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This deliverable 4.4 Risk Management is published under WP4Control and real-time simulation of the construction of the ASHVIN project. Abstract In order to develop comprehensive digital-twin supported site risk management regime it is important to collect data on productivity from well-documented previous construction activities. One of the highest risk activities in construction relates to unknown or unanticipated soil conditions. Soils are naturally occurring, variable materials whose properties depend on stress and strain level and vary temporally. Current design methods deal with uncertainty by assuming conservative estimates of soil properties and calculating the response of the geotechnical structure to some unlikely set of extreme loads. In certain analyses involving soil-structure interaction problems (e.g. soil retaining structures) the loads experienced by structural elements (such as piles, anchors, walls etc.) are directly related to the displacements (strains) experienced. Therefore, only a model that uses the most-likely soil and structure properties at any given point in the life-cycle of a structure to accurately predict the displacement can allow the real safety level (resistance to additional loading) of a structure to be determined. This deliverable uses monitoring data collected from the construction of a deep sea quay wall to determine the real safety level of the wall throughout the construction programme. An advanced finite element model is implemented that can capture the real response. By comparing the measured and predicted response of the wall, a number of updates are initiated that incorporate the knowledge gathered and allow for reduction of uncertainty in a logical and consistent manner. The development of Ports is driven by ever increasing vessel sizes. To replace an existing quay wall to allow for larger vessels means an investment of several 100 million euros and a significant environmental cost in terms of CO2 emissions from new construction. In this report the digital twin developed demonstrated the safety level of the existing wall to several metres of additional dredging.

Lassa fever is a deadly viral illness that is endemic in some parts of West Africa, including Nigeria. A deterministic model in the form of a non-linear system of differential equations is developed to analyse the dynamics and possible control of the disease. The model is tested by fitting it to data from Nigeria’s Lassa fever outbreak using a least-squares fitting routine and the model is shown to provide a reasonable fit to the data. Parameters representing various control measures in the model are estimated using the model fitting. Important epidemiological features of the model such as the basic reproduction number (R0), the disease-free equilibrium, and the endemic equilibrium are determined and analysed. The disease-free equilibrium is shown to be asymptotically stable when R0

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities.

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL., Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.

The ASHVIN Work Package (WP3) “Data fusion for real-time construction monitoring” establishes novel algorithms for extracting the required features to be mapped from the real world to the simulated reality. Deliverable 3.2 entitled “ Digital Twin-based Geo-Monitoring” is one of the public technical deliverables of this WP. It is linked to task 3.3 Geo-Monitoring led by NGEO.&nbsp

Environmental journalists, as gatekeepers, often become arbiters of risk and benefit information. This study explores how their routine news value judgments may influence reporting on marine aquaculture, a growing domestic industry with complex social and ecological impacts. We interviewed New England newspaper journalists using Q methodology, a qualitative dominant mixed-method approach to study shared subjectivity in small samples. Results revealed four distinct reporting perspectives—“state structuralist,” “neighborhood preservationist,” “industrial futurist,” and “local proceduralist”—stemming from the news value and objectivity routines journalists used in news selection. Findings suggest implications for public understanding of, and positionality toward, natural resource use and development.

This study examines how cone penetration test (CPT) parameters, such as cone tip resistance and friction sleeve resistance, can be used to assess the compressibility of fine-grained soils across the Netherlands based on a database of 286 paired CPTs and oedometer tests from across the country. This is done with the aim of refining and simplifying the parameterisation of the Koppejan consolidation coefficients, a procedure which can yield significant error and is prone to misinterpretation. It was found that there is significant potential in using gradient boosting methods to obtain a relationship between the CPT parameters and the Koppejan parameters, with further investigation required into the noise within the dataset and the acquisition of additional high-quality samples. The use of such methods will offer a means of reducing the influence of human error or misinterpretation on the prediction of settlement and provide further confidence in the use of machine learning methods in engineering practice.

Technology acceptance has spawned considerable research in technology adoption, technology use, and technology switching. However, technology choice—i.e., an individual’s selection of a technology from a set of technologies that support similar tasks—has received limited attention in information systems research. This research was aimed at identifying the drivers of technology choice through a series of activities in two universities, in which students chose an information technology tool from various alternatives to complete the given tasks. A thematic analysis was conducted on the reasons for technology choice reported by 249 students, which yielded 18 technology, user, and environmental drivers that influenced individuals’ technology choice. This study provides insights into the drivers generally applicable for technology choice and drivers applicable in specific contexts. Implications for research and practice are discussed.

Aquaculture has been responsible for an impressive growth in the global supply of seafood. As of 2016, more than half of all global seafood production comes from aquaculture. To meet future global seafood demands, there is need and opportunity to expand marine aquaculture production in ways that are both socially and ecologically sustainable. This requires integrating biophysical, social, and engineering sciences. Such interdisciplinary research is difficult due to the complexity and multi-scale aspects of marine aquaculture and inherent challenges researchers face working across disciplines. To this end, we developed a framework based on Elinor Ostrom&rsquo, s social&ndash, ecological system framework (SESF) to guide interdisciplinary research on marine aquaculture. We first present the framework and the social&ndash, ecological system variables relevant to research on marine aquaculture and then illustrate one application of this framework to interdisciplinary research underway in Maine, the largest producer of marine aquaculture products in the United States. We use the framework to compare oyster aquaculture in two study regions, with a focus on factors influencing the social and biophysical carrying capacity. We conclude that the flexibility provided by the SESF is well suited to inform interdisciplinary research on marine aquaculture, especially comparative, cross-case analysis.

This study presents an assessment of the changes in the telecommunications industry and their impact on market returns. Events were identified from a sample of global telecom companies and assessed...

Although the literature frequently examines achieving an integrated supply chain and participating in information sharing with supply chain partners, there is little guidance given to firms on how to progress to a state where these goals can become reality. This paper examines the struggles of one firm in moving toward information sharing with its suppliers and its hopes of achieving an integrated supply chain. This paper reveals lessons learned from the difficulties the firm encountered during the integration process. Despite putting an information system in place, the company discovered that people issues matter as much, if not more, than technology issues.

Information technology implementations continue to be significant endeavors for both research and practice. Although prior studies have extensively examined user training and user support, a consensus is lacking on their conceptualizations. Prior research has argued for direct, as well as indirect, effects of user training and user support on perceived benefits while appealing to different theoretical perspectives. This study clarifies the roles of user training and user support in information technology implementations using data on 302 software implementations. Using a Bayesian model comparison strategy, the authors found that the effects of user training and user support on perceived benefits are mediated by individuals’ perceptions regarding the characteristics of the information technologies. These findings suggest that user training and user support should be treated as enablers in process of implementing information technologies.

Doxorubicin-induced cardiotoxicity (CTX) occurs in 10 to 15% of patients. As such, there is an important need to improve our understanding of the relevance of cardiac mechanics in predicting CTX. The overall objective of our study was to use machine learning algorithms to identify new patterns in

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rifampicin is an antibiotic that is used to treat pulmonary tuberculosis. It induces several cytochrome P450 (CYP) enzymes and some drug transporter proteins; its greatest effect is as an inducer of CYP3A4 in the liver and in the small intestine. • Mechanistic drug–drug interaction studies with prototypic CYP3A4 inducers provide essential information for clinical drug development of new chemical entities that are metabolized by the involved CYP450 enzymes. • Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor being developed for the treatment of chronic obstructive pulmonary disease. • The pharmacological effect is based on the total PDE4 inhibitory activity, which represents the combined PDE4 inhibitory activity of roflumilast and its major active metabolite, roflumilast N-oxide. • In patients with chronic obstructive pulmonary disease, pulmonary tuberculosis can be an accompanying disease. Thus, the drug–drug interaction between rifampicin and roflumilast is of clinical relevance. WHAT THIS STUDY ADDS • The pharmacokinetics of roflumilast and of its major pharmacologically active metabolite roflumilast N-oxide is affected by co-administration of rifampicin. • The potent induction of CYP3A4 and other CYP450 enzymes (such as CYP2C19 and extrahepatic CYP1A1) by rifampicin has led to a 58% decrease in the total PDE4 inhibitory activity of roflumilast. • Co-administration of rifampicin with roflumilast may reduce the therapeutic efficacy of roflumilast. AIMS To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity. METHODS Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 µg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5–15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and Cmax of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated. RESULTS During the steady-state of rifampicin, the AUC0–∞ of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); Cmax by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC0–∞ decreased by 56% (0.44; CI 0.36, 0.55); Cmax increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48). CONCLUSIONS Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.

Although supply chain management and supply chain integration have become topics found within today’s organization as well as topics for researchers from various disciplines, little research has been completed concerning the linkage between business strategy, supply chain strategy, and the resulting decision which an organization makes to enter into an integration initiative. This paper discusses the experience of one organization in formulating a supply chain strategy consistent with its business strategy. The paper concludes with key elements driving the supply chain which emerge from this linkage, a framework for determining the importance of the supply chain to the organization, and a discussion of the benefits gained from creating a tangible incarnation, an enactment, of the firm’s strategy

Psychologists have identified several limitations to, and biases in, human decision-making processes. One such bias is the anchoring and adjustment effect, which has been demonstrated to be robust both inside and outside the experimental laboratory. Some decision support systems (DSS) have been designed to lessen the effects of decision-making limitations with promising results. This study tested a DSS designed to mitigate the effects of the anchoring and adjustment bias. The results show that anchoring and adjustment remains robust within the context of automated decision support. Implications that follow these results are offered.

Introduction Modelling, supported by the USAID Health Policy Initiative and UNAIDS, performed in 2011, indicated that Uganda would need to perform 4.2 million medical male circumcisions (MMCs) to reach 80% prevalence. Since 2010 Uganda has completed 380,000 circumcisions, and has set a national target of 1 million for 2013. Objective To evaluate the relative reach and cost-effectiveness of PrePex compared to the current surgical SMC method and to determine the effect that this might have in helping to achieve the Uganda national SMC targets. Methods A cross-sectional descriptive cost-analysis study conducted at International Hospital Kampala over ten weeks from August to October 2012. Data collected during the performance of 625 circumcisions using PrePex was compared to data previously collected from 10,000 circumcisions using a surgical circumcision method at the same site. Ethical approval was obtained. Results The moderate adverse events (AE) ratio when using the PrePex device was 2% and no severe adverse events were encountered, which is comparable to the surgical method, thus the AE rate has no effect on the reach or cost-effectiveness of PrePex. The unit cost to perform one circumcision using PrePex is $30.55, 35% ($7.90) higher than the current surgical method, but the PrePex method improves operator efficiency by 60%, meaning that a team can perform 24 completed circumcisions compared to 15 by the surgical method. The cost-effectiveness of PrePex, comparing the cost of performing circumcisions to the future cost savings of potentially averted HIV infections, is just 2% less than the current surgical method, at a device cost price of $20. Conclusion PrePex is a viable SMC tool for scale-up with unrivalled potential for superior reach, however national targets can only be met with effective demand creation and availability of trained human resource.

Background Safe Male Circumcision is a proven approach for partial HIV prevention. Several sub Saharan African countries have plans to reach a prevalence of 80% of their adult males circumcised by 2015. These targets require out of ordinary organization, demand creation, timely execution and perhaps the use of SMC devices. Objective To profile Adverse Events rate and acceptance of PrePex, a non surgical device for adult male circumcision. Methods A prospective study, conducted at International Hospital Kampala, Uganda, between August and October 2012. Ethical approval was obtained from Uganda National Council of Science and Technology. Results Of 1,040 men received to undergo SMC, 678 opted for PrePex, 36 were excluded at an initial physical examination screening. 642 were enrolled and consented, and another 17 were excluded before device placement. 625 underwent the procedure. Average age was 24 years (±7). Twelve moderate AEs occurred among 10 participants 12/625, (1.9%). These were all reversible. Five had device displacement, one had an everted foreskin; five had bleeding after the device was removed and one had voiding difficulties. The majority (279 out of 300) of men interviewed complained of some pain within the week of placement. Mean pain score at device placement (using visual analogue scale) was 0.5, at device removal 4.5 and within 2 min of removal the pain score was 1.4. Over 70% of the devices were placed and removed by non-physician clinicians. Presented with a choice, 60% of men chose PrePex over surgical SMC. Close to 90% would recommend the device to their friends. Odour from the necrotic skin was a concern. Removals done 1–2 days earlier than day 7 were beneficial and conferred no extra risk. Conclusion AEs of a moderate or severe nature associated with PrePex were low and reversible. PrePex is feasible for mass safe male circumcision scaling up.

The present study presents a new approach to automatic data clustering and classification problems in large and complex databases and, at the same time, derives specific types of explicit rules describing each cluster. The method works well in both sparse and dense multidimensional data spaces. The members of the data space can be of the same nature or represent different classes. A number of N-dimensional ellipsoids are used for enclosing the data clouds. Due to the geometry of an ellipsoid and its free rotation in space the detection of clusters becomes very efficient. The method is based on genetic algorithms that are used for the optimization of location, orientation and geometric characteristics of the hyper-ellipsoids. The proposed approach can serve as a basis for the development of general knowledge systems for discovering hidden knowledge and unexpected patterns and rules in various large databases.

Animal movements can influence their ecology and demographics. Animal movements are often characterized by path structures with directional persistence. The extent to which directional persistence improves forage success is investigated in this paper using theoretical simulations. It is shown that a movement strategy with directional persistence enables simulated animals to find more forage as compared to a random movement strategy. Situations where resources are chosen with certainty (optimally) are even more successful. Choosing resource with certainty cannot result in directional persistence. However, in cases where animals choose with certainty adjacent cells with resource but continue in their existing direction if none of these have resources then results include directional persistence. It is posited here that this combined strategy is the most effective because if optimal foraging works it is optimally efficient but where foraging is sub-optimal, for a variety of reasons, directional persistence will benefit foraging.

The problems associated with fragmentation of the construction process have been well documented. The adoption of Construction Collaboration Technologies (CCT) has been posited as a solution to the poor levels of communication and information exchange between parties in the construction process. From an Irish context, the potential benefits that CCT have to offer the construction industry are beginning to be realized. Indeed many of the leading stakeholders in the industry are now actively involved in the work of the Construction Information Technology Alliance (CITA) in seeking to improve the use of ICT, including CCT. The problems of fragmentation and resulting levels of poor communication and information exchange are not however, limited to the larger organizations. There is a distinct lack of empirical research into the possibilities for the adoption of CCT within small to medium enterprises (SMEs) involved in project management roles in Ireland and elsewhere. This paper reports upon ongoing research, the aim of which is to assess the potential use of CCT in SME project management organizations. The main focus of the paper is a review of literature pertaining to CCT, specifically in the context of SMEs in the Irish construction industry, and outline the proposed future research. This research will focus on an in-depth case study of a current construction project in Ireland where the lead project management responsibility and associated activities are being carried out by an SME without the use of CCT. This study will include structured interviews with the relevant staff in the project management SME and also with the other SME stakeholder organizations involved in the project. Each interview will include reference to their current use of ICT, their potential for adopting CCT and barriers to such adoption. It is expected that a key outcome of the research shall be a proposed framework for the implementation of CCT in SMEs engaged in construction project management.