In vitro modelling of alveolar repair at the air-liquid interface using alveolar epithelial cells derived from human induced pluripotent stem cells

Research on acute and chronic lung diseases would greatly benefit from reproducible availability of alveolar epithelial cells (AEC). Primary alveolar epithelial cells can be derived from human lung tissue but the quality of these cells is highly donor dependent. Here, we demonstrated that culture of EpCAM+ cells derived from human induced pluripotent stem cells (hiPSC) at the physiological air-liquid interface (ALI) resulted in type 2 AEC-like cells (iAEC2) with alveolar characteristics. iAEC2 cells expressed native AEC2 markers (surfactant proteins and LPCAT-1) and contained lamellar bodies. ALI-iAEC2 were used to study alveolar repair over a period of 2 weeks following mechanical wounding of the cultures and the responses were compared with those obtained using primary AEC2 (pAEC2) isolated from resected lung tissue. Addition of the Wnt/β-catenin activator CHIR99021 reduced wound closure in the iAEC2 cultures but not pAEC2 cultures. This was accompanied by decreased surfactant protein expression and accumulation of podoplanin-positive cells at the wound edge. These results demonstrated the feasibility of studying alveolar repair using hiPSC-AEC2 cultured at the ALI and indicated that this model can be used in the future to study modulation of alveolar repair by (pharmaceutical) compounds

Sources of Variation in Physician Adherence with Clinical Guidelines: Results from a Factorial Experiment

BACKGROUND: Health services research has documented the magnitude of health care variations. Few studies focus on provider level sources of variation in clinical decision making-for example, which primary care providers are likely to follow clinical guidelines, with which types of patient. OBJECTIVES: To estimate: (1) the extent of primary care provider adherence to practice guidelines and the unconfounded influence of (2) patient attributes and (3) physician characteristics on adherence with clinical practice guidelines. DESIGN: In a factorial experiment, primary care providers were shown clinically authentic video vignettes with actors portrayed different “patients” with identical signs of coronary heart disease (CHD). Different types of providers were asked how they would manage the different “patients” with identical CHD symptoms. Measures were taken to protect external validity. RESULTS: Adherence to some guidelines is high (over 50% of physicians would follow a third of the recommended actions), yet there is low adherence to many of them (less than 20% would follow another third). Female patients are less likely than males to receive 4 of 5 types of physical examination (p < .03); older patients are less likely to be advised to stop smoking (p < .03). Race and SES of patients had no effect on provider adherence to guidelines. A physicians’ level of experience (age) appears to be important with certain patients. CONCLUSIONS: Physician adherence with guidelines varies with different types of “patient” and with the length of clinical experience. With this evidence it is possible to appropriately target interventions to reduce health care variations by improving physician adherence with clinical guidelines

Multiple Imputation Ensembles (MIE) for dealing with missing data

Missing data is a significant issue in many real-world datasets, yet there are no robust methods for dealing with it appropriately. In this paper, we propose a robust approach to dealing with missing data in classification problems: Multiple Imputation Ensembles (MIE). Our method integrates two approaches: multiple imputation and ensemble methods and compares two types of ensembles: bagging and stacking. We also propose a robust experimental set-up using 20 benchmark datasets from the UCI machine learning repository. For each dataset, we introduce increasing amounts of data Missing Completely at Random. Firstly, we use a number of single/multiple imputation methods to recover the missing values and then ensemble a number of different classifiers built on the imputed data. We assess the quality of the imputation by using dissimilarity measures. We also evaluate the MIE performance by comparing classification accuracy on the complete and imputed data. Furthermore, we use the accuracy of simple imputation as a benchmark for comparison. We find that our proposed approach combining multiple imputation with ensemble techniques outperform others, particularly as missing data increases

Diabetes status and post-load plasma glucose concentration in relation to site-specific cancer mortality: findings from the original Whitehall study

ObjectiveWhile several studies have reported on the relation of diabetes status with pancreatic cancer risk, the predictive value of this disorder for other malignancies is unclear. Methods: The Whitehall study, a 25year follow-up for mortality experience of 18,006 men with data on post-challenge blood glucose and self-reported diabetes, allowed us to address these issues. Results: There were 2158 cancer deaths at follow-up. Of the 15 cancer outcomes, diabetes status was positively associated with mortality from carcinoma of the pancreas and liver, while the relationship with lung cancer was inverse, after controlling for a range of potential covariates and mediators which included obesity and socioeconomic position. After excluding deaths occurring in the first 10years of follow-up to examine the effect of reverse causality, the magnitude of the relationships for carcinoma of the pancreas and lung was little altered, while for liver cancer it was markedly attenuated. Conclusions: In the present study, diabetes status was related to pancreatic, liver, and lung cancer risk. Cohorts with serially collected data on blood glucose and covariates are required to further examine this area

El cobrador del frac

Publicat a El Periódico. És el mateix article, amb petites variacions, que GoyP/0105 i publicat l'any 1989 a Diario 16

The impacts of Information and Communications Technology (ICT) and E-commerce on bilateral trade flows

This study examines the impact of Internet and e-commerce adoption on bilateral trade flows using a panel of 21 developing- and least-developed countries and 30 OECD countries. Given the commitment of East African Community (EAC) to become the frontrunner in export-led economy across the African continent, special attention is dedicated to analyse the role of ICT and e-commerce on EAC’s export performance. The empirical results indicate that better access to the modern ICT and adoption of e-commerce applications stimulate bilateral trade flows at various levels. The study notes that the efficient use of ICT equipped with high speed internet and secured servers is a crucial milestone for unlocking the e-trade potentials for developing- and least-developed counties

Scattering Of Obliquely Incident Rayleigh Waves by a Surface-Breaking Crack

Recent results on reflection, transmission and scattering of obliquely incident Rayleigh surface waves by an infinitely long surface-breaking crack are reviewed. Sets of crack-opening displacements for infinitely long cracks with various depths are used to construct approximate crack-opening fields for the scattering of a Rayleigh wave by a surface-breaking crack of large length-to-depth ratio. The scattered surface-wave fields for the finite-length crack are subsequently obtained by the use of a representation integral over an appropriate Green’s function and the approximate crack-opening displacements. Polar diagrams are presented for the amplitude of the scattered surface-wave field

Multimarker RT–PCR assay for the detection of minimal residual disease in sentinel lymph nodes of breast cancer patients

The presence of metastases in lymph nodes is the most powerful prognostic factor in breast cancer patients. Routine histological examination of lymph nodes has limited sensitivity for the detection of breast cancer metastases. The aim of the present study was to develop a multimarker reverse transcriptase–polymerase chain reaction (RT—PCR) assay for the detection of minimal residual disease in sentinel nodes of breast cancer patients. RNA was extracted from 30 sentinel lymph nodes (SLN) obtained from 28 patients, three primary breast cancers (positive controls), three lymph nodes from patients with benign diseases, and peripheral blood lymphocytes of 10 healthy volunteers (negative controls). RT–PCR was performed using the following markers; cytokeratin (CK)-19, NY-BR-1 and mammaglobin B. RT–PCR results were compared to enhanced histopathologic examination and immunohistochemistry (IHC). All three positive controls showed strong PCR amplification for all three markers. None of the 13 negative controls was amplified by any of the three markers. Among the 30 SLN analysed, breast cancer metastases were detected in six SLNs by routine histology, in eight by IHC and in 15 by RT–PCR. We conclude that a multimarker RT–PCR assay probing for NY-BR-1, mammaglobin-B, and CK-19 is more sensitive compared to enhanced pathologic examination. This method may prove to be of value in breast cancer staging and prognosis evaluation

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease

BACKGROUND: Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. METHODS: We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. RESULTS: We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CONCLUSIONS: CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles