-chorioallantoic membrane (HET-CAM) test. Silicone hydrogels had stronger affinity for resveratrol, with higher loading and a slower release rate. Ex vivo cornea and sclera permeability tests revealed that resveratrol released from the hydrogels readily accumulated in both tissues but did not cross through. The antibiofilm tests against Pseudomonas aeruginosa and Staphylococcus aureus evidenced that, in general, resveratrol decreased biofilm formation, which correlated with its concentration-dependent antibacterial capability. Preferential adsorption of lysozyme, compared to albumin, might also contribute to the antimicrobial activity. In addition, importantly, the loading of resveratrol in the hydrogels preserved the antioxidant activity, even against photodegradation. Overall, the designed hydrogels can host therapeutically relevant amounts of resveratrol to be sustainedly released on the eye, providing antibiofilm and antioxidant performance.

Statins are receiving increasing attention in the ophthalmic field. Their activity as 3-hydroxy-3-methylglutaryl–CoA (HMG–CoA) reductase inhibitors is clinically used to regulate cholesterol levels and leads to pleiotropic effects, which may help in the management of diabetes-related ocular pathologies. This work aims to design bioinspired contact lenses (CLs) with an affinity for atorvastatin by mimicking the active site of HMG–CoA reductase. Sets of imprinted and nonimprinted 2-hydroxyethyl methacrylate (HEMA) hydrogels were synthesized, varying the contents in functional monomers that bear chemical groups that resemble those present in HMG–CoA reductase, namely, ethylene glycol phenyl ether methacrylate (EGPEM), 2-aminoethyl methacrylate hydrochloride (AEMA), and N-(3-aminopropyl) methacrylamide hydrochloride (APMA). The hydrogels were characterized in terms of suitability as CLs (solvent uptake, light transmission, mechanical properties, and biocompatibility) and capability to load and release atorvastatin. Three sterilization protocols (steam heat, gamma radiation, and high hydrostatic pressure) were implemented and their effects on hydrogel properties were evaluated. Copolymerization of AEMA and, particularly, APMA endowed the hydrogels with a high affinity for atorvastatin (up to 11 mg/g; KN/W > 200). Only high hydrostatic pressure sterilization preserved atorvastatin stability and hydrogel performance. Permeability studies through the porcine cornea and sclera tissues revealed that the amount of atorvastatin accumulated in the cornea and sclera could be effective to treat ocular surface diseases.