Update of the Minimum Information About BIobank Data Sharing (MIABIS) Core Terminology to the 3rd Version.

Introduction: The Minimum Information About BIobank Data Sharing (MIABIS) is a biobank-specific terminology enabling the sharing of biobank-related data for different purposes across a wide range of database implementations. After 4 years in use and with the first version of the individual-level MIABIS component Sample, Sample donor, and Event, it was necessary to revise the terminology, especially to include biobanks that work more in the data domain than with samples. Materials & Methods: Nine use-cases representing different types of biobanks, studies, and networks participated in the development work. They represent types of data, specific sample types, or levels of organization that were not included earlier in MIABIS. To support our revision of the Biobank entity, we conducted a survey of European biobanks to chart the services they provide. An important stakeholder group for biobanks include researchers as the main users of biobanks. To be able to render MIABIS more researcher-friendly, we collected different sample/data requests to analyze the terminology adjustment needs in detail. During the update process, the Core terminology was iteratively reviewed by a large group of experts until a consensus was reached. Results: With this update, MIABIS was adjusted to encompass data-driven biobanks and to include data collections, while also describing the services and capabilities biobanks offer to their users, besides the retrospective samples. The terminology was also extended to accommodate sample and data collections of nonhuman origin. Additionally, a set of organizational attributes was compiled to describe networks. Discussion: The usability of MIABIS Core v3 was increased by extending it to cover more topics of the biobanking domain. Additionally, the focus was on a more general terminology and harmonization of attributes with the individual-level entities Sample, Sample donor, and Event to keep the overall terminology minimal. With this work, the internal semantics of the MIABIS terminology was improved.

Remote Assessment for ALS using Multimodal Dialog Agents: Data Quality, Feasibility and Task Compliance.

We investigate the feasibility, task compliance and audiovisual data quality of a multimodal dialog-based solution for remote assessment of Amyotrophic Lateral Sclerosis (ALS). 53 people with ALS and 52 healthy controls interacted with Tina, a cloud-based conversational agent, in performing speech tasks designed to probe various aspects of motor speech function while their audio and video was recorded. We rated a total of 250 recordings for audio/video quality and participant task compliance, along with the relative frequency of different issues observed. We observed excellent compliance (98%) and audio (95.2%) and visual quality rates (84.8%), resulting in an overall yield of 80.8% recordings that were both compliant and of high quality. Furthermore, recording quality and compliance were not affected by level of speech severity and did not differ significantly across end devices. These findings support the utility of dialog systems for remote monitoring of speech in ALS.

A multimodal dialog approach to mental state characterization in clinically depressed, anxious, and suicidal populations.

Background: The rise of depression, anxiety, and suicide rates has led to increased demand for telemedicine-based mental health screening and remote patient monitoring (RPM) solutions to alleviate the burden on, and enhance the efficiency of, mental health practitioners. Multimodal dialog systems (MDS) that conduct on-demand, structured interviews offer a scalable and cost-effective solution to address this need. Objective: This study evaluates the feasibility of a cloud based MDS agent, Tina, for mental state characterization in participants with depression, anxiety, and suicide risk. Method: Sixty-eight participants were recruited through an online health registry and completed 73 sessions, with 15 (20.6%), 21 (28.8%), and 26 (35.6%) sessions screening positive for depression, anxiety, and suicide risk, respectively using conventional screening instruments. Participants then interacted with Tina as they completed a structured interview designed to elicit calibrated, open-ended responses regarding the participants' feelings and emotional state. Simultaneously, the platform streamed their speech and video recordings in real-time to a HIPAA-compliant cloud server, to compute speech, language, and facial movement-based biomarkers. After their sessions, participants completed user experience surveys. Machine learning models were developed using extracted features and evaluated with the area under the receiver operating characteristic curve (AUC). Results: For both depression and suicide risk, affected individuals tended to have a higher percent pause time, while those positive for anxiety showed reduced lip movement relative to healthy controls. In terms of single-modality classification models, speech features performed best for depression (AUC = 0.64; 95% CI = 0.51-0.78), facial features for anxiety (AUC = 0.57; 95% CI = 0.43-0.71), and text features for suicide risk (AUC = 0.65; 95% CI = 0.52-0.78). Best overall performance was achieved by decision fusion of all models in identifying suicide risk (AUC = 0.76; 95% CI = 0.65-0.87). Participants reported the experience comfortable and shared their feelings. Conclusion: MDS is a feasible, useful, effective, and interpretable solution for RPM in real-world clinical depression, anxiety, and suicidal populations. Facial information is more informative for anxiety classification, while speech and language are more discriminative of depression and suicidality markers. In general, combining speech, language, and facial information improved model performance on all classification tasks.

Spectral signatures of a unique charge density wave in Ta2NiSe7.

Charge Density Waves (CDW) are commonly associated with the presence of near-Fermi level states which are separated from others, or "nested", by a wavector of q. Here we use Angle-Resolved Photo Emission Spectroscopy (ARPES) on the CDW material Ta2NiSe7 and identify a total absence of any plausible nesting of states at the primary CDW wavevector q. Nevertheless we observe spectral intensity on replicas of the hole-like valence bands, shifted by a wavevector of q, which appears with the CDW transition. In contrast, we find that there is a possible nesting at 2q, and associate the characters of these bands with the reported atomic modulations at 2q. Our comprehensive electronic structure perspective shows that the CDW-like transition of Ta2NiSe7 is unique, with the primary wavevector q being unrelated to any low-energy states, but suggests that the reported modulation at 2q, which would plausibly connect low-energy states, might be more important for the overall energetics of the problem.

Organic Molecules as Origin of Visible-Range Single Photon Emission from Hexagonal Boron Nitride and Mica.

The discovery of room-temperature single-photon emitters (SPEs) hosted by two-dimensional hexagonal boron nitride (2D hBN) has sparked intense research interest. Although emitters in the vicinity of 2 eV have been studied extensively, their microscopic identity has remained elusive. The discussion of this class of SPEs has centered on point defects in the hBN crystal lattice, but none of the candidate defect structures have been able to capture the great heterogeneity in emitter properties that is observed experimentally. Employing a widely used sample preparation protocol but disentangling several confounding factors, we demonstrate conclusively that heterogeneous single-photon emission at ∼2 eV associated with hBN originates from organic molecules, presumably aromatic fluorophores. The appearance of those SPEs depends critically on the presence of organic processing residues during sample preparation, and emitters formed during heat treatment are not located within the hBN crystal as previously thought, but at the hBN/substrate interface. We further demonstrate that the same class of SPEs can be observed in a different 2D insulator, fluorophlogopite mica.

GBA/GBN-position on the feedback of incidental findings in biobank-based research: consensus-based workflow for hospital-based biobanks.

Incidental research findings pose a considerable challenge to hospital-based research biobanks since they are acting as intermediaries between healthcare and research. In a joint action the centralized biobank ibdw (Interdisciplinary Bank of Biomaterials and Data Wuerzburg) together with local authorities drafted a coherent concept to manage incidental research findings in full compliance with relevant ethical and data privacy regulations. The concept was developed and elaborated in close collaboration with the German Biobank Alliance (GBA). Comprehensive documentation of all steps guarantees the traceability of the process. By a mandatory assessment of the findings prior to re-identification of the individual concerned, unnecessary measures can be avoided. The individual's "right not to know" is respected according to the stipulations of the informed consent. As a general principle any communication with the individual occurs exclusively through the hospital and by competent physicians with appropriate knowledge and communication skills. We propose this scheme as a blueprint for reporting workflows for incidental research findings at hospital-based biobanks.

Speech, Facial and Fine Motor Features for Conversation-Based Remote Assessment and Monitoring of Parkinson's Disease.

We present a cloud-based multimodal dialogue platform for the remote assessment and monitoring of speech, facial and fine motor function in Parkinson's Disease (PD) at scale, along with a preliminary investigation of the efficacy of the various metrics automatically extracted by the platform. 22 healthy controls and 38 people with Parkinson's Disease (pPD) were instructed to complete four interactive sessions, spaced a week apart, on the platform. Each session involved a battery of tasks designed to elicit speech, facial movements and finger movements. We find that speech, facial kinematic and finger movement dexterity metrics show statistically significant differences between controls and pPD. We further investigate the sensitivity, specificity, reliability and generalisability of these metrics. Our results offer encouraging evidence for the utility of automatically-extracted audiovisual analytics in remote mon-itoring of PD and other movement disorders.

High-resolution pediatric reference intervals for 15 biochemical analytes described using fractional polynomials.

OBJECTIVES: Assessment of children's laboratory test results requires consideration of the extensive changes that occur during physiological development and result in pronounced sex- and age-specific dynamics in many biochemical analytes. Pediatric reference intervals have to account for these dynamics, but ethical and practical challenges limit the availability of appropriate pediatric reference intervals that cover children from birth to adulthood. We have therefore initiated the multi-center data-driven PEDREF project (Next-Generation Pediatric Reference Intervals) to create pediatric reference intervals using data from laboratory information systems. METHODS: We analyzed laboratory test results from 638,683 patients (217,883-982,548 samples per analyte, a median of 603,745 test results per analyte, and 10,298,067 test results in total) performed during patient care in 13 German centers. Test results from children with repeat measurements were discarded, and we estimated the distribution of physiological test results using a validated statistical approach (kosmic). RESULTS: We report continuous pediatric reference intervals and percentile charts for alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, γ-glutamyl-transferase, total protein, albumin, creatinine, urea, sodium, potassium, calcium, chloride, anorganic phosphate, and magnesium. Reference intervals are provided as tables and fractional polynomial functions (i.e., mathematical equations) that can be integrated into laboratory information systems. Additionally, Z-scores and percentiles enable the normalization of test results by age and sex to facilitate their interpretation across age groups. CONCLUSIONS: The provided reference intervals and percentile charts enable precise assessment of laboratory test results in children from birth to adulthood. Our findings highlight the pronounced dynamics in many biochemical analytes in neonates, which require particular consideration in reference intervals to support clinical decision making most effectively.

Higher number of multidisciplinary tumor board meetings per case leads to improved clinical outcome.

BACKGROUND: This analysis aims at evaluating the impact of multidisciplinary tumor boards on clinical outcome of multiple tumor entities, the effect of the specific number of multidisciplinary tumor boards and potential differences between the tumor entities. METHODS: By a matched-pair analysis we compared the response to treatment, overall survival, relapse or disease free survival and progression free survival of patients whose cases were discussed in a tumor board meeting with patients whose cases were not. It was performed with patients registered in the cancer registry of the University of Bonn and diagnosed between 2010 and 2016. After the matching process with a pool of 7262 patients a total of 454 patients with 66 different tumor types were included in this study. RESULTS: First, patients with three or more multidisciplinary tumor board meetings in their history show a significantly better overall survival than patients with no tumor board meeting. Second, response to treatment, relapse free survival and time to progression were not found to be significantly different. Third, there was no significant difference for a specific tumor entity. CONCLUSION: This study revealed a positive impact of a higher number of multidisciplinary tumor boards on the clinical outcome. Also, our analysis hints towards a positive effect of multidisciplinary tumor boards on overall survival.

Extending the Minimum Information About BIobank Data Sharing Terminology to Describe Samples, Sample Donors, and Events.

Introduction: The Minimum Information About BIobank data Sharing (MIABIS) was initiated in 2012. MIABIS aims to create a common biobank terminology to facilitate data sharing in biobanks and sample collections. The MIABIS Core terminology consists of three components describing biobanks, sample collections, and studies, in which information on samples and sample donors is provided at aggregated form. However, there is also a need to describe samples and sample donors at an individual level to allow more elaborate queries on available biobank samples and data. Therefore the MIABIS terminology has now been extended with components describing samples and sample donors at an individual level. Materials and Methods: The components were defined according to specific scope and use cases by a large group of experts, and through several cycles of reviews, according to the new MIABIS governance model of BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium). The guiding principles applied in developing these components included the following terms: model should consider only samples of human origin, model should be applicable to all types of samples and all sample donors, and model should describe the current status of samples stored in a given biobank. Results: A minimal set of standard attributes for defining samples and sample donors is presented here. We added an "event" component to describe attributes that are not directly describing samples or sample donors but are tightly related to them. To better utilize the generic data model, we suggest a procedure by which interoperability can be promoted, using specific MIABIS profiles. Discussion: The MIABIS sample and donor component extensions and the new generic data model complement the existing MIABIS Core 2.0 components, and substantially increase the potential usability of this terminology for better describing biobank samples and sample donors. They also support the use of individual level data about samples and sample donors to obtain accurate and detailed biobank availability queries.

How Clean Is Clean? Recipes for van der Waals Heterostructure Cleanliness Assessment.

Van der Waals (vdW) heterostructures, artificial stacks of two-dimensional materials, present an exciting platform to explore new physical phenomena and unique applications. An important and increasingly recognized factor limiting the electrical and optical performance of heterostructure samples is the presence of interfacial contamination. In published work reporting various heterostructure fabrication methods, evidence for the cleanliness of samples is often presented as optical and atomic force microscopy images, typically exhibiting a completely flat topography. In this work, we demonstrate that such samples may nonetheless contain a uniformly thin layer of contaminants at the heterostructure interface. As alternatives, we propose two robust visualization methods that are highly sensitive to such residues, based on photoluminescence mapping and on selective solvent diffusion. The detection capability and straightforward implementation of these two imaging techniques make them powerful tools to assess and improve the cleanliness of a wide variety of fabrication techniques for heterostructures comprising any combination of vdW materials.

Enhanced Recovery Deviation and Failure After Pancreaticoduodenectomy: Causative Factors and Impact.

BACKGROUND: Enhanced recovery after surgery (ERAS) following pancreaticoduodenectomy (PD) is popular and safe. This study aimed to describe the incidence, causative factors, and clinical impact of deviation from and failure of an ERAS protocol. MATERIALS AND METHODS: A prospective cohort analysis of elective PD patients managed according to an ERAS protocol between October 2015 and June 2018 was performed. Univariate and multivariate analyses identified variables associated with protocol deviation and failure. The relationship between protocol deviation and failure was also explored. RESULTS: A total of 97 patients were identified comprising of 46 females and 51 males. The median age was 68 y (range 17-85). Twenty-one patients (21.6%) suffered serious complications, whereas two (2.1%) died perioperatively. The median length of stay (LoS) was 14 d (6-36). In total, 73 (75.3%) patients deviated, whereas 39 (40.2%) failed the protocol. On univariate analysis, protocol deviation was associated with male gender, surgery time ≥270 min, and prolonged LoS. On multivariate analysis only prolonged LoS remained significant. Only serious complications were associated with protocol failure on multivariate analysis. Protocol deviation was not associated with significant complications nor ERAS protocol failure. CONCLUSIONS: ERAS protocol deviation does not alter the course of those destined to protocol failure. Greater understanding into the causative factors of either protocol deviation or failure may be the only way to personalize care and realize the maximal benefit of ERAS in this specific group of patients.

Next-generation reference intervals for pediatric hematology.

Background Interpreting hematology analytes in children is challenging due to the extensive changes in hematopoiesis that accompany physiological development and lead to pronounced sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, and limitations in current approaches to laboratory test result displays restrict their use when guiding clinical decisions. Methods We employed an improved data-driven approach to create percentile charts from laboratory data collected during patient care in 10 German centers (9,576,910 samples from 358,292 patients, 412,905-1,278,987 samples per analyte). We demonstrate visualization of hematology test results using percentile charts and z-scores (www.pedref.org/hematology) and assess the potential of percentiles and z-scores to support diagnosis of different hematological diseases. Results We created percentile charts for hemoglobin, hematocrit, red cell indices, red cell count, red cell distribution width, white cell count and platelet count in girls and boys from birth to 18 years of age. Comparison of pediatricians evaluating complex clinical scenarios using percentile charts versus conventional/tabular representations shows that percentile charts can enhance physician assessment in selected example cases. Age-specific percentiles and z-scores, compared with absolute test results, improve the identification of children with blood count abnormalities and the discrimination between different hematological diseases. Conclusions The provided reference intervals enable precise assessment of pediatric hematology test results. Representation of test results using percentiles and z-scores facilitates their interpretation and demonstrates the potential of digital approaches to improve clinical decision-making.

[INTRACHOLECYSTIC PAPILLARY-TUBULAR NEOPLASM: A NEW PATHOLOGY OF THE GALLBLADDER?]

INTRODUCTION: The clinicopathologic characterization of tumoral intra-epithelial neoplasms of the gallbladder is fairly limited compared to that of similar tumors of the pancreatobiliary system. Until recently, pre-malignant lesions of the gallbladder were mostly reported as adenomas, which were microscopic and therefore regarded as benign and clinically inconsequential, whereas papillary lesions have been largely regarded as a papillary subtype of gallbladder invasive adenocarcinoma. In an attempt to create a unified terminology for these tumors, the term Intracholecystic papillary-tubular neoplasm (ICPN) was proposed to include all exophytic intra-epithelial tumors of the gallbladder measuring ≥1 cm under one category. A few studies which have retrospectively analyzed tumors fulfilling this category found them to be remarkable analogous to the more well-characterized intra-epithelial tumors of the pancreato-biliary system such as IPMN of the pancreas and IPNB of the bile ducts and as such they also represent an 'adenoma-carcinoma' sequence in the gallbladder. Since then a number of case series have been published which attempted to characterize the clinical and pathological features of these tumors and their relationship with invasive carcinoma. In this paper we report three cases of ICPN which represent different stages of the 'adenoma-carcinoma' sequence.

Pyogenic Liver Abscess with No Predisposing Risk Factors.

Pyogenic liver abscesses (PLA) are an uncommon cause of hospitalization in the United States. The majority of such cases are polymicrobial and are most commonly caused by seeding of infection from the biliary system. PLA is frequently associated with specific comorbidities such as diabetes mellitus, history of liver transplant, underlying hepatobiliary, or pancreatic disease. Herein, we describe a 47-year-old healthy male with no known risk factors associated with PLA who presented to the hospital with acute fever, abdominal pain, and dark colored urine. Initially the patient had a negative right upper quadrant ultrasound. However, the patient continued to have persistent fevers and abnormal liver biochemistries with negative liver serology that led to checking a magnetic resonance cholangiopancreatography which suggested multiple liver abscesses. Computer tomography guided aspiration revealed a monobacterial Streptococcus species within the abscess, which is commonly associated with arterial bacteremia as a source of PLA. Arterial bacteremia is one of most rare causes of PLA. The patient's septic workup was negative for any source of infection. This case demonstrates a patient with no risk factors who was diagnosed with PLA caused by apparent arterial bacteremia with no clear source of infection.

Using REACH registration data to rank the environmental emission potential of persistent and mobile organic chemicals.

Organic chemicals that are persistent and mobile in the aquatic environment exhibit a hazard to contaminate drinking water resources. In this study an emission score model was developed to rank the potential of substances registered under the REACH legislation to be emitted into the environment. It was applied to a list of 2167 REACH registered substances that were previously identified to be persistent and mobile organic chemicals (PMOCs) in groundwater or to be hydrolyzed to form transformation products fulfilling the PMOC criteria. The emission score model is based on the tonnage placed on the European market and on seven emission-related use characteristics (high release to environment, wide dispersive use, intermediate use, closed system use, professional use, consumer use, and substance in article), reported in the companies' registrations under REACH. Applying the model resulted in a list of 1110 substances (936 PMOCs and 174 precursors to PMOCs) that were estimated to be released into the environment, while 1054 substances had indicators of negligible environmental emissions and 3 substances could not be evaluated due to severe data gaps. The 936 PMOCs and the 174 precursors were ranked in two lists with regard to their emission potential. The model was shown to be fit for purpose in terms of suggesting and prioritizing substances for scientific investigations with a focus on environmental water quality. Though targeted for PMOCs, the presented scoring system is illustrative of how REACH registration data can be used to assess the emission potential of various substances.

Probing defect dynamics in monolayer MoS2 via noise nanospectroscopy.

Monolayer molybdenum disulfide (MoS2) has received intense interest as a strong candidate for next-generation electronics. However, the observed electrical properties of monolayer MoS2 exhibit several anomalies: samples universally exhibit unexpectedly low mobilities, n-type characteristics, and large contact resistances regardless of contact metal work function. These anomalies have been attributed to the presence of defects, but the mechanism behind this link has been elusive. Here we report the ionization dynamics of sulfur monovacancy defects in monolayer MoS2 probed via noise nanospectroscopy, realized by combining noise-current analysis with atomic force microscopy. Due to the nanoscale dimension of the in situ channel defined by the tip size, we probe a few monovacancy defects at a time. Monovacancy defects exhibit switching between three distinct ionization configurations, corresponding to charge states 0, -1, and -2. The most probable charge configurations are 0 and -1, providing a plausible mechanism to explain the observed anomalies of MoS2 monolayers.

Pediatric reference intervals for alkaline phosphatase.

BACKGROUND: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. METHODS: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method. RESULTS: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. CONCLUSIONS: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.