SNL-NUMO collaborative : development of a deterministic site characterization tool using multi-model ranking and inference.

Uncertainty in site characterization arises from a lack of data and knowledge about a site and includes uncertainty in the boundary conditions, uncertainty in the characteristics, location, and behavior of major features within an investigation area (e.g., major faults as barriers or conduits), uncertainty in the geologic structure, as well as differences in numerical implementation (e.g., 2-D versus 3-D, finite difference versus finite element, grid resolution, deterministic versus stochastic, etc.). Since the true condition at a site can never be known, selection of the best conceptual model is very difficult. In addition, limiting the understanding to a single conceptualization too early in the process, or before data can support that conceptualization, may lead to confidence in a characterization that is unwarranted as well as to data collection efforts and field investigations that are misdirected and/or redundant. Using a series of numerical modeling experiments, this project examined the application and use of information criteria within the site characterization process. The numerical experiments are based on models of varying complexity that were developed to represent one of two synthetically developed groundwater sites; (1) a fully hypothetical site that represented a complex, multi-layer, multi-faulted site, and (2) a site that was based on the Horonobe site in northern Japan. Each of the synthetic sites were modeled in detail to provide increasingly informative 'field' data over successive iterations to the representing numerical models. The representing numerical models were calibrated to the synthetic site data and then ranked and compared using several different information criteria approaches. Results show, that for the early phases of site characterization, low-parameterized models ranked highest while more complex models generally ranked lowest. In addition, predictive capabilities were also better with the low-parameterized models. For the latter iterations, when more data were available, the information criteria rankings tended to converge on the higher parameterized models. Analysis of the numerical experiments suggest that information criteria rankings can be extremely useful for site characterization, but only when the rankings are placed in context and when the contribution of each bias term is understood

The Myeloid-Related Proteins 8 and 14 Complex, a Novel Ligand of Toll-Like Receptor 4, and Interleukin-1 beta Form a Positive Feedback Mechanism in Systemic-Onset Juvenile Idiopathic Arthritis

Objective. Fever of unknown origin is a diagnostic challenge in children, especially for differentiation of systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) and infectious diseases. We undertook this study to analyze the relevance of myeloid-related proteins (MRPs) 8 and 14, endogenous activators of Toll-like receptor 4, in diagnosis and pathogenesis of systemic-onset JIA. Methods. Serum concentrations of MRP-8/MRP-14 were analyzed in 60 patients with systemic-onset JIA, 85 patients with systemic infections, 40 patients with acute lymphoblastic leukemia, 5 patients with acute myeloblastic leukemia, 18 patients with neonatal-onset multisystem inflammatory disease (NOMID), and 50 healthy controls. In addition, we investigated the link between interieukin-1 beta (IL-1 beta) and MRP-8/MRP-14 in systemic-onset JIA. Results. Serum MRP-8/MRP-14 concentrations were significantly (P <0.001) elevated in patients with active systemic-onset JIA (mean +/- 95% confidence interval 14,920 +/- 4,030 ng/ml) compared with those in healthy controls (340 70 ng/ml), patients with systemic infections (2,640 +/- 720 ng/ml), patients with acute lymphoblastic leukemia (650 280 ng/ml), patients with acute myeloblastic leukemia (840 +/- 940 ng/ml), and patients with NOMID (2,830 +/- 580 ng/ml). In contrast to C-reactive protein levels, MRP-8/MRP-14 concentrations distinguished systemic-onset JIA from infections, with a specificity of 95%. MRP-14 in serum of patients with systemic-onset JIA was a strong inducer of IL-1 beta expression in phagocytes. Conclusion. The analysis of MRP-8/MRP-14 in serum is an excellent tool for the diagnosis of systemic-onset JIA, allowing early differentiation between patients with systemic-onset JIA and those with other inflammatory diseases. MRP-8/MRP-14 and IL-1 beta represent a novel positive feedback mechanism activating phagocytes via 2 major signaling pathways of innate immunity during the pathogenesis of systemic-onset JIA

Towards remote monitoring of sub-seasonal glacier mass balance

This study presents a method that allows continuous monitoring of mass balance for remote or inaccessible glaciers, based on repeated oblique photography. Hourly to daily pictures from two automatic cameras overlooking two large valley glaciers in the Swiss Alps are available for eight ablation seasons (2004–11) in total. We determine the fraction of snow-covered glacier surface from orthorectified and georeferenced images and combine this information with simple accumulation and melt modelling using meteorological data. By applying this approach, the evolution of glacierwide mass balance throughout the ablation period can be directly calculated, based on terrestrial remote-sensing data. Validation against independent in situ mass-balance observations indicates good agreement. Our methodology has considerable potential for the remote determination of mountain glacier mass balance at high temporal resolution and could be applied using both repeated terrestrial and air-/spaceborne observations

Spatial and temporal variability in the snowpack of a High Arctic ice cap: implications for mass-change measurements

Interpretation of ice mass elevation changes observed by satellite altimetry demands quantification of the proportion of elevation change which is attributable to variations in firn densification. Detailed stratigraphic logging of snowpack structure and density was carried out at similar to 1 km intervals along a 47 km transect on Devon Ice Cap, Canada, in spring (pre-melt) and autumn (during/after melt) 2004 and 2006 to characterize seasonal snowpack variability across the full range of snow facies. Simultaneous meteorological measurements were gathered. Spring (pre-melt) snowpacks show low variability over large spatial scales, with low-magnitude changes in density. The end-of-summer/autumn density profiles show high variability in both 2004 and 2006, with vastly different melt regimes generating dissimilar patterns of ice-layer formation over the two melt seasons. Dye-tracing experiments from spring to autumn 2006 reveal that vertical and horizontal distribution of meltwater flow within and below the annual snowpack is strongly affected by the pre-existing, often subtle stratigraphic interfaces in the snowpack, rather than its bulk properties. Strong interannual variability suggests that using a simple relationship between air temperature, elevation and snowpack densification to derive mass change from measurements of elevation change across High Arctic ice caps may be misguided. Melt timing and duration are important extrinsic factors governing snowpack densification and ice-layer formation in summer, rather than averaged air temperatures

Hip Disarticulation for Severe Lower Extremity Infections

Hip disarticulation is rarely performed for infections and variable mortality rates have been reported. We determined the number of deaths following hip disarticulation for severe lower extremity infections in 15 patients. Indications for hip disarticulation were necrotizing soft tissue infections in seven patients and persistent infections of the proximal thigh in eight patients. The most common microorganism was Staphylococcus aureus, present in eight patients. Hip disarticulation was performed emergently in seven patients and electively in eight patients. All patients survived the operation and at 1 month postoperatively 14 of 15 patients were alive. Hip disarticulation for these severe infections had high survival, even when performed emergently for life-threatening infections. We believe hip disarticulation is a reasonable option treating severe infections of the lower extremity and should be part of the armamentarium of the orthopaedic surgeon

Safety of emapalumab in pediatric patients with primary hemophagocytic lymphohistiocytosis: findings from the primary analysis of the pivotal phase 2/3 study.

Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune regulatory disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, the cytokine Interferon gamma (IFNy) is often markedly elevated and is considered a key contributor to the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to transplantation, the only curative therapy. Current conventional therapy for HLH comprises immunochemotherapies, which are associated with opportunistic infections, toxicity, and high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease, or intolerance with conventional HLH therapy. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study and investigate the relationship of adverse events (AE) to dose and duration of treatment

Overall response rate (ORR) with emapalumab in patients with primary hemophagocytic lymphohistiocytosis (HLH): results of a sensitivity analysis.

Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to transplantation, the only potential curative therapy. Conventional HLH therapy comprises immunochemotherapies (namely dexamethasone and etoposide), which, unfortunately, predispose patients to the development of opportunistic infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. Thus, clinical objective response criteria were used to define the primary endpoint of ORR in the pivotal study of emapalumab in primary HLH [1]. These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria [1], clinical considerations from the study’s Scientific Steering Committee, and available experience reported with conventional HLH treatments. Herein, we report on findings of a sensitivity analysis of ORR to emapalumab using various assessment criteria

MobiSeq: De novo SNP discovery in model and non-model species through sequencing the flanking region of transposable elements

In recent years, the availability of reduced representation library (RRL) methods has catalysed an expansion of genome-scale studies to characterize both model and non-model organisms. Most of these methods rely on the use of restriction enzymes to obtain DNA sequences at a genome-wide level. These approaches have been widely used to sequence thousands of markers across individuals for many organisms at a reasonable cost, revolutionizing the field of population genomics. However, there are still some limitations associated with these methods, in particular the high molecular weight DNA required as starting material, the reduced number of common loci among investigated samples, and the short length of the sequenced site-associated DNA. Here, we present MobiSeq, a RRL protocol exploiting simple laboratory techniques, that generates genomic data based on PCR targeted enrichment of transposable elements and the sequencing of the associated flanking region. We validate its performance across 103 DNA extracts derived from three mammalian species: grey wolf (Canis lupus), red deer complex (Cervus sp.) and brown rat (Rattus norvegicus). MobiSeq enables the sequencing of hundreds of thousands loci across the genome and performs SNP discovery with relatively low rates of clonality. Given the ease and flexibility of MobiSeq protocol, the method has the potential to be implemented for marker discovery and population genomics across a wide range of organisms—enabling the exploration of diverse evolutionary and conservation questions

Safety and Efficacy of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Phase II study on the use of emapalumab for therapy of HL