Antibiotic chemotherapy against heterogeneous pathogen populations in complex host tissues

Antibiotic chemotherapy effectively cures many infections caused by susceptible bacterial pathogens. However, in some cases, even extended treatment duration does not completely eradicate the pathogenic bacteria from host tissues. A common model for underlying mechanisms assumes the stochastic formation of bacterial persisters similar to observations in laboratory cultures. However, alternative explanations related to the complexity of infected host tissues could also be relevant. We discuss several of these aspects and emphasize the need for integrated analysis as a basis for new control strategies

Minimal residual disease detection with tumor-specific CD160 correlates with event-free survival in chronic lymphocytic leukemia

In chronic lymphocytic leukemia (CLL), the detection of minimal residual disease (MRD) correlates with outcome in the trial setting. However, MRD assessment does not guide routine clinical management and its assessment remains complex. We incorporated detection of the B cell, tumor-specific antigen CD160 to develop a single-tube, flow cytometry assay (CD160FCA) for CLL MRD to a threshold of 10(−4) to 10(−5). One hundred and eighty-seven patients treated for CLL were enrolled. Utilizing the CD160FCA methodology, there was a high level of comparison between blood and bone marrow (R=0.87, P<0.001). In a validation cohort, CD160FCA and the international standardised approach of the European Research Initiative on CLL group demonstrated high concordance (R=0.91, P<0.01). Patients in complete remission (CR) and CD160FCA negative had longer event-free survival (EFS) (63 vs 16 months, P<0.01) and prolonged time to next treatment (60 vs 15 months, P<0.001) vs MRD positive patients; with a median time to MRD positivity of 36 months. In multivariate analysis, CD160FCA MRD detection was independently predictive of EFS in patients in CR and even predicted EFS in the good-risk cytogenetic subgroup. CD160FCA offers a simple assay for MRD detection in CLL and gives prognostic information across different CLL risk groups

Performance of Sequoyah Containment Anchorage System

Deformation of a steel containment anchorage system during a severe accident may result in a leakage path at the containment boundaries. Current design criteria are based on either ductile or brittle failure modes of headed bolts that do not account for factors such as cracking of the containment basemat or deformation of the anchor bolt that may affect the behavior of the containment anchorage system. The purpose of this study was to investigate the performance of a typical ice condenser containment`s anchorage system. This was accomplished by analyzing the Sequoyah Containment Anchorage System. Based on a strength of materials approach and assuming that the anchor bolts are resisting the uplift caused by the internal pressure, one can estimate that the failure of the anchor bolts would occur at a containment pressure of 79 psig. To verify these results and to calibrate the strength of materials equation, the Sequoyah containment anchorage system was analyzed with the ABAQUS program using a three-dimensional, finite-element model. The model included portions of the steel containment building, shield building, anchor bolt assembly, reinforced concrete mat and soil foundation material

Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed

Three-dimensional analysis of AP600 standard plant shield building roof

The AP600 passive containment vessel is surrounded by a concrete cylindrical shell covered with a truncated conical roof. This roof supports the passive containment cooling system (PCS) annular tank, shield plate and other nonstructural attachments. When the shield building is subjected to different loading combinations as defined in the Standard Review Plan (SRP), some of the sections in the shield building could experience forces in excess of their design values. This report summarized the three-dimensional finite element analysis that was conducted to review the adequacy of the proposed Westinghouse shield building design. The ANSYS finite element software was utilized to analyze the Shield Building Roof (SBR) under dead, snow, wind, thermal and seismic loadings. A three-dimensional model that included a portion of the shield building cylindrical shell, the conical roof and its attachments, the eccentricities at the cone-cylinder connection and at the compression ring and the PCS tank was developed. Mesh sensitivity studies were conducted to select appropriate element size in the cylinder, cone, near air intakes and in the vicinity of the eccentricities. Also, a study was carried out to correctly idealize the water-structure interaction in the PCS tank. Response spectrum analysis was used to calculate the internal forces at different sections in the SBR under Safe Shutdown Earthquake (SSE). Forty-nine structural modes and twenty sloshing modes were used. Two horizontal components of the SSE together with a vertical component were used. Modal stress resultants were combined taking into account the effects of closely spaced modes. The three earthquake directions were combined by the Square Root of the Sum Squares method. Two load combinations were studied. The load combination that included dead, snow, fluid, thermal and seismic loads was selected to be the most critical. Interaction diagrams for critical sections were developed and used to check the design adequacy. The results demonstrated that provided area of steal on each face of several sections of the AP600 SBR was inadequate. This was also noticed when comparing the total provided area of steel per section, i.e., the area of steel on both faces. The discrepancy between Westinghouse results and these reported herein could have resulted from the different finite element mesh sizes and the assumption used in Westinghouse design

PVP2005-71322 INTRODUCTION OF THE ELEMENT INTERACTION TECHNIQUE FOR WELDING ANALYSIS AND SIMULATION

ABSTRACT The residual stresses generated due to welding in pressure components may have several harmful effects such as decrease in the resistance to cycling load and corrosive environments. The analysis of the welding process has been developed extensively in 2D and 3D. The element movement technique has been shown to be very effective in simulating the filler material deposition leading to a reduction in the analysis time. However, when attempted for wider fields of applications, it had some limitations, especially when moving the elements towards the base-plate. In this paper, the element interaction technique is introduced utilizing the concepts of both the element movement and element birth techniques. The new technique is verified versus the currently developed procedures. In this technique, the elements of the weld pool are held in place in contact with the elements of the base-plate and the interaction is made to be a function of time. This gave several flexibilities in modeling the welding process. Hence, the technique is then used to analyze simple fillet welding of a plate and circumferential butt-welding of a pipe. INTRODUCTION The residual stresses generated during welding vary with the change in the welding parameters depending on the procedure of the joining process. Many researches have been done to investigate the residual stress for specific problem. Due to the complexity of the different applications, several assumptions and approximations, such as reducing the model from 3D to 2D, are made to facilitate the analysis. These approximations help mainly in reducing modeling efforts and analysis time. The element birth technique has been used in simulating metal deposition in both 3D and 2D models. Brown and Song [1] have used the technique in an axisymmetric simulation of a fillet-weld of ringstiffened cylinder. Wilkening and Snow [2] have also solved an axisymmetric simulation of a two-pass butt-weld of a cylinder using the element birth technique. Also, for a plate, they assumed that the through thickness variation of the residual stress is insignificant, so they modeled a single-pass butt-weld of plate using 2D plane model of the plate. Bouchard et a

Comprehensive Gene-Based Association Study of a Chromosome 20 Linked Region Implicates Novel Risk Loci for Depressive Symptoms in Psychotic Illness

Background Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants. Methods We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus. Results While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (PempP-value and truncated-product methods, respectively. Conclusions Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci

Neural processing of criticism and positive comments from relatives in individuals with schizotypal personality traits

Objectives. High negative expressed emotion by family members towards schizophrenia patients increases the risk of subsequent relapse. The study aimed to determine whether individuals with high schizotypy (HS) and low schizotypy (LS) would differ in activation of brain areas involved in cognitive control when listening to relative criticism