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This study focused on improving the understanding of the actual extent and spatial impacts of the Rupnik Line as one of the two fortification systems of the Rapallo Border. To this end, the available sources were checked and the understanding about the sectoral division of the Rapallo Border’s elements was derived therefrom. The field investigation done at a micro-location level revealed the real scope of the Rupnik Line fortification facilities. By identifying and recording the individual Rupnik fortification facilities in the Municipality of Žiri and by conducting interviews, we made an overview map showing the locations of these fortification structures. This basis, testifying to the actual condition and extent of the Rupnik Line fortification system at the level of the Municipality of Žiri, made it possible to develop further in-depth research questions regarding the spatial roles and values of this system.

The substantial morbidity and mortality associated with refractory systemic JIA underlies the need for new treatment approaches. However, progress in this area has been limited by the difficulty of enrolling these patients in clinical trials with traditional designs, particularly in patients presenting with the life-threatening macrophage activation syndrome. At the NextGen 2022 conference, there was group consensus that using historical cohorts as a control group to avoid the need for a placebo-arm or drug withdrawal was highly desirable and might be acceptable for clinical trials in MAS to support medication efficacy and safety. However, if historic controls were used in a trial, it would be important to ensure that the historic cohort matches the study group in terms of clinical characteristics (such as disease severity and exposure to other medications), and that disease outcome in both groups is assessed using the same outcome measures. The discussions at the NextGen 2022 conference focused on the potential strategies to achieve these goals. [ABSTRACT FROM AUTHOR]

Objective: Human leukocyte antigen (HLA)‐DRB1*15:01 has been recently associated with interstitial lung disease (LD), eosinophilia, and drug reactions in systemic juvenile idiopathic arthritis (sJIA). Additionally, genetic variants in IL1RN have been linked to poor response to anakinra. We sought to reproduce these findings in a prospective cohort study of patients with new‐onset sJIA treated with anakinra as first‐line therapy. Methods: HLA and IL1RN risk alleles were identified via whole‐genome sequencing. Treatment responses and complications were compared between carriers versus noncarriers. Results: Seventeen of 65 patients (26%) carried HLA‐DRB1*15:01, comparable with the general population, and there was enrichment for HLA‐DRB1*11:01, a known risk locus for sJIA. The rates of clinical inactive disease (CID) at 6 months, 1 year, and 2 years were generally high, irrespective of HLA‐DRB1 or IL1RN variants, but significantly lower in carriers of an HLA‐DRB1*11:01 allele. One patient, an HLA‐DRB1*15:01 carrier, developed sJIA‐LD. Of the three patients with severe drug reactions to biologics, one carried HLA‐DRB1*15:01. The prevalence of eosinophilia did not significantly differ between HLA‐DRB1*15:01 carriers and noncarriers at disease onset (6.2% vs 14.9%, P = 0.67) nor after the start of anakinra (35.3% vs 37.5% in the first 2 years of disease). Conclusion: We observed high rates of CID using anakinra as first‐line treatment irrespective of HLA‐DRB1 or IL1RN variants. Only one of the 17 HLA‐DRB1*15:01 carriers developed sJIA‐LD, and of the three patients with drug reactions to biologics, only one carried HLA‐DRB1*15:01. Although thorough monitoring for the development of drug hypersensitivity and refractory disease courses in sJIA, including sJIA‐LD, remains important, our data support the early start of biologic therapy in patients with new‐onset sJIA irrespective of HLA‐DRB1 background or IL1RN variants. [ABSTRACT FROM AUTHOR]

INTRODUCTION The public comment process is one of the hallmarks of the American administrative state. (1) As the informal notice-and-comment rulemaking procedure has grown into one of the most important [...], With the increased politicization of agency rulemaking and the reduced cost of participating in the notice-and-comment rulemaking process, administrative agencies have, in recent years, found themselves deluged in a flood of public comments. In this Article, we argue that this deluge presents both challenges and opportunities, and we explore how advances in natural language processing technologies can help agencies address the challenges and take advantage of the opportunities created by the recent growth of public participation in the regulatory process. We also examine how scholars of public bureaucracies can use this important new publicly available data to better understand how agencies interact with the public. To illustrate the value of these new tools, we carry out computational text analysis of nearly three million public, comments that were received by administrative agencies over the course of the Obama administration. Our findings indicate that advances in natural language processing technology show great promise for both researchers and policymakers who are interested in understanding, and improving, regulatory decision-making.

Abstract Background Improved, noninvasive biomarkers are needed to accurately detect lupus nephritis (LN) activity. The purpose of this study was to evaluate five S100 proteins (S100A4, S100A6, S100A8/9, and S100A12) in both serum and urine as potential biomarkers of global and renal system-specific disease activity in childhood-onset systemic lupus erythematosus (cSLE). Methods In this multicenter study, S100 proteins were measured in the serum and urine of four cSLE cohorts and healthy control subjects using commercial enzyme-linked immunosorbent assays. Patients were divided into cohorts on the basis of biospecimen availability: (1) longitudinal serum, (2) longitudinal urine, (3) cross-sectional serum, and (4) cross-sectional urine. Global and renal disease activity were defined using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the SLEDAI-2K renal domain score. Nonparametric testing was used for statistical analysis, including the Wilcoxon signed-rank test, Kruskal-Wallis test, Mann-Whitney U test, and Spearman’s rank correlation coefficient. Results All urine S100 proteins were elevated in patients with active LN compared with patients with active extrarenal disease and healthy control subjects. All urine S100 protein levels decreased with LN improvement, with S100A4 demonstrating the most significant decrease. Urine S100A4 levels were also higher with proliferative LN than with membranous LN. S100A4 staining in the kidney localized to mononuclear cells, podocytes, and distal tubular epithelial cells. Regardless of the S100 protein tested, serum levels did not change with cSLE improvement. Conclusions Higher urine S100 levels are associated with increased LN activity in cSLE, whereas serum S100 levels do not correlate with disease activity. Urine S100A4 shows the most promise as an LN activity biomarker, given its pronounced decrease with LN improvement, isolated elevation in urine, and positive staining in resident renal cells.

Safety on the licensed ski slopes in Slovenia, like in many other winter countries, is a complex notion involving, in addition to ski slope owners and operators, several governmental agencies and functionaries, such as inspectors, supervisors, police, medical staff, and others. We cannot assign blame for accidents to them. Our research, in agreement with the Inspectorate of the Republic of Slovenia responsible for Internal Affairs and the Police Academy, focuses on the causes for skiing accidents. We found out that a skier plays an important role in safe-guarding his/her own safety as well as that of fellow skiers on the ski slope. Obligations of the skier using a licensed ski slope are described in 10 internationally endorsed FIS rules of skiing. We obtained data on ski accidents for three consecutive ski seasons between December 2012 and April 2015. We studied whether or not the skiers followed FIS regulations and whether or not they adequately safeguarded their own safety. We also studied who is most often responsible for ski accidents.

The paper focuses on determining reading and writing skills of children at the beginning and at the end of school year and on the introduction of a model test for the Cankar Award Contest. The objective of the present work is to develop a model for the Cankar Award Contest for children in the first year of primary school and to establish whether children in the first class are capable of participating in such a contest. Research on a sample of 55 children has yielded key conclusions about the capabilities of children in initial literacy and confirmed that pupils with advanced competences in the area of reading and writing are able to participate in the Cankar Award Contest, in which previously they could, as a rule, participate from the second class on.

Background: Systemic juvenile idiopathic arthritis (SJIA) is a chronic childhood arthropathy with features of autoinflammation. Early inflammatory SJIA is associated with expansion and activation of neutrophils with a sepsis-like phenotype, but neutrophil phenotypes present in longstanding and clinically inactive disease (CID) are unknown. The objective of this study was to examine activated neutrophil subsets, S100 alarmin release, and gene expression signatures in children with a spectrum of SJIA disease activity.Methods: Highly-purified neutrophils were isolated using a two-step procedure of density-gradient centrifugation followed by magnetic-bead based negative selection prior to flow cytometry or cell culture to quantify S100 protein release. Whole transcriptome gene expression profiles were compared in neutrophils from children with both active SJIA and CID.Results: Patients with SJIA and active systemic features demonstrated a higher proportion of CD16+CD62Llo neutrophil population compared to controls. This neutrophil subset was not seen in patients with CID or patients with active arthritis not exhibiting systemic features. Using imaging flow cytometry, CD16+CD62Llo neutrophils from patients with active SJIA and features of macrophage activation syndrome (MAS) had increased nuclear hypersegmentation compared to CD16+CD62L+ neutrophils. Serum levels of S100A8/A9 and S100A12 were strongly correlated with peripheral blood neutrophil counts. Neutrophils from active SJIA patients did not show enhanced resting S100 protein release; however, regardless of disease activity, neutrophils from SJIA patients did show enhanced S100A8/A9 release upon PMA stimulation compared to control neutrophils. Furthermore, whole transcriptome analysis of highly purified neutrophils from children with active SJIA identified 214 differentially expressed genes (DEG) compared to neutrophils from healthy controls. The most significantly upregulated gene pathway was Immune System Process, including AIM2, IL18RAP, and NLRC4. Interestingly, this gene set showed intermediate levels of expression in neutrophils from patients with long-standing CID yet persistent serum IL-18 elevation. Indeed, all patient samples regardless of disease activity demonstrated elevated inflammatory gene expression, including inflammasome components and S100A8.Conclusion: We identify features of neutrophil activation in SJIA patients with both active disease and CID, including a proinflammatory gene expression signature, reflecting persistent innate immune activation. Taken together, these studies expand understanding of neutrophil function in chronic autoinflammatory disorders such as SJIA.

Polyurethanes have the potential to impart cell-relevant properties like excellent biocompatibility, high and interconnecting porosity and controlled degradability into biomaterials in a relatively simple way. In this context, a biodegradable composite material made of an isocyanate-terminated co-oligoester prepolymer and precipitated calcium carbonated spherulites (up to 60% w/w) was synthesized and investigated with regard to an application as bone substitute in dental and orthodontic application. After foaming the composite material, a predominantly interconnecting porous structure is obtained, which can be easily machined. The compressive strength of the foamed composites increases with raising calcium carbonate content and decreasing calcium carbonate particle size. When stored in an aqueous medium, there is a decrease in pressure stability of the composite, but this decrease is smaller the higher the proportion of the calcium carbonate component is. In vitro cytocompatibility studies of the foamed composites on MC3T3-E1 pre-osteoblasts revealed an excellent cytocompatibility. The in vitro degradation behaviour of foamed composite is characterised by a continuous loss of mass, which is slower with higher calcium carbonate contents. In a first pre-clinical pilot trial the foamed composite bone substitute material (fcm) was successfully evaluated in a model of vertical augmentation in an established animal model on the calvaria and on the lateral mandible of pigs.