Polyvalent Bacterial Lysate with Potential Use to Treatment and Control of Recurrent Urinary Tract Infections.

Overuse of antimicrobials has greatly contributed to the increase in the emergence of multidrug-resistant bacteria, a situation that hinders the control and treatment of infectious diseases. This is the case with urinary tract infections (UTIs), which represent a substantial percentage of worldwide public health problems, thus the need to look for alternatives for their control and treatment. Previous studies have shown the usefulness of autologous bacterial lysates as an alternative for the treatment and control of UTIs. However, a limitation is the high cost of producing individual immunogens. At the same time, an important aspect of vaccines is their immunogenic amplitude, which is the reason why they must be constituted of diverse antigenic components. In the case of UTIs, the etiology of the disease is associated with different bacteria, and even Escherichia coli, the main causal agent of the disease, is made up of several antigenic variants. In this work, we present results on the study of a bacterial lysate composed of 10 serotypes of Escherichia coli and by Klebsiella pneumoniae, Klebsiella aerogenes, Enterococcus faecalis, Proteus mirabilis, Citrobacter freundii, and Staphylococcus haemolyticus. The safety of the compound was tested on cells in culture and in an animal model, and its immunogenic capacity by analysing in vitro human and murine macrophages (cell line J774 A1). The results show that the polyvalent lysate did not cause damage to the cells in culture or alterations in the animal model used. The immunostimulatory activity assay showed that it activates the secretion of TNF-α and IL-6 in human macrophages and TNF-α in murine cells. The obtained results suggest that the polyvalent lysate evaluated can be an alternative for the treatment and control of chronic urinary tract infections, which will reduce the use of antimicrobials.

Model-free decision making resists improved instructions and is enhanced by stimulus-response associations.

Human behaviour may be thought of as supported by two different computational-learning mechanisms, model-free and model-based respectively. In model-free strategies, stimulus-response associations are strengthened when actions are followed by a reward and weakened otherwise. In model-based learning, previous to selecting an action, the current values of the different possible actions are computed based on a detailed model of the environment. Previous research with the two-stage task suggests that participants' behaviour usually shows a mixture of both strategies. But, interestingly, a recent study by da Silva and Hare (2020) found that participants primarily deploy model-based behaviour when they are given detailed instructions about the structure of the task. In the present study, we reproduce this essential experiment. Our results confirm that improved instructions give rise to a stronger model-based component. Crucially, we also found a significant effect of reward that became stronger under conditions that favoured the development of strong stimulus-response associations. This suggests that the effect of reward, often taken as indicator of a model-free component, is related to stimulus-response learning.

State-of-the-art image and video quality assessment with a metric based on an intrinsically non-linear neural summation model.

The development of automatic methods for image and video quality assessment that correlate well with the perception of human observers is a very challenging open problem in vision science, with numerous practical applications in disciplines such as image processing and computer vision, as well as in the media industry. In the past two decades, the goal of image quality research has been to improve upon classical metrics by developing models that emulate some aspects of the visual system, and while the progress has been considerable, state-of-the-art quality assessment methods still share a number of shortcomings, like their performance dropping considerably when they are tested on a database that is quite different from the one used to train them, or their significant limitations in predicting observer scores for high framerate videos. In this work we propose a novel objective method for image and video quality assessment that is based on the recently introduced Intrinsically Non-linear Receptive Field (INRF) formulation, a neural summation model that has been shown to be better at predicting neural activity and visual perception phenomena than the classical linear receptive field. Here we start by optimizing, on a classic image quality database, the four parameters of a very simple INRF-based metric, and proceed to test this metric on three other databases, showing that its performance equals or surpasses that of the state-of-the-art methods, some of them having millions of parameters. Next, we extend to the temporal domain this INRF image quality metric, and test it on several popular video quality datasets; again, the results of our proposed INRF-based video quality metric are shown to be very competitive.

Iridium-Complexed Dipyridyl-Pyridazine Organosilica as a Catalyst for Water Oxidation.

The heterogenization of metal-complex catalysts to be applied in water oxidation reactions is a currently growing field of great scientific impact for the development of energy conversion devices simulating the natural photosynthesis process. The attachment of IrCp*Cl complexes to the dipyridyl-pyridazine N-chelating sites on the surface of SBA-15 promotes the formation of metal bipyridine-like complexes, which can act as catalytic sites in the oxidation of water to dioxygen, the key half-reaction of artificial photosynthetic systems. The efficiency of the heterogeneous catalyst, Ir@NdppzSBA, in cerium(IV)-driven water oxidation was thoroughly evaluated, achieving high catalytic activity even at a long reaction time. The reusability and stability were also examined after three reaction cycles, with a slight loss of activity. A comparison with an analogous homogeneous iridium catalyst revealed the enhanced durability and performance of the heterogeneous system based on the Ir@NdppzSBA catalyst due to the stability of the SBA-15 structure as well as the isolated metal active sites. Thereby, this new versatile synthesis route for the preparation of water oxidation catalysts opens a new avenue for the construction of alternative heterogeneous catalytic systems with high surface area, ease of functionalization, and facile separation to improve the efficiency in the water oxidation reaction.

Visual motion discrimination experiments reveal small differences between males and females.

Recent results have shown that males have lower duration thresholds for motion direction discrimination than females. Measuring contrast thresholds, a previous study has shown that males have a greater sensitivity to fine details and fast flickering stimuli than females, and that females have a higher sensitivity to low spatial frequencies modulated at low temporal frequencies. Here, we present the data of a contrast-detection motion discrimination experiment and a reanalysis of four different motion discrimination experiments where we compare duration thresholds for males and females using different spatial frequencies, stimulus sizes, contrasts, and temporal frequencies (in two experiments, motion surround suppression was measured). Results from the main experiment and the reanalysis show that, in general, the association between sex and contrast and duration thresholds for motion discrimination is not significant, with males and females showing similar data patterns. Only the reanalysis of one out of four studies revealed different duration thresholds between males and females paired with a strong effect size supporting previous results in the literature, although motion surround suppression was identical between groups. Importantly, most of our results do not show significant differences between males and females in contrast and duration thresholds, suggesting that the sex variable may not be as relevant as previously claimed when testing visual motion discrimination.

Ru- and Ir-complex decorated periodic mesoporous organosilicas as sensitizers for artificial photosynthesis.

A versatile and facile strategy based on an inverse electron demand Diels-Alder reaction between 5-norbornen-2-yltriethoxysilane and a tetrazine derivative has been established for the synthesis of a new triethoxysilane precursor containing dipyridylpyridazine units. Such a precursor has been incorporated into the mesostructure of an ethylene-bridged periodic mesoporous organosilica (PMO) material through a one-pot synthesis via a co-condensation method. Upon attachment of Ru- and Ir-complexes to the pendant N-chelating heterocyclic ligands, the resulting decorated PMOs have acted as photosensitizers in artificial photosynthetic systems. The deposition of Pt on these PMOs has allowed us to obtain efficient photocatalytic materials for the hydrogen evolution reaction as a result of electron transfer from the light harvesting Ru- and Ir-complexes to the supported Pt nanoparticles through methyl viologen as an electron relay. They have exhibited total turnover number values of 573 and 846, respectively, under visible light irradiation. The role played by each component and the stability of the photocatalytic systems have been discussed. The present approach paves the way to the synthesis of different materials with coordination sites capable of forming surface complexes to be applied as sensitizers and catalysts.

Silicon Oxycarbide Porous Particles and Film Coating as Strategies for Tenofovir Controlled Release in Vaginal Tablets for HIV Prevention.

Sustained release of antiretroviral drugs is currently the most encouraging strategy for the prevention of the sexual transmission of HIV. Vaginal tablets based on hydrophilic gelling polymers are an interesting dosage form for this purpose, since they can be developed to modify the release of the drug depending on the tablet swelling. Tenofovir is a drug with proven activity in the prevention of HIV-1 infection, and it is possible to have it loaded in the surface of γ-aminopropyl trimethoxy silane-functionalized oxycarbide particles. These particles can be incorporated into the tablets, thus providing a sustained release of the drug. Moreover, the presence of the particles modifies the microstructure of the gel formed, as observed in scanning electron microscopy and Hg porosimetry studies, resulting into a gel with a narrow pore size distribution between 10 and 100 µm. This implies a lower volume of fluid incorporated into the gel during swelling studies, and therefore improved mucoadhesion times in ex vivo test. The coating of the formulations with Eudragit® RS modifies the swelling behavior of the tablets, which not only is decreased in magnitude but also extended in time, and as consequence the drug release is also prolonged for up to 7 days.

Applications of Chitosan in Surgical and Post-Surgical Materials.

The continuous advances in surgical procedures require continuous research regarding materials with surgical applications. Biopolymers are widely studied since they usually provide a biocompatible, biodegradable, and non-toxic material. Among them, chitosan is a promising material for the development of formulations and devices with surgical applications due to its intrinsic bacteriostatic, fungistatic, hemostatic, and analgesic properties. A wide range of products has been manufactured with this polymer, including scaffolds, sponges, hydrogels, meshes, membranes, sutures, fibers, and nanoparticles. The growing interest of researchers in the use of chitosan-based materials for tissue regeneration is obvious due to extensive research in the application of chitosan for the regeneration of bone, nervous tissue, cartilage, and soft tissues. Chitosan can serve as a substance for the administration of cell-growth promoters, as well as a support for cellular growth. Another interesting application of chitosan is hemostasis control, with remarkable results in studies comparing the use of chitosan-based dressings with traditional cotton gauzes. In addition, chitosan-based or chitosan-coated surgical materials provide the formulation with antimicrobial activity that has been highly appreciated not only in dressings but also for surgical sutures or meshes.

Optimized hydration dynamics in mucoadhesive xanthan-based trilayer vaginal films for the controlled release of tenofovir.

Karaya gum, pectin and xanthan gum have been tested as candidates for manufacturing mucoadhesive trilayer films containing ethylcellulose and chitosan for the vaginal administration of the antiviral Tenofovir (TFV). The swelling profile correlated with the amount of mobile dipoles determined by impedance spectroscopy allows the determination of the hydration dynamics of these films. The fast water penetration has been demonstrated to favor the formation of polyelectrolyte complexes (PEC) via hydrogen or ionic bonds which would favor a controlled release. The incorporation of an inorganic drug release regulator induces the weakness of the polymeric chains thus enhancing the ionic mobility via the formation of low molecular weight PECs in films manufactured with karaya gum. Due to the different mechanical properties of the individual components, pectin-based films failed for a potential pharmaceutical formulation. However, mucoadhesive trilayer films produced with xanthan gum have demonstrated a moderate swelling, improved wettability and a controlled release of TFV.

Bigels as drug delivery systems: From their components to their applications.

Bigels are systems that usually result from mixing a hydrogel and an organogel: the aqueous phase is commonly formed by a hydrophilic biopolymer, whereas the organic phase comprises a gelled vegetable oil because of the presence of an organogelator. The proportion of the corresponding gelling agent in each phase, the organogel/hydrogel ratio, and the mixing temperature and speed all need to be taken into consideration for bigel manufacturing. Bigels, which are particularly useful drug delivery systems, have already been formulated for transdermal, buccal, and vaginal routes. Mechanical assessments and microscopy are the most reported characterization techniques. As we review here, their composition and unique structure confer promising drug delivery attributes, such as mucoadhesion, the ability to control drug release, and the possibility of including both hydrophilic and lipophilic drugs in the same system.

Silane Modification of Mesoporous Materials for the Optimization of Antiviral Drug Adsorption and Release Capabilities in Vaginal Media.

Three different functionalities have been incorporated into mesoporous materials by means of a coupling reaction with the siloxanes 3-glycidoxypropyl-trimethoxysilane (GLYMO), 3-methacryloxypropyl-trimethoxysilane (MEMO), and 3-mercaptopropyl-trimethoxysilane (MPTMS). The disposition of the different functional groups, as well as the interaction mechanism, with the mesoporous substrate has been identified. The amount of the antiviral drug acyclovir (ACV) adsorbed depends not only on the available surface area but also on the chemical or physicochemical interactions between functionalities. The drug adsorption isotherm of the materials functionalized with GLYMO and MPTMS follow mechanisms dependent on the different surface coverage and the possibilities to establish physicochemical interactions between the drug molecule and the functionalities. On the contrary, when functionalizing with MEMO, the dominant adsorption mechanism is characteristic of chemically bonded adsorbates. The ACV release kinetics is best fitted to the Weibull model in all the functionalized materials. When the MTPMS is used as a functionalizing agent, the drug diffusion occurs at low kinetics and homogeneously along the mesoporous channels.

Recent advances in electrospun nanofiber vaginal formulations for women's sexual and reproductive health.

Electrospinning is an innovative technique that allows production of nanofibers and microfibers by applying a high voltage to polymer solutions of melts. The properties of these fibers - which include high surface area, high drug loading capacity, and ability to be manufactured from mucoadhesive polymers - may be particularly useful in a myriad of drug delivery and tissue engineering applications. The last decade has witnessed a surge of interest in the application of electrospinning technology for the fabrication of vaginal drug delivery systems for the treatment and prevention of diseases associated with women's sexual and reproductive health, including sexually transmitted infections (e.g. infection with human immunodeficiency virus and herpes simplex virus) vaginitis, preterm birth, contraception, multipurpose prevention technology strategies, cervicovaginal cancer, and general maintenance of vaginal health. Due to their excellent mechanical properties, electrospun scaffolds are also being investigated as next-generation materials in the surgical treatment of pelvic organ prolapse. In this article, we review the latest advances in the field.

Naturally Occurring Polyelectrolytes and Their Use for the Development of Complex-Based Mucoadhesive Drug Delivery Systems: An Overview.

Biopolymers have several advantages for the development of drug delivery systems, since they are biocompatible, biodegradable and easy to obtain from renewable resources. However, their most notable advantage may be their ability to adhere to biological tissues. Many of these biopolymers have ionized forms, known as polyelectrolytes. When combined, polyelectrolytes with opposite charges spontaneously form polyelectrolyte complexes or multilayers, which have great functional versatility. Although only one natural polycation-chitosan has been widely explored until now, it has been combined with many natural polyanions such as pectin, alginate and xanthan gum, among others. These polyelectrolyte complexes have been used to develop multiple mucoadhesive dosage forms such as hydrogels, tablets, microparticles, and films, which have demonstrated extraordinary potential to administer drugs by the ocular, nasal, buccal, oral, and vaginal routes, improving both local and systemic treatments. The advantages observed for these formulations include the increased bioavailability or residence time of the formulation in the administration zone, and the avoidance of invasive administration routes, leading to greater therapeutic compliance.

Smart vaginal bilayer films of Tenofovir based on Eudragit® L100/natural polymer for the prevention of the sexual transmission of HIV.

In the absence of an effective vaccine, vaginal microbicides are essential for preventing the sexual transmission of HIV to women. Antiretroviral vaginal films have emerged as promising choices, especially those offering mucoadhesivity and controlled drug release. Tenofovir-loaded bilayer films based on Eudragit® L100 (EL100) and a biopolymer - gum arabic, karaya gum, pectin or tragacanth gum - were developed in a single-stage process. Cytotoxicity studies in three human cell lines indicated no toxicity of the excipients at the concentrations tested. Raman spectroscopy and SEM confirmed the formation of the two layers and their anchoring. Texture analysis showed no major differences between the batches. The swelling of the film is conditioned by its biopolymer nature and by the amount of EL100, which acts as structuring agent thus enhancing swelling. Tragacanth gum-based batches showed high mucoadhesion regardless the amount of EL100. The controlled release of Tenofovir in simulated vaginal fluid was faster in the presence of simulated seminal fluid due to the dissolution of EL100. Films containing 400 mg of EL100 and tragacanth gum are promising candidates for future studies, as they could sexually safeguard women from HIV for at least one week and ensure greater protection during intercourse.

Achieving visual stability during smooth pursuit eye movements: Directional and confidence judgements favor a recalibration model.

During smooth pursuit eye movements, the visual system is faced with the task of telling apart reafferent retinal motion from motion in the world. While an efference copy signal can be used to predict the amount of reafference to subtract from the image, an image-based adaptive mechanism can ensure the continued accuracy of this computation. Indeed, repeatedly exposing observers to background motion with a fixed direction relative to that of the target that is pursued leads to a shift in their point of subjective stationarity (PSS). We asked whether the effect of exposure reflects adaptation to motion contingent on pursuit direction, recalibration of a reference signal or both. A recalibration account predicts a shift in reference signal (i.e. predicted reafference), resulting in a shift of PSS, but no change in sensitivity. Results show that both directional judgements and confidence judgements about them favor a recalibration account, whereby there is an adaptive shift in the reference signal caused by the prevailing retinal motion during pursuit. We also found that the recalibration effect is specific to the exposed visual hemifield.

Influence of Plasticizers on the pH-Dependent Drug Release and Cellular Interactions of Hydroxypropyl Methylcellulose/Zein Vaginal Anti-HIV Films Containing Tenofovir.

Vaginal films featuring the pH-dependent release of tenofovir (TFV) were developed for the prevention of sexual transmission of human immunodeficiency syndrome (HIV). Films based on hydroxypropyl methylcellulose and zein were prepared incorporating different plasticizers [oleic acid, lactic acid, glycerol, and polyethylene glycol 400 (PEG)] and evaluated for in vitro drug release in an acidic simulated vaginal fluid (pH 4.2) and a slightly alkaline mixture of simulated seminal and vaginal fluids (pH 7.5). Results revealed that optimal biphasic TFV release was possible with proper combination of plasticizers (PEG and oleic acid, 1:7 w/w) and by adjusting the plasticizer/matrix-forming material ratio. The films had similar or higher levels of TFV associated with genital epithelial cells (Ca Ski or HEC-1-A cells) but lower drug permeability compared to the free drug. These data confirm that films have the potential to achieve suitable mucosal levels of TFV with low systemic exposure. The films developed could protect women from HIV sexual transmission.

Development of pH-sensitive vaginal films based on methacrylate copolymers for topical HIV-1 pre-exposure prophylaxis.

Interest is growing in "smart" vaginal microbicides as a strategy to protect women from sexual transmission of human immunodeficiency virus (HIV). The concept is based on the development of products featuring low drug release in acidic media such as vaginal fluid but switch to a fast release profile when the medium becomes neutral or slightly alkaline. This mimics the surge in pH occurring in the vagina after sexual intercourse due to the seminal fluid. Semen is the main vehicle for HIV-1, and increasing antiretroviral drug levels in the vagina upon ejaculation may contribute to enhanced protection against viral sexual transmission. This work explores the use of different pharmaceutical-grade methacrylic acid-based polymers (EudragitⓇ RL, RS, L and S) for developing vaginal films allowing the pH-dependant release of the antiretroviral drug tenofovir (TFV). EudragitⓇ L 100 and EudragitⓇ S 100, containing triethyl citrate as plasticiser, proved to be suitable for manufacturing films with optimal dual in vitro drug-release behaviour. TFV-release can be sustained for several days after film administration and all the drug is released in a few hours in conditions simulating ejaculation. The films' mechanical properties were also deemed suitable for comfortable vaginal administration. Two optimized films were further assessed using HEC-1-A and Ca Ski cell monolayer models and were found to possess favourable drug permeability profiles and drug levels associated to cell monolayer as compared to free TFV. Overall, pH-dependant films containing tenofovir may constitute promising candidates for "smart" vaginal microbicides to protect women from sexual HIV transmission.

Design, fabrication and characterisation of drug-loaded vaginal films: State-of-the-art.

Films have undoubtedly seen the most significant advances in their development in recent years of all the pharmaceutical forms for the vaginal administration of drugs. Films combine the advantages of gels and solid pharmaceutical forms, and their great versatility is largely determined by the numerous polymers that can be used for their fabrication. They may be based on many natural polymers, and cellulose derivatives, polyvinyl alcohol or acrylic derivatives - among others - are also frequently used. The combination of different polymers and the inclusion of plasticizing agents makes them extremely versatility for responding to a range of therapeutic needs. The techniques used to produce films have also undergone substantial development. Although the solvent casting technique is by far the most widely used in fabrication, alternative options have also emerged such as electrospinning, moulding extrusion and 3D printing. Various research groups have proposed a proliferation of assays to characterise vaginal films in recent years, which highlight the importance of the preliminary evaluation and determination of the films' uniformity, in addition to tests to determine their permeability and hydrophilic/hydrophobic coefficient and their mechanical properties, the application of imaging techniques and thermal analysis, and especially the evaluation of the mucoadhesive properties and control over the drug release. This article offers a critical overview of the advances in the development and fabrication of films intended for vaginal drug delivery, and summarises current clinical applications for vaginal films.

Amino Functionalized Micro-Mesoporous Hybrid Particles for the Sustained Release of the Antiretroviral Drug Tenofovir.

The sustained release of an antiretroviral agent to women mucosa has been proved as an excellent strategy to reduce the sexual transmission of HIV. Hybrid micro-mesoporous particles have been synthesized and functionalized with a silane coupling agent followed by loading the antiretroviral tenofovir. It has been observed that the disposition of the silane molecule on the surface of the particles determines the interaction mechanism with the antiretroviral molecule loaded independently on the surface area of the particles. In this sense, available and free amino groups are required to achieve a smart pH-responsive material, a condition that is only achieved in those materials containing a silane chemisorbed monolayer. Moreover, the modulation of the release kinetics attributed to the presence of the silane monolayer covering the mesopores has been confirmed by fitting the releasing curves to the first order and Weibull models. The developed micro-mesoporous particles have been demonstrated to be excellent smart-release vehicles for antiviral agents and can be safely used in polymer mucoadhesive vaginal gels.

Evidence for different spatiotemporal mechanisms using duration thresholds: An individual differences approach.

The study of motion perception through classical psychophysical methods has suggested that independent spatiotemporal filters acting over specific locations in retinal images carry out early motion processing. On the other hand, individual differences approaches have been able to identify a structure of spatiotemporal filters too. In this same fashion-through an individual differences approach-the present study aims to uncover a structure of spatiotemporal frequency selective motion mechanisms. This is done, for the first time, using supra-threshold contrast stimuli in a motion direction discrimination task. Two experiments were performed measuring duration thresholds for drifting 2D Gabor gratings of 0.25, 0.5, 0.75, 1, 1.5, 2, 3 and 6 c/deg. They moved with a speed of 2 deg/sec, with Michelson contrasts of 0.1 or 0.9 (Experiment 1) or had a contrast of 0.9 drifting with a temporal frequency of 2 Hz or 8 Hz (Experiment 2). Principal component analyses uncover three factors in each of four conditions. When Varimax-rotated, these are seen to be selective to spatial frequencies lower than 0.5 c/deg, intermediate ones from 0.5 to 1-1.5 c/deg, and frequencies greater than 1-1.5 c/deg. Direct Oblimin rotations indicate that factors are moderately correlated. Further analyses show very slight differences in the correlational structures between contrast conditions (0.1 vs. 0.9), and no differences between temporal frequency conditions (2 Hz vs. 8 Hz). To conclude, the idea of a three-factor structure in motion processing for low, intermediate, and high spatial frequencies is supported.