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Congenital diarrheal disorders are a group of rare enteropathies that often present with life-threatening diarrhea in the first weeks of life. Enteric anendocrinosis, characterized by a lack of intestinal enteroendocrine cells due to recessively inherited mutations in the Neurogenin-3 (NEUROG3) gene, has been described as a cause of congenital malabsorptive diarrhea. Diabetes mellitus also is typically associated with NEUROG3 mutations, be it early onset or a later presentation. Here we report a case of a 16-year-old male patient with severe malabsorptive diarrhea from birth, who was parenteral nutrition dependent and who developed diabetes mellitus at 11 years old. To the best of our knowledge, only 9 cases of recessively inherited NEUROG3 mutations have been reported in the literature to date. Our patient presents with several remarkable differences compared with previously published cases. This report can contribute by deepening our knowledge on new aspects of such an extremely rare disease. [ABSTRACT FROM AUTHOR]

Abstract: In the recent years, the use of workflows has significantly expanded from its original domain of business processes towards new areas. The increasing demand for individual and more flexible workflows asks for new methods that support domain experts to create, monitor, and adapt workflows. The emergent field of process-oriented case-based reasoning addresses this problem by proposing methods for reasoning with workflows based on experience. New workflows can be constructed by reuse of already available similar workflows from a repository. Hence, methods for the similarity assessment of workflows and for the efficient retrieval of similar workflows from a repository are of core importance. To this end, we describe a new generic model for representing workflows as semantically labeled graphs, together with a related model for knowledge intensive similarity measures. Further, new algorithms for workflow similarity computation, based on A⁎ search are described. A new retrieval algorithm is introduced that goes beyond traditional sequential retrieval for graphs, interweaving similarity computation with case selection. We describe the application of this model and several experimental evaluations of the algorithms in the domain of scientific workflows and in the domain of business workflows, thereby showing its broad applicability. [Copyright &y& Elsevier]

To associate research data to the published results favors their reuse by the scientific community, but this does not afford sufficient guarantees of preservation. To store them in databases solves this contingency and provides visibility, but in Spain there are not many services of this kind. For this reason, we describe, evaluate and discuss the pros and cons of foreign multidisciplinary data repositories that can be useful for researchers and information managers: Dryad, Figshare, Zenodo and Dataverse. It is still early to choose optimally and definitively one or the other application, so we conclude with recommendations to guide the user community and intermediaries. [ABSTRACT FROM AUTHOR]

Computational workflows are a powerful paradigm to represent and manage complex applications, particularly in large-scale distributed scientific data analysis. Workflows represent application components that result in individual computations as well as their interdependences in terms of dataflow. Workflow systems use these representations to manage various aspects of workflow creation and execution for users, such as the automatic assignment of execution resources. This article describes an approach to automating a new aspect of the process: the selection of application components and data sources. We present a novel approach that enables users to specify varying degrees of detail and amount of constraints in a workflow request, including the specification of constraints on input, intermediate or output data in the workflow, abstract workflow component classes rather than specific component implementations, and generic reusable workflow templates that express a pre-defined combination of components. The algorithm elaborates the user request into a set of fully ground workflows with specific choices of data sources and codes to be used so that they can be submitted for mapping and execution. The algorithm searches through the space of possible candidate workflows by creating increasingly more specialized versions of the original template and eliminating candidates that violate constraints cumulated in the candidate workflow as components and data sources are selected. A novel feature of our approach is that it assumes a distributed architecture where data and component catalogues are separate from the workflow system. The algorithm explicitly poses queries to external catalogues, and therefore any reasoning regarding data or component properties is not assumed to occur within the workflow system. We describe our implementation of this approach in the Wings workflow system. This implementation uses the W3C Web Ontology Language and associated reasoners to implement the workflow system as well as the data and component catalogues. This research demonstrates the use of artificial intelligence techniques to support the kinds of automation envisioned by the scientific community for large-scale distributed scientific data analysis. [ABSTRACT FROM AUTHOR]

Workflows, also known as process models, are essential in many science and engineering fields. Workflows express compositions of individual steps or tasks that assembled together account for various aspects of an overall process. When workflows include dozens of components and many links among them, the creation of valid workflows becomes challenging since users have to track many interdependencies and constraints. This article describes principles for assisting users to create valid workflows that are based on two knowledge acquisition systems that we have developed. A shared goal in these projects was to enable end users who do not have computer science backgrounds, such as biologists, military officers or engineers, to create valid end-to-end process models or workflows. Our approach exploits knowledge-rich descriptions of the individual components and their constraints in order to validate the composition, and uses artificial intelligence planning techniques in order to systematically verify formal properties of valid workflows. Both systems analyse partial workflows created by the user, determine whether they are consistent with the background knowledge that the system has, notifies the user of issues to be resolved in the current workflow, and suggests to the user what actions could be taken to correct those issues. [ABSTRACT FROM AUTHOR]

Background: Solitary fibrous tumor (SFT) is a rare ubiquitous mesenchymal neoplasm of probable fibroblastic type with a prominent hemangiopericytoma-like vascular pattern. Since their initial description as arising from the pleura, SFTs have been reported in many extraserosal sites. It is now accepted that this neoplasm is derived from mesenchymal cells but its histogenesis is still not known. Methods: The authors gathered clinical data on 10 patients with SFT. Tissue microarrays were constructed to perform inmunohistochemical tests and we reviewed hematoxilin-eosin-stained slides. Electron-microscopically collected samples were fixed with formalin or Karnovsky reactive and embedded in epoxy resin. Results: The histopathological review showed varying degrees of cell density and mitotic activity, which correlated with clinical behavior. Immunohistochemically most tumors stained positively for vimentin, CD99, and CD34. Ultraestructural study showed some degree of myofibroblastic differentiation in all cases and focal smooth muscle features. In addition, 9 cases showed perivascular undifferentiated cells. Conclusion: SFT is an uncommon neoplasm with different histological patterns and clinical behavior. The authors hypothetize that the perivascular undifferentiated cells that most cases showed might correspond to a quiescent stage of adult stem mesenchymal cell and could be the target of the molecular aberrations implied in its pathogenesis. [ABSTRACT FROM AUTHOR]

Scientific computing has entered a new era of scale and sharing with the arrival of cyberinfrastructure facilities for computational experimentation. A key emerging concept is scientific workflows, which provide a declarative representation of complex scientific applications that can be automatically managed and executed in distributed shared resources. In the coming decades, computational experimentation will push the boundaries of current cyberinfrastructure in terms of inter-disciplinary scope and integrative models of scientific phenomena under study. This paper argues that knowledge-rich workflow environments will provide necessary capabilities for that vision by assisting scientists to validate and vet complex analysis processes and by automating important aspects of scientific exploration and discovery. [ABSTRACT FROM AUTHOR]

The article discusses the ways in which scientific workflows have aided in managing difficult distributed computations and quickened the pace of scientific progress. At a National Science Foundation workshop domain, computer, and social scientists came together to discuss the needs of future scientific applications and the problems facing current workflow technologies. The scientists studied application requirements, workflow representations, dynamic workflows, and system-related challenges. The workshop participants listed various recommendations including continued research in computer science, the integration of workflow representations with other forms of scientific record, and the implementation of long-term, stable partnerships and programs.

This paper argues that interactive knowledge acquisition systems would benefit from a tighter and more thorough incorporation of tutoring and learning principles. Current acquisition systems learn from users in a passive manner, and could instead be designed to incorporate the proactive capabilities that one expects of a good student. We first describe our analysis of the literature on teacher–student interaction and present a compilation of tutoring and learning principles that are relevant to interactive knowledge acquisition systems. We then point out what tutoring and learning principles have been used to date in the acquisition literature, though unintentionally and implicitly, and discuss how a more thorough and explicit representation of these principles would help improve how computers learn from users. We present our design and an initial implementation of an acquisition dialogue system called SLICK that represents acquisition principles and goals explicitly and declaratively, making the system actively reason about various acquisition tasks and generate its interactions dynamically. Finally, we discuss promising directions in designing acquisition systems by structuring interactions with users according to tutoring and learning principles. [Copyright &y& Elsevier]

Youth who exit the nation's foster care system without permanency are at high risk of experiencing difficulties during the transition to adulthood. To present an illustrative test of whether an algorithmic decision aid could be used to identify youth at risk of existing foster care without permanency. For youth placed in foster care between ages 12 and 14, we assessed the risk of exiting care without permanency by age 18 based on their child welfare service involvement history. To develop predictive risk models, 28 years (1991–2018) of child welfare service records from California were used. Performances were evaluated using F1, AUC, and precision and recall scores at k %. Algorithmic racial bias and fairness was also examined. The gradient boosting decision tree and random forest showed the best performance (F1 score =.54–.55, precision score =.62, recall score =.49). Among the top 30 % of youth the model identified as high risk, half of all youth who exited care without permanency were accurately identified four to six years prior to their exit, with a 39 % error rate. Although racial disparities between Black and White youth were observed in imbalanced error rates, calibration and predictive parity were satisfied. Our study illustrates the manner in which potential applications of predictive analytics, including those designed to achieve universal goals of permanency through more targeted allocations of resources, can be tested. It also assesses the model using metrics of fairness. [ABSTRACT FROM AUTHOR]

Electron microscopy is a powerful tool for the assessment of complex lesions in nontumor renal pathology, however it is a time-consuming procedure. We evaluated a simple method to assess morphological signs of chronic rejection in renal allograft that seems to have prognostic significance. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia—PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despite many years of research and its limited success, gemcitabine is still the first line treatment of PDA. New drug combinations and new concepts to improve drug delivery into the tumor, as well as the development of preclinical predictive assays, are being explored and provide optimism and prospects for better therapies. [ABSTRACT FROM AUTHOR]

The authors discuss the amplification of scientific discovery with artificial intelligence (AI). They offer a brief historical overview of the application of AI to the practice of science and discuss systems using AI techniques, such as Internet search engines, the concept of cognitive computing, as demonstrated in the supercomputer Watson from International Business Machines Corp. (IBM), and examples of AI used in data analysis, such as the high-throughput analyzer (Hanalyzer).

This research forms part of the project titled: 'Aesthetic quality research of three Valencian schools', that analyses the effects in detail that images displayed in schools have, as a variable in evaluating educational quality. Through applying Arts Based Educational Research, images displayed on 29 classroom walls in three schools were photographed and analysed based upon their function; they were subsequently classified as educational images, academic images, and comfort-generating images. The results of this research show quantitative, qualitative, and aesthetic values of this visual heritage by using photographic series that are laid out in a chart-like manner, creating a visual message for each classroom. Upon observing these typologies, one perceives: the predominate utilisation of the image and its aesthetics; the differences in visible occurrences between subject matters displayed on the walls; the teacher's intentions when displaying the images. In the conclusions, alternatives are proposed for improving the schools' aesthetical qualities. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about primary ciliary dyskinesia by B. Carlén and U. Stenram in the previous issue.

* Context.--Discrete submucosal necrotic nodules may rarely manifest as colon polyps. Objective.--To characterize the clinical and pathologic features of this lesion, which has been under-studied in the literature. Design.--We conducted an international search to compile a series. For each potential case, photomicrographs were centrally reviewed to confirm the diagnosis. We gathered clinical and pathologic information on each confirmed case. Results.--The final cohort included 25 patients, with 23 having 1 lesion and 2 having several (31 lesions total). Mean patient age was 62 years; 13 patients (52%) were male. Symptoms were nonspecific, although 4 patients (16%) had blood in stool; 14 patients were asymptomatic. Patient history and medications appeared noncontributory. Most cases were located in the right colon (n = 18; 58%). Mean lesion size was 0.4 cm (range, 0.1-1.7 cm). Histology typically showed a centrally necrotic nodule with peripheral fibrosis, chronic inflammation, and sometimes palisading granulomatous inflammation. Percent necrosis ranged from 5% to 95% (average, 70%), and percent fibrosis ranged from 3% to 70% (average, 25%). In 3 cases, degenerated parasitic structures consistent with Anisakis could be seen on hematoxylin-eosin and trichrome special stain. No patient experienced disease recurrence. Conclusions.--Submucosal necrotic nodules can present as colon polyps. Most cases are unifocal, and patients do well on follow-up. At least some examples appear to be caused by Anisakis, implicating patient diet. Patients are often asymptomatic, and many cases show no histologic evidence of the causative agent. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this work was to determine which embryonic morphokinetic parameters up to D3 of in vitro development have predictive value for implantation for the selection of embryos for transfer in clinical practice based upon information generated from embryo transfers with known implantation data (KID). Methods: A total of 800 KID embryos (100% implantation rate (IR) per transfer and 0% IR per transfer) cultured in an incubator with Time-Lapse system were retrospectively analysed. Of them, 140 embryos implanted, whereas 660 did not. Results: The analysis of morphokinetic parameters, together with the embryo morphology assessment on D3, enabled us to develop a hierarchical model that places the classical morphological score, the t4 and t8 morphokinetic values, as the variables with the best prognosis of implantation. Conclusion: In our decision tree, the classical morphological score is the most predictive parameter. Among embryos with better morphological scores, morphokinetics permits deselection of embryos with the lowest implantation potential. [ABSTRACT FROM AUTHOR]

The professional and technical aspects associated with the management of research data have advanced: technical infrastructures or descriptive metadata schemes. There are others, related with the research field, which are still under study due to the need now to make them available as open data. This paper makes a bibliographical review and reference web sites that allow to identify the latest advances and research trends on issues related with research data. Some of them need to be addressed urgently in our opinion and experience in this field: data publication in journals, study of the behaviour of authors and methods to measure the impact of the data. The aim of this work is to highlight the outstanding challenges in a moment when there is a disruptive change in its exchange given the amount of data available as open data. [ABSTRACT FROM AUTHOR]

Background: Recent highly publicized cases of premature patient assignment into clinical trials, resulting from non-reproducible omics analyses, have prompted many to call for a more thorough examination of translational omics and highlighted the critical need for transparency and reproducibility to ensure patient safety. The use of workflow platforms such as Galaxy and Taverna have greatly enhanced the use, transparency and reproducibility of omics analysis pipelines in the research domain and would be an invaluable tool in a clinical setting. However, the use of these workflow platforms requires deep domain expertise that, particularly within the multi-disciplinary fields of translational and clinical omics, may not always be present in a clinical setting. This lack of domain expertise may put patient safety at risk and make these workflow platforms difficult to operationalize in a clinical setting. In contrast, semantic workflows are a different class of workflow platform where resultant workflow runs are transparent, reproducible, and semantically validated. Through semantic enforcement of all datasets, analyses and user-defined rules/ constraints, users are guided through each workflow run, enhancing analytical validity and patient safety. Methods: To evaluate the effectiveness of semantic workflows within translational and clinical omics, we have implemented a clinical omics pipeline for annotating DNA sequence variants identified through next generation sequencing using the Workflow Instance Generation and Specialization (WINGS) semantic workflow platform. Results: We found that the implementation and execution of our clinical omics pipeline in a semantic workflow helped us to meet the requirements for enhanced transparency, reproducibility and analytical validity recommended for clinical omics. We further found that many features of the WINGS platform were particularly primed to help support the critical needs of clinical omics analyses. Conclusions: This is the first implementation and execution of a clinical omics pipeline using semantic workflows. Evaluation of this implementation provides guidance for their use in both translational and clinical settings. [ABSTRACT FROM AUTHOR]

Abstract: Understanding pair-wise activities is an essential step towards studying complex group and crowd behaviors in video. However, such research is often hampered by a lack of datasets that concentrate specifically on Atomic Pair Actions; [Here, we distinguish between the atomic motion of individual objects and the atomic motion of pairs of objects. The term action in Atomic Pair Action means an atomic interaction movement of two objects in video; a pair activity, then, is composed of multiple actions by a pair or multiple pairs of interacting objects (Ahad, 2011; Turaga et al., 2008). Please see Section 1 for details.] in addition, the general dearth in computer vision of a standardized, structured approach for reproducing and analyzing the efficacy of different models limits the ability to compare different approaches. In this paper, we introduce the ISI Atomic Pair Actions dataset, a set of 90 videos that concentrate on the Atomic Pair Actions of objects in video, namely converging, diverging, and moving in parallel. We further incorporate a structured, end-to-end analysis methodology, based on workflows, to easily and automatically allow for standardized testing of state-of-the-art models, as well as inter-operability of varied codebases and incorporation of novel models. We demonstrate the efficacy of our structured framework by testing several models on the new dataset. In addition, we make the full dataset (the videos, along with their associated tracks and ground truth, and the exported workflows) publicly available to the research community for free use and extension at . [Copyright &y& Elsevier]

Knowledge acquisition research concerned with the development of knowledge acquisition tools is in need of a methodological approach to evaluation. This paper describes experimental methodology to conduct studies and experiments of users modifying knowledge bases with knowledge acquisition tools. The paper also reports on the lessons learned from several experiments that have been performed using this methodology. The hope is that it will help others design user evaluations of knowledge acquisition tools. Ideas are discussed for improving the current methodology and some open issues that remain. [ABSTRACT FROM AUTHOR]

Hydrological models are essential in water resources management, but the expertise required to operate them often exceeds that of potential stakeholders. We present an approach that facilitates the dissemination of hydrological models, and its implementation in the Model INTegration (MINT) framework. Our approach follows principles from software engineering to create software components that reveal only selected functionality of models which is of interest to users while abstracting from implementation complexity, and to generate metadata for the model components. This methodology makes the models more findable, accessible, interoperable, and reusable in support of FAIR principles. We showcase our methodology and its implementation in MINT using two case studies. We illustrate how the models SWAT and MODFLOW are turned into software components by hydrology experts, and how users without hydrology expertise can find, adapt, and execute them. The two models differ in terms of represented processes and in model design and structure. Our approach also benefits expert modelers, by simplifying model sharing and the execution of model ensembles. MINT is a general modeling framework that uses artificial intelligence techniques to assist users, and is released as open-source software. • An approach to facilitate model dissemination from expert modelers to non-experts • Methods are proposed to simplify model complexity with software components • Non-experts can easily modify selected parameters and execute models from experts • Our approach makes models more findable, accessible, interoperable, reusable (FAIR) • Various applications benefited from this approach within the MINT framework [ABSTRACT FROM AUTHOR]

Metadata for hydrologic models is rarely organized in machine-readable forms. This lack of formal metadata is important because it limits the ability to catalog, identify, attribute, and understand unique model software; ultimately, it hinders the ability to reproduce past computational studies. Researchers have recently proposed an ontology for scientific software metadata called OntoSoft for addressing this problem. The objective of this research is to evaluate OntoSoft for organizing the metadata associated with a data pre-processing software workflow used in association with the Variable Infiltration Capacity (VIC) hydrologic model. This is accomplished by exploring what metadata are available from online resources and how this metadata aligns with the OntoSoft Ontology. The results suggest that past efforts to document this software resulted in capturing key model metadata in unstructured files that could be formalized into a machine-readable form using the OntoSoft Ontology. [ABSTRACT FROM AUTHOR]

The article discusses steps to be taken by scientists for the care and feeding of their data and associated analyses. It suggests managing scientific data, publishing it online with a digital object identifier, and publishing of the processing steps offering context for data interpretation and reuse. Also shares web links for useful resources including research data repositories Dataverse, Dryad, and FigShare.

Background: Membranous glomerulopathy is a common complication of renal allograft. However, its incidence and prognosis are not well defined, because an undetermined number of them pass undiagnosed under the generic epigraph of chronic allograft nephropathy. Materials and methods: To assess the diagnostic refinement supplied by electron microscopy to conventional light and immunofluorescence procedures the authors reviewed 17 cases of electron microscopy-confirmed membranous glomerulonephritis in kidney allograft. In addition, they searched for other features of graft injury, particularly lesions associated with alloimmune reaction, in order to evaluate the contribution of each lesion to the long-term outcome of the allograft. Results: In 4 of the 17 cases of their series the diagnosis of membranous glomerulopathy was made by electron microscopy. In addition, in 5 samples, lesions of chronic alloimmune rejection were present (in 4 cases the diagnosis was based on electron microscopy findings). At the end point of the study, 3 of the 5 patients with chronic alloimmune injury were in dialysis, 1 had died with functioning allograft, and the fifth suffered severe renal failure but was not in dialysis. On the other hand, 3 of the 12 patients without evidence of alloimmune injury had returned to the dialysis program. Conclusions: Electron microscopy is a useful tool in the assessment of renal allograft pathology and can provide additional morphological features of prognostic relevance. [ABSTRACT FROM AUTHOR]

How easy is it to reproduce the results found in a typical computational biology paper? Either through experience or intuition the reader will already know that the answer is with difficulty or not at all. In this paper we attempt to quantify this difficulty by reproducing a previously published paper for different classes of users (ranging from users with little expertise to domain experts) and suggest ways in which the situation might be improved. Quantification is achieved by estimating the time required to reproduce each of the steps in the method described in the original paper and make them part of an explicit workflow that reproduces the original results. Reproducing the method took several months of effort, and required using new versions and new software that posed challenges to reconstructing and validating the results. The quantification leads to “reproducibility maps” that reveal that novice researchers would only be able to reproduce a few of the steps in the method, and that only expert researchers with advance knowledge of the domain would be able to reproduce the method in its entirety. The workflow itself is published as an online resource together with supporting software and data. The paper concludes with a brief discussion of the complexities of requiring reproducibility in terms of cost versus benefit, and a desiderata with our observations and guidelines for improving reproducibility. This has implications not only in reproducing the work of others from published papers, but reproducing work from one’s own laboratory. [ABSTRACT FROM AUTHOR]

Data analysis processes in scientific applications can be expressed as coarse-grain workflows of complex data processing operations with data flow dependencies between them. Performance optimization of these workflows can be viewed as a search for a set of optimal values in a multidimensional parameter space consisting of input performance parameters to the applications that are known to affect their execution times. While some performance parameters such as grouping of workflow components and their mapping to machines do not affect the accuracy of the analysis, others may dictate trading the output quality of individual components (and of the whole workflow) for performance. This paper describes an integrated framework which is capable of supporting performance optimizations along multiple such parameters. Using two real-world applications in the spatial, multidimensional data analysis domain, we present an experimental evaluation of the proposed framework. [ABSTRACT FROM AUTHOR]

The article focuses on integrating high performance computing (HPC) and grid computing in biomedical research. It mentions that the researcher is faced with the need to efficiently store, manage, and analyze large volumes of semantically complex data in order to synthesize meaningful information. It explores the requirements on software middleware systems by the biomedical research through research pattern templates. It adds that HPC and grid computing can address to the requirement.

The article reports that scientific advances and discoveries are being made more and more frequently through the use of computer simulations rather than actual tests. This process is called in silico testing and it requires powerful computer programs that can handle data management, input parameter management, and multiple dependencies in processing elements. Orchestrating these elements is difficult, and requires workflow engineering in which raw data is received, processed and then made into a scientific conclusion that can be understood and used by scientists.

This paper describes the Pegasus framework that can be used to map complex scientific workflows onto distributed resources. Pegasus enables users to represent the workflows at an abstract level without needing to worry about the particulars of the target execution systems. The paper describes general issues in mapping applications and the functionality of Pegasus. We present the results of improving application performance through workflow restructuring which clusters multiple tasks in a workflow into single entities. A real-life astronomy application is used as the basis for the study. [ABSTRACT FROM AUTHOR]

We describe a newborn boy with a gastric heterotopia located in the nasopharynx, which caused airway obstruction soon after delivery. Gastric heterotopia is an uncommon lesion generally found throughout the alimentary tract, but nasopharynx is an exceptional location. To our knowledge, this is the second reported case of gastric heterotopia located in the nasopharynx, and the first one presenting in a newborn with symptoms at birth and with an associated central nervous system mass. [Copyright &y& Elsevier]

This article presents a set of Reproducibility Enhancement Principles targeting disclosure challenges involving computation. It discusses the sharing of data, software and details of computational environment that generate publishing results in open trusted repositories, the documentation of digital scholarly artifacts, and the need for funding agencies to instigate research programs and pilot studies.