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Additional file 4: Distribution of Sections and Adaptation Choices by Symptom Care Pathway

Additional file 3: Clinical Practice Guideline and Care Pathway Utilization for Symptom Management at Baseline (N=10)

Additional file 1: Care Pathway Template Example

Additional file 2: Options for Adaptations Considering Degree of Bothersome Symptoms

Additional file 5: Results of the Implementation Survey to all Healthcare Professionals across Institutions (N=84)

This preregistration is added to and modifies the original preregistration with the same title. Based on a planned check of a small sample of study data (to confirm that the study was "working" properly) we discovered that our manipulation checks were not performing as intended. This preregistration specifies how we will deal with manipulation checks--the changes we will make in the questions we ask, our predictions for the response patterns, and a revised use of a question formerly used as a manipulation check but now planned to be a substantive measure.

This subproject, part of the larger ADR project, looks at the narrow question of whether feelings of status predict feelings of safety; and further, whether status is preferred to power as a source of safety.

BackgroundRadiographic end points commonly are included in therapeutic trials for systemic sclerosis (SSc)-interstitial lung disease (ILD); however, the relationship between these outcomes and long-term mortality is unclear.Research questionDo short-term changes in radiographic measures of ILD predict long-term survival in patients with SSc?Study design and methodsThe Scleroderma Lung Study (SLS) I and II evaluated the safety and efficacy of cyclophosphamide (in SLS I and II) and mycophenolate mofetil (in SLS II) for the treatment of SSc-ILD. Changes in the extent of ILD over time were assessed on high-resolution CT scans of the chest by quantitative image analysis, an approach that applies a computer-based algorithm to assess changes in the radiographic extent of ILD objectively. Participants subsequently were followed for up to 12 years (SLS I) and 8 years (SLS II). Cox proportional hazards models determined whether the change in the quantitative radiographic extent of ILD predicted survival, adjusting for other known predictors of survival.ResultsAmong SLS I and II participants, 82 and 90 had follow-up imaging scans, respectively, and were included in the analysis. Participants in both trials who showed an increase in the total quantitative radiographic extent of ILD scores of≥ 2%at 12months (SLS I) or 24months (SLS II) experienced significantly worse long-term survival than those with change scores of&nbsp

Additional file 3: Table S2. Association between blood eosinophils and tissue eosinophilic infiltration before BT using generalized linear models.

Additional file 1: Figure S1. Representative microphotographs of endobronchial biopsies obtained from asthma patients before and after thermoplasty, at different magnifications (X100-X400).

Additional file 2: Table S1. Lung function parameters in patients with severe asthma after bronchial thermoplasty.

Additional file 4: Table S3. Histopathological evaluation of endobronchial biopsies before and after bronchial thermoplasty.

Onshore wind development has historically focused on cost-efficiency, which may lead to inequitable turbine distributions and public resistance due to landscape impacts. Using a multi-criteria planning approach, we show how onshore wind capacity targets can be achieved by 2050 in a cost-efficient, equitable and publicly acceptable way. For the case study of Germany, we build on the existing turbine stock and use open data on technically feasible turbine locations and scenicness of landscapes to plan the optimal expansion. The analysis shows that while the trade-off between cost-efficiency and public acceptance is rather weak with about 15% higher costs or scenicness, an equitable distribution has a large impact on these criteria. Although the onshore wind capacity per inhabitant could be distributed about 220% more equitably through the expansion, equity would severely limit planning flexibility by 2050. Our analysis assists stakeholders in resolving the onshore wind expansion trilemma.

The Institute of Materials and Processes, IMP, of the University of Applied Sciences in Karlsruhe, Germany in cooperation with VDI Verein Deutscher Ingenieure e.V, AEN Automotive Engineering Network and their cooperation partners present their competences of AI-based solution approaches in the production engineering field. The online congress KI 4 Industry on November 12 and 13, 2020, showed what opportunities the use of artificial intelligence offers for medium-sized manufacturing companies, SMEs, and where potential fields of application lie. The main purpose of KI 4 Industry is to increase the transfer of knowledge, research and technology from universities to small and medium-sized enterprises, to demystify the term AI and to encourage companies to use AI-based solutions in their own value chain or in their products., Comment: Editors: Matthias Feiner and Manuel Schoellhorn, 72 pages, 48 figures, in German, Conference proceedings KI 4 Industry, 79 pages in total

ObjectiveTo examine changes in the extent of specific patterns of interstitial lung disease (ILD) as they transition from one pattern to another in response to immunosuppressive therapy in systemic sclerosis-related ILD (SSc-ILD).MethodsWe evaluated changes in the quantitative extent of specific lung patterns of ILD using volumetric high-resolution computed tomography (HRCT) scans obtained at baseline and after 2 years of therapy in patients treated with either cyclophosphamide (CYC) for 1 year or mycophenolate mofetil (MMF) for 2 years in Scleroderma Lung Study II. ILD patterns included lung fibrosis, ground glass, honeycombing, and normal lung. Net change was calculated as the difference in the probability of change from one ILD pattern to another. Wilcoxon's signed rank test was used to compare the changes.ResultsForty-seven and 50 patients had baseline and follow-up scans in the CYC and MMF groups, respectively. Mean net improvements reflecting favorable changes from one ILD pattern to another in the whole lung in the CYC and MMF groups, respectively, were as follows: from lung fibrosis to a normal lung pattern, 21% and 19%; from a ground-glass pattern to a normal lung pattern, 30% and 28%; and from lung fibrosis to a ground-glass pattern, 5% and 0.5%. The mean overall improvement in transitioning from a ground-glass pattern or lung fibrosis to a normal lung pattern was significant for both treatments (all P < 0.001).ConclusionSignificantly favorable transitions from both ground-glass and lung fibrosis ILD patterns to a normal lung pattern were observed in patients undergoing immunosuppressive treatment for SSc-ILD, suggesting the usefulness of examining these transitions for insights into the underlying pathobiology of treatment response.

ObjectiveTo investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD).MethodsPatients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm.ResultsBaseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only).ConclusionIn a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

ObjectiveTo compare safety and efficacy outcomes between the cyclophosphamide (CYC) arms of Scleroderma Lung Study (SLS) I and II.MethodsParticipants enrolled in the CYC arms of SLS I (n = 79) and II (n = 69) were included. SLS I and II randomized participants to oral CYC for 1 year and followed patients for an additional year off therapy (in SLS II, patients received placebo in Year 2). Eligibility criteria for SLS I and II were nearly identical. Outcomes included the forced vital capacity (FVC%)-predicted and DLCO%-predicted (measured every 3 mos) and quantitative radiographic extent of interstitial lung disease (measured at 1 and 2 yrs for SLS I and SLS II, respectively). Joint models were created to evaluate the treatment effect on the course of the FVC/DLCO over 2 years while controlling for baseline disease severity.ResultsSLS I and II CYC participants had similar baseline characteristics. After adjusting for baseline disease severity, there was no difference in the course of the FVC%-predicted (p = 0.535) nor the DLCO%-predicted (p = 0.172) between the SLS I and II CYC arms. In both groups, treatment with CYC led to a significant improvement in the FVC%-predicted from 3 to 12 months, but no significant improvement beyond this point. Treatment with CYC had no effect on the DLCO for either group.ConclusionTreatment with 1 year of oral CYC led to similar improvements in lung function in both SLS I and II, although the effects were not sustained following cessation of CYC. These results suggest that increasing the duration of ILD therapy may improve outcomes for patients with systemic sclerosis-ILD.

Adversarial examples (AEs) are images that can mislead deep neural network (DNN) classifiers via introducing slight perturbations into original images. Recent work has shown that detecting AEs can be more effective against AEs than preventing them from being generated. However, the state-of-the-art AE detection still shows a high false positive rate, thereby rejecting a considerable amount of normal images. To address this issue, we propose HAWKEYE, which is a separate neural network that analyzes the output layer of the DNN, and detects AEs. HAWKEYE's AE detector utilizes a quantized version of an input image as a reference, and is trained to distinguish the variation characteristics of the DNN output on an input image from the DNN output on its reference image. We also show that cascading our AE detectors that are trained for different quantization step sizes can drastically reduce a false positive rate, while keeping a detection rate high.

This file contains the following: a brief summary of SVM and Random Forest models for distal regulatory site prediction, PR Metric and Data Preprocessing, PR Results, 1 Figure that describes the pipeline for generating the PR dataset, 1 Figure that summarizes the PR results, and 3 Figures that summarize the Sensitivity analysis for tuning our Convolutional Neural Network. (PDF 421 kb)

ObjectiveTo assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II.MethodsSLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling.ResultsAfter a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data.ConclusionIn addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

Supplemental material, Supplemental_files for Sound analysis of the magnetically levitated left ventricular assist device HeartMate 3™ by Per Sundbom, Michael Roth, Hans Granfeldt, Daniel M Karlsson, Henrik Ahn, Fredrik Gustafsson, Göran Dellgren and Laila Hubbert in The International Journal of Artificial Organs

RationaleThe Scleroderma Lung Study II (SLS II) demonstrated significant improvements in pulmonary function and dyspnea at 24 months compared with baseline when patients with symptomatic scleroderma-related interstitial lung disease (SSc-ILD) were treated with either cyclophosphamide for 1 year (followed for another year on placebo) or mycophenolate mofetil for 2 years in a randomized, double-blind clinical trial. Physiologic and clinical outcomes of SLS II have been published previously.ObjectivesThe aim of the study was to assess changes from baseline in the extent of SSc-ILD on high-resolution computed tomography (HRCT) measured in the SLS II participants using quantitative image analysis after 2 years and to determine whether these HRCT changes were correlated with the changes in physiologic and clinical measures over the same time interval.MethodsNinety-seven of the 142 randomized subjects (cyclophosphamide group, 47 subjects; mycophenolate mofetil group, 50 subjects) participating in SLS II underwent thoracic volumetric thin-section HRCT at both baseline and 24 months. Quantitative computer-aided diagnosis scores using volumetric HRCT scans were obtained using a previously developed computer-aided system. The scores were quantitative lung fibrosis, quantitative ground glass, quantitative honeycomb, and quantitative interstitial lung disease (QILD), the latter representing the sum of quantitative lung fibrosis, quantitative ground glass, and quantitative honeycomb. These scores were obtained both for the whole lung and for individual lobes. Paired t tests were used for the combined (pooled) cyclophosphamide and mycophenolate mofetil groups to compare 24-month changes from baseline in both the whole lung and the lobe of maximal involvement as determined at baseline (worst lobe).ResultsAt the end of the 24-month trial, QILD in the whole lung was significantly reduced by a mean of 2.51% in the pooled groups (adjusted 95% confidence interval, -4.00 to -1.03%; P = 0.001). There was no significant difference in the QILD score improvement between the cyclophosphamide (-2.66%) and mycophenolate (-2.38%) groups when assessed separately (P = 0.88). For the pooled group, the 24-month changes in QILD scores in the whole lung correlated significantly with other outcomes, including 24-month changes in forced vital capacity (ρ = -0.37), single-breath diffusing capacity of the lung for carbon monoxide (ρ = -0.22), and breathlessness as measured by the Transition Dyspnea Index (ρ = -0.26).ConclusionsTreatment of SSc-ILD with either cyclophosphamide for 1 year, followed by placebo for a second year, or mycophenolate for 2 years was associated with a significant reduction (improvement) in the extent of HRCT SSc-ILD assessed by computer-aided diagnosis scores, which correlated well with one or more other measures of treatment response. These findings demonstrate that actual changes in lung structure accompany improvements in physiologic and/or symptomatic measures in SSc-ILD.

Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung. In vitro, while mitochondrial dsDNA is sensed by cGAS-STING in dendritic cells, in macrophages extracellular dsDNA activates STING independent of cGAS after silica exposure. These results reveal an essential function of STING-mediated self-dsDNA sensing after silica exposure, and identify DNase I as a potential therapy for silica-induced lung inflammation., Silica particles induce intereukin-1 (IL-1) response to contribute to lung inflammation, but the underlying mechanism is unclear. Here the authors show that silica induces cell death and release of mitochondria and genomic DNA, which are sensed by STING with or without involving cGAS, respectively, for IL-1 induction and lung inflammation.

OBJECTIVE:To assess the efficacy of mycophenolate mofetil (MMF) and cyclophosphamide (CYC) on modified Rodnan skin score (MRSS) in participants enrolled in the Scleroderma Lung Study (SLS) I and II. METHODS:SLS I participants received daily oral CYC or matching placebo for 1 year, whereas SLS II participants received daily MMF for 2 years or daily oral CYC for 1 year followed by placebo for second year. We assessed the impact of MMF and CYC on the MRSS in SLS II over a 24-month period. We also compared the change in MRSS in patients with diffuse cutaneous systemic sclerosis (dcSSc) assigned to CYC and MMF in SLS II and SLS I versus placebo in SLS I over a 24-month period using a linear mixed model. RESULTS:In SLS II, the baseline mean ± SD MRSS was 14.0 ± 10.6 units for CYC and 15.3 ± 10.4 units for MMF; 58.5% were classified as dcSSc. CYC and MMF were associated with statistically significant improvements in MRSS from baseline over the period of 24 months in dcSSc (P < 0.05 at each time point), but there were no differences between the 2 groups. In the dcSSc subgroup, the change in MRSS from baseline to all 6-month visits was similar in SLS II groups (MMF, CYC, pooled cohort [MMF + CYC]) and in the SLS I CYC group and showed statistically significant improvements compared to SLS I placebo at 12, 18, and 24 months (P < 0.05). CONCLUSION:In SLS II, MMF and CYC treatment resulted in improvements in MRSS in patients with dcSSc over 24 months. In addition, MMF and CYC treatment resulted in statistically significant improvements in MRSS in patients with dcSSc when compared with the SLS I placebo group.

ObjectivesTo assess the reliability and the minimal clinically important differences (MCID) for FVC% predicted in the Scleroderma Lung Study I and II.MethodsUsing data from SLS I and II (N=300), we evaluated the test-retest reliability for FVC% predicted (FVC%; screening vs. baseline) using intra-class correlation (ICC). MCID estimates at 12 months were calculated in the pooled cohort (SLS-I and II) using 2 anchors: Transition Dyspnea Index (≥change of 1.5 units for improvement and worsening, respectively) and the SF-36 Health Transition question: "Compared to one year ago, how would you rate your health in general now?", where "somewhat better" or "somewhat worse" were defined as the MCID estimates. We next assessed the association of MCID estimates for improvement and worsening of FVC% with patient reported outcomes (PROs) and computer-assisted quantitation of extent of fibrosis (QLF) and of total ILD (QILD) on HRCT.ResultsReliability of FVC%, assessed at a mean of 34 days, was 0.93 for the pooled cohort. The MCID estimates for the pooled cohort at 12 months for FVC% improvement ranged from 3.0 % to 5.3% and for worsening from -3.0% to -3.3%. FVC% improvement by ≥MCID was associated with either statistically significant or numerical improvements in some PROs, QILD, and QLF, while FVC% worsening ≥MCID was associated with statistically significant or numerical worsening of PROs, QILD, and QLF.ConclusionFVC% has acceptable test-retest reliability, and we have provided the MCID estimates for FVC% in SSc-ILD based changes at 12 months from baseline in two clinical trials. Clinical trial registration available at www.clinicaltrials.gov, IDs NCT00004563 and NCT00883129.

Background: Interferon lambdas (IFNLs) have important anti-viral/bacterial and immunomodulatory functions in the respiratory tract. How do IFNLs impact COPD and its exacerbations? Methods: Five hundred twenty eight patients were recruited in a prospective observational multicentre cohort (PROMISE) study. The genetic polymorphisms (rs8099917 and rs12979860) within the IFNL3/4 gene region and circulating levels of IFNL3 in COPD patients were determined and associated with disease activity and outcome during a median follow-up of 24 months. Results: The GG genotype significantly influenced severe exacerbation rate (42 vs. 23%; p = 0.032) and time to severe exacerbation (HR = 2.260; p = 0.012). Compared to the TT or TG genotypes, the GG genotype was associated with severe dyspnoea (modified medical research council score ≥ median 3; 22 vs 42%, p = 0.030). The CC genotype of the rs12979860 SNP was associated with a poorer prognosis (body mass index, airflow obstruction, dyspnea and exercise capacity index ≥ median 4; 46 vs. 36% TC vs. 20.5% TT; p = 0.031). Patients with stable COPD and at exacerbation had significantly lower circulating IFNL3 compared to healthy controls (p < 0.001 and p < 0.001, respectively). Circulating IFNL3 correlated to post-bronchodilator FEV1%predicted and the tissue maturation biomarker Pro-collagen 3. Conclusion: IFNL3/4 polymorphisms and circulating IFNL3 may be associated with disease activity and outcomes in COPD. Trial registration: Clinical Trial registration http://www.isrctn.com/ identifier ISRCTN99586989 on 16 April 2008.

ObjectiveTo compare mycophenolate mofetil (MMF) with placebo for the treatment of systemic sclerosis (SSc)-related interstitial lung disease (ILD).MethodsWe included participants enrolled in the placebo arm of Scleroderma Lung Study (SLS) I and the MMF arm of SLS II. SLS I randomized participants to receive either oral cyclophosphamide (CYC) or placebo for 1 year, while SLS II randomized participants to receive either MMF for 2 years or oral CYC for 1 year followed by 1 year of placebo. Eligibility criteria for SLS I and SLS II were nearly identical. The primary outcome was % predicted forced vital capacity (FVC), and key secondary outcomes included % predicted diffusing capacity for carbon monoxide (DLco), the modified Rodnan skin thickness score (MRSS), and dyspnea. Joint models were created to evaluate the treatment effect on the course of these outcomes over 2 years.ResultsAt baseline, the MMF-treated group in SLS II (n = 69) and the placebo-treated group in SLS I (n = 79) had similar percentages of men and women and similar disease duration, SSc subtype, extent of skin disease, and % predicted FVC. MMF-treated patients in SLS II were slightly older (mean ± SD age 52.6 ± 9.7 years versus 48.1 ± 12.4 years; P = 0.0152) and had higher % predicted DLco (mean ± SD 54.0 ± 11.1 versus 46.2 ± 13.3; P = 0.0002) than placebo-treated patients in SLS I. After adjustment for baseline disease severity, treatment with MMF in comparison with placebo was associated with improved % predicted FVC (P

BackgroundCough is a common symptom of scleroderma-related interstitial lung disease (SSc-ILD), but its relationship to other characteristics of SSc-ILD, impact on cough-specific quality of life (QoL), and response to therapy for SSc-ILD have not been well studied.MethodsWe investigated frequent cough (FC) in patients with SSc-ILD (N= 142) enrolled in the Scleroderma Lung Study II, a randomized controlled trial comparing mycophenolate mofetil (MMF) and oral cyclophosphamide (CYC) as treatments for interstitial lung disease (ILD). We determined the impact of FC on QoL (Leicester Cough Questionnaire [LCQ]), evaluated the change in FC in response to treatment for SSc-ILD, and examined the relationship between gastroesophageal reflux disease (GERD) and cough during the trial.ResultsStudy participants who reported FC at baseline (61.3%) reported significantly more dyspnea, exhibited more extensive ILD on high-resolution CT, had a lower diffusing capacity for carbon monoxide, and reported more GERD symptoms than did those without FC. Cough-specific QoL was modestly impaired in patients with FC (total LCQ score, 15.4 ± 3.7; normal range, 3-21 [higher scores indicate worse QoL]). The proportion of patients with FC at baseline declined by 44%and 41%over 2 years in the CYC and MMF treatment arms, respectively, and this decline was significantly related to changes in GERD and ILD severity.ConclusionsFC occurs commonly in SSc-ILD, correlates with both the presence and severity of GERD and ILD at baseline, and declines in parallel with improvements in both ILD and GERD over a 2-year course of therapy. Frequent cough might serve as a useful surrogate marker of treatment response in SSc-ILD trials.Trial registryClinicalTrials.gov; No.: NCT00883129; URL: www.clinicaltrials.gov.

The ensemble Kalman filter (EnKF) is a Monte Carlo-based implementation of the Kalman filter (KF) for extremely high-dimensional, possibly nonlinear, and non-Gaussian state estimation problems. Its ability to handle state dimensions in the order of millions has made the EnKF a popular algorithm in different geoscientific disciplines. Despite a similarly vital need for scalable algorithms in signal processing, e.g., to make sense of the ever increasing amount of sensor data, the EnKF is hardly discussed in our field. This self-contained review is aimed at signal processing researchers and provides all the knowledge to get started with the EnKF. The algorithm is derived in a KF framework, without the often encountered geoscientific terminology. Algorithmic challenges and required extensions of the EnKF are provided, as well as relations to sigma point KF and particle filters. The relevant EnKF literature is summarized in an extensive survey and unique simulation examples, including popular benchmark problems, complement the theory with practical insights. The signal processing perspective highlights new directions of research and facilitates the exchange of potentially beneficial ideas, both for the EnKF and high-dimensional nonlinear and non-Gaussian filtering in general. Funding Agencies|project Scalable Kalman Filters - Swedish Research Council

Simulation of wave propagation in a microearthquake environment is often challenging due to small-scale structural and material heterogeneities. We simulate wave propagation in three different real microearthquake environments using a spectral-element method. In the first example, we compute the full wavefield in 2D and 3D models of an underground ore mine, namely the Pyhaesalmi mine in Finland. In the second example, we simulate wave propagation in a homogeneous velocity model including the actual topography of an unstable rock slope at Aaknes in western Norway. Finally, we compute the full wavefield for a weakly anisotropic cylindrical sample at laboratory scale, which was used for an acoustic emission experiment under triaxial loading. We investigate the characteristic features of wave propagation in those models and compare synthetic waveforms with observed waveforms wherever possible. We illustrate the challenges associated with the spectral-element simulation in those models., Comment: 22 pages, 19 figures, 1 table

In current markets efforts for safety analyses and approval increase. Instead of review-based methods, recent publications demand for a shift of safety considerations to early stages and to bridge the gap between designers and safety experts. This paper develops a modelling method which helps to explicit safety knowledge and model safety functions. It unites existing methods of functional and structural modelling and extends the concept of safety functions. The resulting method, thus contributes to the requested shift and helps to bridge the gap between safety experts and product designers.

The current markets are characterized by an increasing demand for individual products, increasing product complexity and stricter safety regulations. This results in large hazard and safety analysis efforts for each individual product variant. One possible solution to reduce these efforts is the automation of analyses and a preliminary assessment of individual changes. Therefore, several approaches are published to e.g. model safety aspects or evaluate change propagations. However, the approaches fail to directly establish the connection between product changes and safety aspects by a common model. This paper develops a method to identify and assess the potential hazard impact of product changes through a common static model. It builds on a graph-based product model and graph-rewriting. From the state of the art, suitable methods tools and principles are identified and evaluated. Based on this, requirements are derived. The capabilities of existing methods are assessed and the most suitable ones adapted and integrated to the method to assess the potential hazard impact of product changes (MBHPA). The MBHPA reduces the complexity by providing two independent interconnected analyses. To evaluate the product changes, a static propagation analysis is provided. It uses defined graph-rewriting patterns to trace propagations and extract a propagation tree. The affected components in a second step can then be evaluated on their hazard potential. Again graph-rewriting patterns are applied to identify the connected hazards which are visualized in a hazard potential portfolio. The MBHPA is implemented and evaluated with the industrial case of an automated coffee machine. The evaluation underlines that the MBHPA successfully identifies possible propagations and their effect on hazards from a static perspective. It helps to improve safety awareness and traceability and reduces the required experience.

Current markets show an increasing demand for individual products. Therefore, user-driven customization is a new concept which combines early user involvement and self-customization. It has not yet been extensively discussed in research. The implications on current development processes are not known. This paper combines a qualitative exploration (interviews) with a quantitative exploratin (questionnaire survey) and researches the implications of user-driven customization. Thus, it paper contributes to the understanding of user-driven customization and provides a base for consecutive resear

A Knowledge Framework for Safety Analysis of User-Induced Changes

While markets demand for individual products, the importance of safety also continuously increases. Modularization methods are a common approach, but they mainly focus on technical dependencies or other module drivers. From a safety perspective, this leads to non-optimal module concepts, which further increase the efforts connected to safety. To avoid this, safety aspects should be better considered. Thus, this paper presents the safety-oriented Modular Function Deployment (sMFD), which integrates safety aspects in a modularization method. It aims to develop safety-oriented module concepts. Hence, sMFD contributes to a shift of safety considerations to early stages of design and supports the evaluation of alternative concepts. The paper analyses existing modularization methods and assesses their suitability. MFD is identified as most suitable and adapted to support the safety-oriented modularization. Therefore, safety aspects (e.g. safety integrity levels or classes of safety requirements) are defined as module drivers. The resulting sMFD is applied and evaluated in two industrial case studies.

Representative data from a subject at baseline and 12 months in the SLS I. Subject was 61 years old with baseline and 12-month HRCT. Goh and Wells unadjusted stratification >20 (a and b). In whole lung, quantitative lung fibrosis scores (blue dots) are 9.71 % at baseline (c) and 34.25 % at 12 months (d); quantitative ground glass (yellow dots) are 18.38 % at baseline and 25.8 % at 12 months, and QILD score are 38.09 % at baseline and 60.05 % at 12-month follow-up. (PPTX 945 kb)