Selecting the Reaction Path in On-Surface Synthesis through the Electron Chemical Potential in Graphene.

The organometallic on-surface synthesis of the eight-membered sp2 carbon-based ring cyclooctatetraene (C8H8, Cot) with the neighboring rare-earth elements ytterbium and thulium yields fundamentally different products for the two lanthanides, when conducted on graphene (Gr) close to the charge neutrality point. Sandwich-molecular YbCot wires of more than 500 Å length being composed of an alternating sequence of Yb atoms and upright-standing Cot molecules result from the on-surface synthesis with Yb. In contrast, repulsively interacting TmCot dots consisting of a single Cot molecule and a single Tm atom result from the on-surface synthesis with Tm. While the YbCot wires are bound through van der Waals interactions to the substrate, the dots are chemisorbed to Gr via the Tm atoms being more electropositive compared to Yb atoms. When the electron chemical potential in Gr is substantially raised (n-doping) through backside doping from an intercalation layer, the reaction product in the synthesis with Tm can be tuned to TmCot sandwich-molecular wires rather than TmCot dots. By use of density functional theory, it is found that the reduced electronegativity of Gr upon n-doping weakens the binding as well as the charge transfer between the reaction intermediate TmCot dot and Gr. Thus, the assembly of the TmCot dots to long TmCot sandwich-molecular wires becomes energetically favorable. It is thereby demonstrated that the electron chemical potential in Gr can be used as a control parameter in an organometallic on-surface synthesis to tune the outcome of a reaction.

Tailoring magnetic anisotropy by graphene-induced selective skyhook effect on 4f-metals.

From macroscopic heavy-duty permanent magnets to nanodevices, the precise control of the magnetic properties in rare-earth metals is crucial for many applications used in our daily life. Therefore, a detailed understanding and manipulation of the 4f-metals' magnetic properties are key to further boosting the functionalization and efficiency of future applications. We present a proof-of-concept approach consisting of a dysprosium-iridium surface alloy in which graphene adsorption allows us to tailor its magnetic properties. By adsorbing graphene onto a long-range ordered two-dimensional dysprosium-iridium surface alloy, the magnetic 4f-metal atoms are selectively lifted from the surface alloy. This selective skyhook effect introduces a giant magnetic anisotropy in dysprosium atoms as a result of manipulating its geometrical structure within the surface alloy. Introducing and proving this concept by our combined theoretical and experimental approach provides an easy and unambiguous understanding of its underlying mechanism. Our study sets the ground for an alternative path on how to modify the crystal field around 4f-atoms and therefore their magnetic anisotropies.

Atmospheric characterization of terrestrial exoplanets in the mid-infrared: biosignatures, habitability, and diversity.

Exoplanet science is one of the most thriving fields of modern astrophysics. A major goal is the atmospheric characterization of dozens of small, terrestrial exoplanets in order to search for signatures in their atmospheres that indicate biological activity, assess their ability to provide conditions for life as we know it, and investigate their expected atmospheric diversity. None of the currently adopted projects or missions, from ground or in space, can address these goals. In this White Paper, submitted to ESA in response to the Voyage 2050 Call, we argue that a large space-based mission designed to detect and investigate thermal emission spectra of terrestrial exoplanets in the mid-infrared wavelength range provides unique scientific potential to address these goals and surpasses the capabilities of other approaches. While NASA might be focusing on large missions that aim to detect terrestrial planets in reflected light, ESA has the opportunity to take leadership and spearhead the development of a large mid-infrared exoplanet mission within the scope of the "Voyage 2050" long-term plan establishing Europe at the forefront of exoplanet science for decades to come. Given the ambitious science goals of such a mission, additional international partners might be interested in participating and contributing to a roadmap that, in the long run, leads to a successful implementation. A new, dedicated development program funded by ESA to help reduce development and implementation cost and further push some of the required key technologies would be a first important step in this direction. Ultimately, a large mid-infrared exoplanet imaging mission will be needed to help answer one of humankind's most fundamental questions: "How unique is our Earth?"

A full gap above the Fermi level: the charge density wave of monolayer VS2.

In the standard model of charge density wave (CDW) transitions, the displacement along a single phonon mode lowers the total electronic energy by creating a gap at the Fermi level, making the CDW a metal-insulator transition. Here, using scanning tunneling microscopy and spectroscopy and ab initio calculations, we show that VS2 realizes a CDW which stands out of this standard model. There is a full CDW gap residing in the unoccupied states of monolayer VS2. At the Fermi level, the CDW induces a topological metal-metal (Lifshitz) transition. Non-linear coupling of transverse and longitudinal phonons is essential for the formation of the CDW and the full gap above the Fermi level. Additionally, x-ray magnetic circular dichroism reveals the absence of net magnetization in this phase, pointing to coexisting charge and spin density waves in the ground state.

Patient Cohort Identification on Time Series Data Using the OMOP Common Data Model.

BACKGROUND: The identification of patient cohorts for recruiting patients into clinical trials requires an evaluation of study-specific inclusion and exclusion criteria. These criteria are specified depending on corresponding clinical facts. Some of these facts may not be present in the clinical source systems and need to be calculated either in advance or at cohort query runtime (so-called feasibility query). OBJECTIVES: We use the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) as the repository for our clinical data. However, Atlas, the graphical user interface of OMOP, does not offer the functionality to perform calculations on facts data. Therefore, we were in search for a different approach. The objective of this study is to investigate whether the Arden Syntax can be used for feasibility queries on the OMOP CDM to enable on-the-fly calculations at query runtime, to eliminate the need to precalculate data elements that are involved with researchers' criteria specification. METHODS: We implemented a service that reads the facts from the OMOP repository and provides it in a form which an Arden Syntax Medical Logic Module (MLM) can process. Then, we implemented an MLM that applies the eligibility criteria to every patient data set and outputs the list of eligible cases (i.e., performs the feasibility query). RESULTS: The study resulted in an MLM-based feasibility query that identifies cases of overventilation as an example of how an on-the-fly calculation can be realized. The algorithm is split into two MLMs to provide the reusability of the approach. CONCLUSION: We found that MLMs are a suitable technology for feasibility queries on the OMOP CDM. Our method of performing on-the-fly calculations can be employed with any OMOP instance and without touching existing infrastructure like the Extract, Transform and Load pipeline. Therefore, we think that it is a well-suited method to perform on-the-fly calculations on OMOP.

Laquinimod dampens IL-1ß signaling and Th17-polarizing capacity of monocytes in patients with MS.

OBJECTIVE: To assess the impact of laquinimod treatment on monocytes and to investigate the underlying immunomodulatory mechanisms in MS. METHODS: In this cross-sectional study, we performed in vivo and in vitro analyses of cluster of differentiation (CD14+) monocytes isolated from healthy donors (n = 15), untreated (n = 13), and laquinimod-treated patients with MS (n = 14). Their frequency and the expression of surface activation markers were assessed by flow cytometry and the viability by calcein staining. Cytokine concentrations in the supernatants of lipopolysaccharide (LPS)-stimulated monocytes were determined by flow cytometry. The messenger ribonucleic acid (mRNA) expression level of genes involved in cytokine expression was measured by quantitative PCR. The LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activation was determined by the quantification of the phosphorylation level of the p65 subunit. Laquinimod-treated monocytes were cocultured with CD4+ T cells, and the resulting cytokine production was analyzed by flow cytometry after intracellular cytokine staining. The interleukin (IL)-17A concentration of the supernatant was assessed by ELISA. RESULTS: Laquinimod did not alter the frequency or viability of circulating monocytes, but led to an upregulation of CD86 expression. LPS-stimulated monocytes of laquinimod-treated patients with MS secreted less IL-1ß following a downregulation of IL-1ß gene expression. Phosphorylation levels of the NF-κB p65 subunit were reduced after laquinimod treatment, indicating a laquinimod-associated inhibition of the NF-κB pathway. T cells primed with laquinimod-treated monocytes differentiated significantly less into IL-17A-producing T helper (Th)-17 cells. CONCLUSIONS: Our findings suggest that inhibited NF-κB signaling and downregulation of IL-1ß expression in monocytes contributes to the immunomodulatory effects of laquinimod and that the impairment of Th17 polarization might mediate its disease-modifying activity in MS.

A triple-star system with a misaligned and warped circumstellar disk shaped by disk tearing.

Young stars are surrounded by a circumstellar disk of gas and dust, within which planet formation can occur. Gravitational forces in multiple star systems can disrupt the disk. Theoretical models predict that if the disk is misaligned with the orbital plane of the stars, the disk should warp and break into precessing rings, a phenomenon known as disk tearing. We present observations of the triple-star system GW Orionis, finding evidence for disk tearing. Our images show an eccentric ring that is misaligned with the orbital planes and the outer disk. The ring casts shadows on a strongly warped intermediate region of the disk. If planets can form within the warped disk, disk tearing could provide a mechanism for forming wide-separation planets on oblique orbits.

Evaluation of Different Learning Algorithms of Neural Networks for Drug Dosing Recommendations in Pediatrics.

Publicly accessible databases with evidence-based information on drug dosages for children and adolescents are not available in Germany. In previous work a prototypical web-based online platform for pediatric dosing recommendation has been developed. Quality assured maintenance of such a database is a time consuming effort. Recent work has shown that it is possible to use routinely documented data for machine learning approaches in order to create models for future decision support tools. This work describes the development of a prototype for pediatric dosing recommendations on the basis of routine drug prescriptions. Since they are structured for daily clinical use, not for machine learning, they include a substantial proportion of narrative text that requires preprocessing with consideration of medical and pharmaceutical knowledge. Three different learning algorithms have been applied and compared. The genetic algorithm with backpropagation has achieved the highest accuracy in the predictions. Our study constitutes a first step towards pediatric dosing recommendations, but there are multiple additional steps to be taken before a routine use might be considered, such as an evaluation by experienced physicians.

Mapping the Entire Record-An Alternative Approach to Data Access from Medical Logic Modules.

OBJECTIVES: This study aimed to describe an alternative approach for accessing electronic medical records (EMRs) from clinical decision support (CDS) functions based on Arden Syntax Medical Logic Modules, which can be paraphrased as "map the entire record." METHODS: Based on an experimental Arden Syntax processor, we implemented a method to transform patient data from a commercial patient data management system (PDMS) to tree-structured documents termed CDS EMRs. They are encoded in a specific XML format that can be directly transformed to Arden Syntax data types by a mapper natively integrated into the processor. The internal structure of a CDS EMR reflects the tabbed view of an EMR in the graphical user interface of the PDMS. RESULTS: The study resulted in an architecture that provides CDS EMRs in the form of a network service. The approach enables uniform data access from all Medical Logic Modules and requires no mapping parameters except a case number. Measurements within a CDS EMR can be addressed with straightforward path expressions. The approach is in routine use at a German university hospital for more than 2 years. CONCLUSION: This practical approach facilitates the use of CDS functions in the clinical routine at our local hospital. It is transferrable to standard-compliant Arden Syntax processors with moderate effort. Its comprehensibility can also facilitate teaching and development. Moreover, it may lower the entry barrier for the application of the Arden Syntax standard and could therefore promote its dissemination.

Room-temperature solution-phase epitaxial nucleation of PbS quantum dots on rutile TiO2 (100).

Owing to its simplicity and versatility, the successive ionic layer adsorption and reaction (SILAR) method is increasingly being employed to develop low-cost hetero-nanostructured sensitized oxide systems for solar energy conversion, such as solar cells and solar fuels schemes. Understanding the nature of the SILAR quantum dot (QD) nucleation and growth on an insulating oxide is then critical as it will determine the QD density and spatial distribution, as well as the optoelectronic properties of the QD/oxide interfaces (e.g. QD bandgap onset). Here, we demonstrate epitaxial nucleation of lead sulfide (PbS) QDs onto a planar rutile titanium dioxide (100) surface employing the SILAR method. The QDs nucleated by SILAR are crystalline structures characterized by a truncated pyramidal shape, with nucleation occurring preferentially along the rutile (010) and (001) crystal orientations. The PbS QD size distribution is constrained by lattice mismatch causing strain in the lead sulfide. These results highlight the potential of SILAR for the facile growth of high-quality epitaxial nanostructures in liquid phase, under ambient conditions and at room temperature.

A method for the graphical modeling of relative temporal constraints.

Searching for patient cohorts in electronic patient data often requires the definition of temporal constraints between the selection criteria. However, beyond a certain degree of temporal complexity, the non-graphical, form-based approaches implemented in current translational research platforms may be limited when modeling such constraints. In our opinion, there is a need for an easily accessible and implementable, fully graphical method for creating temporal queries. We aim to respond to this challenge with a new graphical notation. Based on Allen's time interval algebra, it allows for modeling temporal queries by arranging simple horizontal bars depicting symbolic time intervals. To make our approach applicable to complex temporal patterns, we apply two extensions: with duration intervals, we enable the inference about relative temporal distances between patient events, and with time interval modifiers, we support counting and excluding patient events, as well as constraining numeric values. We describe how to generate database queries from this notation. We provide a prototypical implementation, consisting of a temporal query modeling frontend and an experimental backend that connects to an i2b2 system. We evaluate our modeling approach on the MIMIC-III database to demonstrate that it can be used for modeling typical temporal phenotyping queries.

Pan-European Data Harmonization for Biobanks in ADOPT BBMRI-ERIC.

BACKGROUND: High-quality clinical data and biological specimens are key for medical research and personalized medicine. The Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium (BBMRI-ERIC) aims to facilitate access to such biological resources. The accompanying ADOPT BBMRI-ERIC project kick-started BBMRI-ERIC by collecting colorectal cancer data from European biobanks. OBJECTIVES: To transform these data into a common representation, a uniform approach for data integration and harmonization had to be developed. This article describes the design and the implementation of a toolset for this task. METHODS: Based on the semantics of a metadata repository, we developed a lexical bag-of-words matcher, capable of semiautomatically mapping local biobank terms to the central ADOPT BBMRI-ERIC terminology. Its algorithm supports fuzzy matching, utilization of synonyms, and sentiment tagging. To process the anonymized instance data based on these mappings, we also developed a data transformation application. RESULTS: The implementation was used to process the data from 10 European biobanks. The lexical matcher automatically and correctly mapped 78.48% of the 1,492 local biobank terms, and human experts were able to complete the remaining mappings. We used the expert-curated mappings to successfully process 147,608 data records from 3,415 patients. CONCLUSION: A generic harmonization approach was created and successfully used for cross-institutional data harmonization across 10 European biobanks. The software tools were made available as open source.

In Search for Methods to Support Electronic Patient Recruitment in a Multi-ICU Clinical Trial.

Antimycotics are substances to treat fungal infections, a frequent cause of death on intensive care units. It is of great importance to administer such drugs only to patients who actually need them, since the unnecessary application leads to the selection of multiresistent fungi, making future therapy more difficult, and represents a significant financial burden for the health care system. Within the scope of a prospective study, which analyses the premature discontinuation of the administration of unnecessary antifungal drugs, two software platforms for recruitment support were implemented and compared at the University Hospital Erlangen. Besides technical aspects, such as the necessary development time and query runtimes, their usability and user friendliness for the clinical users were compared. We found that the practical identification of patient cohorts is possible both with a full featured business intelligence application and with a low effort approach based on language constructs of the Arden Syntax. Furthermore, this pilot evaluation led to important insights related to the clinical documentation context and data quality issues. A comprehensive analysis of the clinical environment and documentation context is essential for the final decision on the tool to be used.

User-Centered Development of an Online Platform for Drug Dosing Recommendations in Pediatrics.

BACKGROUND: Drug therapy in pediatric patients is a complex process. Children are subject to continuous growth and variation in drug-metabolizing enzyme activity, requiring continuous adaption of dosages. In Germany, currently no publicly available database exists that provides evidence-based information on drug dosages in pediatrics. For local drug dosing support, a prototype database has been developed within the Children's Hospital, Erlangen. A user-centered development process was initiated to establish an online platform for evidence-based dosing recommendations, as well as pharmacological and pharmaceutical drug information in pediatrics. OBJECTIVES: The objectives of the study were to survey the demand for such a platform and to assess the usability of the different versions of the developed system. METHODS: The developed prototype was evaluated in a pluralistic walkthrough with prospective end users. After a redesign, the second prototype of the online platform underwent an online usability testing based on a tailored questionnaire and the System Usability Scale (SUS) (n = 12). RESULTS: Eleven of 12 participants expressed a demand for an online platform for pediatric dosing recommendations. The majority of the participants requested the integration of extended features, such as drug-drug interaction alerts, or information on adverse effects, pharmacokinetics, and pharmacodynamics. Particularly noteworthy is the demand for an online calculator; 5 of a total of 15 participants explicitly requested a calculator for dosages (based on age, weight, body surface) and glomerular filtration rate. The usability of the second prototype was rated "good to excellent" with a median SUS of 81.25. CONCLUSION: Local domain experts demand an online platform for pediatric dosing recommendations. The application of the user-centered design approach enabled the development of a prototype suitable for practical use. Multiple additional required functionalities have been identified, whereby the importance of an online calculator for patient-individual dosing recommendations was particularly emphasized.

A REST Service for the Visualization of Clinical Time Series Data in the Context of Clinical Decision Support.

BACKGROUND: University Hospital Erlangen provides clinical decision support (CDS) functions in the intensive care setting, that are based on the Arden Syntax standard. These CDS functions generate extensive output, including patient data charts. In the course of the migration of our CDS platform we revised the charting tool because although the tool was generally perceived as useful, the clinical users reported several shortcomings. OBJECTIVE: During the migration of our CDS platform, we aimed at resolving the reported shortcomings and at developing a reusable and parameterizable charting tool, driven by best practices and requirements of local clinicians. METHODS: We conducted a requirements analysis with local clinicians and searched the literature for well-established guidelines for clinical charts. Using a charting library, we then implemented the tool based on the found criteria and provided it with a REST interface. RESULTS: The criteria catalog included 18 requirements, all of which were successfully implemented. The new charting tool fully replaced the previous implementation in clinical routine. It also provides a web interface that enables clinicians to configure charts without programming skills. CONCLUSION: The new charting tool combines local preferences with best practices for visualization of clinical time series data. With its REST interface and reusable design it can be easily integrated in existing CDS platforms.

Complementing Medical Records with Precalculated Data Items to Facilitate Decision Support and Phenotyping.

The Arden Syntax is a standard for clinical decision support functions in the form of Medical Logic Modules (MLMs). While the data type system of the early versions was limited to flat lists, later versions introduced an object type, supporting complex data structures, even up to entire electronic medical records (EMRs). Such objects are static insofar as their structure cannot be modified at MLM runtime. University Hospital Erlangen uses an experimental Arden Syntax version termed PLAIN, which provides an integrated mapper for arbitrary data structures, including entire EMRs. To facilitate knowledge encoding and reduce MLM complexity, we searched for a way to complement patient records with precalculated data items. We modified the object data type in two ways. The first was to include a statement for the explicit creation of new attributes; the second was to implicitly create an attribute whenever a value is assigned to a previously non-existing attribute. As a proof of concept, we complemented the ventilation section of every accessed EMR with a patient-individual recommendation for the expiratory tidal volume. A means to extend the structure of an object at runtime provides several advantages. The precalculated data items need no longer be calculated by the MLMs themselves, which reduces complexity and facilitates code maintenance. This might be beneficial not only for clinical decision support, but also with respect to the use of Arden Syntax language constructs for phenotyping queries, as well as with respect to the frequently required preprocessing of EMR data.

An Extension of the Arden Syntax to Facilitate Clinical Document Generation.

While clinical information systems usually store patient records in database tables, human interpretations as well as information transfer between institutions often require that clinical data can be represented as documents. To automate document generation from patient data in conjunction with the rich computational facilities of clinical decision support, we propose a template-based extension of the Arden Syntax, and discuss the benefits and limitations observed during a pilot application for patient recruitment. While the original Arden Syntax supports string concatenation as well as the substitution of unnamed placeholders, we integrated an additional method based on embedding expressions into strings. A dedicated parser identifies the expressions and automatically substitutes them at runtime, which can for example be harnessed to display the most recent value from a time series. The resulting mechanism supports the generation of extensive clinical documents without the need to apply specific operators. To evaluate the proposed extension, we implemented an Arden module that identifies an intensive care patient cohort that conforms to the eligibility criteria of a clinical trial and outputs a concise patient overview in different document formats. While string interpolation in the original Arden standard has been tailored to clinical event monitoring, we interpret that our accessible approach usefully extends Arden's data-to-text capabilities. Future research might target the development of an interactive template editor that would hide the complexity of formatting directives and conditional expressions behind a graphical user interface, and explore how computer-linguistic formalisms might facilitate advanced features such as automatic inflections of verbs and nouns.

Europium Cyclooctatetraene Nanowire Carpets: A Low-Dimensional, Organometallic, and Ferromagnetic Insulator.

We investigate the magnetic and electronic properties of europium cyclooctatetraene (EuCot) nanowires by means of low-temperature X-ray magnetic circular dichroism (XMCD) and scanning tunneling microscopy (STM) and spectroscopy (STS). The EuCot nanowires are prepared in situ on a graphene surface. STS measurements identify EuCot as an insulator with a minority band gap of 2.3 eV. By means of Eu M5,4 edge XMCD, orbital and spin magnetic moments of (-0.1 ± 0.3)µB and (+7.0 ± 0.6)µB, respectively, were determined. Field-dependent measurements of the XMCD signal at the Eu M5 edge show hysteresis for grazing X-ray incidence at 5 K, thus confirming EuCot as a ferromagnetic material. Our density functional theory calculations reproduce the experimentally observed minority band gap. Modeling the experimental results theoretically, we find that the effective interatomic exchange interaction between Eu atoms is on the order of millielectronvolts, that magnetocrystalline anisotropy energy is roughly half as big, and that dipolar energy is approximately ten times lower.

Experiences of Transforming a Complex Nephrologic Care and Research Database into i2b2 Using the IDRT Tools.

The secondary use of data from electronic medical records has become an important factor to determine and to identify various causes of disease. For this reason, applications like informatics for integrating biology and the bedside (i2b2) offer a GUI-based front end to select patient cohorts. To make use of those tools, however, clinical data need to be extracted from the Electronic Health Record (EHR) system and integrated into the data schema of i2b2. We used TBase, a documentation system for nephrologic transplantations, as a source system and applied the Integrated Data Repository Toolkit (IDRT) for the Extract, Transform, and Load (ETL) process to load the data into i2b2. Since i2b2 uses an entity-attribute-value (EAV) schema, which is a fundamentally different way of modeling data in comparison to a standard relational schema in TBase, we evaluated if (a) the data relationship of the source system entities can still be represented in the i2b2 schema and if (b) the IDRT is a suitable solution for loading the data of a comprehensive data schema like TBase into i2b2. For that reason, we identified entities in the TBase data schema which were relevant for answering questions on cohort identification. By doing so, we found out that the entities had different structures that needed to be handled differently for the ETL process. Furthermore, the use of IDRT revealed shortcomings with regard to large input data and specific data structures that are part of most modern EHR systems. However, this project also showed that our way of modeling the TBase data in i2b2 has been proven to be successful in terms of answering the most common questions of clinicians on cohort identification.

Investigating the Capabilities of FHIR Search for Clinical Trial Phenotyping.

Clinical trials are the foundation of evidence-based medicine and their computerized support has been a recurring theme in medical informatics. One challenging aspect is the representation of eligibility criteria in a machine-readable format to automate the identification of suitable participants. In this study, we investigate the capabilities for expressing trial eligibility criteria via the search functionality specified in HL7 FHIR, an emerging standard for exchanging healthcare information electronically which also defines a set of operations for searching for health record data. Using a randomly sampled subset of 303 eligibility criteria from ClinicalTrials.gov yielded a 34 % success rate in representing them using the FHIR search semantics. While limitations are present, the FHIR search semantics are a viable tool for supporting preliminary trial eligibility assessment.