Miracle-dz/UniFAR-FTUs huggingface dataset:
International experience with comparative effectiveness research: case studies from England/Wales and Germany.

PURPOSE Although the US has lagged behind international developments in health technology assessment (HTA), renewed interest in HTA in the US has been fueled by the appropriation of $1.1 billion comparative effectiveness research (CER) in 2009 and the debate over health care reform. APPROACH To inform CER practices in the US, we present case studies of HTA from England/Wales and Germany: contrasting methods; relevance to the US; and impact on innovation. FINDINGS The National Institute of Health and Clinical Excellence (NICE) was established in 1999 to inform trusts within the National Health Service of England and Wales. It uses cost-effectiveness analysis to guide the allocation resource across preventative and curative interventions. In Germany, the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) was established in 2004 to inform reimbursement and pricing policies for the statutory sickness funds set by the Gemeinsamer Bundesaursschuss (G-BA). IQWiG evaluates competing technologies within specific therapeutic areas, placing more weight on clinical evidence and the relative efficiency of competing therapies. PRACTICAL IMPLICATIONS Although having deep political and cultural antecedents, differences between NICE and IQWiG can be explained by perspective: the former guiding resource allocation across an entire system (macro-evaluation), the latter focusing on efficiency within the bounds of a particular therapeutic area (micro-evaluation). Given the decentralized nature of the US health care system, and the relative powers of different medical specialties, the IQWiG model presents a more suitable case study to guided CER efforts in the US.
Multiple Structural and Epigenetic Defects in the Human Leukocyte Antigen Class I Antigen Presentation Pathway in a Recurrent Metastatic Melanoma Following Immunotherapy*

Background: Understanding the mechanism of tumor immune resistance can help design effective cancer immunotherapy. Results: A novel tapasin mutation, haplotype loss, and HLA epigenetic repression were identified and characterized in a single tumor population. Conclusion: The first evidence for combined HLA genetic and epigenetic defects in malignant cells was presented. Significance: Combinatorial immunotherapy harnessing T cell responses and DNA demethylation may counteract tumor immune resistance. Scant information is available about the molecular basis of multiple HLA class I antigen-processing machinery defects in malignant cells, although this information contributes to our understanding of the molecular immunoescape mechanisms utilized by tumor cells and may suggest strategies to counteract them. In the present study we reveal a combination of IFN-γ-irreversible structural and epigenetic defects in HLA class I antigen-processing machinery in a recurrent melanoma metastasis after immunotherapy. These defects include loss of tapasin and one HLA haplotype as well as selective silencing of HLA-A3 gene responsiveness to IFN-γ. Tapasin loss is caused by a germ-line frameshift mutation in exon 3 (TAPBP684delA) along with a somatic loss of the other gene copy. Selective silencing of HLA-A3 gene and its IFN-γ responsiveness is associated with promoter CpG methylation nearby site-α and TATA box, reversible after DNA methyltransferase 1 depletion. This treatment combined with tapasin reconstitution and IFN-γ stimulation restored the highest level of HLA class I expression and its ability to elicit cytotoxic T cell responses. These results represent a novel tumor immune evasion mechanism through impairing multiple components at various levels in the HLA class I antigen presentation pathway. These findings may suggest a rational design of combinatorial cancer immunotherapy harnessing DNA demethylation and IFN-γ response.
Exploring intracellular space: function of the Min system in round‐shaped Escherichia coli

The MinCDE proteins help to select cell division sites in normal cylindrical Escherichia coli by oscillating along the long axis, preventing unwanted polar divisions. To determine how the Min system might function in cells with multiple potential division planes, we investigated its role in a round‐cell rodA mutant. Round cells lacking MinCDE were viable, but growth, morphology and positioning of cell division sites were abnormal relative to Min+ cells. In round cells with a long axis, such as those undergoing cell division, green fluorescent protein (GFP) fusions to MinD almost always oscillated parallel to the long axis. However, perfect spheres or irregularly shaped cells exhibited MinD movement to and from multiple sites on the cell surface. A MinE–GFP fusion exhibited similar behavior. These results indicate that the Min proteins can potentially localize anywhere in the cell but tend to move a certain maximum distance from their previous assembly site, thus favoring movement along the cell's long axis. A new model for the spatial control of division planes by the Min system in round cells is proposed.
A simple fully homomorphic encryption scheme available in cloud computing

With continuous expansion of cloud computing, problems of third-party data security become increasingly prominent. However, effective retrieval of encrypted data and other operations are difficult to achieve by traditional cryptogram systems. Thus, a practical simple fully homomorphic encryption scheme, using only elementary modular arithmetic, derived from Gentry cryptosystem is put forward to ensure the privacy-preserving in cloud storage, in which encrypted data can be operated directly without affecting the confidentiality of the encryption systems, so that it can excellently realize the need of cipertext retrieval and other processing in untrusted servers. Compared with the previous protocols Marten van Dijk et al. proposed at Advances in Cryptology-EUROCRYPT 2010 and Craig Gentry proposed in the March 2010 issue of Communications of the ACM, especially in the aspect of cipertext retrieval, the proposed scheme is much more secure and feasible. And the performance evaluation and security analysis demonstrate the practice and validity of the proposed scheme.
Ratio of Tumor to Normal Prostate Tissue Apparent Diffusion Coefficient as a Method for Quantifying DWI of the Prostate.

OBJECTIVE The purpose of this study was to investigate the ability of the apparent diffusion coefficient (ADC) ratio of tumor to normal prostate tissue to overcome inherent variability based on choice of b values, with whole-mount histopathologic analysis as the reference standard for tumor identification. MATERIALS AND METHODS Thirty-nine patients with prostate cancer underwent 3-T MRI, including DWI with b values of 0, 150, 750, and 1000 s/mm(2). ADC maps were derived from four b value combinations. Histologically derived ROIs were defined for prostate tumor and benign prostate tissue to generate a ratio. The concordance correlation coefficient was used to evaluate agreement and reproducibility at different b values. Bland-Altman plots were used to evaluate the pattern of relative measurement difference between b value combinations. The relationship between ADC values and Gleason score was tested by Spearman rank correlation. RESULTS ADC values varied depending on the b value combination selected. The concordance correlation coefficient was higher for ADC ratios (0.883; 95% CI, 0.816-0.927) compared with absolute ADC values for normal tissue (0.873; 95% CI, 0.799-0.921) and tumor (0.792; 95% CI, 0.688-0.864). The ADC ratio concordance correlation coefficient for transition zone tumors was considerably higher than that for the peripheral zone in all cases. Bland-Altman analysis showed higher variation for ADC maps incorporating a b value of zero for both ratio and absolute values. There was a stronger inverse relationship to Gleason score for ADC ratios (rho, -0.354 to -0.456) compared with absolute ADC values (rho, -0.117 to -0.379). CONCLUSION The use of a simple ratio of prostate tumor ADC to normal tissue ADC improved the concordance between different b value combinations and could provide a more robust means of assessing restricted diffusion in the prostate.
Public sector reform according to the new public management model

During the last 30 years or even more many countries implemented certain programs in order to transform the public sector representing a consequence of generating economicfinancial and fiscal pressures. In these countries various initiatives have successively been driven based on liberal principles of the market economy, mainly motivated by similar reasons with a cumulative effect to realize the development goals of the new global environment. A number of these initiatives are based on the same assumptions, so we can talk about the reforms of programs being more or less coherent in their content. One of such programs is the New Public Management (New Public Management, NPM), which was, in the conceptual sense, initiated in the UK and other countries of the AngloSaxon tradition in early 1980s. Although in practical terms a particular manifestation of this model was, as the nucleus, firstly widespread through New Zealand and Australia and later through the Scandinavian countries, those reflections were very extensive, and acquired the form of a paradigm for contemporary changes in the sphere of public sector governance in many continental countries where they experienced an empirical verifica-
Self-sensing control of PMSM motor for wide-speed range operation

This work presents a self-sensing control for permanent-magnet synchronous motor (PMSM) for wide-speed range based on the integration of signal-injection and back-emf tracking methods. It is addressed an evaluation method of the transition region between these approaches based on the harmonic content of the q-axis reference current during self-sensing operation. Based on the procedure, it is established the bandwidth of the rotor position observers in function of the operation speed. It is also addressed the discussion of the attributes of implementation required for integration between the self-sensing techniques. Simulation results are presented showing the performance of the proposed self-sensing wide-speed range system.
A prognostic gene expression index in ovarian cancer—validation across different independent data sets

Ovarian carcinoma has the highest mortality rate among gynaecological malignancies. In this project, we investigated the hypothesis that molecular markers are able to predict outcome of ovarian cancer independently of classical clinical predictors, and that these molecular markers can be validated using independent data sets. We applied a semi‐supervised method for prediction of patient survival. Microarrays from a cohort of 80 ovarian carcinomas (TOC cohort) were used for the development of a predictive model, which was then evaluated in an entirely independent cohort of 118 carcinomas (Duke cohort). A 300‐gene ovarian prognostic index (OPI) was generated and validated in a leave‐one‐out approach in the TOC cohort (Kaplan‐Meier analysis, p = 0.0087). In a second validation step, the prognostic power of the OPI was confirmed in an independent data set (Duke cohort, p = 0.0063). In multivariate analysis, the OPI was independent of the post‐operative residual tumour, the main clinico‐pathological prognostic parameter with an adjusted hazard ratio of 6.4 (TOC cohort, CI 1.8–23.5, p = 0.0049) and 1.9 (Duke cohort, CI 1.2–3.0, p = 0.0068). We constructed a combined score of molecular data (OPI) and clinical parameters (residual tumour), which was able to define patient groups with highly significant differences in survival. The integrated analysis of gene expression data as well as residual tumour can be used for optimized assessment of the prognosis of platinum‐taxol‐treated ovarian cancer. As traditional treatment options are limited, this analysis may be able to optimize clinical management and to identify those patients who would be candidates for new therapeutic strategies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Prostate Cancer Journey: Results of an Online Survey of Men and Their Partners

Background: The initial impact of treatments for men with prostate cancer is well reported in the literature. Less is known about the psychosocial needs of these men as their journey after diagnosis and treatment continues into the months and years. Objective: The objective of this study was to examine and understand the supportive care needs of men diagnosed and treated for prostate cancer at key identifiable periods of their cancer journey. Methods: An international Web-based survey was conducted in 2012, investigating men’s prostate cancer pathways. The survey was based on substantial qualitative research and assessed for validity and reliability before piloting. To provide a unique insight into men living with prostate cancer, the views of partners were also elicited. Results: Completed questionnaires were obtained from 193 men and 40 partners from 6 nations. The physical and psychosocial impact of treatment and need for support varied along the cancer journey. Fear, distress, loss, regret, anxiety, low self-esteem, depression, changes in sexuality, masculinity, and relationships were also described by both men and partners as adverse effects of the diagnosis and treatment for prostate cancer. Conclusions: Wives and partners are a key psychosocial support to men with prostate cancer. They may also provide valuable insight into men’s supportive care needs that men are often unable to recognize themselves. Implications for Practice: Findings suggest that wives and partners of men with prostate cancer can provide nurses and healthcare authorities with a powerful and unique resource in providing supportive care for men who are challenged by prostate cancer.
A Simple Method to Disaggregate Passive Microwave-Based Soil Moisture

This paper develops two alternative approaches for downscaling passive microwave-derived soil moisture. Ground and airborne data collected over the Walnut Gulch experimental watershed during the Monsoon'90 experiment were used to test these approaches. These data consisted of eight micrometeorological stations (METFLUX) and six flights of the L-band Push Broom Microwave Radiometer (PBMR). For each PBMR flight, the 180-m resolution L-band pixels covering the eight METFLUX sites were first aggregated to generate a 500-m ldquocoarse-scalerdquo passive microwave pixel. The coarse-scale-derived soil moisture was then downscaled to the 180-m resolution using two different surface soil moisture indexes (SMIs): (1) the evaporative fraction (EF), which is the ratio of the evapotranspiration to the total energy available at the surface; and (2) the actual EF (AEF), which is defined as the ratio of the actual-to-potential evapotranspiration. It is well known that both SMIs depend on the surface soil moisture. However, they are also influenced by other factors such as vegetation cover, soil type, root-zone soil moisture, and atmospheric conditions. In order to decouple the influence of soil moisture from the other factors, a land surface model was used to account for the heterogeneity of vegetation cover, soil type, and atmospheric conditions. The overall accuracy in the downscaled values was evaluated to 3% (vol.) for EF and 2% (vol.) for AEF under cloud-free conditions. These results illustrate the potential use of satellite-based estimates of instantaneous evapotranspiration on clear-sky days for downscaling the coarse-resolution passive microwave soil moisture.
Smad Signaling in the Rat Model of Monocrotaline Pulmonary Hypertension

Mutations in the bone morphogenetic protein receptor type II (BMPrII) gene have been implicated in the development of familial pulmonary artery hypertension (PAH). The function of BMP signal transduction within the pulmonary vasculature and the role BMPrII mutations have in the development of PAH are incompletely understood. We used the monocrotaline (MCT) model of PAH to examine alterations in Smad signal transduction pathways in vivo. Lungs harvested from Sprague-Dawley rats treated with a single 60-mg/kg intraperitoneal (IP) injection of MCT were compared to saline-treated controls 2 weeks following treatment. Smad 4 was localized by immunohistochemistry to endothelial nuclei of the intra-acinar vessels undergoing remodeling. Smad 4, common to both BMP and transforming growth factor β (TGFβ) signaling, and BMP-specific Smad 1 were significantly decreased in western blot from whole lungs of treated animals, while no change was found for TGFβ-specific Smad 2. MCT-treated rats also had increased expression of phosphorylated Smad 1 (P-Smad 1) but not phosphorylated Smad 2 (P-Smad 2). There was a decrease in the expression of the full BMPrII protein but not its short form variant in MCT-treated rat lungs. The type I receptor Alk1 had increased expression. Collectively, our data indicate that vascular remodeling in the MCT model is associated with alterations in BMP receptors and persistent endothelial Smad 1 signaling.
The interface of mycology and endocrinology.

Message molecules such as hormones or pheromones have been described in non-pathogenic fungi and largely control mating. In one instance, a fungal hormone has a sequence homologous with a mammalian hormone, binds to a mammalian receptor and produces a functional response in a mammalian cell. Some mammalian hormones have also been shown to inhibit or stimulate pathogenic and non-pathogenic fungi, although until recently fungal binders (receptors) had not been demonstrated and the concentrations studied were not physiologic. We studied Paracoccidioides brasiliensis, for human sex hormone binding and functional effect, because of the predominance of paracoccidioidomycosis in males. We found a cytosolic 17-beta-estradiol (E2) binding protein in mycelia with Kd = 13 nM and a capacity of 78 fmol mg-1 protein. E2 prevents mycelium-to-yeast or conidium-to-yeast conversion in vitro at close to physiologic concentrations. In vivo this action could inhibit or delay conversion to the pathogenic form, allowing sufficient time for stimulation of an effective immune response. More recent studies have demonstrated E2 block of fungal proteins associated with mycelium-to-yeast conversion, and effects on methionine uptake. In other studies, a progesterone binder in dermatophytes has been described. Progesterone inhibits the growth of these fungi, a finding which may also relate to the relative resistance of females to dermatophyte infection. A corticosteroid-binding protein has been described in Candida species. (ABSTRACT TRUNCATED AT 250 WORDS)
Transduction of a protein kinase C‐generated signal into the long‐lasting facilitation of glutamate release

The present study investigated the delayed and persistent effects of 4β‐phorbol 12, 13‐dibutyrate (PDBu) on the K+ ‐evoked release of endogenous glutamate and dynorphin B‐like immunoreactivity from a subcellular fraction (P3) that is enriched in hippocampal mossy fiber synaptosomes. It is demonstrated that the alpha, beta, gamma, epsilon, and zeta isoforms of protein kinase C (PKC) are present in the P3 fraction obtained using the guinea pig hippocampus as starting tissue. The K+ ‐evoked release of glutamate was found to be selectively enhanced when mossy fiber‐enriched synaptosomes were preincubated with PDBu for 15 minutes and extensively washed with a PDBu‐free medium. The persistent enhancement of glutamate release observed under this condition was not reversed by the protein kinase inhibitor staurosporine and was desensitized to the potentiating effects of an acute reexposure to PDBu. The overall content and activity of PKC was not substantially altered during the initial 15 minutes of treatment with PDBu (10 μM). More prolonged pretreatments with PDBu altered the substrate specificity of PKC and decreased the content of all PKC isoforms, but did not reverse the facilitation of glutamate release that followed preincubation in the presence of PDBu. It is concluded that the persistent activation of PKC enhances K+ ‐evoked glutamate release from hippocampal mossy fiber‐enriched synaptosomes and that, once established, this presynaptic facilitation is sustained by a process that is no longer directly dependent on continued PKC phosphotransferase activity.
High Ambient Temperature Represses Anthocyanin Biosynthesis through Degradation of HY5

Anthocyanins are flavonoid compounds that protect plant tissues from many environmental stresses including high light irradiance, freezing temperatures, and pathogen infection. Regulation of anthocyanin biosynthesis is intimately associated with environmental changes to enhance plant survival under stressful environmental conditions. Various factors, such as UV, visible light, cold, osmotic stress, and pathogen infection, can induce anthocyanin biosynthesis. In contrast, high temperatures are known to reduce anthocyanin accumulation in many plant species, even drastically in the skin of fruits such as grape berries and apples. However, the mechanisms by which high temperatures regulate anthocyanin biosynthesis in Arabidopsis thaliana remain largely unknown. Here, we show that high ambient temperatures repress anthocyanin biosynthesis through the E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) and the positive regulator of anthocyanin biosynthesis ELONGATED HYPOCOTYL5 (HY5). We show that an increase in ambient temperature decreases expression of genes required in both the early and late steps of the anthocyanin biosynthesis pathway in Arabidopsis seedlings. As a result, seedlings grown at a high temperature (28°C) accumulate less anthocyanin pigment than those grown at a low temperature (17°C). We further show that high temperature induces the degradation of the HY5 protein in a COP1 activity-dependent manner. In agreement with this finding, anthocyanin biosynthesis and accumulation do not respond to ambient temperature changes in cop1 and hy5 mutant plants. The degradation of HY5 derepresses the expression of MYBL2, which partially mediates the high temperature repression of anthocyanin biosynthesis. Overall, our study demonstrates that high ambient temperatures repress anthocyanin biosynthesis through a COP1-HY5 signaling module.
Maternally transferred dioxin‐like compounds can affect the reproductive success of European eel

Reported concentrations of dioxin‐like compounds accumulated in the European eel (Anguilla anguilla) were used to perform a risk assessment for eel larval survival, taking into account a modeled amplification of tissue concentrations with a factor of 1.33 during spawning migration. The calculated concentrations of dioxin‐like compounds finally deposited in the eggs were compared with the internal effect concentrations for survival of early life stages of the European eel; these concentrations, by lack of experimental data, were estimated from a sensitivity distribution based on literature data by assuming that eel larvae are among the 10% most sensitive teleost fish species. Given concentrations of dioxin‐like contaminants and assuming a relatively high sensitivity, it can be expected that larvae from eggs produced by eel from highly contaminated locations in Europe will experience increased mortality as a result of maternally transferred dioxin‐like contaminants. As historical persistent organic pollutant concentrations in eel tissue were higher, this impact must have been stronger in the past. Potential effects of other compounds or effects on the migration, condition, and fertility of the parental animals were not taken into account. It is important to further study the overall impact of contaminants on the reproductive success of the European eel as this may have been underestimated until now. Environ Toxicol Chem 2016;35:241–246. © 2015 SETAC