Analysis of the Flow Distribution in the Back Supporting Structure Manifolds of the HCPB Breeding Blanket for the EU DEMO Fusion Reactor

The European Union Demonstration Fusion Power Reactor (EU DEMO) is facing its preconceptual design phase. In this phase, the research and development activities make extensive use of computational tools, to, e.g., verify the design calculations or to perform parametric analyses aimed at optimization. The design of the breeding blanket (BB), which will be a first-of-a-kind component in EU DEMO, is supported from the thermal-hydraulic point of view by local three-dimensional (3-D) computational fluid dynamics (CFD) analyses, mainly aimed at verifying the heat removal capabilities of the system, and by analyses at the system level using one-dimensional (1-D) codes. This work presents the development and application of a detailed 1-D model of the coolant manifolds for the helium-cooled pebble bed BB concept for EU DEMO. This model, implemented in the GEneral Tokamak THErmal-hydraulic Model (GETTHEM), allows fast analyses to be performed at the global level but still maintain a good level of detail concerning the coolant distribution. The first results obtained with the model prove that 3-D CFD analyses of the manifolds may provide misleading results due to nonrepresentative boundary conditions (BCs), which must be used to avoid having a domain that is too complex. The application of a global model, which is indeed characterized exploiting local analyses, can in turn provide better BCs to the detailed 3-D CFD analyses

Human Papilloma Virus (HPV) status, P16INK4a and p53 overexpression in epithelial malignant and borderline ovarian neoplasms

This investigation is the first to evaluate simultaneously human papilloma virus (HPV) status, p16(INK4a), and p53 immunoreactivity in epithelial ovarian neoplasms. The results were analyzed and correlated with histological type, histological grade, and survival of patients. Subtypes considered are papillary serous and mucinous. Polymerase chain reaction (PCR) analysis, performed in our previous study, had already demonstrated a small number of HPV-positive epithelial ovarian neoplasms. No significant correlation was found between the presence of HPV DNA and subtypes of ovarian neoplasms; thus, HPV cannot be considered responsible for epithelial ovarian neoplasm. Since p16 immunoreactivity was present in many other HPV-negative cases of epithelial ovarian neoplasms, this study suggests that p16 overexpression in some neoplasms of the female genital tract is not related to HPV carcinogenesis. A higher p53 expression rate observed between borderline and malignant serous tumors and between serous and mucinous neoplasms can confirm a recent dualistic model of ovarian carcinogenesis. According to this theory, low-grade serous carcinomas (serous intraepithelial carcinomas, serous borderline neoplasm, and ovarian mucinous neoplasms) (type I tumors) develop from mutations of KAS and BRAF, while high-grade serous carcinomas (type II tumors) develop from mutation of p53. In malignant neoplasms, for univariate analysis, patient survival seems to be related to p53, strong and diffuse p16 overexpression, and the stage of development of neoplasms at the diagnosis. In multinomial logistic regression, used to evaluate the role of staging, grading, p16 and p53 immunopositivity as predictor variables of unfavorable outcome of the disease, only p16 positivity was significantly related to the poor prognosis of the cancer

Party mandates and the politics of attention:Party platforms, public priorities and the policy agenda in Britain

This paper develops an attention-based model of party mandates and policy agendas, where parties and governments are faced with an abundance of issues, and must divide their scarce attention across them. In government, parties must balance their desire to deliver on their electoral mandate (i.e. the “promissory agenda”) with a need to continuously adapt their policy priorities in response to changes in public concerns and to deal with unexpected events and the emergence of new problems (i.e. the “anticipatory agenda”). Parties elected to office also have incentives to respond to issues prioritized by the platforms of their rivals. To test this theory, time series cross-sectional models are used to investigate how the policy content of the legislative program of British government responds to governing and opposition party platforms, the executive agenda, issue priorities of the public and mass medi

Patient to patient transmission of hepatitis B virus: a systematic review of reports on outbreaks between 1992 and 2007

<p>Abstract</p> <p>Background</p> <p>Hepatitis B outbreaks in healthcare settings are still a serious public health concern in high-income countries. To elucidate the most frequent infection pathways and clinical settings involved, we performed a systematic review of hepatitis B virus outbreaks published between 1992 and 2007 within the EU and USA.</p> <p>Methods</p> <p>The research was performed using two different databases: the PubMed Database and the Outbreak Database, the worldwide database for nosocomial outbreaks. Selection of papers was carried out using the Quorom algorithm, and to avoid selection biases, the inclusion criteria were established before the articles were identified.</p> <p>Results</p> <p>Overall, 30 papers were analyzed, reporting on 33 hepatitis B virus outbreaks that involved 471 patients, with 16 fatal cases. Dialysis units accounted for 30.3% of outbreaks followed by medical wards (21.2%), nursing homes (21.2%), surgery wards (15.2), and outpatient clinics (12.1%). The transmission pathways were: multi-vial drugs (30.3%), non-disposable multi-patient capillary blood sampling devices (27.2%), transvenous endomyocardial biopsy procedures (9.1%), and multiple deficiencies in applying standard precautions (9.1%).</p> <p>Conclusion</p> <p>The analysis of transmission pathways showed that some breaches in infection control measures, such as administration of drugs using multi-vial compounds and capillary blood sampling, are the most frequent routes for patient-to-patient transmission of hepatitis B virus. Moreover some outbreak reports underlined that heart-transplant recipients are at risk of contracting hepatitis B virus infection during the transvenous endomyocardial biopsy procedure through indirect contact with infected blood as a result of environmental contamination. To prevent transmission, healthcare workers must adhere to standard precautions and follow fundamental infection control principles, such as the use of sterile, single-use, disposable needles and avoiding the use of multi-vial compounds in all healthcare settings including outpatient settings.</p

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies

Early fetal akinesia sequence: A case report with unusual autoptic features

In this paper we report a case of early onset fetal akinesia, with unusual pathological findings. This is a product of medical abortion of young, healthy, unrelated parents. The mother's obstetrical history revealed two previous early miscarriages and a suspicion of FADS in the second previous gestation. At 17 weeks of gestation, an ultrasound examination disclosed absence of fetal movements, fixed extended knees and deformation of the feet. Amniocentesis showed a normal 46, XX karyotype. Hydrops fetalis and multiple skin webs (pterygia), which are usually present in cases of early fetal akinesia, were absent. A diagnosis of arthrogryposis was made and the pregnancy was terminated at 17 weeks of gestation. Postmortem examination was performed according to the necropsy technique suggested by Langley. Thus, body weight and external measurement, including crown-rump, crown-heel, foot lengths, head, thorax and abdominal circumferences were estimated and compared with standard values for assessment of fetal growth. External dysmorphic features were evaluated prior to the evisceration. On internal examination the location and shape of every organ was evaluated. Every organ, skin, muscles from different parts of the body, the brain and spinal cord were sampled and histologically examined. External examination revealed a female fetus with marked muscular hypoplasia of upper and lower extremities with thin arms and legs and multiple joint contractures of lower extremities. The face showed a flattened nose, micrognatia, hypertelorism, cleft palate and low-set ears. There was also a small nuchal fold. The abdomen was distended with a very thin and almost transparent wall. Histologically, muscles were characterized by severe fibrosis with fatty infiltration and by moderate variability in diameter of muscle fibers. The spinal cord disclosed a paucity of anterior horn motor neurons. We suggest multiple pterygium as a diagnosis. Lethal multiple pterygium syndrome (LMPS) is only a symptom and the precise diagnosis is more likely to be spinal atrophy. We, moreover believe that the paucity of spinal motoneurons could be due to the anomalies of programmed death during fetal development and the consequence of genetic defects

Model updating of a historic concrete bridge by sensitivity- and global optimization-based Latin Hypercube Sampling

In this paper, a self-implemented model updating global optimization procedure is successfully applied to a remarkable case study concerning a historic centennial Reinforced Concrete (RC) bridge with parabolic arches, based on recorded experimental vibrational data and arising identification of modal properties. In order to boost the degree of confidence and robustness of the developed model updating procedure, appropriate computational strategies are proposed at the level of both Sensitivity Analysis (SA) and global optimization. In particular, Latin Hypercube Sampling (LHS) is employed in drawing up both strategies, as a systematic automated way to determine appropriate multi-start sets of initiation points, optimally distributed throughout the parametric domain. The procedure involves a gradient-based method and proposes an interaction algorithm between mechanical FEM solver and numerical computing environment. Moreover, the gradient of the objective function involved in the model updating is analytically derived, instead of by often-used Finite Differences (FD), toward better accuracy and computational efficiency. Comprehensive updating results starting from a first FEM base model are achieved, for the considered case study, and show that the relative eigenfrequency and mode shape estimations are considerably improved, for all the structural modes accounted for within the updating process, with a very good final matching between experimentally extracted and FEM modelled modal properties