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Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Introduction and aim: Mimics of mast cell-derived heparin proteoglycans (HEP-PG) can be tailored to molecules carrying both antiplatelet and anticoagulant properties. These dual antiplatelet and anticoagulant (APAC) constructs can also shield adhesion molecules such as P-selectin and VCAM-1 expressed by endothelial cells upon atherosclerosis development. We hypothesize that via this way, APAC prevents macrophage accumulation and lesion development. In this study, we therefore determined the efficacy of APAC in inhibiting atherosclerosis. Methods Male western-type diet fed apoE-/- mice were equipped with perivascular carotid artery collars to induce atherosclerosis. In this collar model, mRNA expression of adhesion molecules such as ICAM-1, VCAM-1, P-Selectin but also of Platelet Factor 4 (PF4) are significantly upregulated upon lesion development (all P Results APAC treatment did not affect body weight or plasma total cholesterol levels of the mice during the experiment. Interestingly, carotid artery plaque size was reduced by over 50% upon APAC treatment (APAC: 50±10*10E3 versus controls: 102±13*10E3 square µm; P Conclusion We here show that APAC effectively inhibits atherosclerotic lesion development when administered during lesion initiation and may have potential as therapeutic agent to prevent atherosclerosis.

Introduction: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E₂] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. Material and methods: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2–3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). Clinical trial registration: NCT02352090. Results: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change −24%, 95% confidence interval [CI] −32% to −15%; p

Building information models contain a great amount of data in various lifecycle phases throughout building projects. Data is generally not seen as an asset yet building information models’ (BIM) value is recognized. Seeing BIM models value as an asset and maintaining a structured product lifecycle management (PLM) in organization leads to need of productization of BIM Models, just like tangible products. Building information modeling is a known term within the building industry, but product lifecycle management is unconventional. Productization practices that include PLM have few examples in the academia or of use in the building industry. This thesis aims to study the possibilities of productizing building information models to commercial and technical items and presents background to it. Building information models are currently not seen as commercial products, but it is acknowledged they are valuable and have great potential in changing the practices and productivity in the whole building industry. BIM models are not handled as products, and they are not included to order-delivery-invoicing practices and systems as commercial products. BIM models can contain a broad and multidimensional amount of information and some structuring practices of BIM models remind closely of bill of material (BOM) in technical product structures. Information content of BIM models increases and becomes more precise continuously, but to benefit financially of the additional value of BIM models is insufficient in terms of understanding their possibilities in content and commercial value. This thesis presents the definition and current state of the productization practices of BIM models and offers a recommendation to productize BIM models as a part of construction object configuration commercially and technically. The work is done reviewing current literature and via a current state analysis of a case company. Within the thesis, it is recommended to be establish a new product category into construction product offering alongside to hardware, software, and services: BIM products. From the commercial aspect, it is recommended to divide BIM models into three categories based on their status in a commercial product portfolio: open BIM models, BIM model products and BIM model systems. The recommendations of building a BIM model product structure are based on a BIM framework theory, which allows to separate the broad and multidimensional information structures of BIM models in structured and understandable form. The results of this study can be generalized and used in the building industry internationally. The results of this thesis are significant for any organization wanting to change their building information models’ status from technical tools into commercial products in a structured way.Tiivistelmä. Rakennusalan tietomallit sisältävät merkittävän määrän dataa rakennushankkeen eri elinkaaren vaiheissa. Datan ei ole tyypillisesti ajateltu olevan yrityksen pääomaa, mutta kuitenkin on tunnistettu, että tietomalleilla on arvo. Mikäli tietomallien arvo tunnistetaan, ja niitä halutaan alkaa kohtelemaan yrityksen pääomana, johtaa se tuotteen elinkaarenhallinnan (PLM) käytäntöjä noudattavalta organisaatiolta tarpeeseen tuotteistaa tietomallit, kuten fyysiset tuotteetkin. Termeinä tietomalli on tunnettu rakennusalalla, kun taas PLM on harvinaisempi; PLM ja tuotteistuskäytännöt ovat rakennusalalla vähän tutkittuja ja vähän käytössä. Tämän opinnäytetyön tarkoituksena on tutkia mahdollisuuksia siihen, miten tietomallit tuotteistettaisiin kaupallisiksi ja teknisiksi tuotteen osiksi, sekä esittää taustatietoja tietomallien tuotteistukselle. Tällä hetkellä tietomalleja ei ajatella kaupallisina tuotteina, vaikka niiden arvo ja mahdollisuudet jopa koko rakennusalan muuttamiseen ja tuottavuuden parantamiseen tunnistetaan. Tietomalleja ei myöskään käsitellä kuten tuotteita, eivätkä ne ole osa tilaus-toimitus-laskutus-käytäntöjä tai -ohjelmistoja kaupallisina tuotteina. Tietomallit voivat kuitenkin sisältää huomattavan määrän monimuotoista informaatiota, ja jotkut tietomallien rakenteen kuvaukset muistuttavat jopa tuotteistamisesta tuttuja teknisten tuoterakenteiden BOM:a (Bill-of-Material). Tietomallien datasisältö lisääntyy ja tarkentuu jatkuvasti, mutta kuitenkin ymmärrys tietomallien sisältöön liittyvistä kaupallisista mahdollisuuksista on liian vähäistä, jotta niistä voitaisiin hyötyä kaupallisesti. Tämä tutkimus esittelee ja määrittelee tämänhetkiset tietomallien tuotteistuskäytännöt ja tarjoaa ratkaisuehdotuksen tietomallien tekniseen ja kaupalliseen tuotteistukseen osaksi rakennusalan tuotevalikoimaa. Työ on tehty perehtymällä kirjallisuuskatsaukseen ja tekemällä nykytila-analyysi valitusta case-yrityksestä. Tämän työn tuloksena suositellaan uuden tietomalli-tuotekategorian perustamista nykyisten rakennusalan tuotevalikoiman fyysisten tuotteiden (HW), ohjelmistotuotteiden (SW) ja palvelutuotteiden (service) rinnalle. Tutkimuksen perusteella tietomallituotteet olisi myös syytä jakaa kaupallisen käytön perusteella kolmeen pääkategoriaan; ilmaiset tietomallituotteet, kaupalliset tietomallituotteet ja tietomallijärjestelmätuotteet. Tietomallien tuoterakenteen muodostamiseen ehdotetaan käytettävän BIM framework-teoriaa, jonka avulla monimuotoisia tietorakenteita on helpompi strukturoida. Tämän tutkimuksen tuloksia voidaan käyttää yleisesti rakennusalalla niin kansallisesti kuin kansainvälisesti. Tutkimuksen tulokset ovat merkittäviä sellaisille organisaatioille, jotka tunnistavat tietomalliensa datasisällön arvon pääomana ja siten haluavat johdonmukaisesti muuttaa heidän tietomalliensa statuksen teknisestä apuvälineestä kaupalliseksi tuotteeksi ja siten osaksi tuoteportfoliotaan.

Non

Background\ud Type 3 von Willebrand’s disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD.\ud \ud Aims\ud To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients; to investigate any possible clustering of bleeding symptoms within type 3 patients.\ud \ud Methods\ud We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM‐1VWD bleeding questionnaire in patients enrolled in the 3WINTERS‐IPS and MCMDM‐1VWD studies.\ud \ud Results\ud In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15. vs. 6.0 and 5 vs. 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five‐fold over‐represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having VWF:Ag levels

Healthy subjects frequently report minor bleedings that are frequently ‘background noise’ of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non-severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus-based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild-to-moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient-centered initial diagnostic approach that will result in classification of MBD into distinct clinical-pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence-based, disease-specific guidelines under development by the IWG.

BACKGROUND: Uncontrollable bleeding is the leading cause of death in traumatically injured patients. The extent to which direct factor Xa inhibitors interfere with the applied resuscitation measures is presently unknown. STUDY DESIGN AND METHODS: In this study, we investigated the effect of the resuscitation fluid s saline, albumin, fresh frozen plasma (FFP) and solvent/ detergent (S/D)-treated plasma, fibrinogen concentrate, prothrombin complex concentrate (PCC), and combinations thereof on the hemostatic profile of rivaroxaban-anticoagulated whole blood and plasma. We used rivaroxaban-spiked whole blood and plasma from healthy donors, as well as plasma from patients on rivaroxaban, and mimicked a resuscitation approach in a 50% plasma dilution setting. Thromboelastography, thrombin generation, and fibrin generation clot lysis test were assessed using tissue factor to initiate coagulation and tissue plasminogen activator to induce clot lysis. RESULTS: Rivaroxaban resulted in a hypocoagulant state that remained largely unaltered upon subsequent 50% dilution with S/D-treated plasma or FFP. Using SID treated plasma as a diluent, clot stability decreased due to its low (12-antiplasmin. Dilution with saline and albumin induced a profibrinolytic state and further deteriorated the impaired hemostatic potential of rivaroxabananticoagulated blood, even after PCC and fibrinogen support. Combined use of plasma (either FFP or S/D treated) and PCC, however, considerably improved both coagulation and clot stability. CONCLUSION: In the setting of rivaroxaban anticoagulation and major blood loss, transfusing plasma together with PCC may provide the most effective resuscitation approach with the notion that additional antifibrinolytic drug support (e.g., tranexamic acid) is likely required.