Breast Cancer in Low- and Middle-Income Countries: An Emerging and Challenging Epidemic

Breast cancer is a major health care problem that affects more than one million women yearly. While it is traditionally thought of as a disease of the industrialized world, around 45% of breast cancer cases and 55% of breast cancer deaths occur in low and middle income countries. Managing breast cancer in low income countries poses a different set of challenges including access to screening, stage at presentation, adequacy of management and availability of therapeutic interventions. In this paper, we will review the challenges faced in the management of breast cancer in low and middle income countries

Raman Spectroscopic Analysis of Human Skin Tissue Sections Ex-vivo: Evaluation of the Effects of Tissue Processing and Dewaxing

Raman spectroscopy coupled with K-means clustering analysis (KMCA) is employed to elucidate the biochemical structure of human skin tissue sections, and the effects of tissue processing. Both hand and thigh sections of human cadavers were analysed in their unprocessed and formalin fixed paraffin processed (FFPP) and subsequently dewaxed forms. In unprocessed sections, KMCA reveals clear differentiation of the stratum corneum, intermediate underlying epithelium and dermal layers for sections from both anatomical sites. The stratum corneum is seen to be relatively rich in lipidic content; the spectrum of the subjacent layers is strongly influenced by the presence of melanin, while that of the dermis is dominated by the characteristics of collagen. For a given anatomical site, little difference in layer structure and biochemistry is observed between samples from different cadavers. However, the hand and thigh sections are consistently differentiated for all cadavers, largely based on lipidic profiles. In dewaxed FFPP samples, while the stratum corneum, intermediate and dermal layers are clearly differentiated by KMCA of Raman maps of tissue sections, the lipidic contributions to the spectra are significantly reduced, with the result that respective skin layers from different anatomical sites become indistinguishable. While efficient at removing the fixing wax, the tissue processing also efficiently removes the structurally similar lipidic components of the skin layers. In studies of dermatological processes in which lipids play an important role, such as wound healing, dewaxed samples are therefore not appropriate. Removal of the lipids does however accentuate the spectral features of the cellular and protein components, which may be more appropriate for retrospective analysis of disease progression and biochemical analysis using tissue banks

Comparative static curing versus dynamic curing on tablet coating structures

International audienceCuring is generally required to stabilize film coating from aqueous polymer dispersion. This post-coating drying step is traditionally carried out in static conditions, requiring the transfer of solid dosage forms to an oven. But, curing operation performed directly inside the coating equipment stands for an attractive industrial application. Recently, the use of various advanced physico-chemical characterization techniques i.e., X-ray micro-computed tomography, vibrational spectroscopies (near infrared and Raman) and X-ray microdiffraction, allowed new insights into the film-coating structures of dynamically cured tablets. Dynamic curing end-point was efficiently determined after 4 h. The aim of the present work was to elucidate the influence of curing conditions on film-coating structures. Results demonstrated that 24 h of static curing and 4 h of dynamic curing, both performed at 60 degrees C and ambient relative humidity, led to similar coating layers in terms of drug release properties, porosity, water content, structural rearrangement of polymer chains and crystalline distribution. Furthermore, X-ray microdiffraction measurements pointed out different crystalline coating compositions depending on sample storage time. An aging mechanism might have occur during storage, resulting in the crystallization and the upward migration of cetyl alcohol, coupled to the downward migration of crystalline sodium lauryl sulfate within the coating layer. Interestingly, this new study clearly provided further knowledge into film-coating structures after a curing step and confirmed that curing operation could be performed in dynamic conditions

Comprehensive study of dynamic curing effect on tablet coating structure

International audienceThe dissolution method is still widely used to determine curing end-points to ensure long-term stability of film coatings. Nevertheless, the process of curing has not yet been fully investigated. For the first time, joint techniques were used to elucidate the mechanisms of dynamic curing over time from ethylcellulose (Aquacoat (R))-based coated tablets. X-ray micro-computed tomography (X mu CT), Near Infrared (NIR), and Raman spectroscopies as well as X-ray microdiffraction were employed as non-destructive techniques to perform direct measurements on tablets. All techniques indicated that after a dynamic curing period of 4 h, reproducible drug release can be achieved and no changes in the microstructure of the coating were any longer detected. X mu CT analysis highlighted the reduced internal porosity, while both NIR and Raman measurements showed that spectral information remained unaltered after further curing. X-ray microdiffraction revealed densification of the coating layer with a decrease in the overall coating thickness of about 10 pm as a result of curing. In addition, coating heterogeneity attributed to cetyl alcohol was observed from microscopic images and Raman analysis. This observation was confirmed by X-ray microdiffraction that showed that crystalline cetyl alcohol melted and spread over the coating surface with curing. Prior to curing, X-ray microdiffraction also revealed the existence of two coating zones differing in crystalline cetyl alcohol and sodium lauryl sulfate concentrations which could be explained by migration of these constituents within the coating layer. Therefore, the use of non-destructive techniques allowed new insights into tablet coating structures and provided precise determination of the curing end-point compared to traditional dissolution testing. This thorough study may open up new possibilities for process and formulation control

Estimating the Analytical Performance of Raman Spectroscopy for Quantification of Active Ingredients in Human Stratum Corneum

Confocal Raman microscopy (CRM) has become a versatile technique that can be applied routinely to monitor skin penetration of active molecules. In the present study, CRM coupled to multivariate analysis (namely PLSR—partial least squares regression) is used for the quantitative measurement of an active ingredient (AI) applied to isolated (ex vivo) human stratum corneum (SC), using systematically varied doses of resorcinol, as model compound, and the performance is quantified according to key figures of merit defined by regulatory bodies (ICH, FDA, and EMA). A methodology is thus demonstrated to establish the limit of detection (LOD), precision, accuracy, sensitivity (SEN), and selectivity (SEL) of the technique, and the performance according to these key figures of merit is compared to that of similar established methodologies, based on studies available in literature. First, principal components analysis (PCA) was used to examine the variability within the spectral data set collected. Second, ratios calculated from the area under the curve (AUC) of characteristic resorcinol and proteins/lipids bands (1400–1500 cm−1) were used to perform linear regression analysis of the Raman spectra. Third, cross-validated PLSR analysis was applied to perform quantitative analysis in the fingerprint region. The AUC results show clearly that the intensities of Raman features in the spectra collected are linearly correlated to resorcinol concentrations in the SC (R2 = 0.999) despite a heterogeneity in the distribution of the active molecule in the samples. The Root Mean Square Error of Cross-Validation (RMSECV) (0.017 mg resorcinol/mg SC), The Root Mean Square of Prediction (RMSEP) (0.015 mg resorcinol/mg SC), and R2 (0.971) demonstrate the reliability of the linear regression constructed, enabling accurate quantification of resorcinol. Furthermore, the results have enabled the determination, for the first time, of numerical criteria to estimate analytical performances of CRM, including LOD, precision using bias corrected mean square error prediction (BCMSEP), sensitivity, and selectivity, for quantification of the performance of the analytical technique. This is one step further towards demonstrating that Raman spectroscopy complies with international guidelines and to establishing the technique as a reference and approved tool for permeation studies

Monitoring Dermal Penetration and Permeation Kinetics of Topical Products; the Role of Raman Microspectroscopy

The study of human skin represents an important area of research and development in dermatology, toxicology, pharmacology and cosmetology, in order to assess the effects of exogenous agents, their interaction, their absorption mechanism, and/or their toxicity towards the different cutaneous structures. The processes can be parameterised by mathematical models of diffusion, of varying degrees of complexity, and are commonly measured by Franz cell diffusion, in vitro, and tape stripping, in vitro or in vivo, techniques which are recognised by regulatory bodies for commercialisation of dermally applied products. These techniques do not directly provide chemically specific measurement of the penetration and/or permeation of formulations in situ, however. Raman microspectroscopy provides a non-destructive, non-invasive and chemically specific methodology for in vitro, and in vivo investigations, in-situ, and can provide a powerful alternative to the current gold standard methods approved by regulatory bodies. This review provides an analysis of the current state of art of the field of monitoring dermal penetration and permeation kinetics of topical products, in vitro and in vivo, as well as the regulatory requirements of international guidelines governing them. It furthermore outlines developments in the analysis of skin using Raman microspectroscopy, towards the most recent demonstrations of quantitative monitoring of the penetration and permeation kinetics of topical products in situ, for in vitro and in vivo applications, before discussing the challenges and future perspectives of the field

Sur quelques équations aux dérivées partielles fractionnaires, théorie et applications

It is currently established that for general heterogeneous media, the classical Fick's law must be replaced by a nonlocal fractional differential operator. In such situations where anomalous diffusion occurs, the crucial difficulty is the identification of the correct order of the fractional differential operators. In the present paper, order identification of fractional differential operators is studied in the case of stationary and evolution partial differential equations. The novelty of our work is the determination of the exact problem satisfied by the derivative of the solution with respect to the differential order. More precisely, if the solution of our boundary value problem, with a fractional differential order α , is denoted by u (α), we show that (du(α))/dα satisfies the same problem, but with another source term. Our new result allows to carry out an exact computation of the cost functional derivative with respect to the order of derivation to perform more accurate and efficient steepest descent minimization algorithms. It can also be applied in optimal control theory and for sensitivity analysis frameworks. Our method is illustrated in two situations: Fractional Poisson's equation and Taylor-Couette flow problem with fractional time-derivative. In our second work, a generalized time-space fractional equation is considered. We consider the inverse problem of finding the solution of the equation and the source term knowing the spatial mean of the solution at any times with the initial and the boundary conditions. The existence and the continuity with respect to the data of the solution for the direct and the inverse problems are proved by Fourier's method and the Schauder fixed point theorem, in an adequate convex bounded subset. In the third work, fractional Sobolev spaces are introduced for Lipschitz domains in R^d,d≥1 and we show that these spaces represent the natural functional framework for boundary value problems with fractional partial differential operators involving Riemann-Liouville operators. Then, a variational problem is considered in tensor fractional Sobolev spaces such that proper generalized decomposition (PGD) can be performed. After establishing that our problem admits a unique solution in an adequate fractional Sobolev space, we show that the PGD reduction method allows a convergent algorithm toward the theoretical solution. This theoretical result is confirmed by numerical simulations on some boundary value problems. Finally, comparisons with classical methods are presented and we show that the PGD method is more efficient and quick.Il est actuellement établi que pour les milieux hétérogènes généraux, la loi classique de Fick doit être remplacée par un opérateur différentiel fractionnaire non local, on parle alors de diffusion anormale. Dans les situations où l'on a une diffusion anormale, la difficulté cruciale est l’identification de l'ordre de dérivation pour les opérateurs différentiels fractionnaires. Dans le présent mémoire, l’identification de l’ordre des opérateurs différentiels fractionnaires est étudiée dans le cas des équations différentielles partielles stationnaires et d'évolution. La nouveauté de notre travail est la détermination du problème exact satisfait par la dérivée de la solution par rapport à l’ordre de dérivation. Plus précisément, si la solution du problème aux limites avec un ordre différentiel fractionnaire α est notée par u (α), nous montrons que (du(α))/dα satisfait le même problème, mais avec terme source différent. Notre résultat permet de déterminer la dérivée exacte de la fonction coût par rapport à l'ordre de dérivation et d'avoir ainsi des algorithmes de descente du gradient plus précis et plus efficaces. Il peut également être appliqué dans la théorie du contrôle optimal et l'étude de sensitivité paramétrique. Notre méthode est illustrée par des simulations numériques pour un problème aux limites stationnaire et un problème aux limites d'évolution : l’équation fractionnaire de Poisson et le problème d’écoulement de Taylor-Couette avec une dérivée fractionnaire en temps. Dans le second travail, on a considéré une équation fractionnaire spatio-temporelle. Nous considérons le problème inverse consistant à trouver la solution de l’équation et le terme source en connaissant la moyenne spatiale de la solution à tout instant, étant données la condition initiale et les conditions aux bords. L’existence et la continuité par rapport aux données de la solution des problèmes directs inverses sont prouvées par la méthode de Fourier et le théorème du point fixe Schauder, dans un sous-ensemble convexe adéquat. Dans notre troisième travail, les espaces fractionnaires de Sobolev sont introduits pour les domaines de Lipschitz dans Rd,d≥1 et nous montrons que ces espaces sont le cadre fonctionnel naturel pour les problèmes aux limites fractionnaires avec des opérateurs différentiels de Riemann-Liouville. Ensuite, un problème variationnel est considéré dans les espaces fractionnaires de Sobolev tensoriels où une décomposition progressive généralisée (PGD) peut être réalisée. Après avoir établi que notre problème admet une solution unique dans un espace de Sobolev fractionnaire adéquat, nous montrons que la méthode de réduction PGD fournit un algorithme qui converge vers la solution théorique. Ce résultat théorique est confirmé par des simulations numériques sur certains problèmes aux limites. Les comparaisons avec les méthodes classiques sont présentées et montrent que la méthode PGD est plus efficace et plus rapide

On fractional partial differential equations, theory and applications

Il est actuellement établi que pour les milieux hétérogènes généraux, la loi classique de Fick doit être remplacée par un opérateur différentiel fractionnaire non local, on parle alors de diffusion anormale. Dans les situations où l'on a une diffusion anormale, la difficulté cruciale est l’identification de l'ordre de dérivation pour les opérateurs différentiels fractionnaires. Dans le présent mémoire, l’identification de l’ordre des opérateurs différentiels fractionnaires est étudiée dans le cas des équations différentielles partielles stationnaires et d'évolution. La nouveauté de notre travail est la détermination du problème exact satisfait par la dérivée de la solution par rapport à l’ordre de dérivation. Plus précisément, si la solution du problème aux limites avec un ordre différentiel fractionnaire α est notée par u (α), nous montrons que (du(α))/dα satisfait le même problème, mais avec terme source différent. Notre résultat permet de déterminer la dérivée exacte de la fonction coût par rapport à l'ordre de dérivation et d'avoir ainsi des algorithmes de descente du gradient plus précis et plus efficaces. Il peut également être appliqué dans la théorie du contrôle optimal et l'étude de sensitivité paramétrique. Notre méthode est illustrée par des simulations numériques pour un problème aux limites stationnaire et un problème aux limites d'évolution : l’équation fractionnaire de Poisson et le problème d’écoulement de Taylor-Couette avec une dérivée fractionnaire en temps. Dans le second travail, on a considéré une équation fractionnaire spatio-temporelle. Nous considérons le problème inverse consistant à trouver la solution de l’équation et le terme source en connaissant la moyenne spatiale de la solution à tout instant, étant données la condition initiale et les conditions aux bords. L’existence et la continuité par rapport aux données de la solution des problèmes directs inverses sont prouvées par la méthode de Fourier et le théorème du point fixe Schauder, dans un sous-ensemble convexe adéquat. Dans notre troisième travail, les espaces fractionnaires de Sobolev sont introduits pour les domaines de Lipschitz dans Rd,d≥1 et nous montrons que ces espaces sont le cadre fonctionnel naturel pour les problèmes aux limites fractionnaires avec des opérateurs différentiels de Riemann-Liouville. Ensuite, un problème variationnel est considéré dans les espaces fractionnaires de Sobolev tensoriels où une décomposition progressive généralisée (PGD) peut être réalisée. Après avoir établi que notre problème admet une solution unique dans un espace de Sobolev fractionnaire adéquat, nous montrons que la méthode de réduction PGD fournit un algorithme qui converge vers la solution théorique. Ce résultat théorique est confirmé par des simulations numériques sur certains problèmes aux limites. Les comparaisons avec les méthodes classiques sont présentées et montrent que la méthode PGD est plus efficace et plus rapide.It is currently established that for general heterogeneous media, the classical Fick's law must be replaced by a nonlocal fractional differential operator. In such situations where anomalous diffusion occurs, the crucial difficulty is the identification of the correct order of the fractional differential operators. In the present paper, order identification of fractional differential operators is studied in the case of stationary and evolution partial differential equations. The novelty of our work is the determination of the exact problem satisfied by the derivative of the solution with respect to the differential order. More precisely, if the solution of our boundary value problem, with a fractional differential order α , is denoted by u (α), we show that (du(α))/dα satisfies the same problem, but with another source term. Our new result allows to carry out an exact computation of the cost functional derivative with respect to the order of derivation to perform more accurate and efficient steepest descent minimization algorithms. It can also be applied in optimal control theory and for sensitivity analysis frameworks. Our method is illustrated in two situations: Fractional Poisson's equation and Taylor-Couette flow problem with fractional time-derivative. In our second work, a generalized time-space fractional equation is considered. We consider the inverse problem of finding the solution of the equation and the source term knowing the spatial mean of the solution at any times with the initial and the boundary conditions. The existence and the continuity with respect to the data of the solution for the direct and the inverse problems are proved by Fourier's method and the Schauder fixed point theorem, in an adequate convex bounded subset. In the third work, fractional Sobolev spaces are introduced for Lipschitz domains in R^d,d≥1 and we show that these spaces represent the natural functional framework for boundary value problems with fractional partial differential operators involving Riemann-Liouville operators. Then, a variational problem is considered in tensor fractional Sobolev spaces such that proper generalized decomposition (PGD) can be performed. After establishing that our problem admits a unique solution in an adequate fractional Sobolev space, we show that the PGD reduction method allows a convergent algorithm toward the theoretical solution. This theoretical result is confirmed by numerical simulations on some boundary value problems. Finally, comparisons with classical methods are presented and we show that the PGD method is more efficient and quick