The qualitative properties of solutions of a hereditary model of motion of aqueous solutions of polymers, its modification in the limiting case of short relaxation times, and a similar second grade fluid model are studied. Unsteady shear flows are considered. In the first case, their properties are similar to those of motion of a usual viscous fluid. Other models can include weak discontinuities, which are retained in the course of fluid motion. Exact solutions are found by using the group analysis of the examined systems of equations. These solutions describe the fluid motion in a gap between coaxial rotating cylinders, the stagnation point flow, and the motion in a half-space induced by plane rotation . The problem of motion of an aqueous solution of a polymer in a cylindrical tube under the action of a streamwise pressure gradient is considered. In this case, a flow with straight-line trajectories is possible . In contrast to the latter, however, the pressure in the flow considered here depends on all three spatial variables. It was found  that addHereinafter, the symbol 2 (hereafter we use the term “relaxation viscosity”), and D is the strain rate tensor corresponding to the vector field Here If a small amount of a polymer is added to water, the solution viscosity and density remain almost unchanged, in contrast to its rheological properties. System (1), (2) contains two additional parameters: Pavlovskii  replacedEquation (4) is a simplified version of Equation (3): asymptotic expansion with respect to the parameter D [One more possible modification of the model of the model of motion of diluted aqueous solutions of polymers is to introduce an objective derivative of the tensor D . In thisD with respect to time by the objective derivative in Equations (2) and (5) is caused by the necessity of turning the behavior law (4) to a tensor-invariant form [Replacement of the total derivative of the tensor ant form .It is of interest to note that Equation (6) coincides with the momentum equation in the so-called second grade fluid model ,16,17 wiHere The correctness of the boundary-value and initial-boundary-value problems for models of motion of aqueous solutions of polymers was analyzed in ,23,24,25Together with the above-mentioned models, there are alternative models in dynamics of dilute polymer solutions, particularly, the so called Oldroyd-B model; see monograph  and the Similar to the classical Navier-Stokes equations, the equations of model (2), (5) and two other models described in Here s fluids , and alss fluids ). AssumiIt is of interest that the symmetry groups admitted by all three systems where the momentum equation has the form (5), (6), or (7) coincide with each other.Concerning the initial model (1), (2), it is rather difficult to calculate its group properties directly. Nevertheless, the integro-differential Equation (1) can be reduced to a differential equation because the kernel of the Volterra operator is degenerate. Let us differentiate Equation (1) with respect to Equation (8) does not admit the Galilean transformation, though translation over the coordinates The presence of a group of symmetries of the examined systems of equations allows one to construct their invariant solutions. Simple examples of such solutions are provided in the next Section. In System (2), (8) is nonlinear and belongs to none of the classical types. There are no results on solvability of general initial-boundary-value problems for this system. Additional difficulties are induced by the presence of a small parameter at the highest derivative with respect to time in Equation (8) and degeneration of this equation at the solid boundary of the flow region where the no-slip condition As the first example of such problems, let us consider plane unsteady motion of an unbounded fluid with straight-line trajectories. The pressure in this flow is assumed to be constant. The velocity field has the form Let us consider the Cauchy problem for this equation:Here Equation (11) was derived in Reference , where tAssuming that The Cauchy problem (12), (13) reduces to the integral equationThe classical solution of problem (12), (13) satisfies the integral identity2, −1, 2/s.However, for this problem to be solved, there is no need to consider the function Identity (15) reveals one more specific feature of Equation (12): relaxation viscosity is no longer a smoothing factor for solutions of this equation. The smoothness of the solution of the Cauchy problem with respect to the variable u here has the previous form (12), but the pressure starts to depend on Let us now consider the problem of a shear flow of a second-grade fluid (2), (6). The equation for the function Equation (16) shows that the inclusion Let us return to Equation (9) and recall that the value of Let now the fluid fill the half-plane echanics . In the e [We are interested in the root of Equation (17) with a positive real part,tor of e . The penThe solution of the Stokes problem for the hereditary model of motion of an aqueous solution of a polymer (1), (2) leads to the following dispersion relation:At a fixed frequency The above-described solutions of the Cauchy and Stokes problems in models (2), (8) and (2), (5) are the simplest examples of invariant solutions of the corresponding systems of equations. One more example of the invariant solution is an analog of the classical Couette problem of polymer solution motion in a gap between coaxial rotating cylinders. The inner cylinder of radius The boundary conditions for Equation (19) follow from the no-slip condition:Moreover, the initial condition is imposed:2/s, −1.Equation (19) admits separation of variables, which allows one to construct the solution of problem (19)–(21) in the form of the Fourier series in Bessel functions and to study its qualitative properties. One of them is obvious: if the condition tte flow . The resIn the previous Section, we constructed invariant solutions of systems (2), (8) and (2), (5). The set of exact solutions can be extended by seeking for their partially invariant solutions in the sense of Ovsiannikov . Such anAnother example of the partially invariant solution of system (2), (5) is described asThe function Solution (22) is a generalization of the classical Karman solution of Navier-Stokes equations ,42. The ribed in ).As system (2), (5) also admits this group, the above-described algorithm can be applied to this system. This procedure leads to a number of new solutions for this system, and one of them yields an analog of the Karman vortex.Let us note an important specific feature of problem (23), (24). The function ordingly , (Ω/ν)1/In view of (25), The absence of the boundary layer near the solid boundary as on point ,39,40.Let us first consider the motion of an aqueous solution of a polymer with a low concentration in a cylindrical tube under the action of a given streamwise pressure gradient lle flow ,42. HoweThe examined flow is invariant with respect to the group with the operator Here Substitution of Equation (26) into Equations (2), (5) yields the following system of equationsLet us use c involved into Equation (27) differs from zero, then system (27)–(29) cannot have trivial solutions If the function Let us use It is well known that the system of the functions Let the following conditions be satisfied: Let us now assume that the function Let us now consider the solution of system (2), (6) that is invariant with respect to the operators It turns out that system (35), (37) is compatible. A corollary of Equation (37) is the relation Thus, in contrast to the classical Poiseuille flow, the pressure in model (2), (6) depends on all spatial variables. It should be noted that the equations of this model are identical to the equations of the second-grade fluid model under the assumptions that 1=κ (see  for moreIf we consider the invariant solutions (26) of system (2), (6), there are still such solutions where The phenomenological model of polymer solution motion formulated in Reference  containsAnother specific feature of model (2), (6) is the absence of an unsteady analog of the Poiseuille flow with an arbitrary dependence of the pressure gradient The initial model of motion of weakly concentrated polymer solutions written in the differential form (8), (2) contains a small parameter Another problem of a singular disturbance arises in models (2), (5) and (2), (6) if the parameter It was noted above that mathematical problems associated with models of aqueous solutions of polymers and second grade fluids are intensely studied. At the same time, problems of hydrodynamic stability of flows in these media have not been studied to a sufficient level. As far as we know, the problem of the Couette flow stability in such media has not been solved. It would be of interest to calculate the critical Taylor number for this problem and to analyze its behavior as


The mesh point method was utilized for sampling (60×60 m), and the characteristics of soil available nitrogen (AN), available phosphorus (AP) and available potassium (AK) variations in the before sowing, reviving, jointing, and filling stages of winter wheat were analyzed using geostatistical and GIS methods. Moreover, Pearson correlation analysis was used to study the response of wheat growth and development to soil nutrient variations. As the growth stages progressed, 1) each nutrient showed the characteristics of low-high-low and moderate variability. The highest AN and AK contents were found at the reviving stage, while AP reached a turning point at the jointing stage. The order of variability of each nutrient was AN>AP>AK. 2) The nutrient variations first increased and then decreased and showed medium to strong spatial correlation. The three nutrients were strongly spatially correlated in the before sowing stage and moderately spatially correlated during the reviving stage. During the jointing and filling stages, AN had moderate spatial correlation, and AP and AK had strong spatial correlation. The spatial correlation of each nutrient was the weakest in the reviving stage, and the spatial correlation of AN was strongest in the before sowing stage, while the spatial correlations of AP and AK were strongest in the jointing stage. The spatial correlation of each soil nutrient decreased from the before sowing stage to the reviving stage and from the jointing stage to the filling stage, and the spatial correlation increased from the reviving stage to the jointing stage. 3) The soil nutrient content first increased and then decreased, and the grades of the nutrients gradually decreased. 4) The correlation between soil nutrients and wheat growth gradually increased. AN had the highest correlation with wheat growth, followed by AK and AP. The effect of soil nutrients on the growth of wheat at the reviving stage was greater than the effect of nutrients in the current stage. The growth of wheat at the jointing stage was mainly influenced by nutrients in the current stage, while the growth of wheat at the filling stage was influenced by the nutrient contents of both the previous and current stages. Thus, the date of fertilizer supplementation should be postponed properly. In this study, the soil nutrient dynamics and their influence on the growth of wheat during the winter wheat growth period under the traditional field model were well described, and these results could provide a theoretical basis for the precision management of soil nutrients in the northern winter wheat area where the planting environment and cultivation management are relatively uniform.Studying soil nutrient variability and its effect on the growth and development of crops under a traditional tillage mode is the foundation for comprehensively implementing precision agriculture policies at the field scale and ensuring excellent crop management. In this paper, a 28.5 hm Research on soil and crops under field conditions is a key step in advancing precision agriculture from theory to practice. Soil continuously varies in time and space and is the carrier and nutrient source for plant growth –3. The bSoil nutrient variability has long been a research hotspot for scholars throughout the world –10, and Santillano-Cázares et al.  showed tBased on this, the characteristics of the variations in soil nutrients and their effects on wheat growth were analyzed by investigating the traditional cultivation management model for the main winter wheat production areas in China to determine the drawbacks of this model and provide a scientific basis for fertilization in different growth stages of wheat.The research area of this study is located in Tianzhuang town, Huantai County. All necessary permits for the described field study have been obtained from Huantai agricultural bureau. The land accessed is not privately owned or protected. The field study did not involve endangered or protected species. The study did not involve animal husbandry or experimentation.2 and is located in north-central Shandong Province, China . The study area is located in the Huanghuai winter wheat region, which is the most important wheat-producing area in China. The region was classified as having a continental monsoon climate in a warm temperate zone. The climate is mild, and the four seasons are distinct. The average annual air temperature is 12.5°C, and the frost-free period lasts 197 days. The annual average precipitation is 587 mm, which mainly falls in 6~9 months. The terrain is flat with an elevation of 5.7 to 6.8 m a.s.l. The main soil types are cinnamon soil (typic udivitrands), and the winter wheat variety is Jimai 17. The entire process followed the traditional cultivation management mode of the farmers. The main points of the process are as follows: traditional plowing mode was adopted, and the plow depth was 20 cm; basal compound fertilizer [N + P2O5 + K2O < 45% (15-15-15)] was applied before sowing on October 12, 2016, at a dosage of 360 kg/hm2, sowing was planted by equal row spacing (15 cm), and the sowing depth was approximately 5 cm; urea [CO (NH2)2] was applied in the reviving stage on March 5, 2017, at a dosage of 300 kg/hm2. The winter wheat was sowed on October 13, 2016, and harvested on June 10, 2017, for a total growth period of 260 days.The study was conducted in Huantai County, which has an area of 28.5 hmFirst, we collected the basic land use status, soil and topographic maps for Huantai County and obtained the boundary of the study area. Second, a total of 81 sampling points were established according to the standard of uniform grid layout of 60 m×60 m . The cooSoil samples were collected by a five-point cross-sampling method with a sampling depth of 0–20 cm. Mixed soil samples from multiple points were brought back to the laboratory, dried, ground and sieved at 2 mm. Soil available nitrogen (AN) was determined by the method of Cornfield ; availabThe interval method was used to select abnormal values. The interval is , μ is the mean value of the sample data, s is the standard deviation, and the outliers outside the interval are replaced by the normal maximum and minimum values.The eigenvalues of the classical statistical methods include minimum (min), maximum (max), mean, standard deviation (SD), skewness (Skew), kurtosis (Kurt) and coefficient of variation (CV), which can be used to describe the basic physical characteristics of soil nutrients. Among them, the CV is a parameter that can be used to compare the degree of data discretization under different measurement scales. According to the CV classification level, <10% indicates weakly variability, 10% to 100% indicates medium variability, and >100% indicates strong variability . The sinThe spatiotemporal variability of soil nutrients was mainly analyzed by a semivariogram. Moran’s I and fractal dimension (D) were combined to determine the spatial correlation and agglomeration degree at the same time. The formula for Moran’s I is as follows:0/(C0+C) represent the proportion of the variation caused by random factors to the total spatial variation and are often used as the basis of the classification of the spatial variation in variables. When C0/(C0+C) <25%, the system has a strong spatial correlation; when it is between 25% and 75%, the system has a moderate spatial correlation; when it is >75%, the system has a weak spatial correlation [When calculating the value of Moran’s I, it usually gives a threshold that can determine whether to reject the null hypothesis, called Z. If the value of Z is in the range of -1.96–1.96, then P>0.05, indicating that null hypothesis of spatial randomness cannot be rejected; If the value of Z is out of this range (Z > 1.96 or Z < −1.96), then the spatial pattern cannot be the result of random process. In this case, the null hypothesis can be rejected, and the spatial distribution shown is a significant aggregation or dispersion pattern . The valrelation .The spatial distribution map of soil AN, AP and AK in different growth stages was plotted using the ordinary kriging interpolation method. The classification standard for soil nutrients in the interpolation map was formulated according to China’s second national soil survey. AN was divided into 3 categories and 6 grades: high: I, >150 mg/kg, II, 120–150 mg/kg; medium: III, 90–120 mg/kg, IV, 60–90 mg/kg; low: V, 30–60 mg/kg, VI, <30 mg/kg. AP was divided into 3 categories and 7 grades: high: I, >100 mg/kg, II, 60–100 mg/kg; medium: III, 40–60 mg/kg, IV, 20–40 mg/kg, V, 10–20 mg/kg; low: VI, 5–10 mg/kg, VII, <5 mg/kg. AK was divided into 3 categories and 7 grades: high: I, >400 mg/kg, II, 350–400 mg/kg; medium: III, 300–350 mg/kg, IV, 250–300 mg/kg, V, 200–250 mg/kg; low: VI, 150–200 mg/kg, VII, <150 mg/kg. Based on the interpolated nutrient map, the professional viewpoints of landscape ecology were referenced, including 2 landscape level indices: patch number (NP) and patch density (PD) and 1 type level index: the percentage of landscape area (PLAND). A total of 3 indices were selected to quantitatively analyze the spatial dynamic characteristics of soil nutrient variation.The values of SPAD and LAI at different growth stage of wheat and the soil AN, AP, and AK were compared at each point. The correlation coefficient was calculated using Pearson correlation analysis to analyze the response of winter wheat growth to soil nutrient changes.The statistical characteristics of soil nutrients in different growth stages of winter wheat are shown in In general, the soil nutrient contents showed the characteristics of low-high-low and moderate variability at the different growth stages. The AN and AK contents were highest in the reviving stage and AP was in the jointing stage. The AN content in the study area was relatively low, while the AP and AK contents were high according to the grading standard of China’s second national soil survey. The order of the degree of variation in each nutrient was AN>AP>AK. The results of the Kolmogorov-Smirnov test showed that under the 5% test standard, the AN, AP and AK of each growth stage obeyed a normal distribution after logarithmic transformation, which met the requirements for Moran’s I and kriging interpolation.The semivariogram models and parameters for soil nutrients in different growth stages of winter wheat are shown in 2 of the best-fitting model for each nutrient ranged from 0.904 to 0.997, and the root mean square standardized error (RMSSE) ranged from 3.36×10−8 to 6.93×10−5, which indicated that the selected model of the semivariogram was optimal and could adequately reflect the characteristics of the spatial structure and variation trends of soil nutrients throughout the growth period.In general, the semivariogram of the three nutrients were represented by the same model at the before sowing stage, two models at the reviving stage, three models at the jointing stage, and then two models at the filling stage. The characteristics of the soil nutrient variations were greatest at the jointing stage, and the difference first increased and then decreased. The R0 values of AN, AP and AK in the four growth stages were all close to 0, indicating that the variation caused by the test and sampling errors was very small. The C0/ (C0+C) of AN was 10.29% before sowing with strong spatial correlation, and it ranged from 27.09% to 38.67% from the reviving stage to the filling stage, with moderate spatial correlation. The C0/ (C0+C) values of AP at the before sowing, jointing and filling stages were 8.65%, 8.35% and 15.89%, respectively, with strong spatial correlation, and this value was 34.35% at the reviving stage with moderate spatial correlation. The C0/ (C0+C) values of AK at the before sowing, jointing and filling stages were 12.5%, 10.77 and 13.82%, respectively, with strong spatially correlated, and this value was 26.09% at the reviving stage with moderate spatial correlation. Overall, the three nutrients showed moderate to strong spatial correlation with the progression of the growth stages and experienced a process of weakening-strengthening-weakening. These three nutrients were strongly spatially correlated before sowing, and the spatial correlation was moderate during the reviving stage. For the jointing and filling stages, AN exhibited moderate spatial correlation, and AP and AK were strongly spatially correlated. These three nutrients exhibited the weakest spatial correlation at the reviving stage, the spatial correlation of AN was strongest in the before sowing stage, while the spatial correlations of AP and AK were the strongest at the jointing stage.The CThe fractal dimensions of the three nutrients were from 1.817–1.897, 1.887–1.925, 1.853–1.900 and 1.890–1.941 from the before sowing stage to the filling stage, indicating that the soil nutrients in each growth stage had good fractal characteristics and structure. The fractal dimension values showed a process of first increasing then decreasing and then increasing from the before sowing stage. This result indicated that the structure of the soil nutrients became more complex, and the spatial correlation was weakened from the before sowing stage to the reviving stage and from the jointing stage to the filling stage, while the structure of nutrients tended to be consistent, and the spatial correlation increased from the reviving stage to the jointing stage.The Z values of AN, AP and AK in the four growth stages were all >1.96, indicated that the null hypothesis of spatial randomness could be rejected and the spatial distribution was a significant aggregation pattern. The spatial autocorrelation are shown in In general, as the growth progressed, (1) each nutrient showed moderate to strong spatial correlation. (2) The three nutrients exhibited strong spatial correlation during the before sowing stage and moderate spatial correlation during the reviving stage. For the jointing and filling stages, AN exhibited a moderate spatial correlation, and AP and AK exhibited strong spatial correlation. (3) The weakest spatial correlation of the three nutrients was shown at the reviving stage; the strongest spatial correlation of AN was shown before sowing, while the AP and AK exhibited the strongest spatial correlation at the jointing stage. (4) The spatial correlation of soil nutrients decreased from before sowing to the reviving stage, jointing stage and filling stage, and increased from the reviving stage to the jointing stage.The spatial and temporal distribution maps of soil nutrients in the different growth stages of winter wheat are shown in The landscape pattern indices for the interpolation of soil nutrients in different growth stages of winter wheat are shown in Tables The correlation coefficients between soil nutrients and the index of wheat growth are shown in With the increase or decrease in AN content in the soil, the SPAD and LAI values also increased or decreased correspondingly during the period from the reviving stage to the filling stage. With the increase in AP content in the soil, the LAI values also increased correspondingly at the filling stage, while the change in SPAD at the filling stage and the changes in SPAD and LAI at the other three stages were not obvious. These results showed that AP had different effects on wheat growth at different growth stages. The SPAD and LAI values were significantly correlated with the AK content in the soil during the jointing stage to the filling stage, and the correlation coefficients between these two growth stages were not significantly different. This result indicated that AK played an important role during the late growth stage of wheat and had a steady effect on wheat growth compared with AN and AP.The correlation coefficients between the soil nutrient contents at the current stage and the index of wheat growth at the following growth stage are shown in The comparison of Tables In general, the growth status of wheat was closely related to the nutrients in the soil. AN had the highest correlation with wheat growth status, followed by AK and AP. At the reviving stage, the effect of nutrients before sowing on the growth of wheat was slightly higher than the effect of nutrients in the reviving stage. At the jointing stage, the effect of nutrients in the jointing stage on the growth of wheat was much higher than the effect of nutrients in the reviving stage. At the filling stage, the status of wheat growth was affected by the nutrients in the jointing stage and filling stage.(1) Many experimental design methods have the advantages of easy access to data, low cost and small interference, but these conditions are different from the real field environment and management mode, and the conclusions of these studies have great limitations in the application of agricultural extension. Based on this, this research studied the soil nutrients and winter wheat under the traditional tillage model, and the conclusions were more practical and could be more suitable for winter wheat planting areas in northern China.(2) Huantai County is located in the Huanghuai winter wheat area, which is the main wheat production area of China where the planting conditions are superior. It was representative to study the variation in soil nutrients and their correlation with crop growth during the winter wheat growth period. The minimum spatial correlation distance of soil nutrients in each growth stage was 88.2 m, which exceeded the sampling interval (60 m) and indicated that the sampling interval was reasonable. In this study, the dynamic changes in soil nutrient content during the winter wheat growth period were generally consistent with the results of research conducted in Jiangyan City, Jiangsu Province, China .(3) Soil nutrients showed moderate variations during the growth stage of winter wheat, generally showing that the concentrations of AN were slightly higher than those of AP but much larger than those of AK. The reason for this difference was mainly related to fertilization. The high variability of AN was due to the large demand for nitrogen by wheat, and farmers pay great attention to the use of urea. The high variability of AP was related to the chemical behavior of P elements in the soil . The mob0/ (C0+C) values were not stable or effective in describing the structure of the variation when the C0/ (C0+C) values were large in a small area [0/ (C0+C), fractal dimension and Moran’s I was adopted in this research. The results showed that the structure of soil nutrients weakened from before sowing to the reviving stage and from the jointing stage to the filling stage and tended to strengthen from the reviving stage to the jointing stage. This pattern may be caused by field management and nutrient absorption during wheat growth. In particular, urea supplementation at the reviving stage and irrigation at the filling stage were the main reasons for the obvious decreases in soil nutrient correlation. The nutrient uptake of winter wheat peaked at the jointing stage, and the soil nutrient distribution tended to be balanced and then structurally enhanced. Significant changes in soil nutrient correlation were also found during the growth period of tobacco [(4) Single Call area . Therefo tobacco . Wheat i(5) The correlation coefficients between AN and SPAD and LAI values were the highest at all growth stages of winter wheat, followed by those for AK and AP. This result may be related to the differences in the demands for different nutrients during the growth stage of winter wheat. The ratio of nitrogen, phosphorus and potassium absorption in wheat was 3.1:1:3.14 in the brown soil area of western Henan Province, China , which h(1) The contents of three nutrients all showed the characteristics of decreased-increased-decreased and moderate variability. The AN content reached a turning point at the reviving stage, while the AP and AK contents reached turning points at the jointing stage. AN had the largest CV, followed by AP and AK.(2) The three nutrients all showed medium to strong spatial correlation. The three nutrients showed the weakest spatial correlation at the reviving stage; the strongest spatial correlation of AN occurred before sowing, while the strongest spatial correlations of AP and AK were at the jointing stage. The correlation of soil nutrients decreased from before sowing to the reviving stage, from the jointing stage to the filling stage, and increased from the reviving stage to the jointing stage.(3) The high AN contents gradually decreased, and the spatial distribution continuously increased; the high AP contents decreased slightly, the change in the spatial distribution continuity was not obvious; the high AK contents significantly decreased, and the spatial distribution continuity continuously decreased.(4) AN exhibited the highest correlation with wheat growth status, followed by AK and AP. At the reviving stage, the effect of nutrients before sowing on the growth of wheat was slightly higher than that at the reviving stage. At the jointing stage, the effect of the nutrients in the jointing stage on the growth of wheat was much higher than that in the reviving stage. At the filling stage, the status of wheat growth was affected by the nutrients in both the jointing stage and filling stage.The temporal and spatial characteristics of the soil nutrient variations and the response of wheat growth throughout the winter wheat growth period under the traditional tillage model were clearly described, which could provide a scientific basis for the effective guidance for wheat production and the popularization of precision fertilization technology.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.


This is probably the ideal lipophilicity for the fatty acid to interact with the lipid domains of the mucosa. When the same analysis was performed on skin data, the same trend was observed, although the maximum value was reached for C12 (logP approx. 5), in agreement with the higher lipophilicity of the skin. The results obtained in the present work represent a significant advancement in the understanding of the mechanisms of action of fatty acids as buccal penetration enhancers.Buccal mucosa has recently received much attention as a potential route for systemic delivery of drugs, including biologics and vaccines. The aim of this work was to gain insight into the mechanism of fatty acids as buccal permeation enhancers, by studying the effect of a series of medium and long chain fatty acids on the permeation of a model high molecular weight and hydrophilic molecule, fluorescein isothiocyanate labelled dextran  across porcine esophageal epithelium. A parabolic relationship between fatty acid lipophilicity and enhancement was obtained, regardless of the presence and number of double bonds. The relationship, which resembles the well-known relationship between permeability and lipophilicity of transdermal delivery, presents a maximum value in correspondence of C10 (logP  Buccal mucosa has recently received much attention as a potential route for systemic delivery of drugs, including biologics  and vaccThe aim of this work was to gain insight into the mechanism of fatty acids as buccal permeation enhancers, by studying the effect of a series of medium and long chain fatty acids on the permeation of a high molecular weight and hydrophilic model molecule, fluorescein isothiocyanate labelled dextran , across porcine esophageal mucosa, an accepted model of human buccal mucosa .2 of fatty acid. This application procedure was chosen because it allows for a direct assessment of the enhancer activity, avoids drug-enhancer interactions and reduces the risk of mucosa damage.Taking as a reference the factors governing the activity of fatty acids on the skin, the effect of concentration, chain length and number of double bonds was examined. Saturated fatty acids from C6 to C18, and C18 unsaturated fatty acids, with 1, 2 or 3 double bonds, were applied to the epithelium as pretreatment in ethanol solution, at concentration 0.5–15%, corresponding to the application of 0.33–5.0 mg/cmFluorescein isothiocyanate labeled dextran of 4 kDa molecular weight (FD-4), caproic acid (C6), caprylic acid (C8), capric acid (C10), linoleic acid (C18:2) and linolenic acid (C18:3) were purchased from Sigma-Aldrich . Lauric acid (C12) was from Merck , stearic acid (C18) from ACEF  and oleic acid (C18:1) from Alfa Aesar .All reagents and chemicals were used as received and were of analytical grade.The characteristics of the enhancers tested in this work are reported in 2 and a receptor volume of about 4 mL filled with pH 7.4 PBS.In vitro permeation studies were conducted across porcine esophageal epithelium. Pig esophagi  were obtained from a local slaughterhouse within 2 h from the animal sacrifice. The esophageal mucosa was separated from the outer muscle layer with a scalpel and the epithelium was peeled off from the connective tissue after immersion in distilled water at 60 °C for 60 s . Samplesw/v), were applied, in non-occluded conditions, to the epithelium in correspondence of the available diffusion area. After 1 h pretreatment, the donor compartment was filled with 400 µL of FD-4 solution in PBS pH 7.4 (2 mg/mL) and the diffusion of the permeant was monitored up to 5 h. As control, a pretreatment with ethanol 95% was used. A passive diffusion experiment was also performed, without any pretreatment.20 µL of fatty acid ethanol solution . The excitation and emission λ were 490 and 535 nm, respectively. The method was specific and the detector response was linear up to 5 µg/mL with a LOQ of 0.01 µg/mL. Blank experiments ensured no interference of the formulation on FD-4 analysis in the receptor solution.2·h) was calculated as the slope of the regression line at steady state, while the apparent permeability coefficient  was calculated at steady state as:D is the concentration of FD-4 in the donor formulation (2 mg/mL).The cumulative amount of FD-4 recovered in the receptor phase was plotted versus time. The flux of FD-4 across the mucosa  was calculated as the ratio of the permeability coefficients of the permeant in the presence and absence of the fatty acids (passive).n = 3–6).The significance of the differences among the results was assessed using one-way ANOVA followed by a Bonferroni test. All data are reported as mean ± SEM , in agreement with that obtained across porcine buccal epithelium , which 0−8 cm/s .The usefMost fatty acids are classified as safe by the FDA and are approved as inactive ingredients in a number of formulations. As pointed out for the skin , pre-tre2 of mucosa), compared to pre-treatment  for lauric acid (C12). This has been observed also in the skin [Considering saturated fatty acids (panel a), the EF increased with concentration although it leveled off , whereas the activity of linoleic acid seems to decrease with concentration and linolenic acid activity increases with concentration b. The liThe maximum enhancement obtained with unsaturated fatty acids is smaller compared to the maximum EF obtained with saturated fatty acids of shorter chain length see a. This dThe lipid composition of non-keratinized epithelial barriers, such as the buccal mucosa, is quite different compared to the stratum corneum . In partThe comparison of our results with skin permeation data reveals that the experimental conditions are very different. In fact most of the skin permeation data refer to co-administration experiments, in which fatty acids were co-applied with the drug in solutions containing non-volatile co-solvents, which can influence the effect of fatty acids. Additionally, when basic drugs are used, the formation of ion pairs with fatty acids, can induce a further enhancement, due to more favorable partitioning. Concerning the pre-treatment with fatty acids, they are normally applied in occlusive conditions for 1 h , 12 h 3 or even Despite the differences in permeation barriers, experimental conditions and permeant properties (molecular weight and lipophilicity), our results are in general agreement with skin permeation data, in particular with those of co-administration of naloxone with fatty acids of different chain length and unsaturation in propylene glycol , suggestvs. the lipophilicity of the acid . The reapprox. 5, corresponding to lauric acid (C12). Interestingly, when the same analysis was performed on the data of Reference [When the same analysis was performed on the previously cited skin permeation data of naloxone  Figure b a simileference , using aapprox. 5, whereas the mucosa is less lipophilic and has 4 as maximum.In this analysis unsaturated fatty acids fit the general trend, with skin and mucosa, suggesting that partitioning is, if not the most, one of the more relevant properties governing the enhancement. The presence of a different maximum in the two membranes, mucosa and skin, is consistent with the different lipid composition of the two barriers: the stratum corneum is more lipophilic, due to the higher ceramide content, and shows an optimal logP of approx. 4). This is probably the ideal lipophilicity for the fatty acid to penetrate and interact with the lipid domains of the mucosa. When the same analysis was performed on skin data taken from the literature, the same trend was observed, although the maximum value was reached for C12 (logP approx. 5), in agreement with the higher lipophilicity of the skin. Finally, the nature of the solvent, together with the type and length of fatty acid chain, may play an important role in the interaction between fatty acids and the intercellular lipids of the tissue, so the effect of co-solvent has to be studied. This work represents a significant advancement in the understanding of the mechanisms of action of fatty acids as buccal penetration enhancers.This work reports the first attempt to find a structure-activity relationship on the effect of fatty acids on the mucosa permeation of a high molecular weight hydrophilic model compound (FD-4). A parabolic relationship between fatty acid lipophilicity and enhancement obtained, regardless of the presence and number of double bonds, was found. The relationship, which resembles the well-known relationship between permeability and lipophilicity of transdermal delivery, presents a maximum value in correspondence of C10 (logP


Cognitive disorders are a clinical and research challenge; in particular, the mild cognitive disorder (MiCD) requires diagnostic suspicion and tools with adequate performance for its detection. The objective of this study was the validation of a short cognitive test (CATest) for the detection of MiCD in population of 50 years or more. A diagnostic accuracy study was assembled and performed in a prospective cohort. A consecutive sample of 200 Colombian subjects who represented the whole spectrum of the condition of interest allowed us to reach the objective. Validity was determined by concurrent criteria. The cut points were determined by the ROC curves considering the best overall performance and accuracy of the test.CI 95% 61.8 to 79.43), positive predictive value of 75% ( 95% CI 66.79 to 82.42), and area under curve AUC 0.8518 (standard error SE 0.0265). CATest was validated to detection of MiCD at a cut-off point of 18. As a result, scores lower than 18 classified the participants as MiCD. At this cut-off point, CATest showed sensitivity of 84.3% (CI 76 to 90.16), specificity of 71.4%  according to the data reported in the literature. The advantages over other tests are the evaluation of all cognitive domains, time of application, and easy interpretation of results. CATest is a free use alternative for MiCD detection. Aging of population is one of the issues that most concerns the health system , due to Dementia represents a high burden of disease that mainly affects the over 65s , 3. In rDuring the aging process, changes occur within the cognitive domains, many of which go unnoticed, especially if the changes are small and demands on the environment in which the patient operates are small. Other changes, on the contrary, obligate the individual to generate a series of strategies aimed at compensating for the faults observed in the activities of his or her daily life.Cognitive disorders are classified according to the Diagnostic and Statistical Manual of Mental Disorders DSM 5  in mild According to the latest pronouncement of the World Alzheimer Report 2015  which deEvidence on factors that are related to the progression from mild cognitive disorder to major cognitive disorder is becoming more common –17, and Diagnosis of cognitive disorders is important especially in the early stages because many of its causes are potentially reversible such as depression, side effects of medication, excess alcohol, thyroid disease, vitamin deficiencies, and sleep disorders. In addition, even in the case of primary neurodegenerative disorders, early detection allows mitigate factors that are known to lead to more rapid progression of the disease , 16, andAnother benefit of early disease detection that is often overlooked is the extra time an individual will have to arrange their financial and legal obligations regarding end of life care .Science also does not overlook the benefits of early and accurate screening, as it also allows affected people to decide whether or not to participate in clinical trials, including experimental therapy trials that can slow or stop the progression of the disease , 20, a fAt present there are a large number of studies available that represent adequate evidence on the diagnosis of major cognitive disorder. The challenge for health professionals and science lies in the beginning phases of this disorder that go unnoticed for the subject and health care personnel. This limits the ability to predict the emergence of a syndrome of greater complexity and the potential of a high degree of disability for the individual in the future.There are tools that have been validated to detect neurocognitive disorder –27; howeThe aim of this study was validate a tool (cognitive assessment test (CATest)). for the detection of mild cognitive disorder in subjects aged 50 years or older, taking from the literature diagnostic elements with the highest level of diagnostic accuracy for this population, which contribute to a greater operative performance of the tool.Diagnostic test accuracy study assembled in a prospective cohort.A cohort with a total of 200 consecutive Colombian participants enrolled in the National University of Colombia Clinic of Dementia was included. Inclusion criteria were (1) age equal to or greater than 50 years, (2) at least 1-year education, and (3) adequate vision and hearing to complete neuropsychological (NP) testing. Exclusion criteria were (1) history of severe brain trauma; (2) lifetime history of schizophrenia, manic-depressive disorder, or schizoaffective disorder; (3) current alcohol or drug abuse/dependence; (4) obstructive sleep apnea syndrome; and (5) significant disease or unstable medical condition  and thyroid disease with no hormonal substitution.Sample size was calculated in 200 patients; the parameters used in the calculation were prevalence of cognitive disorder 40%, sensitivity 90% or higher, and specificity 80% or higher.A neurological clinical assessment was performed. The review of personal clinical history, mental and neurological examination, cognitive screening tests ; criteria to classification of cognitive disorder from DSM 5  were useCriteria for normal performance were (1) no more than one test score lower than expected within a cognitive domain and (2) no more than two scores lower than expected across domains, with the threshold corresponding to 1.0 standard deviation (SD) below age adjusted control means.NP criteria for MiCD included scores on at least two individual tests within a cognitive domain, greater than 1.0 SD below education and age-corrected. MCD included scores on at least two individual tests within a cognitive domain lower than 2.0 SD.The construction of CATest is the result of a systematic review performed by the National University of Colombia group of neurosciences.CATest includes the following. immediate recovery test: it consists of a list of 5 words, which allows evaluating episodic short-term memory and attentional functions during the first trial. In the test, the subject is asked to repeat 5 words during two trials, and after a short period of time, with distracting elements, he is asked to remember the 5 words. The recovery must be done spontaneously.The clock drawing test: it evaluates different cognitive skills, including attention, visuospatial abilities, abstract conceptualization, and executive control. During the drawing test of the clock, the participants are asked to draw a clock that has all its parts  and indicate on it the time 11:10. The drawing of the circumference, the numbers in correct position and order, and the location of the requested time are qualified. There are no time limits to complete it.The phonological fluency test: it is applied in a time of 1 minute; it has a restrictive character of phonological type, for the production of words limiting the beginning of the same to a letter that is indicated when giving the instruction of the test.TheCATest utilizes 2 letters: “M” or “P”, and the double selection is done to prevent learning bias during the serial application.CATest is rating from 0 to 21, considering 15 points to memory evaluation .Baseline distributions of the demographics, marital status, and education were presented according to the distribution of normality of each variable. A subgroup analysis by diagnostic  was presented.The receiver operational characteristic (ROC) curve analysis  was utilOptimal cut-off point was determined from a sensitivity analysis of the operative characteristics of the test; it included sensitivity, specificity, positive predictive value, negative predictive value, true positive (TP), and false positive (FP) rates, Likelihood ratio (LR + and LR -) as well as diagnostic odds ratio (DOR).Operative characteristics of each cut-off evaluated in the sensitivity analysis were modulated considering the proportion of accurately classified patients and the cost of making a false positive mistake or a false negative mistake. As criteria to define it, FP rate was maximized for MiCD and TP was maximized for MCD.The results were presented with the 95% confidence interval.Data were analyzed with statistical software STATA ® V.13.A total of 339 participants were evaluated between March 2016 and November 2017. 109 were excluded , and 30 participants did not complete the neuropsychological test. 200 participants were included.The prevalence of cognitive disorders in the sample was 51% (95% CI 44.1-57.9) with a prevalence of 32% (CI 95% 25.5-38.5) for MiCD and 19% (CI95% 13.6-24.4) for MCD.The study sample consisted predominantly of women (67%), average age of the participants were between 53 and 66 years (SD 8.84), and there were no differences between the ages by sex in the study with men being on average 66.65 years (95% CI 64.25-69) and women 66.5 years (95% CI 65-67.9) (P 0.9105).The educational level measured as the median of years of schooling was 16, Rank (1-29), and 45% of the participants were married .According to diagnostic category, statistical differences were not found in age of participants in normal performance group and MiCD ; however, the age in MCD group presented statistical differences ( 72.6 (CI95% 69.2-75.9)) .Women represented the highest proportion in the groups of normal performance subjects and MiCD, but this trend was not observed in the group of patients with MCD (women 34.21%) (P < 0.0001).Years of schooling also proved to be a variable that differentiated the groups  (P 0.0001).ROC curves were developed  to selecAs CATest was validated in a sample of patients with cognitive disorder ; a second ROC curve was developed  to selecCATest time application was calculated in the study sample, an average of 3 minutes and 55 seconds (SD 54 seconds). Time of application was varied from analysis by diagnostic groups .As a result of this study we obtain the validation of a new short cognitive test for the detection of MiCD in population with 50 years and older. For screening context, CATest has sensitivity of 84.3% (95% CI 76 to 90.16), specificity of 71.4% (95% CI 61.80 to 79.43), and accuracy of 0.84, which classifies it as a test of moderate accuracy.CATest accuracy can be better (accuracy 0.95) if the purpose is to classify a patient from a population with cognitive disorder (MCD and MiCD); that is, when the objective of the test is to classify the degree of cognitive disorder.In relation to the characteristics that are attributed to a short test , charactA recent meta-analysis  aimed atIn relation to MoCA, CATest presents a similar performance(S: 83% and Sp: 75%) ; howeverThe main strength of this study is the homogeneity of the diagnostic criteria that were defined a priori, as well as the fact that the study was assembled in a cohort, with strict selection criteria for its participants, which reduces the probability of including biases, ensuring internal validity.In contrast, the special susceptibility of diagnostic test studies to the location where they are developed is known by reports in the literature, since the characteristics of the study sample are usually different from those of the general population, compromising external validity. In our study, a Colombian reference center in attention of cognitive disorder was the location; however, preventive measures of this selection bias were controlled with rigorous design, achieving that the sample will be made up of volunteers from a public call in the media. One of the main limitations of this study is the high prevalence of CD in the sample, since it has been reported that it can behave as a bias that directs the results of accuracy towards over estimation . TherefoAnother aspect that should be considered in the interpretation of the results of sensitivity and specificity is the value corresponding to the margin of error that is evident in the wide of the confidence intervals and that are a consequence of the size of the sample used for the validation of the CATest.Future studies are necessary to verify the performance results of CATest in different scenarios  to determine its reliability, as well as studies of direct comparisons with other tests of a similar nature, in order to obtain more precise results.In conclusion, CATest is an alternative with adequate performance for the detection of cognitive disorder after 50 years. The ease of qualification and the short application time make it an attractive proposal for primary care scenarios. Additionally, the free use of restrictions makes CATest a useful alternative in daily clinical practice, educational, and research scenarios.


One year after the extension of the childhood vaccination mandates to the 11 routine vaccinations for children under 2 years old, we estimated vaccination coverage through vaccine reimbursement data. Coverage for children born in 2018 has notably increased. Moreover, vaccine coverage for children and for vaccines not concerned by the law have also shown an increasing trend, supporting a positive impact of the ongoing communication strategy on vaccination, beyond the extension of vaccination mandates. Haemophilus influenza b and hepatitis B antigens at age 2 and 4 months, with a booster dose at 11 months; three doses of the vaccine against invasive pneumococcal diseases with the same schedule; two doses of a vaccine against meningococcal C (MenC) diseases at age 5 and 12 months; and two doses of a vaccine against measles, mumps and rubella (MMR) at age 12 and 16–18 months . We. We12]. www.vaccination-info-service.fr) during the 2017 European Immunization Week. This site provides answers to most of the general public’s questions on vaccines and vaccinations. It has already received more than 6 million consultations. On the occasion of the 2019 European Immunization Week, an additional module of this website, one dedicated to healthcare professionals, was launched. It provides more insights into the various aspects of the National Immunisation Program, safety and effectiveness data, and on the evidence-base supporting the current recommendations.The measles resurgence which started end of 2017 may have contributed to the increase in MMR VC. However, the increasing trend in vaccine coverage for children and vaccinations not concerned by the new mandates is likely to reflect, at least in part, the commitment of the French government in favour of vaccination at a high level, publicly expressed on several occasions by the Minister of Health and the Prime Minister, as well as the implementation, since 2017, by Santé publique France and its partners, of different actions aiming at promoting vaccination and countering vaccine hesitancy. One of the main achievements was the launching of a governmental website dedicated to vaccination  and effective (from 17.3% to 12.5%) ,14. Howe


Then dynamic in vitro digestion of the yogurts was done using the parameters of gastric emptying determined in vivo. Gastric emptying half-times were significantly longer for LV than CT, whereas HV exhibited an intermediate behavior. In vitro gastric digestion showed a quick hydrolysis of caseins, whereas whey proteins were more resistant in the stomach particularly for LV and HV. During the intestinal phase, both whey proteins and caseins were almost fully hydrolyzed. Viscosity was shown to affect the behavior of yogurt in the small intestine.Gastric emptying of food is mainly driven by the caloric concentration, the rheological properties of the chyme, and the physical state (liquid/solid) of food once in the stomach. The present work investigated: (1) The effect of the composition and the viscosity of drinkable yogurts on gastric emptying in pigs, and (2) the behavior of yogurts during dynamic in vitro digestion. Three isocaloric liquid yogurts were manufactured: Two enriched in protein and fiber showing either a low (LV) or high (HV) viscosity, one control enriched in sugar and starch (CT). They were labelled with  Until recently, it was considered that the structure of the food matrix had a limited impact on food digestion and food could be described only according to its composition in proteins, lipids, and carbohydrates. During the last years, new evidences have clearly demonstrated that the food matrix structure plays a key role on the kinetics of transit and hydrolysis of the macronutrients ,2,3,4. SAnother food ingredient that can have beneficial effects on food intake is dietary fiber . Fiber iPost-ingestive signals encoding for nutrient content ,18 and vViscosity has been shown to have an effect on satiation and satiety in multiple studies ,25,26,2713C breath tests that can be biased by the food matrix as recently described [In this context, two fiber and protein-enriched yogurts (similar composition but different viscosity) and a control yogurt were formulated. All three yogurts had similar caloric content. The aim of the present study was to investigate whether protein and fiber enrichment could affect gastric emptying and, consequently, the kinetics of protein digestion. Yogurt digestion was studied using a dynamic in vitro model that had been previously validated against in vivo data . In ordeescribed . Then, aThree isocaloric yogurts with different compositions and structure kindly provided by Senoble  were submitted to in vivo and in vitro assays. The three yogurts, for which the composition is given in −1 at 4 °C was applied (n = 2) on 2 independent batches of the 3 yogurts. Since the study of gastric emptying on pigs and the in vitro digestion experiments occurred up to 15 days after manufacture, viscosity- of yogurts was assessed 4 days (D + 4) and -5 days (D + 15) after manufacture to check for a possible evolution of the viscosity during storage. Typical flow behaviors following the model of Herschel-Bulkley [app) at 100 s−1 were deduced. They were significantly different for the 3 yogurts, but not between the days  geometry on an AR 2000 rheometer . Yogurt was carefully sampled from the center of the cup, deposited on the plate at 4 °C and the cone was slowly lowered into the sample. A logarithm shear rate increase ranging from 0.2 to 100 s-Bulkley  were obsthe days .All procedures were in accordance with the European Community guidelines for the use of laboratory animals (L358-86/609/EEC). The study received prior approval by the local animal ethic committee (agreement number: R-2013-CHM-01). The facilities have the authorization to use animals (agreement number: A35-622) and radioisotopes (agreement number: T35-0282).99mTc-colloid sulfur CK1 , as described in previous studies [The animals used were 11 young Large White sows of about 3 months old and 30–35 kg body weight. During the week before the experiment, the animals were trained to consume the food while in quadrupedal position within a Pavlov stand. Furthermore, they were trained to eat 529 g  of yogurt within 5 min and then stay still for two hours in front of the gamma camera. On the day of experiment, conscious pigs were installed in a Pavlov stand and fed with 529 g of one of the three yogurt radiolabeled with 20 MBq,  studies . The gam1/2, time needed for 50% of the radioactivity to be transferred from the stomach into the small intestine) and the shape of the gastric emptying curve (β) that describes the length of the initial phase and the shape of the curve after the lag phase [The dynamic image series were analyzed with the OSIRIX MD software  and with dedicated software. This software allowed to re-aligns the images to compensate the movements of the animal relative to the camera head during acquisition. Gastric emptying half-time , Rennes CEDEX, France) was used to simulate the digestion of the three yogurts and investigate the kinetics of milk protein hydrolysis during digestion. The gastric emptying half-time and the shape of the gastric emptying curve determined in vivo by gamma-scintigraphy on the three different matrices were entered in the simulator software to simulate the gastric emptying using the Elashoff equation [A dynamic in vitro gastro-intestinal digestion system  in accordance with the manufacturer’s instructions. All samples were diluted with NuPAGE® LDS sample buffer and then treated with 0.5 M DL-dithiothreitol and distilled water. Mark 12 Unstained Standard (Invitrogen) was used as a molecular weight (MW) marker—as a reference of the position of the bands. Gels were fixed in 30% (v/v) ethanol, 10% (v/v) acetic acid, and 60% (v/v) deionized water. They were rinsed in deionized water before staining with Bio-Safe Coomassie stain . Discoloration of gels were performed with water Image analysis of SDS-PAGE gels was carried out using Image Scanner III  Healthcare Europe GbmH, Velizy-Villacoublay, France). After digitization of gels, the bands were selected and their gray intensity determined by densitometry using the software Image Quant TL™ . Densitometry analyses of the SDS-PAGE gels were used for the semi-quantification of protein levels. The percentage of each intact protein remaining in the gastric and intestinal compartment was estimated in comparison with the undigested yogurt sample.Milk protein extent of hydrolysis was assessed during the gastric and the intestinal phase by Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Briefly, the electrophoretic analyses were performed using 4–12% polyacrylamide NuPAGEp < 0.05 was considered statistically significant.The difference of proteolysis kinetics between yogurts was examined by a two-way Analysis of variance (ANOVA) with yogurt and time as factors and with time as a repeated measure using the SAS software 9.3 . Post-hoc comparison was performed using a Tukey test. The value of 1/2 obtained for the LV yogurt was significantly different from the CT yogurt (p < 0.05) with 72.7 ± 5.1 and 57.7 ± 3.9 min (mean ± standard deviation (SD)), respectively. In contrast, although the T1/2 for the HV yogurt was higher than that of the CT yogurt, it was not statistically different (p = 0.12). There was no significant difference between the β factor calculated from the gastric emptying curve of the three yogurts.The results are summarized in The modelling of the mean gastric empting curves is presented in A difference of filling of the proximal part of the small intestine according to the type of yogurt was observed. The control yogurt did not stay in the duodenum but was spread all over the first segments of the small intestine. In contrast, the high viscosity yogurt accumulated in the proximal part of the small intestine, whereas the low viscosity yogurt had a similar behavior to that of the control, as shown in The situation was different for β-lactoglobulin, where whey was the major protein b. In comFinally, α-lactalbumin was sensitive to gastric digestion in the control yogurt with 6.4% being intact after 120 min digestion c. It wasThe present study indicated that enriching a yogurt with protein and fiber slows down gastric emptying. Indeed, the control yogurt, that has an identical caloric content as the low viscosity yogurt but a 2.5-fold reduction in protein content and no fiber, exhibited a 20% lower gastric emptying half-time (57.7 min vs. 72.7 min). This confirms the role that enrichment with milk proteins and fiber plays on the transit of the food in the gastrointestinal tract. Gastric emptying half-time of the control yogurt was lower than that of the high viscosity yogurt, but the difference was not statistically significant. Low and high viscosity yogurts did not show statistical differences in gastric emptying indicating that viscosity of the undigested yogurt was not a crucial parameter impacting gastric emptying in the present study. Finally, no significant differences were observed between the β factors calculated from the gastric emptying curve of the three yogurts. The β factor reflects the shape of the emptying curve and can be highly impacted by the physical state of the food . In the present case, the three test foods were all gels and exhibited emptying curves of exponential power nature, typical for this kind of material. It should also be noted that a high inter-individual variability was observed in this in vivo assay, probably limiting the significance of the differences observed between the three yogurts. Therefore, a new experiment with a higher number of pigs would be required to emphasize the differences of behavior of the three yogurts in the gastrointestinal tract and see whether the high viscosity one is different than that of the control. In the hierarchy of satiating effects, proteins have been shown to be more effective than carbohydrates and fat . The posThe limit of the present study was that low and high viscosity yogurts differed from the control not only by their protein content but also by the presence of fibers. Hence, it is impossible to conclude which of these two components had the most important effect on gastric emptying. The effect of fibers on gastric emptying highly depends on the nature and the characteristics of the molecule and the interaction it can have with the other food constituents. A review systematically investigated the available literature on the relationship between dietary fiber types, appetite, acute and long-term energy intake, and body weight . It was Interestingly, the low and high viscosity yogurts had different behaviors when entering in the small intestine, even though they exhibited similar gastric emptying half-times. The high viscosity yogurt accumulated in the proximal part of the small intestine, whereas the low viscosity yogurt did not stay in the duodenum but spread along the first segments of the small intestine. This could result in different intestinal transit time of the two yogurts. Unfortunately, although this phenomenon was visible for eight out of the 11 pigs used in the study, in the absence of a reference anatomical imaging co-registered with gamma-scintigraphy, we were not able to quantitatively assess the intestinal time of transit of the different yogurts and could not be simulated in the in vitro dynamic digestions. Nevertheless, our data strongly suggest that the effect of yogurt viscosity is not on the time of residence of the yogurt in the stomach, but further in the small intestine. To our knowledge, such a result has never been published.1/2 and β parameters, determined in vivo, allowed for the following of the evolution of the three main milk proteins i.e., casein, β-lactoglobulin, and α-lactalbumin in the gastrointestinal tract. Caseins were shown to be extensively hydrolyzed in the stomach, compared to whey proteins as previously described [Dynamic in vitro digestion using the Tescribed ,41. Caseescribed . In contescribed ,44. In tescribed ,46,47. IFinally, dynamic in vitro digestion also demonstrated that, even though the amounts of milk proteins were 2.5 higher in the low or high viscosity yogurt than in the control one, the milk protein enriched yogurts are still well digested. This confirms that dairy proteins, even at high concentration, are highly digestible, as has been shown previously . Indeed,In the present study, we have not investigated the hormonal profile after the ingestion of the experimental diets. It could be highly interesting to repeat the experiment to identify the alteration in GLP-1, Cholecystokinin (CCK), ghrelin, etc., and other peptides in relation to emptying. This could clarify the mechanisms of action of the milk protein enriched yogurts in generating satiety.


The aim of this study was to analyze the incidence trends of localized and advanced breast cancer (BC) before and during the implementation of the mammography screening program (MSP) in Lithuania.The study period was divided into 2 intervals: the prescreening period (1998-2005) and implementation period (2006-2012). Analysis was performed for 3 age-groups: 0 to 49 years, 50 to 69 (target population), and older than 70.In all age-groups, the incidence of localized BC has shown a steady increase, while the incidence of advanced stage BC has decreased. In the target population, during the study period, the stage I BC incidence increased statistically significantly by 10.3% per year (from 3.3 per 100 000 in 1998 to 12.2 per 100 000 in 2012). The increase in localized BC was faster in the period before the implementation of the MSP than during the implementation in 2006 to 2012 (10.3% and 5.7%). A slightly statistically significant decrease was observed for advanced BC during the study period (−1.1% per year), while during the implementation of the MSP, significant changes were not seen.The results of our study indicate that the implementation of the MSP in Lithuania did not significantly influence trends of localized and advanced BC. Changes observed during the study period, including the prescreening and screening introduction periods, may reflect the general trends in the awareness of BC and improvements in diagnostics. The results of randomized clinical trials conducted in the 1980s in Europe and North America indicate that mammography screening programs (MSPs) reduce the mortality from BC for women aged 50 to 69 years by 20% to 35%.10 The aim of this study was to analyze the incidence trends of localized and advanced BC before and during the implementation of the MSP in the population of Lithuania.In 2005, the MSP started in Lithuania. In a recent report on Cancer screening in the EU, Lithuania was the country with the lowest participation rate (44.9% in 2014) and 1 of 3 countries where central invitation through a screening registry was not implemented.11 The principal sources of information on cancer cases are primary, secondary, and tertiary health-care institutions in the country that are responsible for providing notification when cancer is diagnosed. All physicians, all hospitals, and other institutions in the country must send a notification to the Lithuanian Cancer Registry of all cancer cases that come to their attention. Some pathological laboratories send the respective laboratory notification automatically extracted from laboratory data systems, using a standard format. The notifications, which are supplemented by death certificate information, are built into a database suitable for statistical use. This database contains information on all cancer cases diagnosed in Lithuanian residents since 1978. Since the period 1988 to 1992, the Registry data have been included in the “Cancer Incidence in Five Continents.”12Analysis was based on data from the population-based Cancer Registry. The Lithuanian Cancer Registry is a population-based cancer registry that contains personal and demographic information  as well as information on the diagnosis  and death (date of death and cause of death) of all patients with cancer in Lithuania, where the population size is approximately 3 million residents according to the 2011 census.International Classification of Disease for Oncology, second and third edition, site codes C500-C509, behaviour code 3). Only invasive BC was included because data on carcinoma in situ are not collected by the Registry systematically. During the study period, the TNM system was used for coding the stage of the disease . Corresponding population data by age, sex, and year were available from the Department of Statistics, Lithuania.The study included all cases of invasive female BC reported to the Registry during 1998 to 2012 , which are independently read by 2 radiologists. Both screen-film and digital mammography systems are present. For reporting screening and additional imaging results, the Breast Imaging Reporting and Data System is used, and for the evaluation of breast density, typology according to the American College of Radiology is included.The study period was divided into 2 intervals: the prescreening period (1998-2005) and implementation period (2006-2012). Stage I was defined as tumors with T-stage T1 (≤20 mm diameter and no involvement of lymph nodes); advanced stage (stage II+) included tumors T2, T3, and T4 or any number of affected lymph nodes. Analysis was performed for 3 age-groups: 0 to 49 years, 50 to 69 years (target population), and older than 70 years.14 A maximum number of 3 joinpoints was allowed for the estimations. The APCs were considered statistically significant if P < .05. Joinpoint analysis was performed for all ages combined and age- and stage-specific rates.Joinpoint regression analysis was used to identify points where a statistically significant change over time in the linear slope of the trend occurred. The annual percentage change (APC) was calculated for the trends by means of the generalized linear model using Joinpoint Software, version 3.4.3.From 1998 to 2012, overall 13 874 cases of invasive BC were detected in Lithuanian women. The baseline characteristics of these women are listed in From 1998 to 2012, the age-standardized incidence statistically significantly increased from 56.8 to 71.7 per 100 000 women. The BC incidence rose by 1.6% per year . Age-standardized incidence rates can be found in In all age-groups, the incidence of localized BC showed a steady growth, while the incidence of advanced BC declined. Statistically significant increases in the incidence of localized BC were observed from 1998 to 2012 in all ages combined (+7.9%), in the age group younger than 50 (+3.2%) years, in the target population (+10.2%), and in those older than 70 years (+6.2%). The incidence of the advanced stage statistically significantly decreased by 1.1%, 1.2%, 1.1%, and 1.6% in the all ages, younger than 50 years, 50 to 69 years, older than 70 years groups, respectively.Time trends for the incidence rates by stage and by period of MSP implementation are shown in In the target population during the study period, incidence of stage I BC increased from 3.3 per 100 000 in 1998 to 12.2 per 100 000 in 2012. The increase in the localized BC was faster in the period before implementation of the MSP than during implementation from 2006 to 2012 (10.3% and 5.7%). A slightly statistically significant decrease was observed for advanced BC during all the study periods (−1.0% per year), while statistically significant changes were not seen during implementation of the MSP.In the age-group older than 70 years, similar changes were identified. The incidence of localized BC increased by 13.4% per year before the introduction of the MSP and statistically insignificantly by 4.7% during its introduction. In contrast, in the age-group younger than 50 years, during the introduction of the MSP, the incidence of stage I BC increased statistically significantly. No statistically significant changes in the incidence of advanced BC in the age-group younger than 50 years and in the group over 70 years were identified during the introduction of the MSP.8 The detection rates of “small cancers” are often specified as a quality assurance measure.15 If the screening program significantly reduces the absolute rates of tumors diagnosed at an advanced stage among women attending the screening, a significant reduction in the number of deaths from BC can be observed.17 A decrease in advanced stage BC some years after the introduction of the MSP is an early surrogate indicator for a reduction in mortality.1619 Therefore, the calculation of the trends in BC stage distribution is widely accepted as a tool for monitoring the MSP.It can be expected that after the introduction of an MSP, there is an increase in the incidence rates of early-stage cancers, while the incidence rates of advanced cancers decline and remain persistently lowered.2027 Other studies have demonstrated either no decrease or only nonsignificant declines.2833In our study, we found a statistically significant increase in localized BC and a decrease in advanced BC during all the observational periods—before and during the introduction of the MSP. Data from other studies, with considerable differences in design, tumor stage grouping, duration of observations, and statistical methods, are controversial. Some of them clearly stated a reduction in the incidence rate of advanced BC, associated with the introduction of organized mammography screening.In our study, the incidence rates of stage I BC in the target population increased during the study period. A similar trend was seen in the older age-group, which was partly affected by the MSP. In our study during the introduction of the MSP, we also observed a statistically significantly increased incidence of stage I BC in the age-group younger than 50 years.25 Investigators from Italy examined the data from 700 municipalities, with a total population of 692 824 women, aged 55 to 74 years, and concluded that a significant and stable decrease in the incidence of late-stage BC was observed from the third year of screening onward, where the incidence rate ratio varied between 0.81 (in years 3-4 of screening) and 0.71 (in years 7-8)26. Simbrich et al in Germany observed a marked and statistically significant decline in the advanced BC rates after implementation of an MSP, mainly in women aged 55 to 69 years but not in the adjacent groups.27 This decrease was seen after a step-up introduction period. In this study, additionally, the incidence rates of stage I cancers clearly increased after the introduction of the MSP. The effect of the implementation of the Dutch BC screening program was analyzed, which demonstrated that the overall invasive BC rates grew mainly due to an increase in the T1 tumors, and the lymph node negative T1 tumors (T1N0), particularly in the age category 50 to 69.21 In women aged 50 to 69, there was a significant decline in the incidence of large tumors with lymph node or distant metastases (T2+/N+/M1). This reduction in advanced disease preceded the observed significant BC mortality reduction to a comparable extent by approximately 2 years. The analysis from the small Dutch region Limburg showed a decrease in the incidence of stage II to IV cancers: The incidence rate of stage II to IV tumors was 10% lower in 1995  than the incidence rates from 1987 to 1990 (before screening).24 A decline by 15% was observed for the incidence rate of node-positive BC 5 years after the MSP was introduced. A study to assess the impact of the National Health Service breast screening program on the overall and stage-specific incidence of BC was conducted in East Anglia.23 The study results clearly showed a significant growth in the detection of early-stage cancer in the age-group 50 to 64 years, corresponding with the introduction of screening in the region. The highest incidence increase occurred in 1991, two years after the introduction of screening. The estimated reduction in the advanced stages was 7% to 19% six years after the start of the screening.A study from Rhode Island during an MSP identified a decrease in the median diameter of the tumor from 2 to 1.5 cm with a significant decrease in the incidence of stage III and IV cancers. There was an increase in the incidence of stage I and II BC for women aged 50 to 64 years and in stage I for women older than 65 years.2835In our study, during implementation of the MSP, no statistically significant changes in the incidence of advanced BC were detected in the target population. This corresponds to the data of other studies, where a decrease in the incidence rate of advanced BC was not determined.33 The study showed the increase in the annual incidence of localized BC among women aged 50 to 69 years from 63.9 per 100 000 before the introduction of screening to 141.2 per 100 000 afterward. The change in incidence of the localized stage was significantly higher in the age-group that was eligible for screening compared to the younger age-group, with a relative ratio of 1.97 , or P < .001, comparing 50 to 69 versus 20 to 49. Nederend et al conducted a population-based study in the Netherlands from 1997 to 2008 with the main aim of determining trends in the incidence of advanced BC with screening mammography.29 In this study, after 12 years of biennial screening, a decline in advanced BC was not observed. Jorgensen et al assessed the association between screening in Denmark and tumor size and concluded that BC screening was not associated with a reduction in the incidence of advanced cancer. 34 These authors suggest that one-third of tumors diagnosed during screening represent overdiagnosis. Very similar results and conclusions were made by the researches from Australia who evaluated trends in stage-specific BC incidence in New South Wales.35 A systematic review by Autier et al focused on incidence trends in areas where mammography screening is practiced.31 They stated that in population studies in Europe, North America, and Australia, only small declines in advanced BC incidence were observed, although BC mortality fell dramatically after 1990 in the areas included in this study.Having reviewed the Norwegian MSP, Lousdal et al found no decline in the incidence of late-stage cancers in the target population (women 50 to 69 years old) compared to an unscreened group (women 20-49 years old).10In our study, we found positive changes in the incidence of BC in Lithuania from 1998 to 2012; namely, the incidence of localized BC increased, while the incidence of advanced BC decreased. Changes were seen in all age-groups, those affected by screening and those not affected, which generally reflects the improving oncology situation in our country. If the MSP works as intended, the decrease (at a lower level) in the incidence of advanced stages would also be seen in the women older than 70 years, since a lot of the cancers found at screening will be the ones which without screening would have been diagnosed after 70 years. However, after the initiation of the MSP, the decrease in advanced BC was not statistically significant in this age-group. The improvement in stage distribution can be attributed to notable changes that occurred in Lithuania during the past 2 decades. Major efforts have been made to increase BC awareness. In addition, more advanced imaging equipment was acquired. Digital mammography, breast magnetic resonance imaging, and X-ray-guided stereotactic biopsy became available in the country. However, our analysis cannot distinguish the effect of screening from the effect of the awareness of BC and better diagnostic possibilities. The low participation rate is the main limitation of the MSP in our country. It started at 18% of the targeted population in the first round (2005-2007) and reached 44.9% in the fifth round. It does not reach the recommended levels in European guidelines, and in a recent report on cancer screening in the EU, Lithuania was the country with the lowest participation rate.Analysis of the trends in BC stage distribution over time is an attractively simple mean of evaluating population-based service screening. This fact has led to a large number of such studies. Such trend studies have several limitations that can influence the results. At first, background incidence rates could be potentially influenced by the changes in risk factors prevalence in general population . In addition, results can be affected by the extent of opportunistic screening before MSP and the performance indicators of current MSP. The main limitations of our study include: limited follow-up after the introduction of MSP; low participation rate in the screening; opportunistic screening prior to the introduction of an organized program; and no data about carcinoma in situ. Limited follow-up in our study could have an impact on our results, as during the initial screening a lot of advanced cancers will be found, since there has been no previous screening to detect them. Looking at women aged 50 to 69 years in 2006 to 2012 data includes more initial screenings than subsequent screenings, so on it can be hardly expected to find a significant decrease in advanced cancers. In the other countries where the MSP has been identified as having an impact on the decline in advanced-stage BC, the participation rate in the program was much higher, as well as a longer follow-up period was applied. This study is only the first step in evaluating the MSP in Lithuania and its impact on the incidence trends of localized and advanced BC after the start of the MSP. The changes in BC incidence by stage described in the article can be due to problems with the implementation of the program, meaning the lack of participation rather than the usefulness of the MSP.The results of our study indicate that the implementation of the MSP in Lithuania did not influence significantly trends of localized and advanced BC. Changes observed during the study period, including the prescreening and screening introduction periods, may reflect the influence of the general trends in the awareness of BC and improvements in diagnostics.