Preparation and characterisation of free flowing solid lipid based drug delivery systems using a twin screw extruder

In this study, a continuous manufacturing process was developed for adsorbing liquid self-emulsifying drug delivery system (SEDDS) on mesoporous silica carriers in order to produce solid free flowing SEDDS powders. An optimized liquid SEDDS, consisting of Labrafil M 1944 CS, Labrasol and Capryol 90 (15, 80, 5 %w/w), was developed. The formulation spontaneously formed a homogenous emulsion with a droplet size of less than 200 nm (in water) and possessed pH robustness (pH 1.2, pH 6.8). Two grades of mesoporous silica were investigated as solid carriers, namely Syloid XDP 3050 and 3150. A twin screw extruder, setup in the granulation configuration, was employed to assess the mixing and adsorption of liquid SEDDS onto silica particles in a continuous process. Screw configuration, ratio of solid carrier to liquid SEDDS, powder and liquid feed rates and screw speed were identified as important parameters. These parameters were tested and optimized to achieve free flowing solid SEDDS. The maximum lipid loading of Syloid XDP 3050 and 3150 was 1:2 and 1:2 to less than 1:3 ratios, respectively. Although increasing liquid SEDDS loading increased the cohesive properties of the silica particles, the resulting powders afforded acceptable flow rate indexes as determined by powder rheometry. Similar self-emulsification behaviour was observed for solid and liquid SEDDS. With increasing lipid loading, the droplet size of emulsified solid SEDDS increased and changed from a unimodal to a bimodal size distributions. This effect was more pronounced for Syloid XDP3050. Syloid XDP 3150 was less sensitive to droplet size changes as its z-average diameters at 1:2-1:3 ratio were similar to the optimized liquid SEDDS. Targeting a lipid loading ratio of 2:1, process parameters were varied to maximise material throughput. The investigated continuous process of adsorbing liquid SEDDs onto solid carriers produced solid SEDDS with good flow properties. Syloid XDP 3150 seemed more robust to the process than Syloid XDP 3050

Incidence of Insomnia in OSA patients and its correlations with parameters of polysomnography

Background/Aims: Prevalence of insomnia in obstructive sleep apnoea (OSA) patients has been estimated in many studies and has been found to be a frequent symptom (38% in a recent review 1).Our study aims to estimate the incidence of insomnia in Greek patients presenting to a public hospital sleep clinic, and correlate it with the severity of OSA and parameters of polysomnography (PSG). Methods: 100 patients who visited the sleep unit of the General Hospital ‘Evangelismos’ completed the Athens Insomnia Scale (AIS) and underwent a polysomnographic study. 56% were men, with mean age 54,7±12,5 years and BMI 31,5±6,2. Results: 70% of patients had insomnia. Insomnia (AIS≥6) and OSA (AHI≥5) were coexistent in 71,4 %. There was no correlation between insomnia and severity of OSA. A strong positive correlation was found/evident between difficulty in initiating sleep and number of hypopneas (r: 0,20 p:0,049), diminished functioning during the day and leg movements (r:0,21 p:0,050) and between daytime sleepiness and wake after sleep onset (WASO) (r:0,2 p:0,038). A negative correlation was found between overnight awakenings and sleep efficiency (r: -0,23 p: 0,021). Also, negative correlation was found between early morning awakening and minimum SpO2 (r=0.27, p=0,021), and between insufficient duration of sleep (r:-0,22 p: 0,021) and minimum SpO2. Conclusions: We found a high incidence of insomnia in patients with OSA, which does not correlate with severity of OSA. Contrary to many other studies, insomnia was not more common in women. More studies are required to clarify the significance of the positive correlation between insomnia and number of hypopneas and minimum SpO2

Progress report on the MEDAMI 2019 and CTR research at the DMIL in i3M

[EN] This contribution reports on the recently held MEDAMI 2019 workshop in Valencia (15-17th May 2019). This workshop is about advanced molecular imaging and the main topic of this last edition was Imaging in Immunotherapy. Around 70 attenders met together during three days. This meeting made it possible to join medical doctors and instrumentalists. In MEDAMI 2019 it was exposed the new immunotherapies from a clinical and research point of view. It was shown the already observed improvements when using these therapies. At the same time, we heard about the difficulties and limitations of current molecular imaging in this particular field. It was clear that improvements in system sensitivity and resolution are demanded. Timing information can be utilized in different ways to improve the image quality in PET systems. Precise Coincidence Time Resolution (CTR) improves the signal-to-noise ratio and, therefore, the image contrast, allowing for instance to distinguish low uptake tumors, multicentric lesions, or tumor heterogeneity, to name but a few. Both high time resolution and angular coverage in a PET system can improve the effective sensitivity. An example of a system benchmarking the timing resolution is the Siemens Biograph Vision with 214 ps FWHM, enhancing the detectability. The Explorer total-body PET from UC Davis improves the system sensitivity by having a 2 meters long PET scanner. Deep investigations, from different research groups, are being carried out to further push the limits of timing resolution. This work also describes some of the projects on high timing performance that are being carried out at the Detector for Molecular Imaging Lab (DMIL) at the Institute for Instrumentation in Molecular Imaging (i3M) in Valencia. The DMIL group has extensively worked on detectors and implementation of PET systems enabling the use of accurate timing information. In this progress report we describe the results obtained at the DMIL regarding timing determination in gamma-ray detectors both based on monolithic and pixelated crystals. Although with 15 min thick LYSO blocks it was tough to obtain values of CTR below 500 ps when using analog SiPMs and ASIC-based readout, this was improved down to 250 ps if small 3 mm size and 6 mm height pixels under the one-to-one coupling approach were enabled. This type of approach, the one-to-one coupling, seems to benefit from the light collection in a single photosensor element and, therefore, to improve the timing properties. Monolithic blocks offer, on the contrary, advantages such as photon depth of interaction. In order to separate Compton and photoelectric events we have thought of a detector block design with a high aspect ratio, using LYSO crystals of 51 mm size vs. 3 mm thickness, read-out by the four lateral sides. We have demonstrated the possibility to reach below 2 mm FWHM spatial resolution with an energy resolution of 12%.The DMIL work presented in this paper has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. 695536). It has also been supported by the Spanish Ministerio de Economia, Industria y Competitividad under Grant TEC2016-79884-C2-1-R. The author would like to thank all current and former members of the DMIL at i3M for their continuous contributions to this work.González Martínez, AJ.; Barrio, J.; Lamprou, E.; Ilisie, V.; Sánchez Martínez, F.; Benlloch Baviera, JM. (2020). Progress report on the MEDAMI 2019 and CTR research at the DMIL in i3M. Il Nuovo cimento C. 43(1):1-10. https://doi.org/10.1393/ncc/i2020-20005-8S11043

Generation of optical Schrödinger cat states in intense laser-matter interactions

The physics of intense laser–matter interactions1,2 is described by treating the light pulses classically, anticipating no need to access optical measurements beyond the classical limit. However, the quantum nature of the electromagnetic fields is always present3. Here we demonstrate that intense laser–atom interactions may lead to the generation of highly non-classical light states. This was achieved by using the process of high-harmonic generation in atoms4,5, in which the photons of a driving laser pulse of infrared frequency are upconverted into photons of higher frequencies in the extreme ultraviolet spectral range. The quantum state of the fundamental mode after the interaction, when conditioned on the high-harmonic generation, is a so-called Schrödinger cat state, which corresponds to a superposition of two distinct coherent states: the initial state of the laser and the coherent state reduced in amplitude that results from the interaction with atoms. The results open the path for investigations towards the control of the non-classical states, exploiting conditioning approaches on physical processes relevant to high-harmonic generation.Peer ReviewedPostprint (author's final draft

Evacuating Two Robots from a Disk: A Second Cut

We present an improved algorithm for the problem of evacuating two robots from the unit disk via an unknown exit on the boundary. Robots start at the center of the disk, move at unit speed, and can only communicate locally. Our algorithm improves previous results by Brandt et al. [CIAC'17] by introducing a second detour through the interior of the disk. This allows for an improved evacuation time of $5.6234$. The best known lower bound of $5.255$ was shown by Czyzowicz et al. [CIAC'15].Comment: 19 pages, 5 figures. This is the full version of the paper with the same title accepted in the 26th International Colloquium on Structural Information and Communication Complexity (SIROCCO'19

Quantum optical analysis of high-order harmonic generation in H2+_2^+ molecular ions

We present a comprehensive theoretical investigation of high-order harmonic generation in H$_2^+$ molecular ions within a quantum optical framework. Our study focuses on characterizing various quantum optical and quantum information measures, highlighting the versatility of HHG in two-center molecules towards quantum technology applications. We demonstrate the emergence of entanglement between electron and light states after the laser-matter interaction. We also identify the possibility of obtaining non-classical states of light in targeted frequency modes by conditioning on specific electronic quantum states, which turn out to be crucial in the generation of highly non-classical entangled states between distinct sets of harmonic modes. Our findings open up avenues for studying strong-laser field-driven interactions in molecular systems, and suggest their applicability to quantum technology applications.Comment: 21 pages (14 main text + 7 appendix), 9 figures (8 main text + 1 appendix

The BTZ black hole with a time-dependent boundary

The non-rotating BTZ solution is expressed in terms of coordinates that allow for an arbitrary time-dependent scale factor in the boundary metric. We provide explicit expressions for the coordinate transformation that generates this form of the metric, and determine the regions of the complete Penrose diagram that are convered by our parametrization. This construction is utilized in order to compute the stress-energy tensor of the dual CFT on a time-dependent background. We study in detail the expansion of radial null geodesic congruences in the BTZ background for various forms of the scale factor of the boundary metric. We also discuss the relevance of our construction for the holographic calculation of the entanglement entropy of the dual CFT on time-dependent backgrounds.Comment: 14 pages, 13 figures, title changed in journal, conformal diagrams added, references added, final version to appear in Classical and Quantum Gravit

Frog nest foams exhibit pharmaceutical foam-like properties

Foams have frequently been used as systems for the delivery of cosmetic and therapeutic molecules; however, there is high variability in the foamability and long-term stability of synthetic foams. The development of pharmaceutical foams that exhibit desirable foaming properties, delivering appropriate amounts of the active pharmaceutical ingredient (API) and that have excellent biocompatibility is of great interest. The production of stable foams is rare in the natural world; however, certain species of frogs have adopted foam production as a means of providing a protective environment for their eggs and larvae from predators and parasites, to prevent desiccation, to control gaseous exchange, to buffer temperature extremes, and to reduce UV damage. These foams show great stability (up to 10 days in tropical environments) and are highly biocompatible due to the sensitive nature of amphibian skin. This work demonstrates for the first time that nests of the túngara frog ( Engystomops pustulosus ) are stable ex situ with useful physiochemical and biocompatible properties and are capable of encapsulating a range of compounds, including antibiotics. These protein foam mixtures share some properties with pharmaceutical foams and may find utility in a range of pharmaceutical applications such as topical drug delivery systems

TOF studies for dedicated PET with open geometries

[EN] Recently, two novel PET devices have been developed with open geometries, namely: breast and prostate-dedicated scanners. The breast-dedicated system comprises two detector rings of twelve modules with a field of view of 170 mm x 170 mm x 94 mm. Each module consists of a continuous trapezoidal LYSO crystal and a PSPMT. The system has the capability to vary the opening of the rings up to 60 mm in order to allow the insertion of a needle to perform a biopsy procedure. The prostate system has an open geometry consisting on two parallel plates separated 28 cm. One panel includes 18 detectors organized in a 6 x 3 matrix while the second one comprises 6 detectors organized in a 3 x 2 matrix. All detectors are formed by continuous LYSO crystals of 50 mm x 50 mm x15 mm, and a SiPM array of 12 x 12 individual photo-detectors. The system geometry is asymmetric maximizing the sensitivity of the system at the prostate location, located at about 2/3 in the abdomen-anus distance. The reconstructed images for PET scanners with open geometries present severe artifacts due to this peculiarity. These artifacts can be minimized using Time Of Flight information (TOF). In this work we present a TOF resolution study for open geometries. With this aim, the dedicated breast and prostate systems have been simulated using GATE (8.1 version) with different TOF resolutions in order to determine the image quality improvements that can be achieved with the existing TOF-dedicated electronics currently present in the market. The images have been reconstructed using the LMOS algorithm including TOF modeling in the calculation of the voxel-Line Of Response emission probabilities.This work was supported in part by the Spanish Government Grants TEC2016-79884-C2 and RTC-2016-5186-1 and by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 695536).Moliner, L.; Ilisie, V.; González Martínez, AJ.; Oliver-Gil, S.; Gonzalez, A.; Giménez-Alventosa, V.; Cañizares, G.... (2019). TOF studies for dedicated PET with open geometries. Journal of Instrumentation. 14:1-8. https://doi.org/10.1088/1748-0221/14/02/C02006S181

A prospective cohort study of factors associated with the digital cushion thickness in dairy cattle.

Key factors such as stage of lactation, parity and body fat reserves have been associated with the digital cushion thickness, however, there are discrepancies between the results of previously published studies. The objective of this study was to examine the association of stage of lactation, body fat reserves, parity, and lesion incidence with the digital cushion thickness (DCT) in a large cohort of intensively monitored cows. Across 4 UK farms, 2,352 cows were prospectively enrolled and assessed at 4 time points; before calving (T1-Precalving), immediately post-calving (T2-Calving), in early lactation (T3-Early) and late lactation (T4-Late). At each time point body condition score was recorded, the presence of sole lesions (sole ulcers and sole hemorrhage) and white line lesions were assessed by veterinarians, and an ultrasound image was taken to retrospectively measure the back-fat thickness in the pelvic (BFT) region and the digital cushion on the hind left lateral claw. Mixed effects multivariable linear regression models, with the cow as a random effect were fit to examine the association between explanatory variables and the DCT. Explanatory variables tested were farm, parity, stage of lactation, body condition score, BFT, height, the presence of a lesion at the time of measurement, the chronicity of a lesion during early lactation, predicted maximum daily milk yield and the rate of milk production rise in early lactation. Stage of lactation and farm were both associated with the DCT, however an interaction was present and this DCT pattern of change was farm dependent. Two distinct patterns emerged; one indicated the nadir to occur shortly after calving, the other indicated the nadir to occur during early lactation. Neither back fat thickness nor BCS were significantly associated with the DCT. Heifers displayed thinner digital cushions compared with multiparous cows, however, this effect was dependent on the stage of lactation, with heifers having a thinner digital cushion up until late lactation, by which time the DCT was commensurate with multiparous animals. Sole lesions and white line lesions at the time of measurement were associated with the DCT (sole lesion; Estimate: -0.07mm, 95% CI: -0.14-0.00, P = 0.039, white line lesion; Estimate: 0.28mm, 95% CI: 0.15-0.42, P < 0.001)