Optimisation et évaluation d’un nouveau test PAMPA amélioré pour la prédiction de l’absorption intestinale de médicaments

Ce mémoire rapporte l’optimisation et l’évaluation d’une nouvelle version du test PAMPA (Parallel Artificial Membrane Permeability Assay) appelée Néo-PAMPA. Ce test qui permet la prédiction de l’absorption intestinale de médicaments consiste en l’utilisation d’une membrane modèle de la paroi intestinale composée d’une bicouche lipidique déposée sur un coussin de polydopamine recouvrant un filtre poreux. En effet, nous nous sommes intéressés lors de ce projet à la mise en place d’une membrane artificielle qui serait plus représentative de la paroi intestinale humaine. Nous avons pu déterminer, suite à une étude comparative des propriétés de huit médicaments ainsi que les coefficients de perméabilité obtenus, que les filtres en polycarbonate présentaient le meilleur choix de support solide pour la membrane. Nous avons également vérifié la déposition du coussin de polydopamine qui apporte le caractère fluide à la bicouche lipidique. Les résultats des tests de perméabilité ont démontré que le coussin de polymère n’obstrue pas les pores du filtre après un dépôt de 4h. Nous avons par la suite étudié la déposition de la bicouche lipidique sur le filtre recouvert de polydopamine. Pour ce faire, deux méthodes de préparation de liposomes ainsi que plusieurs tailles de liposomes ont été testées. Aussi, la composition en phospholipides a été sujette à plusieurs changements. Tous ces travaux d’optimisation ont permis d’aboutir à des liposomes préparés selon la méthode du « film lipidique » à partir d’un mélange de dioléoylphosphatidylcholine (DOPC) et de cholestérol. Une dernière étape d’optimisation de la déposition de la bicouche reste à améliorer. Enfin, le test standard Caco-2, qui consiste à évaluer la perméabilité des médicaments à travers une monocouche de cellules cancéreuses du colon humain, a été implémenté avec succès dans le but de comparer des données de perméabilité avec un test de référence.This essay reports the optimization and evaluation of a new version of the Parallel Artificial Membrane Permeability Assay (PAMPA), called Neo-PAMPA. This test, used for the prediction of the drugs’ intestinal absorption, involves the use of a model intestine cell membrane in which a lipid bilayer is supported on a polymeric cushion deposited on a filter. In this project, we are interested in the development of an artificial membrane that is more representative of the human intestinal wall. We determined, based on a comparative study of the properties of 8 drug candidates and their permeability coefficients obtained, that polycarbonate filters were the best choice of solid support for the membrane. We also verified the deposition time of the polydopamine cushion that brings the fluid nature to our membrane. The results from the permeability tests showed that the polymer cushion do not clog the pores of the filter after a 4h deposition. Then, we studied the deposition of the lipid bilayer on the polydopamine-coated filter. To do this, two methods of liposome preparation as well as several liposome sizes were tested. Moreover, several phospholipid compositions were tested. According to our evaluation, liposomes prepared according to the "lipid film" method from a mixture of DOPC and cholesterol are better suited. Nevertheless, a final optimization step for the bilayer deposition is still required. Finally, the gold standard Caco-2 assay used to assess the drug permeability across a monolayer of human Colon Colorectal adenocarcinoma cells was successfully implemented for permeability data comparison

Two step runge-KUTTA-nystrom method for solving second-order ordinary differential equations

In this research, methods that will be able to solve the second order initial value problem (IVP) directly are developed. These methods are in the scheme of a multi-step method which is known as the two-step method. The two-step method has an advantage as it can estimate the solution with less function evaluations compared to the one-step method. The selection of step size is also important in obtaining more accurate and efficient results. Smaller step sizes will produce a more accurate result, but it lengthens the execution time. Two-Step Runge-Kutta (TSRK) method were derived to solve first-order Ordinary Differential Equations (ODE). The order conditions of TSRK method were obtained by using Taylor series expansion. The explicit TSRK method was derived and its stability were investigated. It was then analyzed experimentally. The numerical results obtained were analyzed by making comparisons with the existing methods in terms of maximum global error, number of steps taken and function evaluations. The explicit Two-Step Runge-Kutta-Nyström (TSRKN) method was derived with reference to the technique of deriving the TSRK method. The order conditions of TSRKN method were also obtained by using Taylor series expansion. The strategies in choosing the free parameters were also discussed. The stability of the methods derived were also investigated. The explicit TSRKN method was then analyzed experimentally and comparisons of the numerical results obtained were made with the existing methods in terms of maximum global error, number of steps taken and function evaluations. Next, we discussed the derivation of an embedded pair of the TSRKN (ETSRKN) methods for solving second order ODE. Variable step size codes were developed and numerical results were compared with the existing methods in terms of maximum global error, number of steps taken and function evaluations. The ETSRKN were then used to solve second-order Fuzzy Differential Equation (FDE). We observe that ETSRKN gives better accuracy at the end point of fuzzy interval compared to other existing methods. In conclusion, the methods developed in this thesis are able to solve the system of second-order differential equation (DE) which consists of ODE and FDE directly

Pigmented Lesion on the Cheek: A Quiz

International audienceQui

COVID-19 and pregnancy: An umbrella review of clinical presentation, vertical transmission, and maternal and perinatal outcomes

Background We conducted an overview of systematic reviews (SRs) summarizing the best evidence regarding the effect of COVID-19 on maternal and child health following Cochrane methods and PRISMA statement for reporting (PROSPERO-CRD42020208783). Methods We searched literature databases and COVID-19 research websites from January to October 2020. We selected relevant SRs reporting adequate search strategy, data synthesis, risk of bias assessment, and/or individual description of included studies describing COVID-19 and pregnancy outcomes. Pair of reviewers independently selected studies through COVIDENCE web-software, performed the data extraction, and assessed its quality through the AMSTAR-2 tool. Discrepancies were resolved by consensus. Each SR’s results were synthesized and for the most recent, relevant, comprehensive, and with the highest quality, by predefined criteria, we presented GRADE evidence tables. Results We included 66 SRs of observational studies out of 608 references retrieved and most (61/66) had "critically low" overall quality. We found a relatively low degree of primary study overlap across SRs. The most frequent COVID-19 clinical findings during pregnancy were fever (28–100%), mild respiratory symptoms (20–79%), raised C-reactive protein (28–96%), lymphopenia (34–80%), and pneumonia signs in diagnostic imaging (7–99%). The most frequent maternal outcomes were C-section (23–96%) and preterm delivery (14–64%). Most of their babies were asymptomatic (16–93%) or presented fever (0–50%), low birth weight (5–43%) or preterm delivery (2–69%). The odds ratio (OR) of receiving invasive ventilation for COVID-19 versus non-COVID-19 pregnant women was 1.88 (95% Confidence Interval [CI] 1.36–2.60) and the OR that their babies were admitted to neonatal intensive care unit was 3.13 (95%CI 2.05–4.78). The risk of congenital transmission or via breast milk was estimated to be low, but close contacts may carry risks. Conclusion This comprehensive overview supports that pregnant women with COVID-19 may be at increased risk of adverse pregnancy and birth outcomes and low risk of congenital transmission.Fil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bardach, Ariel Esteban. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Comandé, Daniel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Berrueta, Mabel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Argento, Fernando J.. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Rodriguez Cairoli, Federico. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Zamora, Natalia. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Santa María, Victoria. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Xiong, Xu. University of Tulane; Estados UnidosFil: Zaraa, Sabra. University of Washington; Estados UnidosFil: Mazzoni, Agustina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Buekens, Pierre. University of Tulane; Estados Unido

Diagnosis of oral pigmentations and malignant transformations

AbstractBackgroundOral pigmentation is a common finding in the mouth. Pigmentation can be either normal or abnormal discoloration of oral mucous membrane. The purpose of this review mainly focuses on the main oral pigmented lesions, in order to help the clinicians establish a better approach towards the patients with pigmented oral lesions and to provide thorough knowledge regarding such lesions for patient reassurance, early definitive diagnosis and prompt treatment.MethodsRelevant data concerning oral pigmented lesions, clinical features and the possibility of malignant transformation of such lesions were reviewed thoroughly from pubmed literature published in English. Pigmented lesions affecting the skin were not included in our review.ResultsFew pigmented lesions have been identified and their tendency to become malignant has been reported in the literature. The oral lesions showing malignant transformation reported were mostly case series. Unfortunately, due to lack of long-term studies, follow ups and randomized controlled studies in this respect it was difficult to draw a statistical analysis. This information is quite crucial for general dental practitioners to improve their understanding regarding oral lesions and to differentiate between normal and diseased conditions, so that they can master the skill of differential diagnosis, definitive diagnosis and prompt treatment.ConclusionOral pigmentation may present as focal, multifocal or diffused macular or tumefactive lesions. They may greatly vary in color as blue, purple, brown, gray or black depending on the quantity and site of melanin in the tissues [1]. Etiology of pigmentation can be multi factorial. Mostly pigmentation is physiologic but at times it can be a precursor of severe diseases.Lesions may be caused by localized harmless accumulations of melanin, hemosiderin or exogenous metals or they may be a sign of underlying systemic or genetic disease. A few lesions may be associated with life-threatening medical conditions that require immediate intervention. The differential diagnosis for any pigmented lesion is extensive, as it includes examples of endogenous and exogenous pigmentations. Although biopsy is a helpful and necessary aid in the diagnosis of focally pigmented lesions, with diffuse pigmentation lesions require a thorough dental and medical history and laboratory investigations

Severe cutaneous reactions to drugs in the setting of a general hospital

Abstract: BACKGROUND: Cutaneous drug reactions are frequently found. Assessing the clinical and epidemiological profile of severe forms is extremely relevant for their better recognition and management. Few studies have assessed the severe forms of cutaneous drug reactions in patients hospitalized in our setting. OBJECTIVES: To assess the clinical and epidemiological aspects of severe cutaneous adverse reactions to drugs in a tertiary hospital in Porto Alegre, Brazil. METHODS: All cases of severe cutaneous adverse reactions to drugs in patients hospitalized from January/2005 to December/2010 were retrospectively analyzed for clinical and epidemiological variables. Cases of Stevens- Johnson Syndrome, Toxic Epidermal Necrolysis, drug hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms and acute generalized exanthematous pustulosis were included. RESULTS: An occurrence rate of 1 serious reaction for every 3,048 inpatients was found (total of 173,767 inpatients admitted in the period). Drug Reaction with Eosinophilia and Systemic Symptoms was the most frequent presentation. The drugs most frequently involved were anticonvulsants (40.4%), antibiotics (26.3%), and analgesics/anti-inflammatory drugs (10.5%). Thirty seven patients (64.9%) were admitted to hospital because of the cutaneous drug reaction. Ten patients (17.5%) died and in most of those (60%), the drug causing the reaction could not be determined. CONCLUSIONS: The frequency of severe cutaneous adverse reactions to drugs in our setting is significant. Drug Reaction with Eosinophilia and Systemic Symptoms seems to be the most frequent presentation of severe cutaneous drug reactions. Most patients developed cutaneous drug reactions outside the hospital. Mortality rates were higher for Toxic Epidermal Necrolysis and this presentation significantly affected older people. Not knowing the drug causing the reaction was related to mortality

Maternal and neonatal data collection systems in low- and middle-income countries: Scoping review protocol

Background: Pregnant women and neonates represent one of the most vulnerable groups, especially in low- and middle-income countries (LMICs). A recent analysis reported that most vaccine pharmacovigilance systems in LMICs consist of spontaneous (passive) adverse event reporting. Thus, LMICs need effective active surveillance approaches, such as pregnancy registries. We intend to identify currently active maternal and neonatal data collection systems in LMICs, with the potential to inform active safety electronic surveillance for novel vaccines using standardized definitions. Methods: A scoping review will be conducted based on established methodology. Multiple databases of indexed and grey literature will be searched with a specific focus on existing electronic and paper-electronic systems in LMICs that collect continuous, prospective, and individual-level data from antenatal care, delivery, neonatal care (up to 28 days), and postpartum (up to 42 days) at the facility and community level, at the national and district level, and at large hospitals. Also, experts will be contacted to identify unpublished information on relevant data collection systems. General and specific descriptions of Health Information Systems (HIS) extracted from the different sources will be combined and duplicated HIS will be removed, producing a list of unique statements. We will present a final list of Maternal, Newborn, and Child Health systems considered flexible enough to be updated with necessary improvements to detect, assess and respond to safety concerns during the introduction of vaccines and other maternal health interventions. Selected experts will participate in an in-person consultation meeting to select up to three systems to be further explored in situ. Results and knowledge gaps will be synthesized after expert consultation.Fil: Berrueta, Mabel. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Bardach, Ariel Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Ciapponi, Agustín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Xiong, Xu. University of Tulane; Estados UnidosFil: Stergachis, Andy. University of Washington; Estados UnidosFil: Zaraa, Sabra. University of Washington; Estados UnidosFil: Buekens, Pierre. University of Tulane; Estados UnidosFil: Absalon, Judith. No especifíca;Fil: Anderson, Steve. No especifíca;Fil: Althabe, Fernando. Instituto de Efectividad Clínica y Sanitaria; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Madhi, Shabir A.. No especifíca;Fil: McClure, Elizabeth. No especifíca;Fil: Munoz, Flor M.. No especifíca;Fil: Mwamwitwa, Kissa W.. No especifíca;Fil: Nakimuli, Annettee. No especifíca;Fil: Clark Nelson, Jennifer. No especifíca;Fil: Noguchi, Lisa. No especifíca;Fil: Panagiotakopoulos, Lakshmi. No especifíca;Fil: Sevene, Esperanca. No especifíca;Fil: Zuber, Patrick. No especifíca;Fil: Belizan, Maria. No especifíca;Fil: Bergel, Eduardo. No especifíca;Fil: Rodriguez Cairoli, Federico. No especifíca;Fil: Castellanos, Fabricio. No especifíca;Fil: Ciganda, Alvaro. No especifíca;Fil: Comande, Daniel. No especifíca;Fil: Pingray, Veronica. No especifíca