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B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5’-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r –0·33, Plinear < 0·0001), serum amyloid A (SAA) (r –0·23, Plinear = 0·003), IL-6 (r –0·39, Plinear < 0·0001), IL-8 (r –0·20, Plinear = 0·02) and TNFα (r –0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r –0·14), SAA (r –0·14) and TNFα (r –0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.
In the context of cross-disciplinary and cross-company cooperation, several challenges in developing manufacturing systems are revealed through industrial use cases. To tackle these challenges, two propositions are used in parallel. First, coupling technical models representing different content areas facilitates the detection of boundary crossing consequences, either by using a posteriori or a priori connection. Second, it is necessary to enrich these coupled technical models with team and organizational models as interventions focusing on the collaboration between individuals and teams within broader organizational conditions. Accordingly, a combined interdisciplinary approach is proposed. The feasibility and benefits of the approach is proven with an industrial use case. The use case shows that inconsistencies among teams can be identified by coupling engineering models and that an integrated organizational model can release the modelling process from communication barriers.
To evaluate the association between novel pre- and post-operative biomarker levels and 30-day unplanned readmission or mortality after paediatric congenital heart surgery.
Children aged 18 years or younger undergoing congenital heart surgery (n = 162) at Johns Hopkins Hospital from 2010 to 2014 were enrolled in the prospective cohort. Collected novel pre- and post-operative biomarkers include soluble suppression of tumorgenicity 2, galectin-3, N-terminal prohormone of brain natriuretic peptide, and glial fibrillary acidic protein. A model based on clinical variables from the Society of Thoracic Surgery database was developed and evaluated against two augmented models.
Unplanned readmission or mortality within 30 days of cardiac surgery occurred among 21 (13%) children. The clinical model augmented with pre-operative biomarkers demonstrated a statistically significant improvement over the clinical model alone with a receiver-operating characteristics curve of 0.754 (95% confidence interval: 0.65–0.86) compared to 0.617 (95% confidence interval: 0.47–0.76; p-value: 0.012). The clinical model augmented with pre- and post-operative biomarkers demonstrated a significant improvement over the clinical model alone, with a receiver-operating characteristics curve of 0.802 (95% confidence interval: 0.72–0.89; p-value: 0.003).
Novel biomarkers add significant predictive value when assessing the likelihood of unplanned readmission or mortality after paediatric congenital heart surgery. Further exploration of the utility of these novel biomarkers during the pre- or post-operative period to identify early risk of mortality or readmission will aid in determining the clinical utility and application of these biomarkers into routine risk assessment.
In today's engineering projects, interdisciplinary work leads to an increase in interfaces between different departments and domains. As each stakeholder pursues different goals and tasks, a heterogeneous model landscape is required. In each domain, a variety of different model and software implementations provide the essential basis for efficient work. On the interfaces, the risk of model inconsistencies increases. To handle occurring inconsistencies, various approaches have been presented. For model-based systems engineering projects, rule-based methods are considered as the most suitable technique. However, said approaches require a high manual effort in identifying model dependencies and establishing consistency rules. Unfortunately, in particular these steps are not well described and supported. Therefore, this paper presents an easily applicable approach for the identification of model dependencies in interdisciplinary projects. The method is supported by a software implementation and is directly integrated in engineering workflows. A first industrial case study has shown positive effects of the approach and revealed further research goals.
We argue that the roles of attacker and defender in asymmetric intergroup conflict are structurally ambiguous and their perception is likely to be subjectively biased. Although this allows for endogenous selection into each role, we argue that claiming the role of the defender likely is more advantageous for conflict participants.
THE SHORT TEXT Essay on Being has been dated to about 1763 or 1764. It has received relatively little attention. Aside from the commentaries to the editions by Wolfgang Proß and by Ulrich Gaier, the most extensive discussion has been by Hans Adler. Not even the impact of Martin Heidegger's book Sein und Zeit (1927) was sufficient to pull into view Herder's role as a precursor. Nor did the interest in and discussion of Friedrich Hölderlin's “Urteil und Sein” draw Herder's essay along in its wake. Some pertinent observations have been made, notably in a discussion, “Herder's Epistemology,” by Marion Heinz and Heinrich Clairmont in the context of a survey of current Herder scholarship. They stress that although it was not published during his lifetime, the essay is worthy of some scrutiny: “But since the Versuch über das Sein is foundational for Herder's thought in this area, and since essential elements of it—especially the doctrines of Being and of space, time, and force as the basic concepts of human experience—remain constant throughout the metamorphoses of his epistemological conception, it is important to trace the essay's lines of argumentation.” Heinz and Clairmont seem confident about how to approach the essay. They contextualize it with Kant, whose lectures on metaphysics Herder attended in 1763, and in reference to Hume, even though neither is mentioned in the text. Useful as those signposts are, they only mark the beginnings of efforts to see and to locate, to place the Essay on Being. In addition to its fragmentary, disjointed form, the text is difficult to situate because it seems to fall out of line with Herder's other primary concerns. Nor is it easy to align with genres such as the essay, treatise, or exegetical commentary, especially given its poetic tone.
Herder is known for his pioneering work in many areas: cultural studies, anthropology, folklore, world history, aesthetics, and the history of literature come to mind immediately. However, one field where he is only gradually gaining acceptance is philosophy, where the opposition of Kant to Herder's philosophy of history proved quite a barrier.
OBJECTIVES/SPECIFIC AIMS: Objectives and goals of this study will be to: (1) compare fecal microbiota and fecal organic acids in irritable bowel syndrome (IBS) patients and controls and (2) investigate the association between colonic transit and fecal microbiota in IBS patients and controls. METHODS/STUDY POPULATION: We propose an investigation of fecal organic acids, colonic transit and fecal microbiota in 36 IBS patients and 18 healthy controls. The target population will be adults ages 18–65 years meeting Rome IV criteria for IBS (both diarrhea- and constipation-predominant, IBS-D and IBS-C) and asymptomatic controls. Exclusion criteria are: (a) history of microscopic colitis, inflammatory bowel disease, celiac disease, visceral cancer, chronic infectious disease, immunodeficiency, uncontrolled thyroid disease, liver disease, or elevated AST/ALT>2.0× the upper limit of normal, (b) prior radiation therapy of the abdomen or abdominal surgeries with the exception of appendectomy or cholecystectomy >6 months before study initiation, (c) ingestion of prescription, over the counter, or herbal medications affecting gastrointestinal transit or study interpretation within 6 months of study initiation for controls or within 2 days before study initiation for IBS patients, (d) pregnant females, (e) antibiotic usage within 3 months before study participation, (f) prebiotic or probiotic usage within the 2 weeks before study initiation, (g) tobacco users. Primary outcomes will be fecal bile acid excretion and profile, short-chain fatty acid excretion and profile, colonic transit, and fecal microbiota. Secondary outcomes will be stool characteristics based on responses to validated bowel diaries. Stool samples will be collected from participants during the last 2 days of a 4-day 100 g fat diet and split into 3 samples for fecal microbiota, SCFA, and bile acid analysis and frozen. Frozen aliquots will be shipped to the Metabolite Profiling Facility at Purdue University and the Mayo Clinic Department of Laboratory Medicine and Pathology for SCFA and bile acid measurements, respectively. Analysis of fecal microbiota will be performed in the research laboratory of Dr David Nelson in collaboration with bioinformatics expertise affiliated with the Nelson lab. Colonic transit time will be measured with the previously validated method using radio-opaque markers. Generalized linear models will be used as the analysis framework for comparing study endpoints among groups. RESULTS/ANTICIPATED RESULTS: This study seeks to examine the innovative concept that specific microbial signatures are associated with increased fecal excretion of organic acids to provide unique insights on a potential mechanistic link between altered intraluminal organic acids and fecal microbiota. DISCUSSION/SIGNIFICANCE OF IMPACT: Results may lead to development of targets for novel therapies and diagnostic biomarkers for IBS, emphasizing the role of the fecal metabolome.
We examined relationships between measures of total knee arthroplasty (TKA) “appropriateness” constructs and surgeon TKA recommendations in people with knee osteoarthritis (OA). Although TKA is highly effective, fifteen to thirty percent of recipients report dissatisfaction and/or little or no symptom improvement. More appropriate selection of surgical candidates may improve both patient outcomes and healthcare resource use, but no validated appropriateness criteria exist currently in Canada.
Patients 30 years of age or older with knee OA referred for surgical consultation at two large joint arthroplasty centres in Alberta, Canada were invited to participate. Participants completed a standardized pre-consult questionnaire, which included the following sociodemographics and validated measures of appropriateness constructs for TKA: knee symptoms; non-surgical management; patient readiness for and expectations of TKA; and net patient benefit. Post-consultation, surgeons were asked to confirm knee OA and their recommendation. We used multivariable logistic regression to examine the relationship between measures of appropriateness constructs and receipt of surgeon TKA recommendation.
Of 3,009 patients approached, 2,360 completed the questionnaire and 2,064 (sixty-nine percent) were eligible at surgical consultation (mean age 65.7 years, standard deviation 9.1; fifty-nine percent were women); 1,495 (seventy-two percent) were recommended for TKA. The likelihood of receiving a TKA recommendation was independently associated with: knee symptoms (odds ratio [OR] per unit increase in pain intensity, 1.19 (95% confidence interval [CI]: 1.11–1.27)); prior non-surgical OA management (OR for prior knee injection, 1.53 (95% CI: 1.21–1.94)); readiness for surgery (OR if definitely/probably willing to undergo TKA, 3.03 (95% CI: 1.99–4.59)); and TKA expectations (OR outcome “very important”: ability to perform daily activities, 1.40 (95% CI: 1.04–1.88); straighten the knee/leg 1.42 (95% CI: 1.13–1.80); participate in exercise/sports 0.75 (95% CI: 0.58–0.98)).
In our cohort of patients with confirmed knee OA who consulted a surgeon for TKA, appropriateness constructs were significantly associated with receipt of a TKA recommendation. Research is ongoing to evaluate the predictive validity of these measures for patient-reported outcomes associated with TKA.
We argue that, in addition to the positive effects and functionality of morality for interactions among in-group members as outlined in the target article, morality may also fuel aggression and conflict in interactions between morality-based out-groups. We summarize empirical evidence showing that negative cognitions, emotions, and behaviors are particularly likely to appear between out-groups with opposing moral convictions.
This paper aims to situate functional abstraction in light of systems thinking. While function does not extensively appear in systems thinking literature, the literature does identify function as part of systems thinking that enables us to recognize and connect that function has a role in building a systems thinking approach for students. A systems thinking approach is valuable for students since it helps them view a system holistically. In this research, we measure how well students are able to abstract function. We asked students to generate functions for two different products and examined how students taught functional modeling and function enumeration compare to students who are only taught function enumeration. The student responses were examined using a rubric that we developed and validated for assessing function. This rubric may be used to classify functions by correctness (correct, partially correct, and incorrect) and categories (high level, interface, low level, and ambiguous). On questions where students were not explicitly asked to write a high-level function or low-level function, and so on, students who were taught functional modeling were able to better demonstrate systems thinking in their responses (low-level and interface functions) than those students who were only taught function enumeration.
Research and industrial practice have produced a host of function models and modeling approaches over the last decades. Each of these is meant to support designers in their design endeavors. Industrial practice is excessively diversified in terms of contextual requirements, aims, and adopted processes; this automatically begs the question which of the existing models should be selected for application in a specific situation. This paper sets out to contribute to this discourse. It strives to benchmark the fairly novel integrated function modeling (IFM) framework against the well-established function structures modeling approach. The paper comparatively investigates the respective capabilities of the approaches, following the benchmarking protocol used earlier in relation to this Special Issue. Function structures are used as reference as they represent one of the most widespread function modeling approaches in research and practice. Both function structures and the IFM framework are exemplarily applied for modeling a glue gun. The gradual generation and refinement of the models is used to showcase their respective benefits and shortcomings. Eventually, the IFM framework is found to excel over function structures in terms of comprehensiveness and support for different types of function analyses. Finally, future research directions are proposed.
Modular product design is an efficient strategy to let manufacturing companies meet the customers’ requirements by offering a wide variety and customization of products and significantly saving time and cost during engineering and production (Fei et al., 2011). Despite numerous approaches for function modeling and modular product design (Srinivasan et al., 2012; Eckert, 2013; Vermaas, 2013) that have been developed in the last decades, carrying out an efficient product variants’ design process is still an open issue for many manufacturing companies. The proposed approaches offer numerous ways to model information about product functionality, but each approach is useful and particularly well suited for different applications and domains (Summers et al., 2013). The present research compares the existing approaches for product variants design and defines a function-based model to support product design and redesign according to a modular framework, merging qualitative technical issues with business-oriented evaluation. Such a framework has been used to develop a multiuser IT platform, composed of a knowledge-based engine and four different tools to support designers and engineers in product variants creation, management, and configuration, from product functional modeling to cost estimation and life cycle assessment. The proposed model has been tested on industrial cases in the context of household appliances. Experimental results demonstrates that, after a preliminary context analysis and a proper knowledge base creation, such a model supports a more conscious decision-making and promote collaboration within an interdisciplinary design team. Finally, the case study shows the necessity, but in the meanwhile the insufficiency, of a functional decomposition as the only representation viewpoint.
This paper introduces a rigorous framework for function modeling of complex multidisciplinary systems based on the system state flow diagram (SSFD). The work addresses the need for a consistent methodology to support solution-neutral function-based system decomposition analysis, facilitating the design, modeling, and analysis of complex systems architectures. A rigorous basis for the SSFD is established by defining conventions for states and function definitions and a representation scheme, underpinned by a critical review of existing literature. A set of heuristics are introduced to support the function decomposition analysis and to facilitate the deployment of the methodology with strong practitioner guidelines. The SSFD heuristics extend the existing framework of Otto and Wood (2001) by introducing a conditional fork node heuristic, to facilitate analysis and aggregation of function models across multiple modes of operation of the system. The empirical validation of the SSFD function modeling framework is discussed in relation to its application to two case studies: a benchmark problem (glue gun) set for the engineering design community; and an industrial case study of an electric vehicle powertrain. Based on the evidence from the two case studies presented in the paper, a critical evaluation of the SSFD function modeling methodology is discussed based on the function benchmarking framework established by Summers et al. (2013), considering the representation, modeling, cognitive, and reasoning characteristics. The significance of this paper is that it establishes a rigorous reference framework for the SSFD function representation and a consistent methodology to guide the practitioner with its deployment, facilitating its impact to industrial practice.
Functional modeling is an analytical approach to design problems that is widely taught in certain academic communities but not often used by practitioners. This approach can be applied in multiple ways to formalize the understanding of the systems, to support the synthesis of the design in the development of a new product, or to support the analysis and improvement of existing systems incrementally. The type of usage depends on the objectives that are targeted. The objectives can be categorized into two key groups: discovering a totally new solution, or improving an existing one. This article proposes to use the functional modeling approach to achieve three goals: to support the representation of physics-based reasoning, to use this physics-based reasoning to assess design options, and finally to support innovative ideation. The exemplification of the function-based approach is presented via a case study of a glue gun proposed for this Special Issue. A reverse engineering approach is applied, and the authors seek an incremental improvement of the solution. As the physics-based reasoning model presented in this article is heavily dependent on the quality of the functional model, the authors propose a general approach to limit the interpretability of the functional representations by mapping the functional vocabulary with elementary structural blocks derived from bond graph theory. The physics-based reasoning approach is supported by a mathematical framework that is summarized in the article. The physics-based reasoning model is used for discovering the limitations of solutions in the form of internal contradictions and guiding the design ideation effort.