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Introduction: Current guidelines recommend prophylactic treatment of hemophilia B with the missing coagulation factor IX, either with standard half-life or extended half-life products. Extended half-life products have half-lives three to six times longer than the former, allowing a reduction in the number of weekly injections and therefore, potentially impacting on treatment adherence and quality of life. Albutrepenonacog alfa is an extended half-life fusion protein of coagulation factor IX with recombinant human albumin, indicated for both on-demand and prophylactic treatment for bleeding in patients with hemophilia B of all ages. Areas covered: The authors review the clinical and pharmacokinetic characteristics of albutrepenonacog alfa, as well as the available information regarding trough levels and real-world evidence. Given the availability of other factor IX products in the market, indirect comparisons of clinical and pharmacokinetic characteristics are presented. Expert opinion: The authors exhibit their expert opinion on which patient profiles are candidates for prophylactic treatment with albutrepenonacog alfa, and on the management of patients in terms of dosing, regimens of administration and protocols for switching the treatment.

Psoriasis is an immune-mediated inflammatory disease (IMID) which may have a major impact on a patient's life, especially when the disease is moderate to severe. There is evidence that treatment of psoriasis during the first years is conservative and frequently based on topical agents which rarely clear lesions. Treatment with systemic agents including biologics is often undertaken only when topical agents have proved unsuitable, even in patients with moderate to severe disease. However, there is evidence that in other IMIDs (rheumatoid arthritis and Crohn's disease), targeted systemic treatment given early in the treatment pathway may improve long-term patient outcomes. We hypothesize that a patient-centered therapeutic approach, undertaken early in the psoriasis treatment pathway ("early intervention") with the goal of complete clearance, may improve control of cutaneous symptoms and may also modify disease course and burden. Critical points to address when designing an early intervention study would include: the definition of psoriasis disease activity; patient selection; intervention selection; and dosing strategies.

For manufacturing companies, quality management is a key feature for increasing the competitiveness, productivity, profitability, and sustainability of their systems. Quality improvement (QI) methods aim to achieve high-quality parts without reducing performance. The Industry 4.0 framework brought technological developments that cannot be used by traditional QI methods, such as Six Sigma, Lean, Lean Six, the Theory of Constraints, and Total Quality Management, which are widely used in manufacturing companies. The need for higher manufacturing sustainability and market requirements has led to the search for alternative QI methods with superior performance to traditional QI methods such as Zero-Defect Manufacturing (ZDM). The current paper is a position paper with a goal to present the ZDM approach and providing a clear definition about ZDM to align everyone in one common understanding of ZDM. Many researchers and manufactures are skeptical about ZDM, therefore, numerous argumentative questions have been created and answered, to convince them why they should migrate from traditional QI methods to ZDM. The migration to ZDM has already started, to support this statement numerous facts from the literature have been presented. Finally, several directions were identified, demonstrating that there is still plenty of room for research in several domains.

This study evaluates and compares several machine learning methods on the effects of different parameters in the hydrothermal carbonisation (HTC) process of macroalgae Sargassum horneri. Reaction temperature, residence time, biomass particle size, the amount of catalyst and loaded biomass were considered as inputs and three variables of BET, higher heating value (HHV) and energy recovery were regarded as outputs. For analysing the input parameters, the Taguchi method was used for experimental designs and the obtained results were utilised here as training sets. Various data mining approaches like support vector machine (SVM), group method of data handling, decision tree, random forest, radial basis function, adaptive neuro-fuzzy inference system (ANFIS) and multilayer perceptron (MLP) neural network were implemented to model the problem and two different optimisation techniques named BAT and Grasshopper Optimisation Algorithm (GOA) were employed with MLP and ANFIS model for optimising. By comparing different statistical parameters such as Average Absolute Relative Deviation (AARD), coefficient of determination (R-2), Root Mean Square Error (RMSE) and Standard Deviation (SD), It is found out that SVM method has a considerably better performance relative to other methods for estimating both the BET, HHV and energy recovery parameters. Furthermore, coupling of MLP and ANFIS with GOA increases the accuracy of these models for BET, HHV and energy recovery estimations.

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimers disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

The market share of generic medicines in France is low compared to other European countries. This perspective paper provides an overview of the generic medicines retail market in France and how the current policy environment may affect the long-term sustainability. Looking at the French generic medicines retail market and the surrounding regulatory framework, all conditions seem to be in place to create a healthy generic medicines market: the country has well-respected regulatory authorities, generic medicines enter the market in a timely manner and prices of generic medicines are competitive compared with other European countries. Despite the success of the demand-side policies targeted at pharmacists and patients, those targeted at physicians were less successful due to a lack of enforcement and a lack of trust in generic medicines by French physicians. Recommendations to increase the use of generic medicines in France round off this perspective paper.

The aim of this work was to evaluate three carbon materials as anodes in microbial fuel cells (MFCs), clarifying their influence on the generation of electricity and on the treatability of winery wastewater, a highly organic-loaded waste. The electrode materials tested were carbon felt, carbon cloth and carbon paper and they were used at the same time as anode and cathode in the tests. The MFC equipped with carbon felt reached the highest voltage and power (72 mV and 420 mW m−2, respectively), while the lowest values were observed when carbon paper was used as electrode (0.2 mV and 8.37·10−6 mW m−2, respectively). Chemical oxygen demand (COD) removal from the wastewater was observed to depend on the electrode material, as well. When carbon felt was used, the MFC showed the highest average organic matter consumption rate (650 mg COD L−1 d−1), whereas by using carbon paper the rate decreased to 270 mg COD L−1 d−1. Therefore, both electricity generation and organic matter removal are strongly related not to the chemical composition of the electrode (which was graphite carbon in the three electrodes), but to its surface features and, consequently, to the amount of biomass adhered to the electrode surface.

In this paper we consider the location of stops along the edges of an already existing public transportation network. The positive effect of new stops is given by the better access of the passengers to the public transport network, while the passengers’ traveling time increases due to the additional stopping activities of the trains, which is a negative effect for the passengers. The problem has been treated in the literature where the most common model is to cover all demand points with a minimal number of new stops. In this paper, we follow this line and seek for a set of new stops covering all demand points but instead of minimizing the number of new stops we minimize the additional passengers’ traveling time due to the new stops. For computing this additional traveling time we do not only take the stopping times of the vehicles but also acceleration and deceleration of the vehicles into account. We show that the problem is NP-hard, but we are able to derive a finite candidate set and two tractable IP formulations. For linear networks we show that the problem is polynomially solvable. We also discuss the differences to the common models from literature showing that minimizing the number of new stops does not necessarily lead to a solution with minimal additional traveling times for the passengers. We finally provide a case study showing that our new model decreases the traveling times for the passengers while still achieving the minimal number of new stops.

© 2015 EDGAR G. DAYLIGHT. In the popular imagination, the relevance of Turing's theoretical ideas to people producing actual machines was significant and appreciated by everybody involved in computing from the moment he published his 1936 paper ‘On Computable Numbers’. Careful historians are aware that this popular conception is deeply misleading. We know from previous work by Campbell-Kelly, Aspray, Akera, Olley, Priestley, Daylight, Mounier-Kuhn, Haigh, and others that several computing pioneers, including Aiken, Eckert, Mauchly, and Zuse, did not depend on (let alone were they aware of) Turing's 1936 universal-machine concept. Furthermore, it is not clear whether any substance in von Neumann's celebrated 1945 ‘First Draft Report on the EDVAC’ is influenced in any identifiable way by Turing's work. This raises the questions: (i) When does Turing enter the field? (ii) Why did the Association for Computing Machinery (ACM) honor Turing by associating his name to ACM's most prestigious award, the Turing Award? Previous authors have been rather vague about these questions, suggesting some date between 1950 and the early 1960s as the point at which Turing is retroactively integrated into the foundations of computing and associating him in some way with the movement to develop something that people call computer science. In this paper, based on detailed examination of hitherto overlooked primary sources, attempts are made to reconstruct networks of scholars and ideas prevalent in the 1950s, and to identify a specific group of (Formula presented.) actors interested in theorizing about computations in computers and attracted to the idea of language as a frame in which to understand computation. By going back to Turing's 1936 paper and, more importantly, to re-cast versions of Turing's work published during the 1950s (Rosenbloom, Kleene, Markov), I identify the factors that made this group of scholars particularly interested in Turing's work and provided the original vector by which Turing became to be appreciated in retrospect as the father of computer science. ispartof: HISTORY AND PHILOSOPHY OF LOGIC vol:36 issue:3 pages:205-228 ispartof: location:BELGIUM, Ghent Univ, Ghent status: published

This paper studies whether time series predictability is consistent with risk-based asset pricing models. Whereas earlier papers – e.g. Kirby (1998), Cecchetti, et al. (2000) and Avramov (2004) – show that returns are too predictable to be explained by rational asset pricing, we find that the predictability typically found in linear forecasting models is not necessarily larger than can be expected from rational asset pricing. More specifically, when preferences are summarized by habit persistence with habit and risk aversion parameters equal to 0.97 and 4.8 (or greater) respectively, a degree of predictability is obtained that is compatible with the predictability found in the recent literature.

This paper reports a new design of microstrip directional coupler with high directivity. This directional coupler uses corrugated coupled lines and floating conductor in the ground plane of microstrip to enhance coupling. Based on this structure, directional coupler having 4.4% bandwidth has been designed at 4500 MHz with 10 dB coupling and 35 dB directivity. The designed directional coupler has been fabricated and tested for the validity of the design. Measured results are presented in this paper.

The Italic consonant stem ablative in -ĕ is usually regarded as an anomalous instance of locative contamination in the ablative singular case endings. This interpretation has long been recognized as problematic, given that the Italic ablative is functionally the result of syncretism with the Proto-Indo-European instrumental, rather than the locative. In addition, it is difficult to reconcile the traditional view with the early Latin epigraphic evidence, which suggests that the Latin consonant stem ending, like the ablative singular endings of all other declensions, once had a final dental (-ĕd). This paper reviews the evidence for the origin and reconstruction of the Italic consonant stem ablative within the broader context of the early development of the Italic case system. It provides further arguments against the conventional locative etymology, and concludes that the consonant reflex can plausibly be aligned with the regular reflexes in other declensions if it is instead derived from a zero-grade instrumental ending ispartof: Symbolae Osloenses vol:94 issue:1 pages:1-23 status: Published online

Background: Schizophrenia spectrum disorders (SSD) are mental diseases caused by a combination of genetic susceptibility and a number of environmental factors. Among these factors, the role of traumatic events suffered in childhood, as well as that of substance use, have been of particular research interest. Objectives: To conduct a systematic review to clarify whether there is an interaction between childhood trauma and substance use related to the diagnosis or symptoms of SSD. It was also the objective of this review to collate the associations that may exist between the three variables of the study (trauma, substance use and psychosis). Methods: We conducted a systematic search resulting in 240 articles. We considered all of the original articles that explored childhood trauma and substance use in patients suffering from SSD. Results: Twenty-three articles were selected for this review. Several of the reviewed papers found associations between childhood trauma and substance use with SSD, as well as interactions between trauma and drug use on SSD. Conclusions: The results suggest that childhood trauma and substance usemay be present at the basis of psychosis. This double hit on the pathogenesis could have clinical implications, since each of these impacts could be considered a window of opportunity for the primary prevention of SSD.

Introduction: It is well recognized that a lesion that does not cause a hemodynamically significant stenosis can trigger a sudden cardiac event through plaque rupture. As a diagnostic tool, intravascular imaging was developed to circumvent limitations of coronary angiography; however, none of the intravascular imaging devices are individually able to provide complete assessment of the plaque morphology, geometry, physiology and biology. Therefore, over the past few years an effort was made to develop hybrid intravascular imaging catheters to provide more complete evaluation of coronary plaque pathobiology.Areas covered: This paper aims to give an overview of the recent developments on 1) single-modality intravascular imaging devices; 2) hybrid intravascular imaging devices and 3) the hemodynamic analysis in models reconstructed from the fusion of intravascular imaging and angiographic data.Expert commentary: Within five years, most of the hybrid imaging techniques which are now in pre-clinical phase will be utilized in the clinical arena, as NIRS-IVUS. Software for online blood simulation is likely to be developed that will enable ESS calculation while the patient is in the catheterization laboratory

A systematic review was conducted to investigate event-related potentials (ERPs) in response to food and non-food stimuli among individuals with eating and weight disorders. Limiting the search to studies that have analysed ERPs relating to motivated attention and inhibitory control, 19 research papers were extracted from a systematic search in PubMed, Ovid, and Web of Science (2000-2018). An enhanced attentional bias towards food over non-food images (as indexed by P3(00) and LPP amplitudes) was evident for all populations. Individuals with binge eating disorder showed an enhanced attentional response to food cues compared to healthy controls. Inhibitory control-related ERP components (N2(00) and P3a) increased during food-specific no-go trials, but did not differentiate overweight from healthy' weight groups. The N2 amplitude to food pictures were positively correlated with caloric intake and food craving among individuals with obesity and binge eating disorder, respectively, while P3(00) was sensitive to hunger levels among overweight and obese females. The heterogeneity of stimuli/paradigms adopted, component timescales extracted, ERPs analysed, and data presented has challenged this review's ability to produce a robust synthesis of results. Some recommendations for future research are discussed.

Introduction: Diagnosing and managing drug hypersensitivity is challenging because there are no clear limits between different types of drug reactions. Distinguishing between type A (predictable) and type B (hypersensitivity) reactions when a drug is introduced on the market is not easy. When many people use a drug, adverse reactions can occur, conditioned by diverse genetic profiles, viral infections or concomitant therapy. Occasionally the only tool clinicians have on which to base the diagnosis is the clinical history. Skins tests or in vitro tests sometimes have low sensitivity or are unavailable, and drug provocation tests may be dangerous or strictly forbidden in case of severe cutaneous reactions. Areas covered: This paper reviews the diagnosis and management of the two main types of immunological reactions: IgE-mediated immediate drug hypersensitivity reactions (IDHRs) and non-immediate drug hypersensitivity reactions (NIDHRs). Expert commentary: Although Europe and the United States use different diagnostic methods, patients with history of drug hypersensitivity must avoid the suspicious drug, and clinicians must assess tolerance to safe alternatives under medical surveillance. Sometimes desensitization may be required. There is a consensus about the need to perform genetic testing for specific drugs and give patients proper documentation to prevent future exposure to culprit drugs.

Introduction: Diagnosing and managing drug hypersensitivity is challenging because there are no clear limits between different types of drug reactions. Distinguishing between type A (predictable) and type B (hypersensitivity) reactions when a drug is introduced on the market is not easy. When many people use a drug, adverse reactions can occur, conditioned by diverse genetic profiles, viral infections or concomitant therapy. Occasionally the only tool clinicians have on which to base the diagnosis is the clinical history. Skins tests or in vitro tests sometimes have low sensitivity or are unavailable, and drug provocation tests may be dangerous or strictly forbidden in case of severe cutaneous reactions. Areas covered: This paper reviews the diagnosis and management of the two main types of immunological reactions: IgE-mediated immediate drug hypersensitivity reactions (IDHRs) and non-immediate drug hypersensitivity reactions (NIDHRs). Expert commentary: Although Europe and the United States use different diagnostic methods, patients with history of drug hypersensitivity must avoid the suspicious drug, and clinicians must assess tolerance to safe alternatives under medical surveillance. Sometimes desensitization may be required. There is a consensus about the need to perform genetic testing for specific drugs and give patients proper documentation to prevent future exposure to culprit drugs.

New frequency-domain 2-stability criteria are derived for nonlinear discrete-time MIMO systems, having a linear time-invariant block with the transfer function (z), in negative feedback with an aperiodic matrix gain A(k), k = 0, 1, 2,..., and a linear combination of a vector of certain classes of (generalised) first-and-third-quadrant non-monotone nonlinearities.(center dot), having arguments with constant and time-varying delays, but without restrictions on their slopes. The framework does not employ Lyapunov-Krasovskii functionals involving linear matrix inequalities (LMIs) or their equivalent. The new stability criteria seem to be the most general for nonlinear and time variying time-delay systems, and have the following structure: (1) positive definiteness of the real part (as evaluated on | z| = 1) of the product of (z) and an algebraic sum of general causal and anticausal matrix multiplier functions of z. (2) An upper bound on the L1-norm of the inverse Fourier transform of the multiplier function, the L1-norm being weighted by certain novel, quantitative characteristic parameters (CPs) of the nonlinearities.(center dot) without the asumptions of monotonicity, slope restrictions and the like. And (3) constraints on certain global averages of the generalised eigenvalues of (A(k + 1), A(k)), k = 1, 2,..., that are expressed in terms of (i) CPs of the nonlinearities, (ii) their coefficients, and, in general, (iii) time-delays in their arguments, a trade-off among all the three being possible. These global averages imply a restriction on the rate of variation of A(k) in a new sense. The literature results turn out to be special cases of the results of the present paper. Examples illustrate the stability theorems.

In this opinion paper, we, a group of scientists from environmental-, geo-, ocean- and information science, argue visual data exploration should become a common analytics approach in Earth system science due to its potential for analysis and interpretation of large and complex spatio-temporal data. We discuss the challenges that appear such as synthesis of heterogeneous data from various sources, reducing the amount of information and facilitating multidisciplinary, collaborative research. We argue that to fully exploit the potential of visual data exploration, several bottlenecks and challenges have to be addressed: providing an efficient data management and an integrated modular workflow, developing and applying suitable visual exploration concepts and methods with the help of effective and tailored tools as well as generating and raising the awareness of visual data exploration and education. We are convinced visual data exploration is worth the effort since it significantly facilitates insight into environmental data and derivation of knowledge from it.

Introduction: Neuroblastoma is the most common solid extracranial tumor of childhood. Outcome for children with high-risk neuroblastoma remains suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment with dismal prognosis. Areas covered: This paper presents a short review of the state of the art in the current treatment of high-risk neuroblastoma. An updated review of new targeted therapies in this group of patients is also presented. Expert opinion: In order to improve prognosis for high-risk patients there is an urgent need to better understand spatial and temporal heterogeneity and obtain new predictive preclinical models in neuroblastoma. Combination strategies with conventional chemotherapy and/or other targeted therapies may overcome current ALK inhibitors resistance. Improvement of international and transatlantic cooperation to speed clinical trials accrual is needed.

Response Surface Methodology (RSM) is a collection of mathematical and statistical techniques useful for developing, improving, and optimizing processes. Applications of RSM can be found in e.g. chemical, engineering and clinical sciences. Still, there does not seem to be an established code of practice for the automated application of RSM in the field of simulation optimization. In this paper our aim is to find the best settings for an automated RSM procedure when there is very little information about the objective function. We present a framework of the RSM procedures for finding optimal solutions and emphasize the use of both stopping rules and restart procedures. Various versions of the RSM algorithms are compared on a number of test functions, including a simulation model for cancer screening. The results show that considerable improvement is possible over the proposed settings in the existing literature. Accordingly, we give general recommendations on the application of automated RSM algori...

At Bloemenveiling Aalsmeer (VBA), about 19 million flowers have to be distributed daily to customers in a building of 1 million?m2 within a few hours. With the increasing daily number of customer orders, the congestion in the main distribution area increases. As a consequence, the makespan exceeds the available time, and flowers arrive too late at the customers. This paper investigates the concept of zoning in the distribution process, where distributors work in teams for a fixed group of customers in a specific zone of the distribution area. Customers are assigned to zones to balance workload. We show by simulation that this way of organizing the distribution process reduces congestion and leads to considerable improvements in both makespan and transaction lead time.

In this paper we present a parsimonious multivariate model for exchange rate volatilities based on logarithmic high–low ranges of daily exchange rates. The multivariate stochastic volatility model decomposes the log range of each exchange rate into two independent latent factors, which could be interpreted as the underlying currency specific components. Owing to the empirical normality of the logarithmic range measure the model can be estimated conveniently with the standard Kalman filter methodology. Our results show that our model fits the exchange rate data quite well. Exchange rate news seems to be currency specific and allows identification of currency contributions to both exchange rate levels and exchange rate volatilities.

This paper describes a participatory foresight method developed and tested by the authors. The method of cultural perspective images, rooted in grid-group of cultural theory, was used in an experimental dialogue among companies and a selection of other stakeholders directly or indirectly involved in the food chain of farmed salmon. The method is used to map different future outlooks based on distinct worldviews and management styles present in the food chain and its social environment. Drawing cultural perspective images helps to foresee when cultural perspectives are commensurable or not. Its use also supports efforts to define a shared future beyond the immediate concerns of competition and cost pressures and to enhance strategic transparency between the cultures in food chains and society.

The study of the sum of two independent phase-type (PH)-distributed variables, each of them being asso- ciated with a Markovian process with one absorbing state, is considered in this paper. The distribution function of the variable sum is computed, obtaining a new PH-distributed function of higher order. As the order increases in the new function, the exponential function of a block upper triangular matrix is calculated in terms of its respective blocks to reduce the dimension of the problem. The obtained results are applied to bladder carcinoma data., This study has been funded by the Vicerrectorado de Investigacion de la Universitat Politecnica de Valencia. Code 2406.

Introduction: HIV-1 integrase strand transfer inhibitors (INSTIs) are a novel class of antiretroviral drugs with a good safety profile. Several INSTIs have been developed clinically. Areas covered: The purpose of this review is to examine the safety data of the three FDA-approved INSTIs: Raltegravir (RAL), Elvitegravir (EVG) and Dolutegravir (DTG). The most relevant papers related to the safety profile of integrase inhibitors were selected and summarized. Expert opinion: INSTIs have demonstrated a favorable safety profile in Phase II and III trials. The most common clinical adverse events reported were diarrhea, nausea and headache. DTG and cobicistat, a component of Stribild (TM), increase serum creatinine and decrease estimated creatinine clearance due to inhibition of active tubular secretion of creatinine without affecting renal glomerular function. INSTIs intrinsic potency, together with an outstanding safety profile, preludes an important role for these drugs to build up highly active antiretroviral treatment (HAART) in the near future.

This paper describes two cases with khat- and two with psilocybin-induced psychoses and draws attention to the medical and social consequences of the use of these drugs.Two male patients are presented who developed relapsing and short-lasting psychotic episodes after chewing kath leaves. In addition, two male patients are reported who showed an acute exacerbation of psychosis after ingestion of psilocybin mushrooms. In addition, a review of the literature is presented.The khat-induced psychotic symptoms disappeared without any treatment within one week. One of the patients with a psilocybin-induced psychosis was treated with risperidone. In the other, symptomatology subsided in a few days. No somatic medical complications occurred.Adequate psychiatric diagnosis and treatment of the psychoses and the negative social consequences of the use of these drugs are stressed as well as the delineation from functional psychoses in cases of chronic use. The latter applies to patients with psychiatric comorbidity in particular.

Virtual metrology (VM) involves estimating a product's quality directly from production process data without physically measuring it. This enables the product quality of each unit of production to be monitored in real time, while preserving the process efficiency. Initially developed for the semiconductor industry, VM has recently been examined for use in other industrial fields. VM is enabled by components such as quality estimators and drift detectors. It enhances various industrial applications such as machine control and sampling decision systems. The literature lacks a comprehensive summary and a systematic review of the state of the art in VM. To fill this gap, this study followed a systematic methodology to conduct a complete and structured literature review of VM. This paper presents a detailed analysis of the 199 papers that we identified based on our search and selection criteria. Following our methodological framework, we assigned these papers to categories and highlighted shortcomings. Finally, we discussed VM's use in various industrial fields, underlining its potential for every manufacturing industry. This study and the proposed framework are useful for both practitioners and academicians since they raise crucial theoretical and managerial questions as well as provide suggestions for further research on this critical topic.

Self-assessment of performance using the European Foundation for Quality Management (EFQM) Model for Excellence is widespread amongst European organizations. The paper reports the development of a model, based on the evidential reasoning approach from multiple attribute decision-making (MADM), which it is argued helps to reduce the subjectivity of the scoring of an organization's performance against the criteria of the EFQM Model and brings a degree of science into the self-assessment process. The development of the MADM model is based on the people management criteria of the 1998 version of the EFQM Model and tests have been undertaken using two self-assessment submission documents from a major multi-utility organization.

This paper aims to examine how a complex supply chain yields cost reduction benefits through the global integration of production and distribution decisions. The research is motivated by a complex real world supply chain planning problem facing a large automotive company. A mixed-integer nonlinear production-distribution planning model is solved using a customised memetic algorithm. The performance and effectiveness of the developed model and solution approach in achieving the global optimisation is investigated through experiments comparing the numerical results from the proposed integrated approach with those of a typical non-integrated (hierarchical) productiondistribution optimisation.

In this paper, the orderbatching problem in warehouses is investigated. Batching, or clustering orders together in the picking process to form a single picking route, reduces travel time and, as such, this phenomenon can be encountered in many warehouses. The reason for its importance is that orderpicking is a labour intensive process and, by using good batching methods, substantial savings can be obtained. The batching and routing problems are complex to solve. In practice, simple methods are used for the batching problem, such as first-come first-served (FCFS), i.e. combine orders in the route in the arriving sequence until the pick-device is full. Once clusters of orders have been formed, the calculation of the travel time for the routes requires the solution of a number of travelling salesman problems (one for each route). Two groups of heuristic algorithms are evaluated: the Seed algorithms and the somewhat more complex (and CPU time consuming) Time Savings algorithms. The performance of the algorithms is evaluated using two different routing strategies: the so-called S-shape and Largest gap strategies, which are well known in theory and practice. The heuristics are compared for travel time, number of batches formed and also for robustness. An algorithm is robust if it can be applied to any warehousing situation and still yield good results. Since the problem has to be implemented in existing Warehouse Management Systems and has to be solved online many times a day, the simplicity, transparancy and CPU time are also important in most warehousing situations. It is demonstrated that even simple order batching methods lead to significant improvement compared to FCFS. Seed algorithms are best in conjunction with S-shape and a large capacity of the pick device. Time savings algorithms perform best in conjunction with Largest gap and small pick device capacity. If CPU time becomes important, then using simple Seed algorithms should be considered.

Introduction: The lamivudine (3TC) + stavudine (d4T) combination is still widely used as part of first-line therapy for HIV-1-infected patients in low-resource countries. This review is intended to assess the benefits and risks in terms of safety of d4T + 3TC-based combination antiretroviral therapy (ART) for the treatment of HIV-1 infection. Areas covered: The most relevant papers related to the safety of d4T + 3TC-based ART were selected and summarized. Expert opinion: In industrialized countries, the 3TC + d4T combination is not recommended for initial therapy because of long-term metabolic toxicities associated with d4T. In developing countries, it may have a role in the treatment of HIV-infected patients if there is no other chance for starting antiretroviral therapy.

8 pags, 2 figs, In this paper we present an alternative formulation of the well-known integral equation approximations designed to keep a consistent approach to the determination of thermodynamic properties in the case of density-dependent interactions. Obviously, residual inconsistencies inherent to the approximate character of the closure relations of the Ornstein-Zernike equation will not be corrected. In this connection, we will show how this approach is particularly successful when applied in conjunction with approximations in which the aforementioned inconsistencies are minimal, as is the case of the optimised Reference Hypernetted Chain equation. As a case study we will consider the Derjaguin-Landau-Verwey-Overbeek model of charged colloids which is one of the simplest realisations of density-dependent interactions., E.L. and C.F.T. acknowledge support from the Dirección General de Universidades e Investigación de la Comunidad de Madrid under Grant S0505/ESP/0299, program MOSSNOHO-CM, and from the Dirección General de Investigación Científica y Técnica (Ministerio de Ciencia en Innovación) under grants no. MAT2007-65711-C04-04 (E.L) and FIS2008-03801/FIS (C.F.T.).

This paper presents the spectrum of the bremsstrahlung emission accompanying the α-decay of 226Ra (E α=4.8 MeV) by measuring the α−γ coincidences. We analyze the spectrum by using the model presented in our previous study on the α-decay of 214Po (E α=7.7 MeV). We compare the experimental data with the quantum mechanical calculation and find a good agreement between theory and experiment. We analyze the bremsstrahlung emission contributions from the tunneling and external regions of the nucleus barrier into the total spectrum, and find destructive interference between these contributions.

In this paper, we report efficient implementations of the linear sieve and the cubic sieve methods for computing discrete logarithms over prime fields. We demonstrate through empirical performance measures that for a special class of primes the cubic sieve method runs about two times faster than the linear sieve method even in cases of small prime fields of the size about 150 bits. We also provide a heuristic estimate of the number of solutions of the congruence $X^{3}?=?Y^{2}Z$ (mod p) that is of central importance in the cubic sieve method.

While the relationship between market orientation and performance has been examined extensively in the literature, relatively little attention has been given to the antecedents of market orientation. So the basic question of how to develop a market driven organisation remains to a large extent unanswered. The capabilities framework provides a useful conduit through which this issue can be approached, since it recognises that firms are innately heterogeneous because the different resources or capabilities they possess. However, this area has been accused of being tautological in nature, and requires further extensive empirical analysis. This paper presents a theoretical framework that uses the decomposition of the market-sensing capability as a way to facilitate understanding of the creation of market orientation. Thus it will not only add to the literature on the antecedents of market orientation, but also offers an empirical analysis of a significant capability. Furthermore, this model addresses the question of the relationship between market orientation and learning orientation, and proposes that a learning orientation precedes a market orientation. KEYWORDS: Market orientation; learning orientation; market-sensing capability

This paper reports on variation in the ways that instrumental and vocal students at tertiary level experience, or understand, learning. Five related conceptions of learning are described ranging from quite limiting views to expansive views. Students who only experience learning music within a limiting conception will focus their attention on the technical aspects of playing or singing. Students who experience learning music within the expansive conception are able to focus on more meaningful aspects of music if the learning environment supports their view. Understanding the ways that instrumental and vocal students experience learning may have implications for the development of learning environments that will encourage students to adopt a more sophisticated learning framework resulting in higher quality learning outcomes.

In recent years, the issue of Brownfield site development - the re-use of previously used urban land - has gained a significant place in the planning agenda. However, not all Brownfield sites are derelict or contaminated land, some are significant as environmental amenities - be it part of wider ecosystem or a green area for the local population. The growing concern to include environmental aspects into the public debate have lead the Environment Agency, the Jackson Environment Institute and the Centre for Advanced Spatial Analysis to commission a short term pilot study to evaluate the contribution of a GIS for decision support and for "discussion support".In this paper, we describe how the state-of-the-art in geographic information (GI) and GI Science (GISc) can be used in a short term and limited project to achieve a practical and usable system. We are drawing on developments in information availability, as made accessible through the World Wide Web and research themes in GISc ranging from Multimedia GIS to Public Participation GIS.

In the metal cutting industry, manufacturers have strived to increase energy efficiency and to reduce environmental burdens through the use of dust collectors and waste disposers. It is more beneficial and efficient to apply the front-of-pipe technology that prevents the sources of pollutants and minimises energy use through the redesign of products and the change of process planning and machining operations. In particular, process planning for the environment, called eco-process planning, is central to increasing energy efficiency and reducing environmental burdens because process planning decisions greatly influence machining performance. At present, greenability, a term used to indicate environmental friendliness, has been little considered as a major concern in the process planning stage because process planning decisions have focused on improving productivity aspects that include speed, cost and quality. Thus, it is essential to develop an eco-process planning approach that enables the harmonisation and enhancement of greenability performance while improving productivity performance, termed green productivity (GP). This paper presents the development of a GP-based process planning algorithm that enables the derivation of process parameters for improving GP in machining operations. The core mechanism of the algorithm is the realisation of the process improvement cycle that measures GP performance by the collection of machining data, quantifies this performance by categorical representation and predicts the performance through prediction models. To show the feasibility and applicability of the proposed algorithm, we have conducted an experiment and implemented a prototype system for a turning machining process.

Since the complex engineered system involves multi-disciplinary, co-simulation is the key technique to the performance analysis. However, the co-simulation is hindered by heterogeneous sub-systems and ununified environments. In this paper, a Cognitive Twin (CT) to support the co-simulation of the complex engineered system is introduced. It is a generic approach that can be applied in many complex engineered systems such as the aerospace field, automotive system, the Internet of Things, manufacturing systems, etc. CT adopts an ontology model to develop cognition capability based on CT architecture. Then, a unified ontology modelling approach based on GOPPRR (graph, object, point, property, role, relationship) is presented to support an accurate semantic description of the topology between digital entities that use FMI 2.0 as the interconnection standard. Besides, four types of information are included in the ontology model to form the knowledge in co-simulation. Finally, the co-simulation is automatically executed using the cognition capability. Furthermore, a master-slave algorithm is deployed to establish a unified co-simulation environment. The flexibility of CT is evaluated using a gas turbine case. The results demonstrate that the complication in the co-simulation of complex engineered systems is solved by the unified ontology modelling approach and the architecture of CT.

Functional data are typically modeled as sample paths of smooth stochastic processes in order to mitigate the fact that they are often observed discretely and noisily, occasionally irregularly and sparsely. The smoothness assumption is imposed to allow for the use of smoothing techniques that annihilate the noise. At the same time, imposing the smoothness assumption excludes a considerable range of stochastic processes, most notably diffusion processes. Under perfect observation of the sample paths, such processes would not need to be excluded from the realm of functional data analysis. In this paper, we introduce a careful modification of existing methods, dubbed the "reflected triangle estimator", and show that this allows for the functional data analysis of processes with nowhere differentiable sample paths, even when these are discretely and noisily observed, including under irregular and sparse designs. Our estimator matches the established rates of convergence for processes with smooth paths, and furthermore attains the same optimal rates as one would get under perfect observation. Thus, with reflected triangle estimation, the scope of applicability of much of the methodology developed for discretely/irregularly/noisily/sparsely sampled functional data is considerably extended. By way of simulation it is shown that the advantages furnished are reflected in practice, hinting at potential closer links with the field of diffusion inference.

Funding Information: The SlabSTRESS (Slab Structural RESponse for Seismic European Design) experimental campaign is part of the Transnational Access activities of the SERA (Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe) project. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 730900. Publisher Copyright: © 2022 The Author(s). Published with license by Taylor & Francis Group, LLC. Strengthening of flat slab-column connections to resist imposed lateral drifts is often required for older reinforced concrete structures in which the flat slabs were typically designed to resist gravity load only or have been designed for less stringent requirements. The complex stress state around the columns means that strong experimental evidence is required for the repair and strengthening techniques to be adopted with confidence in practice. Although a significant amount of research has been devoted to strengthening of slab-column connections, a series of limitations still remain. A thorough literature review revealed that only relatively thin and isolated specimens have been tested under seismic-type loading and realistic strengthening scenarios. To overcome these limitations, a full-scale two-story flat slab building specimen was tested at the European Commission’s Joint Research Centre–ELSA Laboratory in Ispra, Italy. This paper describes and analyzes the results obtained from the last of a series of phases, on repaired and strengthened internal and external slab-column connections using post-installed bolts. Compared with previous tests, the full-scale building specimen has a thicker slab (200 mm), realistic slab continuity conditions and the connections were strengthened after they suffered damage from gravity loading and previous lateral loading phases. The results show that post-installed bolts are efficient even under the described conditions (i.e. damaged and repaired specimens with realistic thickness), and punching shear failure was prevented in the strengthened connections. publishersversion published

This paper evaluates the variability of binder rheology for different ageing levels and the influence of ageing at different testing temperatures. Three different ageing levels were applied on a single type of bitumen with a penetration grade of 70/100.The artificial ageing of the binder was performed using the rolling thin-film oven test and the pressure ageing vessel. The rheological behaviour was investigated at low temperatures with the bending beam rheometer (BBR) and at medium and high temperatures with the dynamic shear rheometer (DSR). Several experiments were conducted to determine the range of stiffness and complex modulus results, the type of distribution comparing real and theoretical models, and the effects of ageing on the variability of the rheological behaviour. It was shown that not only the mean results from BBR and DSR tests change with ageing, but also the variability of the results changes with ageing. This would have an impact on mechanistic-empirical pavement design because it would influence the calculated stresses and strains as well as the calculated reliability.

As a key enabling technology of Industry 4.0, Digital Twin (DT) has been widely applied to various industrial domains covering different lifecycle phases of products and systems. To fully realize the Industry 4.0 vision, it is necessary to integrate multiple relevant DTs of a system according to a specific mission. This requires integrating all available data, information and knowledge related to the system across its entire lifecycle. It is a challenging task due to the high complexity of modern industrial systems. Semantic technologies such as ontology and knowledge graphs provide potential solutions by empowering DTs with augmented cognitive capabilities. The Cognitive Digital Twin (CDT) concept has been recently proposed which reveals a promising evolution of the current DT concept towards a more intelligent, comprehensive, and full lifecycle representation of complex systems. This paper reviews existing studies relevant to the CDT concept, and further explores its definitions and key features. To facilitate CDT development, a reference architecture is proposed based on the RAMI4.0 and some other existing architectures. Moreover, some key enabling technologies and several application scenarios of CDT are introduced. The challenges and opportunities are discussed in the end to boost future studies.

The use of ontologies in the context of product lifecycle management (PLM) is gaining importance and popularity, while at the same time it generates a lot of controversy in discussions within scientific and engineering communities. Yet, what is ontology? What challenges have been addressed so far? What role does ontology play? Do we really need ontology? These are the core questions this paper seeks to address. We propose to conduct a comprehensive study of the concept of Ontology firstly in its domain of origin, Philosophy, and secondly in information science. Based on the understanding of this concept and an in-depth analysis of the state of the art, seven key roles of ontology are defined. These roles serve as a framework describing the general state of research on the use of ontologies in the context of PLM.

Artificial water storage, originated by the construction of dams, is essential for the sustainable health and welfare of civilizations since it supplies water for human consumption, irrigation and energy production. Furthermore, dam reservoirs are used for recreation, navigation and they provide safety in the downstream valleys against extreme flood events and droughts. All reservoirs are subjected to sedimentation which, without adequate prevention and mitigation counter-measures, threatens their sustainability. As well as the evident loss of storage capacity, the adequate and safe operation of water intakes and bottom outlets belonging to the vital outlet structures can be affected by the deposition of sediments in the reservoir. This Vision Paper first addresses the state-of-the-art and the main scientific advances in terms of prevention and mitigation measures against sedimentation in reservoirs. Then, the main research challenges, which result from the assessment of what are the remaining open questions, are pointed out. The emerging research methodologies to study sedimentation processes are also discussed.

The paper presents the analysis of fluid–structure interaction occurring during hydraulic transients in pipe coils by means of a four-equation model. The purpose is to understand and describe the effect of the coil movement on the transient wave. The four-equation model couples the transient pipe flow with the axial movement of the pipe-wall neglecting radial inertia, flexure and torsion of the piping system. Three models have been developed: the first simplifying the coil to a straight pipe with a moving valve, the second model assuming independent axial deformation in each coil ring, and the third model that includes dry friction dissipation. The first allows an easier generalization of the method; however, it does not allow the complete description of the phenomenon; the second and third models fit better the experimental observations in the pipe coil facility, suggesting that its behaviour is dominated by the independent movement of the rings.

This paper proposes a set of distributed real-time optimisation schemes for the steady-state optimisation of parametrically and structurally uncertain systems that are composed of multiple interconnected subsystems. These schemes are derived in the framework of modifier adaptation and use uncertain system models of varying complexity. Consequently, each distributed modifier-adaptation scheme imposes different requirements on the available plant measurements, the communication network, and the control architecture. We prove that every scheme can converge to the plant optimum despite model uncertainty and compare the main features of each approach. Finally, we illustrate our findings via a numerical example.

The QC-MDPC code-based KEM BIKE is one of the Round-3 candidates of the NIST PQC standardization project. Its Round-2 specification document described variants claiming to have IND-CCA security. The security proof used the Fujisaki-Okamoto transformation and a decoder targeting a Decoding Failure Rate (DFR) of 2(-128) (for Level-1 security). However, several aspects needed to be amended in order for the IND-CCA proof to hold. The main issue is that using a decoder with DFR of 2(-128) does not necessarily imply that the underlying PKE is delta-correct with delta = 2(-128), as required. In this paper, we handle the necessary aspects to ensure the security claim is correct. In particular, we close the gap in the proof by defining the notion of message-agnostic PKE. We show that the PKEs underlying the BIKE versions are message-agnostic. This implies that BIKE with a decoder that has a sufficiently low DFR is also an IND-CCA KEM.

Ontologies provide an opportunity to tackle the interoperability challenge in digital manufacturing. Although ontologies have been used in numerous industrial projects, the problem of semantic interoperability in the industry is still unresolved. One reason for the lack of success of ontologies in the industry is that most industrial ontologies have been developed based on local needs without taking wider applications into account or attempting to learn from earlier ontology initiatives or reuse the existing ontologies. In this position paper, we argue that for widespread adoption and implementation of ontologies, more systematic and coordinated efforts are needed with the participation of industry, academia, and government at an international level. We also hypothesise that a coordinated and systematic ontology development effort will incrementally lead to the creation of an ecosystem of interoperable software applications that support consistent data access and reasoning across the product life cycle. We discuss why efforts such as Industrial Ontology Foundry (IOF) can promote a methodological ontology development process by introducing modular, and reusable ontologies. We draw examples from two domain areas, namely supply chain management and production planning and scheduling, to demonstrate how industrial notions can be analysed ontologically according to IOF procedures and methods.