Rapid and reproducible characterization of sickling during automated deoxygenation in sickle cell disease patients

In sickle cell disease (SCD), sickle hemoglobin (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These sickled RBCs have strongly reduced deformability, leading to vaso-occlusive crises and chronic hemolytic anemia. To date, there are no reliable laboratory parameters or assays capable of predicting disease severity or monitoring treatment effects. We here report on the oxygenscan, a newly developed method to measure RBC deformability (expressed as Elongation Index - EI) as a function of pO2. Upon a standardized, 22 minute, automated cycle of deoxygenation (pO2 median 16 mmHg ± 0.17) and reoxygenation, a number of clinically relevant parameters are produced in a highly reproducible manner (coefficients of variation <5%). In particular, physiological modulators of oxygen affinity, such as, pH and 2,3-diphosphoglycerate showed a significant correlation (respectively R = ‑0.993 and R = 0.980) with Point of Sickling (PoS5%), which is defined as the pO2 where a 5% decrease in EI is observed during deoxygenation. Furthermore, in vitro treatment with antisickling agents, including GBT440, which alter the oxygen affinity of hemoglobin, caused a reproducible left-shift of the PoS, indicating improved deformability at lower oxygen tensions. When RBCs from 21 SCD patients were analyzed, we observed a significantly higher PoS in untreated homozygous SCD patients compared to treated patients and other genotypes. We conclude that the oxygenscan is a state-of-the-art technique that allows for rapid analysis of sickling behavior in SCD patients. The method is promising for personalized treatment, development of new treatment strategies and could have potential in prediction of complications

The impact of low-frequency and rare variants on lipid levels

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing

The co-creation of values-in-use at the front end of infrastructure development programs

There has been recent academic interest in programs as value creation processes. Scholars focus particularly on the front end of programs as opportunities for clients to create value. At the front end, client and market partners can actively co-produce value through co-creation sessions. This paper investigates what stakeholders do in co-creation sessions and how this contributes to the co-creation of value at the front end of programs. We used an action research approach combined with participant observation, document analysis, and interviews with participants to study stakeholder engagement in co-creation sessions at the front end of a Dutch infrastructure development program. The findings show that the client intended to realize a value (value-for-firm) that was competing with market partners' values. By engaging in co-creation sessions with the client, market partners and knowledge partners co-created three sets of values (value-in-use) as follows: commercial, intellectual and collaborative values. The findings contribute to the academic debate on value creation in programs with an in-depth understanding of co-creation sessions at the front end

Improving the performance of civil engineering projects through the integrated design process

Purpose: Civil engineering projects around the world have been underperforming for a long time. While the complexity of these projects will continue to increase, there is an urgent need to perform better. Although the integrated design process is critical for project success, the literature lacks studies describing the link to project performance. Therefore, this study aims to investigate the dominant variables that affect the integrated design process and consequently project performance. Design/methodology/approach: A multiple case study was conducted to determine the dominant variables that affect the integrated design process and project performance. The research included four projects. Semi-structured interviews were the main source of data. Findings: The cases indicated that the extent to which an integrated approach is achieved in the design process is essential for project performance. This applies to the integration of stakeholders’ interests as well as the integration of disciplines. Above all, it was concluded that the project team participants’ competencies for integration are a dominant factor for project performance, as the integrated design process has changed from a technical challenge to an integrative one. Originality/value: This study provides insights into the dominant variable of the integrated design process that affects project performance, which is underexposed in the literature. The study results reveal the importance of competencies related to integration and adoption of the design problem context, which are not yet included in civil engineering design methods. In this respect, empathy is introduced as a new and critical competence for the civil engineering industry, which needs further research.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Integral Design and Managemen

Knowledge Management and Organizational Capabilities in Project settings: Unpacking Project-based Learning

Over the last 20 years, there has been an increase in the study of project-based learning to deploy knowledge management strategies and the concept of organizational capability. We address this topic in the context of infrastructure development projects. Through a review of existing literature complemented by pilot empirical research carried out in MultiWaterWork program, and Gaasperdammer tunnel project in the Netherlands, Hong Kong–Zhuhai–Macau Bridge in China and Crossrail in the UK, research propositions are presented on the relationship among knowledge management, project-based learning, and organizational capabilities. The findings reject the position of knowledge management as a best practice toolkit for immediate use and emphasize that there is no pure copy-paste knowledge learned from one project to another. Learning is proposed as the missing link between project capabilities and knowledge management. The study then focuses on the contribution of sets of project capabilities to achieve project performance. It is suggested that the critical role of learning in the development of project capabilities should be on the future research agenda of infrastructure development projects.Integral Design & Managemen

Empathic Ability as a Driver for Project Management

Empathy is receiving increasing attention as it can contribute to the collaboration and connectedness required for today's global challenges. A similar trend reveals itself at the scale of project management, given the change from technological to integration-driven challenges in projects. The necessary integrated approach affects the key competencies sought in project team participants. Since empathy enhances one's feeling for and understanding of the project participants’ interests, it could support the integration assignment. Therefore, focusing on the Dutch civil engineering industry, this study investigated whether the project team's empathic ability drives project performance. The results suggest a positive correlation between the team's empathic abilities and performance. Additionally, the study provides insights into the industry's current level of empathic ability, prompting the conclusion that there is room to improve performance by increasing the project teams’ empathic abilities.Integral Design & Managemen

The co-creation of values-in-use at the front end of infrastructure development programs

There has been recent academic interest in programs as value creation processes. Scholars focus particularly on the front end of programs as opportunities for clients to create value. At the front end, client and market partners can actively co-produce value through co-creation sessions. This paper investigates what stakeholders do in co-creation sessions and how this contributes to the co-creation of value at the front end of programs. We used an action research approach combined with participant observation, document analysis, and interviews with participants to study stakeholder engagement in co-creation sessions at the front end of a Dutch infrastructure development program. The findings show that the client intended to realize a value (value-for-firm) that was competing with market partners' values. By engaging in co-creation sessions with the client, market partners and knowledge partners co-created three sets of values (value-in-use) as follows: commercial, intellectual and collaborative values. The findings contribute to the academic debate on value creation in programs with an in-depth understanding of co-creation sessions at the front end.Accepted Author ManuscriptIntegral Design and Managemen