Modeling Coupled Thermal-Hydrological-Chemical Processes in the Unsaturated Fractured Rock of Yucca Mountain, Nevada: Heterogeneity and Seepage

An understanding of processes affecting seepage into emplacement tunnels is needed for correctly predicting the performance of underground radioactive waste repositories. It has been previously estimated that the capillary and vaporization barriers in the unsaturated fractured rock of Yucca Mountain are enough to prevent seepage under present day infiltration conditions. It has also been thought that a substantially elevated infiltration flux will be required to cause seepage after the thermal period is over. While coupled thermal-hydrological-chemical (THC) changes in Yucca Mountain host rock due to repository heating has been previously investigated, those THC models did not incorporate elements of the seepage model. In this paper, we combine the THC processes in unsaturated fractured rock with the processes affecting seepage. We observe that the THC processes alter the hydrological properties of the fractured rock through mineral precipitation and dissolution. We show that such alteration in the hydrological properties of the rock often leads to local flow channeling. We conclude that such local flow channeling may result in seepage under certain conditions, even with nonelevated infiltration fluxes

Cause-specific long-term mortality in survivors of childhood cancer in Switzerland: A population-based study.

Survivors of childhood cancer have a higher mortality than the general population. We describe cause-specific long-term mortality in a population-based cohort of childhood cancer survivors. We included all children diagnosed with cancer in Switzerland (1976-2007) at age 0-14 years, who survived ≥5 years after diagnosis and followed survivors until December 31, 2012. We obtained causes of death (COD) from the Swiss mortality statistics and used data from the Swiss general population to calculate age-, calendar year-, and sex-standardized mortality ratios (SMR), and absolute excess risks (AER) for different COD, by Poisson regression. We included 3,965 survivors and 49,704 person years at risk. Of these, 246 (6.2%) died, which was 11 times higher than expected (SMR 11.0). Mortality was particularly high for diseases of the respiratory (SMR 14.8) and circulatory system (SMR 12.7), and for second cancers (SMR 11.6). The pattern of cause-specific mortality differed by primary cancer diagnosis, and changed with time since diagnosis. In the first 10 years after 5-year survival, 78.9% of excess deaths were caused by recurrence of the original cancer (AER 46.1). Twenty-five years after diagnosis, only 36.5% (AER 9.1) were caused by recurrence, 21.3% by second cancers (AER 5.3) and 33.3% by circulatory diseases (AER 8.3). Our study confirms an elevated mortality in survivors of childhood cancer for at least 30 years after diagnosis with an increased proportion of deaths caused by late toxicities of the treatment. The results underline the importance of clinical follow-up continuing years after the end of treatment for childhood cancer

Constitutive phosphorylation of MDC1 physically links the MRE11–RAD50–NBS1 complex to damaged chromatin

The MRE11–RAD50–Nijmegen breakage syndrome 1 (NBS1 [MRN]) complex accumulates at sites of DNA double-strand breaks (DSBs) in microscopically discernible nuclear foci. Focus formation by the MRN complex is dependent on MDC1, a large nuclear protein that directly interacts with phosphorylated H2AX. In this study, we identified a region in MDC1 that is essential for the focal accumulation of the MRN complex at sites of DNA damage. This region contains multiple conserved acidic sequence motifs that are constitutively phosphorylated in vivo. We show that these motifs are efficiently phosphorylated by caseine kinase 2 (CK2) in vitro and directly interact with the N-terminal forkhead-associated domain of NBS1 in a phosphorylation-dependent manner. Mutation of these conserved motifs in MDC1 or depletion of CK2 by small interfering RNA disrupts the interaction between MDC1 and NBS1 and abrogates accumulation of the MRN complex at sites of DNA DSBs in vivo. Thus, our data reveal the mechanism by which MDC1 physically couples the MRN complex to damaged chromatin

Long-term HIV infection and antiretroviral therapy are associated with bone microstructure alterations in premenopausal women

Summary: We evaluated the influence of long-term HIV infection and its treatment on distal tibia and radius microstructure. Premenopausal eumenorrheic HIV-positive women displayed trabecular and cortical microstructure alterations, which could contribute to increased bone fragility in those patients. Introduction: Bone fragility is an emerging issue in HIV-infected patients. Dual-energy X-ray absorptiometry (DXA) quantified areal bone mineral density (BMD) predicts fracture risk, but a significant proportion of fracture risk results from microstructural alterations. Methods: We studied the influence of long-term HIV infection on bone microstructure as evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 22 HIV-positive (+ve) premenopausal eumenorrheic women and 44 age- and body mass index (BMI)-matched HIV-negative (−ve) controls. All subjects completed questionnaires regarding calcium/protein intakes and physical activity, and underwent DXA and HR-pQCT examinations for BMD and peripheral skeleton microstructure, respectively. A risk factor analysis of tibia trabecular density using linear mixed models was conducted. Results: In HIV+ve women on successful antiretroviral therapy (undetectable HIV-RNA, median CD4 cell count, 626), infection duration was 16.5 ± 3.5 (mean ± SD) years; median BMI was 22 (IQR, 21-26) kg/m2. More HIV+ve women were smokers (82 versus 50%, p = 0.013). Compared to controls, HIV+ve women had lower lumbar spine (spine T-score −0.70 vs −0.03, p = 0.014), but similar proximal femur BMD. At distal tibia, HIV+ve women had a 14.1% lower trabecular density and a 13.2% reduction in trabecular number compared to HIV−ve women (p = 0.013 and 0.029, respectively). HR-pQCT differences in distal radius were significant for cortical density (−3.0%; p = 0.029). Conclusions: Compared with HIV−ve subjects, premenopausal HIV+ve treated women had trabecular and cortical bone alterations. Adjusted analysis revealed that HIV status was the only determinant of between group tibia trabecular density differences. The latter could contribute to increased bone fragility in HIV+ve patient

Coercion-resistant Proxy Voting

In general, most elections follow the principle of equality, or as it came to be known, the principle of “one man – one vote”. However, this principle might pose difficulties for voters, who are not well informed regarding the particular matter that is voted on. In order to address this issue, a new form of voting has been proposed, namely proxy voting. In proxy voting, each voter has the possibility to delegate her voting right to another voter, so called proxy, that she considers a trusted expert on the matter. In this paper we propose an end-to-end verifiable Internet voting scheme, which to the best of our knowledge is the first scheme to address voter coercion in the proxy voting setting

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

External validation of the Predicting Asthma Risk in Children tool in a clinical cohort

INTRODUCTION: The Predicting Asthma Risk in Children (PARC) tool uses questionnaire-based respiratory symptoms collected from preschool children to predict asthma risk 5 years later. The tool was developed and validated in population cohorts but not validated using a clinical cohort. We aimed to externally validate the PARC tool in a pediatric pulmonology clinic setting. METHODS: The Swiss Paediatric Airway Cohort (SPAC) is a prospective cohort of children seen in pediatric pulmonology clinics across Switzerland. We included children aged 1-6 years with cough or wheeze at baseline who completed the 2-year follow-up questionnaire. The outcome was defined as current wheeze plus use of asthma medication. We assessed performance using: sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), area under the curve (AUC), scaled Brier's score, and Nagelkerke's R$^{2}$ scores. We compared performance in SPAC to that in the original population, the Leicester Respiratory Cohort (LRC). RESULTS: Among 346 children included, 125 (36%) reported the outcome after 2 years. At a PARC score of 4: sensitivity was higher (95% vs. 79%), specificity lower (14% vs. 57%), and NPV and PPV comparable (0.84 vs. 0.87 and 0.37 vs. 0.42) in SPAC versus LRC. AUC (0.71 vs. 0.78), R$^{2}$ (0.18 vs. 0.28) and Brier's scores (0.13 vs. 0.22) were lower in SPAC. CONCLUSIONS: The PARC tool shows some clinical utility, particularly for ruling out the development of asthma in young children, but performance limitations highlight the need for new prediction tools to be developed specifically for the clinical setting

A Raman spectroscopic study of arsenite and thioarsenite species in aqueous solution at 25°C

The Raman spectra of thioarsenite and arsenite species in aqueous solution were obtained at room temperature. Solutions at constant ΣAs + ΣS of 0.1 and 0.5 mol kg(-1 )were prepared with various ΣS/ΣAs ratios (0.1–9.0) and pH values (~7–13.2). Our data suggest that the speciation of As under the conditions investigated is more complicated than previously thought. The Raman measurements offer evidence for at least six separate S-bearing As species whose principal bands are centered near 365, 385, 390, 400, 415 and 420 cm(-1). The data suggest that at least two different species may give rise to bands at 385 cm(-1), bringing the probable minimum number of species to seven. Several additional species are possible but could not be resolved definitively. In general, the relative proportions of these species are dependent on total As concentration, ΣS/ΣAs ratio and pH. At very low ΣS/ΣAs ratios we also observe Raman bands attributable to the dissociation products of H(3)AsO(3)(aq). Although we were unable to assign precise stoichiometries for the various thioarsenite species, we were able to map out general pH and ΣS/ΣAs conditions under which the various thioarsenite and arsenite species are predominant. This study provides a basis for more detailed Raman spectroscopic and other types of investigations of the nature of thioarsenite species