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Humans are the most versatile tool users among animals. Accordingly, our manual skills evolved alongside the shape of the hand. In the future, further evolution may take place: humans may merge with their tools, and technology may integrate into our biology in a way that blurs the line between the two. So, the question is whether humans can embody a bionic tool (i.e., experience it as part of their body) and thus if this would affect behavior. We investigated in virtual reality how the substitution of the hand with a virtual grafting of an end-effector, either non-naturalistic (a bionic tool) or naturalistic (a hand), impacts embodiment and behavior. Across four experiments, we show that the virtual grafting of a bionic tool elicits a sense of embodiment similar to or even stronger than its natural counterpart. In conclusion, the natural usage of bionic tools can rewire the evolution of human behavior., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

The large number of studies involving nanoparticles for cancer therapy is due to their peculiar features: they protect loaded active molecules while extending circulation time and can extravasate from the blood flow to the tumor to deliver drugs directly in the target area. Mathematical modeling can provide a preliminary in silico exploration of design space to optimize an experimental activity that often relies on a trial-and-error approach. However, because of the characteristic size of these vectors (10-1000 nm), numerous phenomena of interest occur at different time and length scales, making a single modeling technique insufficient to fully characterize the system of interest. In this work we employed a multiscale modeling approach, which bridges the phenomena of interest across different scales, to study the in vitro release from polymeric core/shell nanoparticles for cancer therapy loaded with an active compound assembled as a hydrophobic ion pair. The "computational microscope" provided by molecular dynamics simulations was used to track drug molecules through the release process at an atomic scale. The outcomes suggested that the drug is mainly partitioned in the polymer and released as hydrophobic ion pair rather than a free molecule, and that the hydrophobic ion pair is preferentially partitioned in Tween 20 micelles in the release media. A model at macroscale, aimed at describing the release rate and elucidating the release mechanism, was developed according to the results from molecular simulations and validated against experimental data. The outcomes provided insights that are challenging to be obtained experimentally and which supported the development and validation of a release model at macroscale. Overall, the adopted multiscale approach corroborated the experimental findings and provided significant insights into the mechanisms of release.

About one-third of stroke survivors present unilateral spatial neglect (USN) that negatively impacts the rehabilitation outcome. We reported the study protocol and usability results of an eye-tracking (ET) biofeedback immersive virtual reality (iVR) protocol. Healthy controls and stroke patients with and without USN underwent a single session of the three iVR tasks. The system usability scale (SUS), adverse events (AEs), and ET data were collected and analyzed via parametric analysis. Twelve healthy controls (six young adults and six older adults) and seven patients with a diagnosis of single ischemic stroke (four without USN and three with confirmed diagnosis of USN) completed the usability investigation. SUS results showed good acceptability of the system for healthy controls and stroke patients without USN. ET results showed a lower performance for patients with USN concerning healthy controls and stroke patients without USN, in particular in the exploration of the left visual field. The results showed that the proposed iVR-ET biofeedback protocol is a safe and well-tolerated technique in patients with USN. The real-time feedback can induce a performance response supporting its investigation such as a treatment approach.

Crystals of active pharmaceutical ingredients (API) are prone to triboelectric charging due to their dielectric nature. This characteristic, coupled with their typically low density and often large aspect ratio, poses significant challenges in the manufacturing process. The pharmaceutical industry frequently encounters issues during the secondary processing of APIs, such as particle adhesion to walls, clump formation, unreliable flow, and the need for careful handling to mitigate the risk of fire and explosions. These challenges are further intensified by the limited availability of powder quantities for testing, particularly in the early stages of drug development. Therefore, it is highly desirable to develop predictive tools that can assess the triboelectric propensity of APIs. In this study, Density Functional Theory calculations are employed to predict the effective work function of different facets of aspirin and paracetamol crystals, both in a vacuum and in the presence of water molecules on their surfaces. The calculations reveal significant variations in the work function across different facets and materials. Moreover, the adsorption of water molecules induces a shift in the work function. These findings underscore the considerable impact of distinct surface terminations and the presence of molecular water on the calculated effective work function of pharmaceuticals. Consequently, this approach offers a valuable predictive tool for determining the triboelectric propensity of APIs., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Inoculants with beneficial microorganisms comprise both selected strains and carriers that ensure a favorable microenvironment for cell survival and stability. Formulations of inoculants using synthetic polymers as carriers are common. However, only a few studies are available in the literature regarding the formulation of inoculants using natural biomolecules as carriers. Exopolysaccharides (EPS) are biomolecules produced by a vast array of microbial species, including symbiotic nitrogen-fixing bacteria, commonly known as rhizobia. EPS perform several functions, such as the protection against the deleterious effects of diverse environmental soil stresses. Two Rhizobium tropici strains and one Paraburkholderia strain were selected after semiquantitative analysis by scanning electron microscopy (SEM) of their EPS production in liquid YMA medium. Their EPS were characterized through a series of analytical techniques, aiming at their use in the formulation of plant inoculants. In addition, the effect of the carbon source on EPS yield was evaluated. Multi-stage fragmentation analysis showed the presence of xylose, glucose, galactose, galacturonic acid, and glucuronic acid in EPS chemical composition, which was confirmed by FT-IR spectra and 13 C NMR spectroscopy. Thermal stability (thermogravimetric) was close to 270 °C and viscosity ranged from 120 to 1053.3 mPa.s. Surface morphology (SEM) was rough and irregular, with a cross-linked spongy matrix, which, together with the hydrophilic functional groups, confers water holding capacity. The present study showed that the three EPS have potential as microorganism carriers for formulation of microbial inoculants to be applied in plants., (© 2022. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

This is a monocentric and cross-sectional study conducted at the COVID-19 Division of the Obstetrical and Gynecological Unit and Intensive Care Units (ICUs) of Policlinico di Bari, in Bari, Italy, between September 2020 and April 2022. This study aimed to identify the prevalence of severe-critical COVID-19 illness requiring access to the Intensive Care Unit (ICU) among 287 pregnant patients, and possible correlations between the SARS-CoV-2 variants, the specific pandemic wave (dominated by wild, Alpha, Delta, and Omicron strains), and severe-critical adverse maternal outcomes. The prevalence of severe-critical COVID-19 illness was 2.8% (8/287), reaching 4.9% (8/163) excluding the 4th wave (Omicron dominant). The Delta variant determined the highest risk ratio and odds for access to the ICU due to severe-critical COVID-19-related symptoms compared to the other variants (wild, Alpha, Omicron). During the third wave (Delta), the ICU cases underwent a higher rate of hyperimmune plasma infusion (75%), antibiotic therapy (75%), and remdesivir (33%); all of the patients were intubated. During the Omicron wave, the patients were asymptomatic or with few symptoms: most of them (70%) were vaccinated with a median of two doses. The maternal outcome worsened in the case of Alpha and, especially, Delta variants for severe-critical COVID-19-related symptoms and ICU access.

An unmodified, non-spherical, hydride-dehydride (HDH) Ti-6Al-4V powder having a substantial economic advantage over spherical, atomized Ti-6Al-4V alloy powder was used to fabricate a range of test components and aerospace-related products utilizing laser beam powder-bed fusion processing. The as-built products, utilizing optimized processing parameters, had a Rockwell-C scale (HRC) hardness of 44.6. Following heat treatments which included annealing at 704 °C, HIP at ~926 °C (average), and HIP + anneal, the HRC hardnesses were observed to be 43.9, 40.7, and 40.4, respectively. The corresponding tensile yield stress, UTS, and elongation for these heat treatments averaged 1.19 GPa, 1.22 GPa, 8.7%; 1.03 GPa, 1.08 GPa, 16.7%; 1.04 GPa, 1.09 GPa, 16.1%, respectively. The HIP yield strength and elongation of 1.03 GPa and 16.7% are comparable to the best commercial, wrought Ti-6Al-4V products. The corresponding HIP component microstructures consisted of elongated small grains (~125 microns diameter) containing fine, alpha/beta lamellae.

Powders are usually dispensed, blended, and transferred between different manufacturing steps in so-called Intermediate Bulk Containers (IBCs), and discharge from an IBC plays a critical role in the ability to manufacture high-quality tablets. To better understand IBC discharge, the flow behavior of selected excipients was comprehensively characterized using a number of techniques including the Hausner ratio/Carr's index, Erweka flow test, FlowPro flow test, shear test and wall friction test as well as FT4 powder rheometer experiments. Jenike's hopper design methodology was then used to predict the minimum non-arching outlet diameter and the mode of flow. Furthermore, the discharge rate from an IBC was predicted using a simple model that takes into account gravity and aerodynamic drag. The predictions were experimentally verified by measuring the discharge rate from a 20 L IBC using five commonly-used excipients. The small-scale Erweka flow test provided the best prediction of the full-scale IBC discharge experiment. Furthermore, a simple model that relied only on the particle size of the material and the diameter of the discharge opening was found to predict the IBC discharge rate remarkably well., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Real-world experience is typically multimodal. Evidence indicates that the facilitation in the detection of multisensory stimuli is modulated by the perceptual load, the amount of information involved in the processing of the stimuli. Here, we used a realistic virtual reality environment while concomitantly acquiring Electroencephalography (EEG) and Galvanic Skin Response (GSR) to investigate how multisensory signals impact target detection in two conditions, high and low perceptual load. Different multimodal stimuli (auditory and vibrotactile) were presented, alone or in combination with the visual target. Results showed that only in the high load condition, multisensory stimuli significantly improve performance, compared to visual stimulation alone. Multisensory stimulation also decreases the EEG-based workload. Instead, the perceived workload, according to the "NASA Task Load Index" questionnaire, was reduced only by the trimodal condition (i.e., visual, auditory, tactile). This trimodal stimulation was more effective in enhancing the sense of presence, that is the feeling of being in the virtual environment, compared to the bimodal or unimodal stimulation. Also, we show that in the high load task, the GSR components are higher compared to the low load condition. Finally, the multimodal stimulation (Visual-Audio-Tactile-VAT and Visual-Audio-VA) induced a significant decrease in latency, and a significant increase in the amplitude of the P300 potentials with respect to the unimodal (visual) and visual and tactile bimodal stimulation, suggesting a faster and more effective processing and detection of stimuli if auditory stimulation is included. Overall, these findings provide insights into the relationship between multisensory integration and human behavior and cognition.

The objective of this study was to characterize the rheology of a pharmaceutical material in the context of the µ(I)-rheology model and to use this model to predict powder flow in a manufacturing operation that is relevant to pharmaceutical manufacturing. The rheology of microcrystalline cellulose spheres was therefore characterized in terms of the μ(I)-rheology model using a modified Malvern Kinexus rheometer. As an example of an important problem in pharmaceutical manufacturing, the flow of these particles from a hopper was studied experimentally and numerically using a continuum Navier-Stokes solver based on the Volume-Of-Fluid (VOF) interface-capturing numerical method. The work shows that the rheology of this typical pharmaceutical material can be measured using a modified annular shear rheometer and that the results can be interpreted in terms of the μ(I)-rheology model. It is demonstrated that both the simulation results and the experimental data show a constant hopper discharge rate. It is noted that the model can suffer from ill-posedness and it is shown how an increasingly fine grid resolution can result in predictions that are not entirely physically realistic. This shortcoming of the numerical framework implies that caution is required when making a one-to-one comparison with experimental data., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We combined virtual reality and multisensory bodily illusion with the aim to characterize and reduce the perceptual (body overestimation) and the cognitive-emotional (body dissatisfaction) components of body image distortion (BID) in anorexia nervosa (AN). For each participant (20 anorexics, 20 healthy controls) we built personalized avatars that reproduced their own body size, shape, and verisimilar increases and losses of their original weight. Body overestimation and dissatisfaction were measured by asking participants to choose the avatar that best resembled their real and ideal body. Results show higher body dissatisfaction in AN, caused by the desire of a thinner body, and no body-size overestimation. Interpersonal multisensory stimulation (IMS) was then applied on the avatar reproducing participant's perceived body, and on the two avatars which reproduced increases and losses of 15% of it, all presented with a first-person perspective (1PP). Embodiment was stronger after synchronous IMS in both groups, but did not reduce BID in participants with AN. Interestingly, anorexics reported more negative emotions after embodying the fattest avatar, which scaled with symptoms severity. Overall, our findings suggest that the cognitive-emotional, more than the perceptual component of BID is severely altered in AN and that perspective (1PP vs. 3PP) from which a body is evaluated may play a crucial role. Future research and clinical trials might take advantage of virtual reality to reduce the emotional distress related to body dissatisfaction.

Polymer films based on mixtures of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) have been widely used to coat pellets and tablets to modify the release profile of drugs. For three different EC/HPC films we used 1 H and 19 F MRI in combination with a designed release cell to monitor the drug, polymer and water in 5 dimensional (5D) datasets; three spatial, one diffusion or relaxation and a temporal dimension, in real time. We observed that the water inflow through the films correlated with the initiation of the dissolution of the drug in the tablet beneath the film. Leaching of the pore forming HPC further accelerated water penetration and resulted in a drug release onset after a hydrostatic pressure was generated below the film indicated by positional changes of the film. For the more permeable film, both water ingress and drug egress showed a large variability of release over the film surface indicating the heterogeneity of the system. Furthermore, the 1 H diffusion dataset revealed the formation of a gel layer of HPC at the film surface. We conclude that the setup presented provides a significant level of details, which are not achieved with traditional methods., (Copyright © 2019 Elsevier B.V. All rights reserved.)

New solutions in operational environments are often, among objective measurements, evaluated by using subjective assessment and judgment from experts. Anyhow, it has been demonstrated that subjective measures suffer from poor resolution due to a high intra and inter-operator variability. Also, performance measures, if available, could provide just partial information, since an operator could achieve the same performance but experiencing a different workload. In this study, we aimed to demonstrate: (i) the higher resolution of neurophysiological measures in comparison to subjective ones; and (ii) how the simultaneous employment of neurophysiological measures and behavioral ones could allow a holistic assessment of operational tools. In this regard, we tested the effectiveness of an electroencephalography (EEG)-based neurophysiological index (W EEG index) in comparing two different solutions (i.e., Normal and Augmented) in terms of experienced workload. In this regard, 16 professional air traffic controllers (ATCOs) have been asked to perform two operational scenarios. Galvanic Skin Response (GSR) has also been recorded to evaluate the level of arousal (i.e., operator involvement) during the two scenarios execution. NASA-TLX questionnaire has been used to evaluate the perceived workload, and an expert was asked to assess performance achieved by the ATCOs. Finally, reaction times on specific operational events relevant for the assessment of the two solutions, have also been collected. Results highlighted that the Augmented solution induced a local increase in subjects performance (Reaction times). At the same time, this solution induced an increase in the workload experienced by the participants (W EEG ). Anyhow, this increase is still acceptable, since it did not negatively impact the performance and has to be intended only as a consequence of the higher engagement of the ATCOs. This behavioral effect is totally in line with physiological results obtained in terms of arousal (GSR), that increased during the scenario with augmentation. Subjective measures (NASA-TLX) did not highlight any significant variation in perceived workload. These results suggest that neurophysiological measure provide additional information than behavioral and subjective ones, even at a level of few seconds, and its employment during the pre-operational activities (e.g., design process) could allow a more holistic and accurate evaluation of new solutions.

There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing., (Copyright © 2019 Elsevier B.V. All rights reserved.)

According to the most recent World Health Organization statistics, malaria infected approximately 219 million people in 2017, with an estimate of 435,000 deaths (World Health Organization, 2018). Communities isolated from cities are the most deprived of access to the necessary hospital facilities. Herein we report the development of a transdermal bioadhesive containing artemether (ART), an alternative, potentially lifesaving, treatment regimen for malaria in low-resource settings. Bioadhesives were prepared from an aqueous blend of hydroxyethylcellulose (4.5% w/w), ART, propoxylated-ethoxylated-cetyl-alcohol, polysorbate 80, propyleneglycol, glycerine, mineral oil, and oleic acid. In this study, the average pore size of bioadhesive 5.5b was 52.6 ± 15.31 μm. Differential scanning calorimetry and thermogravimetric analyses confirm the thermal stability of ART bioadhesives at room temperature. Tensile tests indicated good mechanical properties for bioadhesive 5.5b, when compared to 5.5a, where 5.5b showed elastic modulus 0.19 MPa, elongation at break 204%, tensile stress 0.31 MPa, tensile strength at break 0.23 MPa. Bioadhesion assays suggested that formulations containing surfactants had higher detachment forces. Permeation studies demonstrated that the best outcome was achieved with a bioadhesive containing 25 mg ART (5.5b) that after 24 h released 6971 ± 125 μg, which represents approximately 28% of drug permeation. Data reported presents a promising candidate for a new antimalarial transdermal formulation., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

This study aims at investigating the possibility to employ neurophysiological measures to assess the humanmachine interaction effectiveness. Such a measure can be used to compare new technologies or solutions, with the final purpose to enhance operator's experience and increase safety. In the present work, two different interaction modalities (Normal and Augmented) related to Air Traffic Management field have been compared, by involving 10 professional air traffic controllers in a control tower simulated environment. Experimental task consisted in locating aircrafts in different airspace positions by using the sense of hearing. In one modality (i.e. "Normal"), all the sound sources (aircrafts) had the same amplification factor. In the "Augmented" modality, the amplification factor of the sound sources located along the participant head sagittal axis was increased, while the intensity of sound sources located outside this axis decreased. In other words, when the user oriented his head toward the aircraft position, the related sound was amplified. Performance data, subjective questionnaires (i.e. NASA-TLX) and neurophysiological measures (i.e. EEG-based) related to the experienced workload have been collected. Results showed higher significant performance achieved by the users during the "Augmented" modality with respect to the "Normal" one, supported by a significant decreasing in experienced workload, evaluated by using EEG-based index. In addition, Performance and EEG-based workload index showed a significant negative correlation. On the contrary, subjective workload analysis did not show any significant trend. This result is a demonstration of the higher effectiveness of neurophysiological measures with respect to subjective ones for Human-Computer Interaction assessment.

The aim of this work was to investigate how manufacturing conditions influence phase-separated films of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) with different molecular weights of HPC. Two HPC grades, SSL and M, with weight average molecular weights (M w ) of 30×10 3 g/mol and 365×10 3 g/mol, respectively, were combined with EC 10 cps (70:30w/w EC/HPC) and spray-coated from ethanol solutions onto a rotating drum under well-controlled process conditions. Generally, a low spray rate resulted in a more rapid film drying process and, consequently, in smaller HPC-rich domains in the phase-separated film structure. For EC/HPC films with the low M w HPC (SSL) the most rapid drying process resulted in a shift from a HPC-discontinuous to a partly bicontinuous structure and an increase in the permeability for water. In contrast, films containing the high M w HPC (M) all showed bicontinuous structures, which resulted in overall higher water permeabilities and polymer release compared to the low M w films. Interestingly, a maximum in permeability was observed for the high M w films at intermediate spray rates. Below this spray rate the permeability decreased due to a lower amount of polymer released and at higher spray rates, the permeability decreased due to a loss of pore connectivity (or increased tortuosity). To conclude, this study shows that different M w systems of EC/HPC can respond differently to variations in manufacturing conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Biological systems are highly sensitive to changes in their environment. Indeed, the molecular basis of the environmental stress response suggests that the specialized stress responses share more commonalities than previously believed. Here, we used the nematode C. elegans to gain insight into the role of Rho signaling during two common environmental challenges, oxidative and thermal stress. In response to heat shock (HS), wild type (N2) worms demonstrated reduced viability which was rescued by genetic suppression of CDC42 and RHO-1. Visualization of F-actin by phalloidin-rhodamine underscored a strict correlation between the levels of F-actin following GTPase suppression and survival. Additionally, genetic ablation of OSG-1, a Guanine Nucleotide Exchange Factor (GEF) previously implicated in oxidative stress, was associated with constitutively lower levels of F-actin and increased mortality. However, upon an oxidative insult F-actin stability decreased in N2 worms, a rescue of this affect was observed in OSG-1 null worms, consistent with the resistance exhibited by these worms to oxidative stress (OS). Together these data suggest that during conditions of thermal or oxidative stress Rho signaling promotes vulnerability by altering actin dynamics. Thus, the stability of the actin cytoskeleton, in part through a conserved mechanism mediated by Rho signaling, is a crucial factor for the cell's survival to environmental challenges., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease ® and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease ® films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51μm) of the coating layer controlling the drug release rate., (Copyright © 2017. Published by Elsevier B.V.)

Purpose: A prospective phase 1-2 clinical trial aimed at determining the recommended postoperative dose of simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT) in a large series of patients with high-risk and intermediate-risk endometrial cancer (HIR-EC) is presented. The study also evaluated the association between rate and severity of toxicity and comorbidities and the clinical outcomes., Methods and Materials: Two SIB-VMAT dose levels were investigated for boost to the vaginal vault, whereas the pelvic lymph nodes were always treated with 45 Gy. The first cohort received a SIB-VMAT dose of 55 Gy in 25 consecutive 2.2-Gy fractions, and the subsequent cohort received higher doses (60 Gy in 2.4-Gy fractions)., Results: Seventy consecutive HIR-EC patients, roughly half of whom were obese (47.1%) or overweight (37.1%), with Charlson Age-Comorbidity Index >2 (48.5%), were enrolled. Thirty-one patients (44.3%) were administered adjuvant chemotherapy before starting radiation therapy. All patients (n=35 per dose level) completed irradiation without any dose-limiting toxicity. Proctitis (any grade) was associated with radiation therapy dose (P=.001); not so enterocolitis. Grade ≥2 gastrointestinal (GI) and genitourinary (GU) toxicity were recorded in 17 (24.3%) and 14 patients (20.0%), respectively, and were not associated with radiation dose. As for late toxicity, none of patients experienced late grade ≥3 GI or grade ≥2 GU toxicity. The 3-year late grade ≥2 GI and GU toxicity-free survival were 92.8% and 100%, respectively, with no difference between the 2 dose levels. With a median follow-up period of 25 months (range, 4-60 months), relapse/progression of disease was observed in 10 of 70 patients (14.2%). The 3-year cumulative incidence of recurrence was 1.5% (95% confidence interval (CI): 0.2-10.7), whereas the 3-year disease-free survival was 81.3% (95% CI: 65.0-90.0)., Conclusions: This clinical study showed the feasibility of this technique and its good profile in terms of acute and late toxicity at the recommended doses even in aged and frail patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Understanding how the pore structure influences the mass transport through a porous material is important in several applications, not the least in the design of polymer film coatings intended to control drug release. In this study, a polymer film made of ethyl cellulose and hydroxypropyl cellulose was investigated. The 3D structure of the films was first experimentally characterized using confocal laser scanning microscopy data and then mathematically reconstructed for the whole film thickness. Lattice Boltzmann simulations were performed to compute the effective diffusion coefficient of water in the film and the results were compared to experimental data. The local porosities and pore sizes were also analyzed to determine how the properties of the internal film structure affect the water effective diffusion coefficient. The results show that the top part of the film has lower porosity, lower pore size, and lower connectivity, which results in a much lower effective diffusion coefficient in this part, largely determining the diffusion rate through the entire film. Furthermore, the local effective diffusion coefficients were not proportional to the local film porosity, indicating that the results cannot be explained by a single tortuosity factor. In summary, the proposed methodology of combining microscopy data, mass transport simulations, and pore space analysis can give valuable insights on how the film structure affects the mass transport through the film.

Drug release from oral pharmaceutical formulations can be modified by applying a polymeric coating film with controlled mass transport properties. Interaction of the coating film with water may crucially influence its composition and permeability to both water and drug. Understanding this interaction between film microstructure, wetting, and mass transport is important for the development of new coatings. We present a novel method for controlled wetting of polymer coating films in an environmental scanning electron microscope, providing direct visual information about the processes occurring as the film goes from dry to wet. Free films made of phase-separated blends of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) were used as a model system, and the blend ratio was varied to study the effect on the water transport properties. Local variations in water transport through the EC/HPC films were directly observed, enabling the immediate analysis of the structure-mass transport relationships. The leaching of HPC could be studied by evaporating water from the films in situ. Significant differences were observed between films of varying composition. The method provides a valuable complement to the current approach of making distinct diffusion and microscopy experiments for studying the dynamic interaction of polymer films with water.

The major aims of this work were to study the effect of the molecular weight (Mw) of ethyl cellulose (EC) on the drug release profile from metoprolol succinate pellets coated with films comprising EC and hydroxypropyl cellulose (HPC) with a weight ratio of 70:30, and to understand the mechanisms behind the different release profiles. A broad range of Mws was used, and the kinetics of drug release and HPC leaching followed. The higher the Mw of EC, the slower the HPC leaching and the drug release processes. Drug release occurred by diffusion through the pores created in the coating by the HPC leaching. A novel method was used to explain the differences in the release profiles: the effective diffusion coefficient (De) of the drug in the coating film was determined using a mechanistic model and compared to the amount of HPC leached. A linear dependence was found between De and the amount of HPC leached and, importantly, the value of the proportionality constant decreased with increasing Mw of EC. This suggests that the Mw of EC affects the drug release profile by affecting the phase separated microstructure of the coating and the hindrance it imparts to drug diffusion., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The major aim of this work was to study the effect of two process parameters, temperature and coating flow, on permeability to water and structure of free films sprayed from mixtures of ethyl cellulose (EC), hydroxypropyl cellulose (HPC), and ethanol. The films were sprayed in a new spraying setup that was developed to mimic the film coating process in a fluid bed and to provide well controlled conditions. EC and HPC phase separated during the film drying process, and EC- and HPC-rich domains were formed. The process parameters had a great impact on the structure and the permeability to water of the films. The longer the time before the film structure was locked by a high film viscosity, that is, the lower the temperature and the higher the coating flow, the larger the domains and the lower the film permeability. The effective diffusion coefficient of water in the films varied by about six times within the range of the process parameters studied. Structures of sprayed films and water effective diffusion coefficients in sprayed films were compared to those of cast films. For the cast films, the domains were bigger, and the permeability to water was significantly lower compared to those of the sprayed films. The results indicate that the process parameters can be used as a mean to regulate structure and permeability of coating films undergoing phase separation., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In cardiovascular surgery, reduced organ perfusion and oxygen delivery contribute to increased postoperative morbidity and prolonged intensive care unit stay. Goal-directed therapy (GDT), a perioperative haemodynamic strategy aiming to increase cardiac output, is helpful in preventing postoperative complications, but studies in the context of cardiovascular surgery have produced conflicting results. The purpose of the present meta-analysis is to determine the effects of perioperative haemodynamic goal-directed therapy on mortality and morbidity in cardiac and vascular surgery. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched until July 2011. Randomized controlled trials reporting on adult cardiac or vascular surgical patients managed with perioperative GDT or according to routine haemodynamic practice were included. Primary outcome measures were mortality and morbidity. Data synthesis was obtained by using odds ratio (OR) with 95% confidence interval (CI) by a random effects model. An OR <1 favoured GDT. Statistical heterogeneity was assessed by Q and I(2) statistics. Eleven articles (five cardiac surgery and six vascular procedures), enrolling a total sample of 1179 patients, were included in the analysis. As compared with routine haemodynamic practice, perioperative GDT did not reduce mortality in either cardiac or vascular surgery (pooled OR 0.87; 95% CI 0.37-2.02; statistical power 64%). GDT significantly reduced the number of cardiac patients with complications (OR 0.34; 95% CI 0.18-0.63; P = 0.0006), but no effect was observed in vascular patients (OR, 0.84; 95% CI 0.45-1.56; P = 0.58). Perioperative GDT prevents postoperative complications in cardiac surgery patients, while it has no effect in vascular surgery. The different characteristics and comorbidities of the population enrolled could explain these conflicting results. More trials conforming to the characteristics of low-risk-of-bias studies and enrolling a larger and well-defined population of patients are needed to better clarify the effect of GDT in the specific setting of cardiovascular surgery.

The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: Infectious complications are the main causes of postoperative morbidity. The early timing of their promoting factors is the rationale for perioperative strategies attempting to reduce them. Our aim was to determine the effects of perioperative haemodynamic goal-directed therapy on postoperative infection rates., Methods: We performed a systematic review and meta-analysis. MEDLINE, EMBASE, The Cochrane Library and the DARE databases were searched up to March 2011. Randomised, controlled trials of major surgery in adult patients managed with perioperative goal-directed therapy or according to routine haemodynamic practice were included. Primary outcome measure was specific type of infection., Results: Twenty-six randomised, controlled trials with a combined total of 4,188 participants met our inclusion criteria. Perioperative goal-directed therapy significantly reduced surgical site infections (pooled OR 0.58, 95% CI 0.46 to 0.74; P < 0.0001), pneumonia (pooled OR 0.71, 95% CI 0.55 to 0.92; P = 0.009), and urinary tract infections (pooled OR 0.44, 95% CI 0.22 to 0.84; P = 0.02). A significant benefit was found regarding total infectious episodes (OR 0.40, 95% CI 0.28 to 0.58; P < 0.00001)., Conclusions: Flow-directed haemodynamic therapy designed to optimise oxygen delivery protects surgical patients against postoperative hospital-acquired infections and must be strongly encouraged, particularly in the high-risk surgical population.