2,281 research outputs found

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Primary liver cancer, consisting primarily of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a heterogeneous malignancy with a dismal prognosis, resulting in the third leading cause of cancer mortality worldwide [1, 2]. It is characterized by unique histological features, late-stage diagnosis, a highly variable mutational landscape, and high levels of heterogeneity in biology and etiology [3-5]. Treatment options are limited, with surgical intervention the main curative option, although not available for the majority of patients which are diagnosed in an advanced stage. Major contributing factors to the complexity and limited treatment options are the interactions between primary tumor cells, non-neoplastic stromal and immune cells, and the extracellular matrix (ECM). ECM dysregulation plays a prominent role in multiple facets of liver cancer, including initiation and progression [6, 7]. HCC often develops in already damaged environments containing large areas of inflammation and fibrosis, while CCA is commonly characterized by significant desmoplasia, extensive formation of connective tissue surrounding the tumor [8, 9]. Thus, to gain a better understanding of liver cancer biology, sophisticated in vitro tumor models need to incorporate comprehensively the various aspects that together dictate liver cancer progression. Therefore, the aim of this thesis is to create in vitro liver cancer models through organoid technology approaches, allowing for novel insights into liver cancer biology and, in turn, providing potential avenues for therapeutic testing. To model primary epithelial liver cancer cells, organoid technology is employed in part I. To study and characterize the role of ECM in liver cancer, decellularization of tumor tissue, adjacent liver tissue, and distant metastatic organs (i.e. lung and lymph node) is described, characterized, and combined with organoid technology to create improved tissue engineered models for liver cancer in part II of this thesis. Chapter 1 provides a brief introduction into the concepts of liver cancer, cellular heterogeneity, decellularization and organoid technology. It also explains the rationale behind the work presented in this thesis. In-depth analysis of organoid technology and contrasting it to different in vitro cell culture systems employed for liver cancer modeling is done in chapter 2. Reliable establishment of liver cancer organoids is crucial for advancing translational applications of organoids, such as personalized medicine. Therefore, as described in chapter 3, a multi-center analysis was performed on establishment of liver cancer organoids. This revealed a global establishment efficiency rate of 28.2% (19.3% for hepatocellular carcinoma organoids (HCCO) and 36% for cholangiocarcinoma organoids (CCAO)). Additionally, potential solutions and future perspectives for increasing establishment are provided. Liver cancer organoids consist of solely primary epithelial tumor cells. To engineer an in vitro tumor model with the possibility of immunotherapy testing, CCAO were combined with immune cells in chapter 4. Co-culture of CCAO with peripheral blood mononuclear cells and/or allogenic T cells revealed an effective anti-tumor immune response, with distinct interpatient heterogeneity. These cytotoxic effects were mediated by cell-cell contact and release of soluble factors, albeit indirect killing through soluble factors was only observed in one organoid line. Thus, this model provided a first step towards developing immunotherapy for CCA on an individual patient level. Personalized medicine success is dependent on an organoids ability to recapitulate patient tissue faithfully. Therefore, in chapter 5 a novel organoid system was created in which branching morphogenesis was induced in cholangiocyte and CCA organoids. Branching cholangiocyte organoids self-organized into tubular structures, with high similarity to primary cholangiocytes, based on single-cell sequencing and functionality. Similarly, branching CCAO obtain a different morphology in vitro more similar to primary tumors. Moreover, these branching CCAO have a higher correlation to the transcriptomic profile of patient-paired tumor tissue and an increased drug resistance to gemcitabine and cisplatin, the standard chemotherapy regimen for CCA patients in the clinic. As discussed, CCAO represent the epithelial compartment of CCA. Proliferation, invasion, and metastasis of epithelial tumor cells is highly influenced by the interaction with their cellular and extracellular environment. The remodeling of various properties of the extracellular matrix (ECM), including stiffness, composition, alignment, and integrity, influences tumor progression. In chapter 6 the alterations of the ECM in solid tumors and the translational impact of our increased understanding of these alterations is discussed. The success of ECM-related cancer therapy development requires an intimate understanding of the malignancy-induced changes to the ECM. This principle was applied to liver cancer in chapter 7, whereby through a integrative molecular and mechanical approach the dysregulation of liver cancer ECM was characterized. An optimized agitation-based decellularization protocol was established for primary liver cancer (HCC and CCA) and paired adjacent tissue (HCC-ADJ and CCA-ADJ). Novel malignancy-related ECM protein signatures were found, which were previously overlooked in liver cancer transcriptomic data. Additionally, the mechanical characteristics were probed, which revealed divergent macro- and micro-scale mechanical properties and a higher alignment of collagen in CCA. This study provided a better understanding of ECM alterations during liver cancer as well as a potential scaffold for culture of organoids. This was applied to CCA in chapter 8 by combining decellularized CCA tumor ECM and tumor-free liver ECM with CCAO to study cell-matrix interactions. Culture of CCAO in tumor ECM resulted in a transcriptome closely resembling in vivo patient tumor tissue, and was accompanied by an increase in chemo resistance. In tumor-free liver ECM, devoid of desmoplasia, CCAO initiated a desmoplastic reaction through increased collagen production. If desmoplasia was already present, distinct ECM proteins were produced by the organoids. These were tumor-related proteins associated with poor patient survival. To extend this method of studying cell-matrix interactions to a metastatic setting, lung and lymph node tissue was decellularized and recellularized with CCAO in chapter 9, as these are common locations of metastasis in CCA. Decellularization resulted in removal of cells while preserving ECM structure and protein composition, linked to tissue-specific functioning hallmarks. Recellularization revealed that lung and lymph node ECM induced different gene expression profiles in the organoids, related to cancer stem cell phenotype, cell-ECM integrin binding, and epithelial-to-mesenchymal transition. Furthermore, the metabolic activity of CCAO in lung and lymph node was significantly influenced by the metastatic location, the original characteristics of the patient tumor, and the donor of the target organ. The previously described in vitro tumor models utilized decellularized scaffolds with native structure. Decellularized ECM can also be used for creation of tissue-specific hydrogels through digestion and gelation procedures. These hydrogels were created from both porcine and human livers in chapter 10. The liver ECM-based hydrogels were used to initiate and culture healthy cholangiocyte organoids, which maintained cholangiocyte marker expression, thus providing an alternative for initiation of organoids in BME. Building upon this, in chapter 11 human liver ECM-based extracts were used in combination with a one-step microfluidic encapsulation method to produce size standardized CCAO. The established system can facilitate the reduction of size variability conventionally seen in organoid culture by providing uniform scaffolding. Encapsulated CCAO retained their stem cell phenotype and were amendable to drug screening, showing the feasibility of scalable production of CCAO for throughput drug screening approaches. Lastly, Chapter 12 provides a global discussion and future outlook on tumor tissue engineering strategies for liver cancer, using organoid technology and decellularization. Combining multiple aspects of liver cancer, both cellular and extracellular, with tissue engineering strategies provides advanced tumor models that can delineate fundamental mechanistic insights as well as provide a platform for drug screening approaches.<br/

    Dataflow Programming and Acceleration of Computationally-Intensive Algorithms

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    The volume of unstructured textual information continues to grow due to recent technological advancements. This resulted in an exponential growth of information generated in various formats, including blogs, posts, social networking, and enterprise documents. Numerous Enterprise Architecture (EA) documents are also created daily, such as reports, contracts, agreements, frameworks, architecture requirements, designs, and operational guides. The processing and computation of this massive amount of unstructured information necessitate substantial computing capabilities and the implementation of new techniques. It is critical to manage this unstructured information through a centralized knowledge management platform. Knowledge management is the process of managing information within an organization. This involves creating, collecting, organizing, and storing information in a way that makes it easily accessible and usable. The research involved the development textual knowledge management system, and two use cases were considered for extracting textual knowledge from documents. The first case study focused on the safety-critical documents of a railway enterprise. Safety is of paramount importance in the railway industry. There are several EA documents including manuals, operational procedures, and technical guidelines that contain critical information. Digitalization of these documents is essential for analysing vast amounts of textual knowledge that exist in these documents to improve the safety and security of railway operations. A case study was conducted between the University of Huddersfield and the Railway Safety Standard Board (RSSB) to analyse EA safety documents using Natural language processing (NLP). A graphical user interface was developed that includes various document processing features such as semantic search, document mapping, text summarization, and visualization of key trends. For the second case study, open-source data was utilized, and textual knowledge was extracted. Several features were also developed, including kernel distribution, analysis offkey trends, and sentiment analysis of words (such as unique, positive, and negative) within the documents. Additionally, a heterogeneous framework was designed using CPU/GPU and FPGAs to analyse the computational performance of document mapping

    It doesn't end with closure:Optimizing health care throughout life after esophageal atresia repair

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    It doesn't end with closure:Optimizing health care throughout life after esophageal atresia repair

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    A clinical decision support system for detecting and mitigating potentially inappropriate medications

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    Background: Medication errors are a leading cause of preventable harm to patients. In older adults, the impact of ageing on the therapeutic effectiveness and safety of drugs is a significant concern, especially for those over 65. Consequently, certain medications called Potentially Inappropriate Medications (PIMs) can be dangerous in the elderly and should be avoided. Tackling PIMs by health professionals and patients can be time-consuming and error-prone, as the criteria underlying the definition of PIMs are complex and subject to frequent updates. Moreover, the criteria are not available in a representation that health systems can interpret and reason with directly. Objectives: This thesis aims to demonstrate the feasibility of using an ontology/rule-based approach in a clinical knowledge base to identify potentially inappropriate medication(PIM). In addition, how constraint solvers can be used effectively to suggest alternative medications and administration schedules to solve or minimise PIM undesirable side effects. Methodology: To address these objectives, we propose a novel integrated approach using formal rules to represent the PIMs criteria and inference engines to perform the reasoning presented in the context of a Clinical Decision Support System (CDSS). The approach aims to detect, solve, or minimise undesirable side-effects of PIMs through an ontology (knowledge base) and inference engines incorporating multiple reasoning approaches. Contributions: The main contribution lies in the framework to formalise PIMs, including the steps required to define guideline requisites to create inference rules to detect and propose alternative drugs to inappropriate medications. No formalisation of the selected guideline (Beers Criteria) can be found in the literature, and hence, this thesis provides a novel ontology for it. Moreover, our process of minimising undesirable side effects offers a novel approach that enhances and optimises the drug rescheduling process, providing a more accurate way to minimise the effect of drug interactions in clinical practice

    Rethink Digital Health Innovation: Understanding Socio-Technical Interoperability as Guiding Concept

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    Diese Dissertation sucht nach einem theoretischem GrundgerĂŒst, um komplexe, digitale Gesundheitsinnovationen so zu entwickeln, dass sie bessere Erfolgsaussichten haben, auch in der alltĂ€glichen Versorgungspraxis anzukommen. Denn obwohl es weder am Bedarf von noch an Ideen fĂŒr digitale Gesundheitsinnovationen mangelt, bleibt die Flut an erfolgreich in der Praxis etablierten Lösungen leider aus. Dieser unzureichende Diffusionserfolg einer entwickelten Lösung - gern auch als Pilotitis pathologisiert - offenbart sich insbesondere dann, wenn die geplante Innovation mit grĂ¶ĂŸeren Ambitionen und KomplexitĂ€t verbunden ist. Dem geĂŒbten Kritiker werden sofort ketzerische Gegenfragen in den Sinn kommen. Beispielsweise was denn unter komplexen, digitalen Gesundheitsinnovationen verstanden werden soll und ob es ĂŒberhaupt möglich ist, eine universale Lösungsformel zu finden, die eine erfolgreiche Diffusion digitaler Gesundheitsinnovationen garantieren kann. Beide Fragen sind nicht nur berechtigt, sondern mĂŒnden letztlich auch in zwei ForschungsstrĂ€nge, welchen ich mich in dieser Dissertation explizit widme. In einem ersten Block erarbeite ich eine Abgrenzung jener digitalen Gesundheitsinnovationen, welche derzeit in Literatur und Praxis besondere Aufmerksamkeit aufgrund ihres hohen Potentials zur Versorgungsverbesserung und ihrer resultierenden KomplexitĂ€t gewidmet ist. Genauer gesagt untersuche ich dominante Zielstellungen und welche Herausforderung mit ihnen einhergehen. Innerhalb der Arbeiten in diesem Forschungsstrang kristallisieren sich vier Zielstellungen heraus: 1. die UnterstĂŒtzung kontinuierlicher, gemeinschaftlicher Versorgungsprozesse ĂŒber diverse Leistungserbringer (auch als inter-organisationale Versorgungspfade bekannt); 2. die aktive Einbeziehung der Patient:innen in ihre Versorgungsprozesse (auch als Patient Empowerment oder Patient Engagement bekannt); 3. die StĂ€rkung der sektoren-ĂŒbergreifenden Zusammenarbeit zwischen Wissenschaft und Versorgungpraxis bis hin zu lernenden Gesundheitssystemen und 4. die Etablierung daten-zentrierter Wertschöpfung fĂŒr das Gesundheitswesen aufgrund steigender bzgl. VerfĂŒgbarkeit valider Daten, neuen Verarbeitungsmethoden (Stichwort KĂŒnstliche Intelligenz) sowie den zahlreichen Nutzungsmöglichkeiten. Im Fokus dieser Dissertation stehen daher weniger die autarken, klar abgrenzbaren Innovationen (bspw. eine Symptomtagebuch-App zur Beschwerdedokumentation). Vielmehr adressiert diese Doktorarbeit jene Innovationsvorhaben, welche eine oder mehrere der o.g. Zielstellung verfolgen, ein weiteres technologisches Puzzleteil in komplexe Informationssystemlandschaften hinzufĂŒgen und somit im Zusammenspiel mit diversen weiteren IT-Systemen zur Verbesserung der Gesundheitsversorgung und/ oder ihrer Organisation beitragen. In der Auseinandersetzung mit diesen Zielstellungen und verbundenen Herausforderungen der Systementwicklung rĂŒckte das Problem fragmentierter IT-Systemlandschaften des Gesundheitswesens in den Mittelpunkt. Darunter wird der unerfreuliche Zustand verstanden, dass unterschiedliche Informations- und Anwendungssysteme nicht wie gewĂŒnscht miteinander interagieren können. So kommt es zu Unterbrechungen von InformationsflĂŒssen und Versorgungsprozessen, welche anderweitig durch fehleranfĂ€llige ZusatzaufwĂ€nde (bspw. Doppeldokumentation) aufgefangen werden mĂŒssen. Um diesen EinschrĂ€nkungen der EffektivitĂ€t und Effizienz zu begegnen, mĂŒssen eben jene IT-System-Silos abgebaut werden. Alle o.g. Zielstellungen ordnen sich dieser defragmentierenden Wirkung unter, in dem sie 1. verschiedene Leistungserbringer, 2. Versorgungsteams und Patient:innen, 3. Wissenschaft und Versorgung oder 4. diverse Datenquellen und moderne Auswertungstechnologien zusammenfĂŒhren wollen. Doch nun kommt es zu einem komplexen Ringschluss. Einerseits suchen die in dieser Arbeit thematisierten digitalen Gesundheitsinnovationen Wege zur Defragmentierung der Informationssystemlandschaften. Andererseits ist ihre eingeschrĂ€nkte Erfolgsquote u.a. in eben jener bestehenden Fragmentierung begrĂŒndet, die sie aufzulösen suchen. Mit diesem Erkenntnisgewinn eröffnet sich der zweite Forschungsstrang dieser Arbeit, der sich mit der Eigenschaft der 'InteroperabilitĂ€t' intensiv auseinandersetzt. Er untersucht, wie diese Eigenschaft eine zentrale Rolle fĂŒr Innovationsvorhaben in der Digital Health DomĂ€ne einnehmen soll. Denn InteroperabilitĂ€t beschreibt, vereinfacht ausgedrĂŒckt, die FĂ€higkeit von zwei oder mehreren Systemen miteinander gemeinsame Aufgaben zu erfĂŒllen. Sie reprĂ€sentiert somit das Kernanliegen der identifizierten Zielstellungen und ist Dreh- und Angelpunkt, wenn eine entwickelte Lösung in eine konkrete Zielumgebung integriert werden soll. Von einem technisch-dominierten Blickwinkel aus betrachtet, geht es hierbei um die GewĂ€hrleistung von validen, performanten und sicheren Kommunikationsszenarien, sodass die o.g. InformationsflussbrĂŒche zwischen technischen Teilsystemen abgebaut werden. Ein rein technisches InteroperabilitĂ€tsverstĂ€ndnis genĂŒgt jedoch nicht, um die Vielfalt an Diffusionsbarrieren von digitalen Gesundheitsinnovationen zu umfassen. Denn beispielsweise das Fehlen adĂ€quater VergĂŒtungsoptionen innerhalb der gesetzlichen Rahmenbedingungen oder eine mangelhafte PassfĂ€higkeit fĂŒr den bestimmten Versorgungsprozess sind keine rein technischen Probleme. Vielmehr kommt hier eine Grundhaltung der Wirtschaftsinformatik zum Tragen, die Informationssysteme - auch die des Gesundheitswesens - als sozio-technische Systeme begreift und dabei Technologie stets im Zusammenhang mit Menschen, die sie nutzen, von ihr beeinflusst werden oder sie organisieren, betrachtet. Soll eine digitale Gesundheitsinnovation, die einen Mehrwert gemĂ€ĂŸ der o.g. Zielstellungen verspricht, in eine existierende Informationssystemlandschaft der Gesundheitsversorgung integriert werden, so muss sie aus technischen sowie nicht-technischen Gesichtspunkten 'interoperabel' sein. Zwar ist die Notwendigkeit von InteroperabilitĂ€t in der Wissenschaft, Politik und Praxis bekannt und auch positive Bewegungen der DomĂ€ne hin zu mehr InteroperabilitĂ€t sind zu verspĂŒren. Jedoch dominiert dabei einerseits ein technisches VerstĂ€ndnis und andererseits bleibt das Potential dieser Eigenschaft als Leitmotiv fĂŒr das Innovationsmanagement bislang weitestgehend ungenutzt. An genau dieser Stelle knĂŒpft nun der Hauptbeitrag dieser Doktorarbeit an, in dem sie eine sozio-technische Konzeptualisierung und Kontextualisierung von InteroperabilitĂ€t fĂŒr kĂŒnftige digitale Gesundheitsinnovationen vorschlĂ€gt. Literatur- und expertenbasiert wird ein Rahmenwerk erarbeitet - das Digital Health Innovation Interoperability Framework - das insbesondere Innovatoren und Innovationsfördernde dabei unterstĂŒtzen soll, die Diffusionswahrscheinlichkeit in die Praxis zu erhöhen. Nun sind mit diesem Framework viele Erkenntnisse und Botschaften verbunden, die ich fĂŒr diesen Prolog wie folgt zusammenfassen möchte: 1. Um die Entwicklung digitaler Gesundheitsinnovationen bestmöglich auf eine erfolgreiche Integration in eine bestimmte Zielumgebung auszurichten, sind die Realisierung eines neuartigen Wertversprechens sowie die GewĂ€hrleistung sozio-technischer InteroperabilitĂ€t die zwei zusammenhĂ€ngenden Hauptaufgaben eines Innovationsprozesses. 2. Die GewĂ€hrleistung von InteroperabilitĂ€t ist eine aktiv zu verantwortende Managementaufgabe und wird durch projektspezifische Bedingungen sowie von externen und internen Dynamiken beeinflusst. 3. Sozio-technische InteroperabilitĂ€t im Kontext digitaler Gesundheitsinnovationen kann ĂŒber sieben, interdependente Ebenen definiert werden: Politische und regulatorische Bedingungen; Vertragsbedingungen; Versorgungs- und GeschĂ€ftsprozesse; Nutzung; Information; Anwendungen; IT-Infrastruktur. 4. Um InteroperabilitĂ€t auf jeder dieser Ebenen zu gewĂ€hrleisten, sind Strategien differenziert zu definieren, welche auf einem Kontinuum zwischen KompatibilitĂ€tsanforderungen aufseiten der Innovation und der Motivation von Anpassungen aufseiten der Zielumgebung verortet werden können. 5. Das Streben nach mehr InteroperabilitĂ€t fördert sowohl den nachhaltigen Erfolg der einzelnen digitalen Gesundheitsinnovation als auch die Defragmentierung existierender Informationssystemlandschaften und trĂ€gt somit zur Verbesserung des Gesundheitswesens bei. Zugegeben: die letzte dieser fĂŒnf Botschaften trĂ€gt eher die FĂ€rbung einer Überzeugung, als dass sie ein Ergebnis wissenschaftlicher BeweisfĂŒhrung ist. Dennoch empfinde ich diese, wenn auch persönliche Erkenntnis als Maxim der DomĂ€ne, der ich mich zugehörig fĂŒhle - der IT-Systementwicklung des Gesundheitswesens

    Business Functions Capabilities and Small and Medium Enterprises’ Internationalization

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    Ineffective global expansion can adversely affect small and medium enterprises (SMEs) business outcomes. Business leaders are concerned with developing effective global expansion strategies to penetrate potential international markets, thus enhancing sustainability. Grounded in the business management systems theory, the purpose of this qualitative multi-case study was to explore strategies that leaders of Sub-Saharan Africa manufacturing SMEs use for global expansion. The participants were five manufacturing value-adding SME leaders participating in export markets. Using Yin’s five steps data analysis process, six themes emerged: (a) enterprise characterization, (b) understanding the enterprise’s product, (c) intra-enterprise factor-based strategies for export participation, (d) the enterprise’s external factor-based strategies for successful export venture, (e) global expansion strategies, and (f) serendipitous findings. A key recommendation for SME leaders is to analyze the critical components of their products and prepare to adjust them to the demand dimensions of the target market. The implications for positive social change include the potential to increase the enterprise’s wealth, increase employment, reduce poverty for all value chain participants, and growth in gross domestic product

    Talking about personal recovery in bipolar disorder: Integrating health research, natural language processing, and corpus linguistics to analyse peer online support forum posts

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    Background: Personal recovery, ‘living a satisfying, hopeful and contributing lifeeven with the limitations caused by the illness’ (Anthony, 1993) is of particular value in bipolar disorder where symptoms often persist despite treatment. So far, personal recovery has only been studied in researcher-constructed environments (interviews, focus groups). Support forum posts can serve as a complementary naturalistic data source. Objective: The overarching aim of this thesis was to study personal recovery experiences that people living with bipolar disorder have shared in online support forums through integrating health research, NLP, and corpus linguistics in a mixed methods approach within a pragmatic research paradigm, while considering ethical issues and involving people with lived experience. Methods: This mixed-methods study analysed: 1) previous qualitative evidence on personal recovery in bipolar disorder from interviews and focus groups 2) who self-reports a bipolar disorder diagnosis on the online discussion platform Reddit 3) the relationship of mood and posting in mental health-specific Reddit forums (subreddits) 4) discussions of personal recovery in bipolar disorder subreddits. Results: A systematic review of qualitative evidence resulted in the first framework for personal recovery in bipolar disorder, POETIC (Purpose & meaning, Optimism & hope, Empowerment, Tensions, Identity, Connectedness). Mainly young or middle-aged US-based adults self-report a bipolar disorder diagnosis on Reddit. Of these, those experiencing more intense emotions appear to be more likely to post in mental health support subreddits. Their personal recovery-related discussions in bipolar disorder subreddits primarily focussed on three domains: Purpose & meaning (particularly reproductive decisions, work), Connectedness (romantic relationships, social support), Empowerment (self-management, personal responsibility). Support forum data highlighted personal recovery issues that exclusively or more frequently came up online compared to previous evidence from interviews and focus groups. Conclusion: This project is the first to analyse non-reactive data on personal recovery in bipolar disorder. Indicating the key areas that people focus on in personal recovery when posting freely and the language they use provides a helpful starting point for formal and informal carers to understand the concerns of people diagnosed with bipolar disorder and to consider how best to offer support
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