Adherence, persistence and treatment switching in psoriasis.

Aim: This study aims to investigate drug utilization patterns in the treatment of psoriasis (PsO) from 1 to 5 years in a real-life setting with Adalimumab (Ada), Etanercept (Eta), Ustekinumab (Ust), Golimumab (Gol), Ixekizumab (Ixe), Secukinumab (Sec) and Apremilast (Apr). Materials & methods: Data from an observational study were used to calculate adherence using the Proportion of Days Covered (PDC) method and persistence. Results & conclusion: Treatment adherence was found to be good for all the drugs studied across all years of analysis, while persistence was suboptimal, showing a marked decrease from the third year of study onward. In the treatment of PsO, greater attention needs to be paid to treatment persistence.

This summary explains that when a patient follows their doctor's medication instructions and continues using the same medication over time to treat a condition like psoriasis, they can expect safer and more effective outcomes. This study examined these aspects to assess how different medications perform over the long term and to explore ways to improve their prescription. The findings highlight that the main issue is not so much in following instructions but in continuing to use the same medication throughout the treatment duration. Raising awareness among healthcare professionals about these issues is crucial to help patients maintain consistent therapy over time and improve their care pathway.

Macroscopic Biaxial Order in Multilayer Films of Bent-Core Liquid Crystals Deposited by Combined Langmuir-Blodgett/Langmuir-Schaefer Technique.

Bent-core liquid crystals, a class of mesogenic compounds with non-linear molecular structures, are well known for their unconventional mesophases, characterized by complex molecular (and supramolecular) ordering and often featuring biaxial and polar properties. In the nematic phase, their unique behavior is manifested in the formation of nano-sized biaxial clusters of layered molecules (cybotactic groups). While this prompted their consideration in the quest for nematic biaxiality, experimental evidence indicates that the cybotactic order is only short-ranged and that the nematic phase is macroscopically uniaxial. By combining atomic force microscopy, neutron reflectivity and wide-angle grazing-incidence X-ray scattering, here, we demonstrate that multilayer films of a bent-core nematic, deposited on silicon by a combined Langmuir-Blodgett and Langmuir-Schaefer approach, exhibit macroscopic in-plane ordering, with the long molecular axis tilted with respect to the sample surface and the short molecular axis (i.e., the apex bisector) aligned along the film compression direction. We thus propose the use of Langmuir films as an effective way to study and control the complex anchoring properties of bent-core liquid crystals.

ADA_ETA_BIO2021: real-world evaluation of adherence, persistence, and cost-effectiveness of originator and biosimilar biologic drugs in the treatment of rheumatoid arthritis: a multicenter study in Italy.

OBJECTIVES: The objective was to assess the adherence, persistence, and costs of bDMARDs through a multicentre study of nine Italian hospital pharmacies. METHODS: The drugs analysed were Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab and Tocilizumab.Adult subjects with Rheumatoid Arthritis were considered in the analysis.In this study, we calculated the following metrics: Adherence to treatment was evaluated as dose-intensity, which is the ratio between the amount of medication received and probably taken by the patient at home (Received Daily Dose, RDD) and the amount prescribed by the clinician (Prescribed Daily Dose, PDD). Persistence was calculated as the number of days between the first and last dispensing of the same drug. Lastly, costs were assessed based on persistence to treatment and normalized for adherence. RESULTS: Adherence to treatment was found to be above 0.8 for all drugs studied. The median persistence for a 5-year treatment period was 1.4 years for Abatacept, 1.7 years for Adalimumab, 1.8 years for Certolizumab, 1.4 years for Etanercept, 1.3 years for Golimumab, and 1.6 years for Tocilizumab. CONCLUSIONS: This multicentre retrospective observational study of bDMARDs used in the treatment of RA showed that, for all the drugs studied, there was no problem with adherence to treatment but rather a difficulty in maintaining treatment with the same drug over time.

The influence of mannose-based esters on the mesophase behaviour of lyotropic liquid crystalline nanosystems as drug delivery vectors.

Lyotropic Liquid Crystalline (LLC) nanoparticles represent an emerging class of smart, biocompatible, and biodegradable systems for the delivery of drugs. Among these, structures with complex 3D architectures such as cubosomes are of particular interest. These are non- lamellar assemblies having hydrophobic and hydrophilic portions able to carry drugs of different nature. They can further be modulated including suitable additives to control the release of the active payload, and to promote an active targeting. Starting from monoolein (GMO) cubic phase, different concentrations of mannose-based esters were added, and the eventual structural modifications were monitored to ascertain the effects of the presence of glycolipids. Moreover, the structural properties of these nanosystems loaded with Dexamethasone (DEX), a very well-known anti-inflammatory steroid, were also studied. Experiments were carried out by synchrotron Small Angle X-ray Scattering (SAXS), Raman Microspectroscopy (RMS) and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) measurements. The drug delivery potential (i.e. entrapment efficiency and release properties) of the obtained nanoparticles was evaluated. Finally, in vitro cytocompatibility and anti-inflammatory activity studies of the prepared formulations were carried out. Inclusion of mannose-based surfactants up to 10 mol% influenced the structural parameters of Im3m cubic phase and swollen cubic phases were obtained with the different glycolipids with lattice parameters significantly higher than GMO. A complete cytocompatibility and an increased DEX activity were observed, thus suggesting the possibility to use GMO/glycolipids nanoparticles to formulate innovative drug delivery systems.

A survey on preferences, attitudes, and perspectives of Italian urology trainees: implications of the novel national residency matching program.

BACKGROUND: Since 2014, a new residency program selection process has been established with a national examination. The aim of this study was to assess characteristics, career goals, and practice preferences of current Italian urology residents. METHODS: A web-based survey of 25 items performed from May 2021 to September 2021 was sent to 585 Italian urology residents. Descriptive analyses were conducted to describe the surveys' domains: demographics characteristics, studies, plans for fellowship training, interest in the urology field, and career expectations. RESULTS: Four hundred and one residents completed the online survey (response rate 68.5%). Most residents were male (70.3%), with a median of 29 (IQR 28-31) years. Urology was the first chosen School in 325 (81.0%) cases, and 174 (43.4%) trainees have chosen to remain in the same University. Uro-oncology was the main field, and endourology the main subspeciality of interest, respectively. More than 40.0% of residents expressed a good level of satisfaction for the training urological course. 232 (57.2%) residents were strongly interested in seeking a hospital career, followed by private career (43.4%) and academic career (20%). CONCLUSIONS: After the introduction of the novel national residency matching program the Italian Urology trainees showed a good satisfaction level. Further improvements of the Italian residency programs should be focused on the training network within and outside the main School of Urology.

A multicentre study with real-world data of the use of palbociclib in the treatment of breast cancer: Treatment duration correlates with dose reductions.

OBJECTIVE: Palbociclib, a highly selective reversible CDK4-6 kinase inhibitor, is indicated in combination with an aromatase inhibitor or in combination with fulvestrant in women who had received prior endocrine treatment. Studies have demonstrated the efficacy of palbociclib in combination with fulvestrant in increasing progression-free survival in patients who relapsed or progressed on previous endocrine therapy, or in combination with aromatase inhibitor in patients who had not received previous treatments. We analysed the prescribing patterns of palbociclib in real practice correlating it with the evidence of treatment-related toxicity management and to time-to-treatment discontinuation and treatment adherence. METHODS: For the observational, retrospective study, data were collected from five Italian hospital centres that prescribed palbociclib between April 2017 and April 2020. Each centre provided data derived from an administrative database of adult patients treated with palbociclib for the two therapeutic indications.Treatment adherence was calculated using the proportion of days covered method while time-to-treatment discontinuation was defined as the difference between the first and last date treatment was administered plus the days ideally covered by the last date treatment was given. RESULTS: There were 375 patients enrolled during the study period, of whom 159 were treated with palbociclib and aromatase inhibitor and 216 were treated with palbociclib and fulvestrant. The time-to-treatment discontinuation was 8.9 months in the case of P + f (95% CI: 7.1-12.7) and 13.7 months in the case of P + ia (95% CI: 8.9-17.5). In both cohorts, treatments that received at least one dose reduction had a statistically higher time-to-treatment discontinuation than those without dose reduction (17.7 months vs. 9.2 and 16.6 vs. 7.4).The mean adherence in our study was 0.9 and remained high in treatments with one dose reduction (0.83) and this with two dose reductions (0.87). CONCLUSION: Based on these findings, it appears that the management of toxicities through reducing doses, as required by the Summary of Product Characteristics, results in a better outcome in terms of therapy duration, and therefore time to failure due to progression or toxicity.

Anomalous conduction in one-dimensional particle lattices: Wave-turbulence approach.

One-dimensional particle chains are fundamental models to explain anomalous thermal conduction in low-dimensional solids such as nanotubes and nanowires. In these systems the thermal energy is carried by phonons, i.e., propagating lattice oscillations that interact via nonlinear resonance. The average energy transfer between the phonons can be described by the wave kinetic equation, derived directly from the microscopic dynamics. Here we use the spatially nonhomogeneous wave kinetic equation of the prototypical ß-Fermi-Pasta-Ulam-Tsingou model, to study thermal conduction in one-dimensional particle chains on a mesoscale description. By means of numerical simulations, we study two complementary aspects of thermal conduction: in the presence of thermostats setting different temperatures at the two ends and propagation of a temperature perturbation over an equilibrium background. Our main findings are as follows. (i) The anomalous scaling of the conductivity with the system size, in close agreement with the known results from the microscopic dynamics, is due to a nontrivial interplay between high and low wave numbers. (ii) The high-wave-number phonons relax to local thermodynamic equilibrium transporting energy diffusively, in the manner of Fourier. (iii) The low-wave-number phonons are nearly noninteracting and transfer energy ballistically. These results present perspectives for the applicability of the full nonhomogeneous wave kinetic equation to study thermal propagation.

Nanoscale Structure of Langmuir-Blodgett Film of Bent-Core Molecules.

Bent-core mesogens (BCMs) are a class of thermotropic liquid crystals featuring several unconventional properties. However, the interpretation and technological exploitation of their unique behavior have been hampered by the difficulty of controlling their anchoring at surfaces. To tackle this issue, we report the nanoscale structural characterization of BCM films prepared using the Langmuir-Blodgett technique. Even though BCMs are quite different from typical amphiphilic molecules, we demonstrate that stable molecular films form over water, which can then be transferred onto silicon substrates. The combination of Brewster angle microscopy, atomic force microscopy, and X-ray reflectivity measurements shows that the molecules, once transferred onto a solid substrate, form a bilayer structure with a bottom layer of flat molecules and an upper layer of upright molecules. These results suggest that Langmuir-Blodgett films of BCMs can provide a useful means to control the alignment of this class of liquid crystals.

Adherence, Persistence, and Effectiveness in Real Life. Multicenter Long-Term Study on the Use of Pirfenidone and Nintedanib in the Treatment of Idiopathic Pulmonary Fibrosis.

BACKGROUND: In the treatment of idiopathic pulmonary fibrosis (IPF), nintedanib and pirfenidone, with their different mechanisms of action, lead to a reduction in the rate of progression of the fibrosis process measured by the reduction of functional decline, and, in particular, the decrease in forced vital capacity (FVC) and of the diffusion capacity of the lungs for carbon monoxide (DLCO). The objective of this study was to analyze real-life adherence, persistence and efficacy in the use of pirfenidone and nintedanib in the treatment of IPF. METHODS: A non-interventional multicenter retrospective observational pharmacological study in real-life treat-ment at 1 and 2 years was conducted. Furthermore, we analyzed the levels of FVC and DLCO at 6 and 12 months, respectively, from the start of treatment. RESULTS: We identified 144 patients in the period between January 2013 and April 2019. From the point of view of adherence, there is no difference between the two drugs, even though patients who used pirfenidone had increasingly higher values: 0.90 vs 0.89, in the first year, and 0.91 vs 0.84, in the second year. In the first year of treatment, the percentage of persistent patients was 67% and 76%, while in the second year, it dropped to 47% and 53% for pirfenidone and nintedanib, respectively. CONCLUSION: The stratification of the adherence values as a function of the response to treatment in terms of FVC at 12 months for both study drugs showed that patients with optimal response scored adherence of more than 90%.

Cubic and Hexagonal Mesophases for Protein Encapsulation: Structural Effects of Insulin Confinement.

Monoolein-based cubic and hexagonal mesophases were investigated as matrices for insulin loading, at low pH, as a function of temperature and in the presence of increasing amounts of oleic acid, as a structural stabilizer for the hexagonal phase. Synchrotron small angle X-ray diffraction, rheological measurements, and attenuated total reflection-Fourier transform infrared spectroscopy were used to study the effects of insulin loading on the lipid mesophases and of the effect of protein confinement in the 2D- and 3D-lipid matrix water channels on its stability and unfolding behavior. We found that insulin encapsulation has only little effects both on the mesophase structures and on the viscoelastic properties of lipid systems, whereas protein confinement affects the response of the secondary structure of insulin to thermal changes in a different manner according to the specific mesophase: in the cubic structure, the unfolding toward an unordered structure is favored, while the prevalence of parallel ß-sheets, and nuclei for fibril formation, is observed in hexagonal structures.

Synchrotron Characterization of Hexagonal and Cubic Lipidic Phases Loaded with Azolate/Phosphane Gold(I) Compounds: A New Approach to the Uploading of Gold(I)-Based Drugs.

Gold(I) phosphane compounds have recently attracted a renewed interest as potential new protagonists in cancer therapy. A class of phosphane gold(I) complexes containing azolate ligands has been successfully tested against several cancer cell lines and, in particular, against basal-like breast (BLB) cancer, a form characterized by strongly severe diagnosis and short life lapse after classic chemotherapy. Even though the anticancer activity of gold(I) phosphane compounds is thoroughly ascertained, no study has been devoted to the possibility of their delivery in nanovectors. Herein, nonlamellar lyotropic liquid crystalline lipid nanosystems, a promising class of smart materials, have been used to encapsulate gold(I) azolate/phosphane complexes. In particular, ((triphenylphosphine)-gold(I)-(4,5-dichloroimidazolyl-1H-1yl)) (C-I) and ((triphenylphosphine)-gold(I)-(4,5-dicyanoimidazolyl-1H-1yl)) (C-II) have been encapsulated in three different lipid matrices: monoolein (GMO), phytantriol (PHYT) and dioleoyl-phosphatidylethanolamine (DOPE). An integrated experimental approach involving X-ray diffraction and UV resonant Raman (UVRR) spectroscopy, based on synchrotron light and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, has been employed to establish the effects of drug encapsulation on the structure and phase behavior of the host mesophases. The results indicate that gold(I) complexes C-I and C-II are successfully encapsulated in the three lipid matrices as evidenced by the drug-induced phase transitions or by the changes in the mesophase lattice parameters observed in X-ray diffraction experiments and by the spectral changes occurring in UV resonant Raman spectra upon loading the lipid matrices with C-I and C-II.

Nanostructure of Unconventional Liquid Crystals Investigated by Synchrotron Radiation.

The macroscopic properties of novel liquid crystal (LC) systems-LCs with unconventional molecular structure as well as conventional LCs in unconventional geometries-directly descend from their mesoscopic structural organization. While X-ray diffraction (XRD) is an obvious choice to investigate their nanoscale structure, conventional diffractometry is often hampered by experimental difficulties: the low scattering power and short-range positional order of the materials, resulting in weak and diffuse diffraction features; the need to perform measurements in challenging conditions, e.g., under magnetic and/or electric fields, on thin films, or at high temperatures; and the necessity to probe micron-sized volumes to tell the local structural properties from their macroscopic average. Synchrotron XRD allows these problems to be circumvented thanks to the superior diffraction capabilities (brilliance, q-range, energy and space resolution) and advanced sample environment available at synchrotron beamlines. Here, we highlight the potentiality of synchrotron XRD in the field of LCs by reviewing a selection of experiments on three unconventional LC systems: the potentially biaxial and polar nematic phase of bent-core mesogens; the very high-temperature nematic phase of all-aromatic LCs; and polymer-dispersed liquid crystals. In all these cases, synchrotron XRD unveils subtle nanostructural features that are reflected into macroscopic properties of great interest from both fundamental and technological points of view.

Coexistence of Ballistic and Fourier Regimes in the ß Fermi-Pasta-Ulam-Tsingou Lattice.

Commonly, thermal transport properties of one-dimensional systems are found to be anomalous. Here, we perform a numerical and theoretical study of the ß-Fermi-Pasta-Ulam-Tsingou chain, considered a prototypical model for one-dimensional anharmonic crystals, in contact with thermostats at different temperatures. We give evidence that, in steady state conditions, the local wave energy spectrum can be naturally split into modes that are essentially ballistic (noninteracting or scarcely interacting) and kinetic modes (interacting enough to relax to local thermodynamic equilibrium). We show numerically that the well-known divergence of the energy conductivity is related to how the transition region between these two sets of modes shifts in k space with the system size L, due to properties of the collision integral of the system. Moreover, we show that the kinetic modes are responsible for a macroscopic behavior compatible with Fourier's law. Our work sheds light on the long-standing problem of the applicability of standard thermodynamics in one-dimensional nonlinear chains, testbed for understanding the thermal properties of nanotubes and nanowires.

Yield-stress fluids in porous media: a comparison of viscoplastic and elastoviscoplastic flows.

A numerical and theoretical study of yield-stress fluid flows in two types of model porous media is presented. We focus on viscoplastic and elastoviscoplastic flows to reveal some differences and similarities between these two classes of flows. Small elastic effects increase the pressure drop and also the size of unyielded regions in the flow which is the consequence of different stress solutions compare to viscoplastic flows. Yet, the velocity fields in the viscoplastic and elastoviscoplastic flows are comparable for small elastic effects. By increasing the yield stress, the difference in the pressure drops between the two classes of flows becomes smaller and smaller for both considered geometries. When the elastic effects increase, the elastoviscoplastic flow becomes time-dependent and some oscillations in the flow can be observed. Focusing on the regime of very large yield stress effects in the viscoplastic flow, we address in detail the interesting limit of 'flow/no flow': yield-stress fluids can resist small imposed pressure gradients and remain quiescent. The critical pressure gradient which should be exceeded to guarantee a continuous flow in the porous media will be reported. Finally, we propose a theoretical framework for studying the 'yield limit' in the porous media.

Numerical simulations of vorticity banding of emulsions in shear flows.

Multiphase shear flows often show banded structures that affect the global behavior of complex fluids e.g. in microdevices. Here we investigate numerically the banding of emulsions, i.e. the formation of regions of high and low volume fractions, alternated in the vorticity direction and aligned with the flow (shear bands). These bands are associated with a decrease of the effective viscosity of the system. To understand the mechanism of experimentally observed banding, we have performed interface-resolved simulations of the two-fluid system. The experiments were performed starting with a random distribution of droplets, which under the applied shear, evolve in time resulting in a phase separation. To numerically reproduce this process, the banded structures are initialized in a narrow channel confined by two walls moving in opposite directions. We find that the initial banded distribution is stable when droplets are free to merge and unstable when coalescence is prevented. In this case, additionally, the effective viscosity of the system increases, resembling the rheological behavior of suspensions of deformable particles. Droplet coalescence, on the other hand, allows emulsions to reduce the total surface of the system and, hence, the energy dissipation associated with the deformation, which in turn reduces the effective viscosity.

Strong graphene oxide nanocomposites from aqueous hybrid liquid crystals.

Combining polymers with small amounts of stiff carbon-based nanofillers such as graphene or graphene oxide is expected to yield low-density nanocomposites with exceptional mechanical properties. However, such nanocomposites have remained elusive because of incompatibilities between fillers and polymers that are further compounded by processing difficulties. Here we report a water-based process to obtain highly reinforced nanocomposite films by simple mixing of two liquid crystalline solutions: a colloidal nematic phase comprised of graphene oxide platelets and a nematic phase formed by a rod-like high-performance aramid. Upon drying the resulting hybrid biaxial nematic phase, we obtain robust, structural nanocomposites reinforced with graphene oxide.

Lyotropic Liquid-Crystalline Nanosystems as Drug Delivery Agents for 5-Fluorouracil: Structure and Cytotoxicity.

Lyotropic cubic liquid-crystalline systems have received increasing attention due to their unique microstructural and physicochemical properties as efficient nanocarriers for drug delivery. We report the preparation and characterization of bulk phases and cubosome dispersions of phytantriol loaded with the anticancer drug 5-fluorouracil, in neutral and anionic forms. In both cases, a Pn3m cubic phase was observed. The phytantriol phase behavior can be influenced by the addition of ionic agents, and, to this purpose, a positively charged lipid, such as N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride salt (DOTAP), was included in the studied formulations. It was found to induce a variation of the spontaneous membrane curvature of the phytantriol lipid bilayer, generating a transition from the Pn3m to the Im3m cubic phase. When 5-fluorouracil, in its anionic form (5-FUs), was encapsulated in these latter systems, a further transition to the HII hexagonal phase was observed as a consequence of the formation of a complex phytantriol/DOTAP/5-FUs. The physicochemical characterization was performed with various complementary techniques including synchrotron small-angle X-ray scattering, dynamic light scattering, and attenuated total reflection Fourier transform infrared and UV resonance Raman spectroscopies. Encapsulation of 5-fluorouracil in the corresponding nanodispersions was evaluated, and their in vitro cytotoxicity was assessed in MDA-MB-231 cell line. Phytantriol cubosomes containing 5-fluorouracil showed a higher toxicity compared with the bare drug solution, and hence they represent potential nanocarriers in the delivery of 5-fluorouracil for cancer therapy.

Search for microscopic and macroscopic biaxiality in the cybotactic nematic phase of new oxadiazole bent-core mesogens.

The possibility of biaxial orientational order in nematic liquid crystals is a subject of intense current interest. We explore the tendencies toward local and global biaxial ordering in the recently synthesized trimethylated oxadiazole-based bent-core mesogens with a pronounced asymmetric (bow-type) shape of molecules. The combination of x-ray diffraction and optical studies suggests that the biaxial order is expressed differently at the short- and long-range scales. Locally, at the scale of a few molecules, x-ray-diffraction data demonstrate biaxial packing. However, above the mesoscopic scale, the global orientational order in all three compounds is uniaxial, as evidenced by uniform homeotropic alignment of the nematic phase which is optically tested over the entire temperature range and by the observations of topological defects induced by individual and aggregated colloidal spheres in the nematic bulk.

Micrometer-Scale Ordering of Silicon-Containing Block Copolymer Thin Films via High-Temperature Thermal Treatments.

Block copolymer (BCP) self-assembly is expected to complement conventional optical lithography for the fabrication of next-generation microelectronic devices. In this regard, silicon-containing BCPs with a high Flory-Huggins interaction parameter (χ) are extremely appealing because they form high-resolution nanostructures with characteristic dimensions below 10 nm. However, due to their slow self-assembly kinetics and low thermal stability, these silicon-containing high-χ BCPs are usually processed by solvent vapor annealing or in solvent-rich ambient at a low annealing temperature, significantly increasing the complexity of the facilities and of the procedures. In this work, the self-assembly of cylinder-forming polystyrene-block-poly(dimethylsiloxane-random-vinylmethylsiloxane) (PS-b-P(DMS-r-VMS)) BCP on flat substrates is promoted by means of a simple thermal treatment at high temperatures. Homogeneous PS-b-P(DMS-r-VMS) thin films covering the entire sample surface are obtained without any evidence of dewetting phenomena. The BCP arranges in a single layer of cylindrical P(DMS-r-VMS) nanostructures parallel-oriented with respect to the substrate. By properly adjusting the surface functionalization, the heating rate, the annealing temperature, and the processing time, one can obtain correlation length values larger than 1 µm in a time scale fully compatible with the stringent requirements of the microelectronic industry.

Molecular ordering in the high-temperature nematic phase of an all-aromatic liquid crystal.

We report the structural characterization of the nematic phase of 2,6-biphenyl naphthalene (PPNPP). This lath-like all-aromatic mesogen provides a valuable benchmark for classical theories of nematic order. PPNPP exhibits a very high temperature nematic phase (417-489 °C) above an enantiotropic smectic A phase. X-ray diffraction reveals a surprisingly strong tendency towards molecular layering in the nematic phase, indicative of "normal cybotaxis" (i.e. SmA-like stratification within clusters of mesogens). Although stronger at low temperatures, the layering is evident well above the smectic A-nematic transition. The nematic order parameter is evaluated as a function of temperature from the broadening of the wide-angle diffuse diffraction feature. Measured values of the orientational order parameter are slightly larger than those predicted by the Maier-Saupe theory over the entire nematic range except for a narrow region just below the clearing point where they significantly drop below the theoretical prediction.