Technical product risk assessment: Standards, integration in the erm model and uncertainty modeling

European Union has accomplished, through introducing New Approach to technical harmonization and standardization, a breakthrough in the field of technical products safety and in assessing their conformity, in such a manner that it integrated products safety requirements into the process of products development. This is achieved by quantifying risk levels with the aim of determining the scope of the required safety measures and systems. The theory of probability is used as a tool for modeling uncertainties in the assessment of that risk. In the last forty years are developed new mathematical theories have proven to be better at modeling uncertainty when we have not enough data about uncertainty events which is usually the case in product development. Bayesian networks based on modeling of subjective probability and Evidence networks based on Dempster-Shafer theory of belief functions proved to be an excellent tool for modeling uncertainty when we do not have enough information about all events aspect

Critical thermodynamics of the two-dimensional +/-J Ising spin glass

We compute the exact partition function of 2d Ising spin glasses with binary couplings. In these systems, the ground state is highly degenerate and is separated from the first excited state by a gap of size 4J. Nevertheless, we find that the low temperature specific heat density scales as exp(-2J/T), corresponding to an ``effective'' gap of size 2J; in addition, an associated cross-over length scale grows as exp(J/T). We justify these scalings via the degeneracy of the low-lying excitations and by the way low energy domain walls proliferate in this model

Domain wall entropy of the bimodal two-dimensional Ising spin glass

We report calculations of the domain wall entropy for the bimodal two-dimensional Ising spin glass in the critical ground state. The L * L system sizes are large with L up to 256. We find that it is possible to fit the variance of the domain wall entropy to a power function of L. However, the quality of the data distributions are unsatisfactory with large L > 96. Consequently, it is not possible to reliably determine the fractal dimension of the domain walls.Comment: 4 pages, 2 figures, submitted to PR

Susceptibility genes and phenotype modifiers in Prion diseases

Prion diseases show remarkable clinical and neuropathological heterogeneity. All reported cases with definite variant Creutzfeldt-Jakob disease (vCJD) were homozygous at PRNP codon 129. Heterozygosity at codon 219 has been shown to be protective against sporadic CJD (sCJD). Copy number variants (CNVs) are a novel source of genetic variability associated with susceptibility to neuropsychiatric disorders. Aims: Hypotheses tested: · The clinico-pathological phenotype of prion disease is modified by investigation findings, co-deposition of amyloid beta, tau proteins and/or candidate genetic variation. · The MRC Scale can be used for analysis of disease progression in CJD · Copy number variation alters the risk of prion disease in the UK and Papua New Guinea (PNG) Methods: Case reports illustrated genetic susceptibility and phenotypic heterogeneity. The MRC Scale was used to assess disease progression and study power in sCJD. Real-time PCR and gene sequencing were used to assess the role of candidate genes in clinico-pathological heterogeneity. GWAS were used to assess the role of CNVs as susceptibility loci to prion diseases. Results: Two patients with vCJD were heterozygous at codon 219. The MRC scale could be administered daily requiring only 90 patients to provide sufficient study power. Amyloid-β deposition was significantly influenced by APOE ε4 haplotype in definite sCJD. Prion protein and hyperphosphorylated tau deposition were influenced by MAPTH1c haplotype. CNV duplications at chromosome 10 and 14 were significantly enriched in cases when compared to controls. The finding was confirmed using real-time PCR but was not replicated in the German cohort. Analysis using Penn CNV revealed a nominally significant association of CNV deletion at PARK2 gene. Conclusion: Heterozygosity at codon 219 is protective against sCJD but may confer susceptibility to vCJD. Patient stratification and assessments using MRC Scale allowed adequate study power to justify future therapeutic trials. MAPTH1c haplotype played a role in both prion and tau protein deposition. Chromosome 10 and 14 duplications and deletion at PARK2 gene may play a role in prion disease susceptibility

Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves

MicroRNA-551b expression profile in low and high-grade cervical intraepithelial neoplasia

OBJECTIVE: To evaluate the expression of microRNA (miR)-551b in patients with low and high grade cervical intraepithelial neoplasia (CIN) and to find an association with high-risk Human Papillomavirus (HR-HPV) infection-related prognostic biomarkers. PATIENTS AND METHODS: The expression level of miR-551b was determined in 50 paraffin-embedded cervical specimens (10 normal squamous epithelium, 18 condylomas, 8 CIN1, and 14 CIN2-3) using quantitative Real-time polymerase chain reaction (qRT-PCR). χ2-test compared miR-551b expression in different diagnosis groups. An Ordered Logistic Regression and a Probit correlation were made to correlate miR-551b expression levels with the cervical tissue histological findings. The immunohistochemical distribution of p16 and Ki-67 according to histopathological findings was also assessed. RESULTS: The distribution of the miR-551b expression profile was significantly lower in CIN1-3 samples compared to other histological diagnosis groups (condyloma and negative). The expression levels were inversely correlated to the cervical pathological grade, from negative to CIN2-3. A 1% increase in miR-551b expression level produced an increase of 19% to the probability of a minor histological grade diagnosis in a range from negative to CIN2-3 and an increase of 13% to the probability of a negative histological grade diagnosis. Among the cases with miR-551b expression < 0.02 (considered as cut-off value) a significant statistical correlation was found between p16 and Ki-67 expression and the diagnosis of CIN2-3. CONCLUSIONS: O ur d ata s howed a s ignificant inverse correlation between miR-551b expression and the histological grading of the lesions, suggesting a tumor suppressive function in the different stages of cervical dysplasia

Cervical carcinogenesis, bacterial vaginosis, HPV-mRNA test and relapse of CIN2+ after loop electrosurgical excision procedure (LEEP)

OBJECTIVE: The aim of the study was to evaluate the relationship between bacterial vaginosis (BV) and relapse of cervical intraepithelial neoplasia grade 2 or more (CIN2+) after Loop electrosurgical excision procedure (LEEP). PATIENTS AND METHODS: One hundred four patients who underwent LEEP for CIN2+ were followed up every six months for three years. Fifty-three were negative for BV and fifty-one were positive. Each clinical control included Pap test, colposcopy, Amsel criteria test, HPV-DNA, and HPV-mRNA test. RESULTS: Patients’ age, presence of BV, positivity to HPV-DNA and HPV-mRNA tests were analyzed. The average age of patients was 42.5 ± 8.92 years (median: 42.5; range from 27 to 58 years). The minimum follow-up was 6 months and maximum 36 months (average: 22.8 ± 4.53; median: 24). The 10% of the patients with HPV-mRNA test negative had relapsed, compared to 45% of patients with HPV-mRNA test positive. Among the 53 patients without BV the 20% had relapsed compared with 23% of 51 patients with diagnosis of BV. CONCLUSIONS: There is no evidence for higher percentage of relapse in patients with BV, submitted to excisional procedure for CIN2+ associated to HPV-m-RNA test positivity. There is only a correlation among BV and relapse of CIN2+ lesions after LEEP

Energy gap of the bimodal two-dimensional Ising spin glass

An exact algorithm is used to compute the degeneracies of the excited states of the bimodal Ising spin glass in two dimensions. It is found that the specific heat at arbitrary low temperature is not a self-averaging quantity and has a distribution that is neither normal or lognormal. Nevertheless, it is possible to estimate the most likely value and this is found to scale as L^3 T^(-2) exp(-4J/kT), for a L*L lattice. Our analysis also explains, for the first time, why a correlation length \xi ~ exp(2J/kT) is consistent with an energy gap of 2J. Our method allows us to obtain results for up to 10^5 disorder realizations with L <= 64. Distributions of second and third excitations are also shown.Comment: 4 pages, 4 figure

Large random correlations in individual mean field spin glass samples

We argue that complex systems must possess long range correlations and illustrate this idea on the example of the mean field spin glass model. Defined on the complete graph, this model has no genuine concept of distance, but the long range character of correlations is translated into a broad distribution of the spin-spin correlation coefficients for almost all realizations of the random couplings. When we sample the whole phase space we find that this distribution is so broad indeed that at low temperatures it essentially becomes uniform, with all possible correlation values appearing with the same probability. The distribution of correlations inside a single phase space valley is also studied and found to be much narrower.Comment: Added a few references and a comment phras