In Vitro Modelling of Osteogenesis Imperfecta with Patient-Derived Induced Mesenchymal Stem Cells.

(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2, NANOG, and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR, TFAP2A, and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73, CD105, and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells.

Objective Priors for Invariant e-Values in the Presence of Nuisance Parameters.

This paper aims to contribute to refining the e-values for testing precise hypotheses, especially when dealing with nuisance parameters, leveraging the effectiveness of asymptotic expansions of the posterior. The proposed approach offers the advantage of bypassing the need for elicitation of priors and reference functions for the nuisance parameters and the multidimensional integration step. For this purpose, starting from a Laplace approximation, a posterior distribution for the parameter of interest is only considered and then a suitable objective matching prior is introduced, ensuring that the posterior mode aligns with an equivariant frequentist estimator. Consequently, both Highest Probability Density credible sets and the e-value remain invariant. Some targeted and challenging examples are discussed.

The Importance of Reading the Skin: Cutaneous Metastases of Pancreatic Cancer, a Systematic Review.

BACKGROUND: Pancreatic cancer is notorious for its aggressive nature and low survival rate, with less than 10% of patients surviving beyond five years. Early detection is difficult, but skin metastases can be a rare but significant indicator. This systematic review focuses on the epidemiology, clinical features, and histology of skin metastases from pancreatic cancer to determine their importance in early diagnosis and overall management of the disease. MATERIALS AND METHODS: Following PRISMA guidelines, we conducted an exhaustive search of MEDLINE/PubMed, EMBASE, and SCOPUS databases up to June 2023, using specific keywords. Four independent investigators screened the studies using predefined criteria, and two investigators checked the accuracy and consistency of the data extraction. We assessed the quality of the trials using adapted criteria from the Joanna Briggs Institute. A narrative synthesis rather than a meta-analysis was chosen because of the different study designs. RESULTS: The final analysis included 57 patients with skin metastases from pancreatic cancer. Cutaneous metastases, although rare, presented with approximately equal gender distribution and a mean age of 63.4 years. Predominantly non-umbilical (77%), these metastases showed clinical diversity, ranging from asymptomatic nodules to painful or ulcerated lesions. Notably, skin metastases often preceded the diagnosis of primary pancreatic cancer (58%). Primary tumor characteristics revealed different localizations, with adenocarcinoma being the most prevalent histological type (77%). A significant association (p = 0.008) was observed between pancreatic tumor location and the timing of presentation of skin metastases. Tumors located in the body and tail of the pancreas were more likely to manifest skin metastases as an initial clinical manifestation (62.2%) than those in the head of the pancreas (20.8%). CONCLUSIONS: In conclusion, although skin metastases are rare, they are important indicators of pancreatic cancer, highlighting the need for multidisciplinary healthcare collaboration and thorough skin examination. Recognizing them could lead to earlier diagnosis, which is crucial in a cancer with limited treatment options.

Tratamiento de la infección por virus de la hepatitis C en hemodiálisis / Treatment of infection due to hepatitis C virus in haemodialysis

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Estenose aórtica e doença coronariana: análise dos fatores de risco / Aortic stenosis and coronary disease: analysis of risk factors

OBJETIVO: Analisar aspectos clínico-laboratoriais da presença de doença coronariana em pacientes portadores de estenose aórtica e analisar a influência de fatores de risco para o desenvolvimento de coronariopatia obstrutiva. MÉTODOS: Estudamos 65 pacientes portadores de estenose aórtica severa com indicação de cirurgia, com idade entre 51 a 85 anos, entre os quais havia 40 mulheres. Da realização da cinecoronariografia resultaram dois grupos: 26(40 por cento) com coronariopatia obstrutiva e 39(60 por cento) sem lesões em artérias coronárias. Foram analisados os antecedentes pessoais para doença coronariana (hábito de fumar, dislipidemia, diabetes mellitus, hipertensão arterial, antecedentes familiares, sedentarismo e alcoolismo), eletrocardiograma, ecocardiograma com Doppler e exames laboratoriais (glicemia, colesterol total e frações, triglicérides, Apo A1 e B, fibrinogênio, lipoproteina(a) e taxa fracional de remoção de triglicérides e colesterol nos dois grupos. RESULTADOS: Na análise da idade, o grupo com coronariopatia obstrutiva apresentou faixa etária mais elevada com significância estatística (p<0,0001). A identificação de sinais de isquemia em parede anterior no eletrocardiograma apresentou relação significante com obstrução em artéria interventricular anterior (p<0,002). A análise univariada mostrou diferença significante entre os grupos em relação às médias das variáveis gradiente aórtico (p= 0,041), HDL (p=0,042) e fibrinogênio (p=0,047). O grupo com doença coronariana apresentou média do gradiente e HDL menor que os sem coronariopatia obstrutiva. Na variável fibrinogênio, o grupo sem doença coronariana apresentou média com níveis menores comparados aos dos portadores de coronariopatia. A análise multivariada pelo método da regressão logística mostrou como variável independente para coronariopatia os níveis de fibrinogênio ( p<0,039). CONCLUSÃO: O fibrinogênio foi fator de risco independente para a associação de coronariopatia obstrutiva com estenose aórtica.