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Salivary gland tumors (SGTs) are a relevant, highly diverse subgroup of head and neck tumors whose entity determination can be difficult. Confocal Raman imaging in combination with multivariate data analysis may possibly support their correct classification. For the analysis of the translational potential of Raman imaging in SGT determination, a multi-stage evaluation process is necessary. By measuring a sample set of Warthin tumor, pleomorphic adenoma and non-tumor salivary gland tissue, Raman data were obtained and a thorough Raman band analysis was performed. This evaluation revealed highly overlapping Raman patterns with only minor spectral differences. Consequently, a principal component analysis (PCA) was calculated and further combined with a discriminant analysis (DA) to enable the best possible distinction. The PCA-DA model was characterized by accuracy, sensitivity, selectivity and precision values above 90% and validated by predicting model-unknown Raman spectra, of which 93% were classified correctly. Thus, we state our PCA-DA to be suitable for parotid tumor and non-salivary salivary gland tissue discrimination and prediction. For evaluation of the translational potential, further validation steps are necessary.
Fragestellung: Das klinische Standardverfahren und Referenz der Schlafmessung und der Klassifizierung der einzelnen Schlafstadien ist die Polysomnographie (PSG). Alternative Ansätze zu diesem aufwändigen Verfahren könnten einige Vorteile bieten, wenn die Messungen auf eine komfortablere Weise durchgeführt werden. Das Hauptziel dieser Forschung Studie ist es, einen Algorithmus für die automatische Klassifizierung von Schlafstadien zu entwickeln, der ausschließlich Bewegungs- und Atmungssignale verwendet [1].
Patienten und Methoden: Nach der Analyse der aktuellen Forschungsarbeiten haben wir multinomiale logistische Regression als Grundlage für den Ansatz gewählt [2]. Um die Genauigkeit der Auswertung zu erhöhen, wurden vier Features entwickelt, die aus Bewegungs- und Atemsignalen abgeleitet wurden. Für die Auswertung wurden die nächtlichen Aufzeichnungen von 35 Personen verwendet, die von der Charité-Universitätsmedizin Berlin zur Verfügung gestellt wurden. Das Durchschnittsalter der Teilnehmer betrug 38,6 +/– 14,5 Jahre und der BMI lag bei durchschnittlich 24,4 +/– 4,9 kg/m2. Da der Algorithmus mit drei Stadien arbeitet, wurden die Stadien N1, N2 und N3 zum NREM-Stadium zusammengeführt. Der verfügbare Datensatz wurde strikt aufgeteilt: in einen Trainingsdatensatz von etwa 100 h und in einen Testdatensatz mit etwa 160 h nächtlicher Aufzeichnungen. Beide Datensätze wiesen ein ähnliches Verhältnis zwischen Männern und Frauen auf, und der durchschnittliche BMI wies keine signifikante Abweichung auf.
Ergebnisse: Der Algorithmus wurde implementiert und lieferte erfolgreiche Ergebnisse: die Genauigkeit der Erkennung von Wach-/NREM-/REM-Phasen liegt bei 73 %, mit einem Cohen’s Kappa von 0,44 für die analysierten 19.324 Schlafepochen von jeweils 30 s. Die beobachtete gewisse Überschätzung der NREM-Phase lässt sich teilweise durch ihre Prävalenz in einem typischen Schlafmuster erklären. Selbst die Verwendung eines ausbalancierten Trainingsdatensatzes konnte dieses Problem nicht vollständig lösen.
Schlussfolgerungen: Die erreichten Ergebnisse haben die Tauglichkeit des Ansatzes prinzipiell bestätigt. Dieser hat den Vorteil, dass nur Bewegungs- und Atemsignale verwendet werden, die mit weniger Aufwand und komfortabler für Benutzer aufgezeichnet werden können als z. B. Herz- oder EEG-Signale. Daher stellt das neue System eine deutliche Verbesserung im Vergleich zu bestehenden Ansätzen dar. Die Zusammenführung der beschriebenen algorithmischen Software mit dem in [1] beschriebenen Hardwaresystem zur Messung von Atem- und Körperbewegungssignalen zu einem autonomen, berührungslosen System zur kontinuierlichen Schlafüberwachung ist eine mögliche Richtung zukünftiger Arbeiten.
Gender Marketing gewinnt sowohl in der Marketing-Theorie als auch in der Unternehmenspraxis zunehmend an Bedeutung. Der Unterschied zwischen den Geschlechtern zeigt sich nicht nur in unterschiedlichen Fähigkeiten und Einstellungen, sondern auch in verschiedenen Bedürfnissen und im Kaufverhalten. Viele Produkte werden von Männern für Männer entwickelt. Produkte, die sich speziell an Frauen richten, werden häufig gemäß dem Motto „pink it and shrink it“ auf den Markt gebracht. Eine erfolgreiche Umsetzung von Gender-Aspekten ist für Unternehmen eine wichtige Marketing-Herausforderung für die Zukunft.
Introduction: Telemedicine reduces greenhouse gas emissions (CO2eq); however, results of studies vary extremely in dependence of the setting. This is the first study to focus on effects of telemedicine on CO2 imprint of primary care.
Methods: We conducted a comprehensive retrospective study to analyze total CO2eq emissions of kilometers (km) saved by telemedical consultations. We categorized prevented and provoked patient journeys, including pharmacy visits. We calculated CO2eq emission savings through primary care telemedical consultations in comparison to those that would have occurred without telemedicine. We used the comprehensive footprint approach, including all telemedical cases and the CO2eq emissions by the telemedicine center infrastructure. In order to determine the net ratio of CO2eq emissions avoided by the telemedical center, we calculated the emissions associated with the provision of telemedical consultations (including also the total consumption of physicians’ workstations) and subtracted them from the total of avoided CO2eq emissions. Furthermore, we also considered patient cases in our calculation that needed to have an in-person visit after the telemedical consultation. We calculated the savings taking into account the source of the consumed energy (renewable or not).
Results: 433 890 telemedical consultations overall helped save 1 800 391 km in travel. On average, 1 telemedical consultation saved 4.15 km of individual transport and consumed 0.15 kWh. We detected savings in almost every cluster of patients. After subtracting the CO2eq emissions caused by the telemedical center, the data reveal savings of 247.1 net tons of CO2eq emissions in total and of 0.57 kg CO2eq per telemedical consultation. The comprehensive footprint approach thus indicated a reduced footprint due to telemedicine in primary care.
Discussion: Integrating a telemedical center into the health care system reduces the CO2 footprint of primary care medicine; this is true even in a densely populated country with little use of cars like Switzerland. The insight of this study complements previous studies that focused on narrower aspects of telemedical consultations.
Recent advances in artificial intelligence have enabled promising applications in neurosurgery that can enhance patient outcomes and minimize risks. This paper presents a novel system that utilizes AI to aid neurosurgeons in precisely identifying and localizing brain tumors. The system was trained on a dataset of brain MRI scans and utilized deep learning algorithms for segmentation and classification. Evaluation of the system on a separate set of brain MRI scans demonstrated an average Dice similarity coefficient of 0.87. The system was also evaluated through a user experience test involving the Department of Neurosurgery at the University Hospital Ulm, with results showing significant improvements in accuracy, efficiency, and reduced cognitive load and stress levels. Additionally, the system has demonstrated adaptability to various surgical scenarios and provides personalized guidance to users. These findings indicate the potential for AI to enhance the quality of neurosurgical interventions and improve patient outcomes. Future work will explore integrating this system with robotic surgical tools for minimally invasive surgeries.
Purpose
For the modeling, execution, and control of complex, non-standardized intraoperative processes, a modeling language is needed that reflects the variability of interventions. As the established Business Process Model and Notation (BPMN) reaches its limits in terms of flexibility, the Case Management Model and Notation (CMMN) was considered as it addresses weakly structured processes.
Methods
To analyze the suitability of the modeling languages, BPMN and CMMN models of a Robot-Assisted Minimally Invasive Esophagectomy and Cochlea Implantation were derived and integrated into a situation recognition workflow. Test cases were used to contrast the differences and compare the advantages and disadvantages of the models concerning modeling, execution, and control. Furthermore, the impact on transferability was investigated.
Results
Compared to BPMN, CMMN allows flexibility for modeling intraoperative processes while remaining understandable. Although more effort and process knowledge are needed for execution and control within a situation recognition system, CMMN enables better transferability of the models and therefore the system. Concluding, CMMN should be chosen as a supplement to BPMN for flexible process parts that can only be covered insufficiently by BPMN, or otherwise as a replacement for the entire process.
Conclusion
CMMN offers the flexibility for variable, weakly structured process parts, and is thus suitable for surgical interventions. A combination of both notations could allow optimal use of their advantages and support the transferability of the situation recognition system.
The scoring of sleep stages is one of the essential tasks in sleep analysis. Since a manual procedure requires considerable human and financial resources, and incorporates some subjectivity, an automated approach could result in several advantages. There have been many developments in this area, and in order to provide a comprehensive overview, it is essential to review relevant recent works and summarise the characteristics of the approaches, which is the main aim of this article. To achieve it, we examined articles published between 2018 and 2022 that dealt with the automated scoring of sleep stages. In the final selection for in-depth analysis, 125 articles were included after reviewing a total of 515 publications. The results revealed that automatic scoring demonstrates good quality (with Cohen's kappa up to over 0.80 and accuracy up to over 90%) in analysing EEG/EEG + EOG + EMG signals. At the same time, it should be noted that there has been no breakthrough in the quality of results using these signals in recent years. Systems involving other signals that could potentially be acquired more conveniently for the user (e.g. respiratory, cardiac or movement signals) remain more challenging in the implementation with a high level of reliability but have considerable innovation capability. In general, automatic sleep stage scoring has excellent potential to assist medical professionals while providing an objective assessment.
Sleep is extremely important for physical and mental health. Although polysomnography is an established approach in sleep analysis, it is quite intrusive and expensive. Consequently, developing a non-invasive and non-intrusive home sleep monitoring system with minimal influence on patients, that can reliably and accurately measure cardiorespiratory parameters, is of great interest. The aim of this study is to validate a non-invasive and unobtrusive cardiorespiratory parameter monitoring system based on an accelerometer sensor. This system includes a special holder to install the system under the bed mattress. The additional aim is to determine the optimum relative system position (in relation to the subject) at which the most accurate and precise values of measured parameters could be achieved. The data were collected from 23 subjects (13 males and 10 females). The obtained ballistocardiogram signal was sequentially processed using a sixth-order Butterworth bandpass filter and a moving average filter. As a result, an average error (compared to reference values) of 2.24 beats per minute for heart rate and 1.52 breaths per minute for respiratory rate was achieved, regardless of the subject’s sleep position. For males and females, the errors were 2.28 bpm and 2.19 bpm for heart rate and 1.41 rpm and 1.30 rpm for respiratory rate. We determined that placing the sensor and system at chest level is the preferred configuration for cardiorespiratory measurement. Further studies of the system’s performance in larger groups of subjects are required, despite the promising results of the current tests in healthy subjects.
In order to ensure sufficient recovery of the human body and brain, healthy sleep is indispensable. For this purpose, appropriate therapy should be initiated at an early stage in the case of sleep disorders. For some sleep disorders (e.g., insomnia), a sleep diary is essential for diagnosis and therapy monitoring. However, subjective measurement with a sleep diary has several disadvantages, requiring regular action from the user and leading to decreased comfort and potential data loss. To automate sleep monitoring and increase user comfort, one could consider replacing a sleep diary with an automatic measurement, such as a smartwatch, which would not disturb sleep. To obtain accurate results on the evaluation of the possibility of such a replacement, a field study was conducted with a total of 166 overnight recordings, followed by an analysis of the results. In this evaluation, objective sleep measurement with a Samsung Galaxy Watch 4 was compared to a subjective approach with a sleep diary, which is a standard method in sleep medicine. The focus was on comparing four relevant sleep characteristics: falling asleep time, waking up time, total sleep time (TST), and sleep efficiency (SE). After evaluating the results, it was concluded that a smartwatch could replace subjective measurement to determine falling asleep and waking up time, considering some level of inaccuracy. In the case of SE, substitution was also proved to be possible. However, some individual recordings showed a higher discrepancy in results between the two approaches. For its part, the evaluation of the TST measurement currently does not allow us to recommend substituting the measurement method for this sleep parameter. The appropriateness of replacing sleep diary measurement with a smartwatch depends on the acceptable levels of discrepancy. We propose four levels of similarity of results, defining ranges of absolute differences between objective and subjective measurements. By considering the values in the provided table and knowing the required accuracy, it is possible to determine the suitability of substitution in each individual case. The introduction of a “similarity level” parameter increases the adaptability and reusability of study findings in individual practical cases.
Background: Polysomnography (PSG) is the gold standard for detecting obstructive sleep apnea (OSA). However, this technique has many disadvantages when using it outside the hospital or for daily use. Portable monitors (PMs) aim to streamline the OSA detection process through deep learning (DL).
Materials and methods: We studied how to detect OSA events and calculate the apnea-hypopnea index (AHI) by using deep learning models that aim to be implemented on PMs. Several deep learning models are presented after being trained on polysomnography data from the National Sleep Research Resource (NSRR) repository. The best hyperparameters for the DL architecture are presented. In addition, emphasis is focused on model explainability techniques, concretely on Gradient-weighted Class Activation Mapping (Grad-CAM).
Results: The results for the best DL model are presented and analyzed. The interpretability of the DL model is also analyzed by studying the regions of the signals that are most relevant for the model to make the decision. The model that yields the best result is a one-dimensional convolutional neural network (1D-CNN) with 84.3% accuracy.
Conclusion: The use of PMs using machine learning techniques for detecting OSA events still has a long way to go. However, our method for developing explainable DL models demonstrates that PMs appear to be a promising alternative to PSG in the future for the detection of obstructive apnea events and the automatic calculation of AHI.
In dieser Arbeit werden Anforderungen an ein digitales Referenzmodell der Cell and Gene Therapy (CGT) Supply Chain mittels systematischer Literaturrecherche unter partieller Anwendung der Preferred-Reporting-Items-for-Systematic-Reviews-and-Meta-Analyses(PRISMA)-2020-Methode erarbeitet und erläutert. Die Ergebnisse der Literaturrecherche untermauern, dass die CGT Supply Chain standardisierte und automatisierte Prozesse benötigt, gewissen Transportanforderungen gerecht werden sowie eine lückenlose Rückverfolgbarkeit gewährleisten können muss. Die Anforderungen an das Referenzmodell lehnen sich z. T. an die Anforderungen des klassischen Supply-Chain-Operations-Reference(SCOR)-Modells an, bedürfen jedoch einer Veränderung und Weiterentwicklung unter Beachtung der Besonderheiten der CGT Supply Chain. Auf Basis eines Referenzmodells für die CGT Supply Chain, das die aus dieser Arbeit identifizierten Anforderungen beachtet, kann eine übergeordnete Managementplattform aufgebaut werden. Mit der digitalen Abbildung und Vernetzung aller Aktivitäten ist der Grundstein für die Integration in ein Enterprise-Resource-Planning(ERP)-System zum effektiven Data und Process Mining gelegt. Durch eine zunehmend bessere Datenqualität und -quantität entlang der Prozesse der CGT Supply Chain lassen sich verstärkt Informationen über die Prozesse selbst generieren, aus denen weitere Verbesserungsansätze hervorgehen. Eine CGT-Managementplattform bildet demnach die Grundlage für alle Prozesse innerhalb der CGT Supply Chain für einen kontinuierlichen Verbesserungsprozess.
Due to the wide variety of benign and malignant salivary gland tumors, classification and malignant behavior determination based on histomorphological criteria can be difficult and sometimes impossible. Spectroscopical procedures can acquire molecular biological information without destroying the tissue within the measurement processes. Since several tissue preparation procedures exist, our study investigated the impact of these preparations on the chemical composition of healthy and tumorous salivary gland tissue by Fourier-transform infrared (FTIR) microspectroscopy. Sequential tissue cross-sections were prepared from native, formalin-fixed and formalin-fixed paraffin-embedded (FFPE) tissue and analyzed. The FFPE cross-sections were dewaxed and remeasured. By using principal component analysis (PCA) combined with a discriminant analysis (DA), robust models for the distinction of sample preparations were built individually for each parotid tissue type. As a result, the PCA-DA model evaluation showed a high similarity between native and formalin-fixed tissues based on their chemical composition. Thus, formalin-fixed tissues are highly representative of the native samples and facilitate a transfer from scientific laboratory analysis into the clinical routine due to their robust nature. Furthermore, the dewaxing of the cross-sections entails the loss of molecular information. Our study successfully demonstrated how FTIR microspectroscopy can be used as a powerful tool within existing clinical workflows.
Die prä-, intra- und postoperative Entitäts- und Dignitätsbestimmung von Speicheldrüsen-tumoren (ST) allein anhand von histomorphologischen Kriterien ist häufig mit großen Unsicherheiten verbunden.
Die Spektren der Raman-Spektroskopie (RS) und der Infrarot-Spektroskopie (IS) enthalten Informationen zu der molekularen Zusammensetzung des untersuchten Gewebes. Ziel der Arbeit war die Etablierung eines Gewebe-Aufarbeitungs-Workflows und die Analyse des Einflusses der Fixierung auf die spektrale Bioinformation. Zudem wird ein Überblick über den Einsatz der RS und IS im Kopf-Hals Bereich gegeben.
Es wurden 10 mm dicke, konsekutive kryo-, formalin- und paraffinfixierte ST-Gewebeschnitte von Zystadenolymphomen (n=5) und pleomorphen Adenomen (n=4) mit der RS und IS untersucht und die Daten multivariat ausgewertet. Die Messungen erfolgten in Korrelation zur Histomorphologie über einen korrespondierenden HE-Schnitt sowohl im Tumorgewebe als auch im gesunden Speicheldrüsengewebe.
In der Mittelwertspektrenanalyse zeigte sich eine deutliche Paraffin-Signatur, Formalin-Fixierung hatte keinen wesentlichen Einfluss. Dies konnte durch die Hauptkomponentenanalyse (PCA) bestätigt werden. Eine Diskriminierung von Tumor- und Nicht-Tumorgewebe durch die PCA und gekoppelte Diskriminanzanalyse war ebenfalls mit beiden spektroskopischen Methoden mit einer hohen Sensitivität möglich.
Für eine Translation von spektralen Verfahren ist das Wissen über Einflussfaktoren auf die spektrale Bioinformation der Gewebeaufarbeitung und -fixierung unabdingbar. Die Integration spektraler Verfahren additiv in bestehende Arbeitsabläufe ist möglich. Der Einfluss der Formalinfixierung auf die spektrale Bioinformation ist gering. Die bioinformatische Analyse der umfangreichen Datensätze ist herausfordernd.
IZKF Würzburg
Rational behavior is a standard assumption in science. Indeed, rationality is required for environmental action towards net-zero emissions or public health interventions during the SARS-CoV-2 pandemic. Yet, little is known about the elements of rationality. This paper explores a dualism of rationality comprised of optimality and consistency. By designing a new guessing game, we experimentally uncover and disentangle two building blocks of human rationality: the notions of optimality and consistency. We find evidence that rationality is largely associated to optimality and weakly to consistency. Remarkably, under uncertainty, rationality gradually shifts to a heuristic notion. Our findings provide insights to better understand human decision making.
Purpose
Supporting the surgeon during surgery is one of the main goals of intelligent ORs. The OR-Pad project aims to optimize the information flow within the perioperative area. A shared information space should enable appropriate preparation and provision of relevant information at any time before, during, and after surgery.
Methods
Based on previous work on an interaction concept and system architecture for the sterile OR-Pad system, we designed a user interface for mobile and intraoperative (stationary) use, focusing on the most important functionalities like clear information provision to reduce information overload. The concepts were transferred into a high-fidelity prototype for demonstration purposes. The prototype was evaluated from different perspectives, including a usability study.
Results
The prototype’s central element is a timeline displaying all available case information chronologically, like radiological images, labor findings, or notes. This information space can be adapted for individual purposes (e.g., highlighting a tumor, filtering for own material). With the mobile and intraoperative mode of the system, relevant information can be added, preselected, viewed, and extended during the perioperative process. Overall, the evaluation showed good results and confirmed the vision of the information system.
Conclusion
The high-fidelity prototype of the information system OR-Pad focuses on supporting the surgeon via a timeline making all available case information accessible before, during, and after surgery. The information space can be personalized to enable targeted support. Further development is reasonable to optimize the approach and address missing or insufficient aspects, like the holding arm and sterility concept or new desired features.
Background
Personalized medicine requires the integration and analysis of vast amounts of patient data to realize individualized care. With Surgomics, we aim to facilitate personalized therapy recommendations in surgery by integration of intraoperative surgical data and their analysis with machine learning methods to leverage the potential of this data in analogy to Radiomics and Genomics.
Methods
We defined Surgomics as the entirety of surgomic features that are process characteristics of a surgical procedure automatically derived from multimodal intraoperative data to quantify processes in the operating room. In a multidisciplinary team we discussed potential data sources like endoscopic videos, vital sign monitoring, medical devices and instruments and respective surgomic features. Subsequently, an online questionnaire was sent to experts from surgery and (computer) science at multiple centers for rating the features’ clinical relevance and technical feasibility.
Results
In total, 52 surgomic features were identified and assigned to eight feature categories. Based on the expert survey (n = 66 participants) the feature category with the highest clinical relevance as rated by surgeons was “surgical skill and quality of performance” for morbidity and mortality (9.0 ± 1.3 on a numerical rating scale from 1 to 10) as well as for long-term (oncological) outcome (8.2 ± 1.8). The feature category with the highest feasibility to be automatically extracted as rated by (computer) scientists was “Instrument” (8.5 ± 1.7). Among the surgomic features ranked as most relevant in their respective category were “intraoperative adverse events”, “action performed with instruments”, “vital sign monitoring”, and “difficulty of surgery”.
Conclusion
Surgomics is a promising concept for the analysis of intraoperative data. Surgomics may be used together with preoperative features from clinical data and Radiomics to predict postoperative morbidity, mortality and long-term outcome, as well as to provide tailored feedback for surgeons.
The imaging and force-distance curve modes of atomic force microscopy (AFM) are explored to compare the morphological and mechanical signatures of platelets from patients diagnosed with classical neurodegenerative diseases (NDDs) and healthy individuals. Our data demonstrate the potential of AFM to distinguish between the three NDDs-Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD), and normal healthy platelets. The common features of platelets in the three pathologies are reduced membrane surface roughness, area and height, and enhanced nanomechanics in comparison with healthy cells. These changes might be related to general phenomena associated with reorganization in the platelet membrane morphology and cytoskeleton, a key factor for all platelets’ functions. Importantly, the platelets’ signatures are modified to a different extent in the three pathologies, most significant in ALS, less pronounced in PD and the least in AD platelets, which shows the specificity associated with each pathology. Moreover, different degree of activation, distinct pseudopodia and nanocluster formation characterize ALS, PD and AD platelets. The strongest alterations in the biophysical properties correlate with the highest activation of ALS platelets, which reflect the most significant changes in their nanoarchitecture. The specific platelet signatures that mark each of the studied pathologies can be added as novel biomarkers to the currently used diagnostic tools.
Purpose
Context awareness in the operating room (OR) is important to realize targeted assistance to support actors during surgery. A situation recognition system (SRS) is used to interpret intraoperative events and derive an intraoperative situation from these. To achieve a modular system architecture, it is desirable to de-couple the SRS from other system components. This leads to the need of an interface between such an SRS and context-aware systems (CAS). This work aims to provide an open standardized interface to enable loose coupling of the SRS with varying CAS to allow vendor-independent device orchestrations.
Methods
A requirements analysis investigated limiting factors that currently prevent the integration of CAS in today's ORs. These elicited requirements enabled the selection of a suitable base architecture. We examined how to specify this architecture with the constraints of an interoperability standard. The resulting middleware was integrated into a prototypic SRS and our system for intraoperative support, the OR-Pad, as exemplary CAS for evaluating whether our solution can enable context-aware assistance during simulated orthopedical interventions.
Results
The emerging Service-oriented Device Connectivity (SDC) standard series was selected to specify and implement a middleware for providing the interpreted contextual information while the SRS and CAS are loosely coupled. The results were verified within a proof of concept study using the OR-Pad demonstration scenario. The fulfillment of the CAS’ requirements to act context-aware, conformity to the SDC standard series, and the effort for integrating the middleware in individual systems were evaluated. The semantically unambiguous encoding of contextual information depends on the further standardization process of the SDC nomenclature. The discussion of the validity of these results proved the applicability and transferability of the middleware.
Conclusion
The specified and implemented SDC-based middleware shows the feasibility of loose coupling an SRS with unknown CAS to realize context-aware assistance in the OR.
Purpose
Artificial intelligence (AI), in particular deep neural networks, has achieved remarkable results for medical image analysis in several applications. Yet the lack of explainability of deep neural models is considered the principal restriction before applying these methods in clinical practice.
Methods
In this study, we propose a NeuroXAI framework for explainable AI of deep learning networks to increase the trust of medical experts. NeuroXAI implements seven state-of-the-art explanation methods providing visualization maps to help make deep learning models transparent.
Results
NeuroXAI has been applied to two applications of the most widely investigated problems in brain imaging analysis, i.e., image classification and segmentation using magnetic resonance (MR) modality. Visual attention maps of multiple XAI methods have been generated and compared for both applications. Another experiment demonstrated that NeuroXAI can provide information flow visualization on internal layers of a segmentation CNN.
Conclusion
Due to its open architecture, ease of implementation, and scalability to new XAI methods, NeuroXAI could be utilized to assist radiologists and medical professionals in the detection and diagnosis of brain tumors in the clinical routine of cancer patients. The code of NeuroXAI is publicly accessible at https://github.com/razeineldin/NeuroXAI.
Background
Although teledermatology has been proven internationally to be an effective and safe addition to the care of patients in primary care, there are few pilot projects implementing teledermatology in routine outpatient care in Germany. The aim of this cluster randomized controlled trial was to evaluate whether referrals to dermatologists are reduced by implementing a store-and-forward teleconsultation system in general practitioner practices.
Methods
Eight counties were cluster randomized to the intervention and control conditions. During the 1-year intervention period between July 2018 and June 2019, 46 general practitioner practices in the 4 intervention counties implemented a store-and-forward teledermatology system with Patient Data Management System interoperability. It allowed practice teams to initiate teleconsultations for patients with dermatologic complaints. In the four control counties, treatment as usual was performed. As primary outcome, number of referrals was calculated from routine health care data. Poisson regression was used to compare referral rates between the intervention practices and 342 control practices.
Results
The primary analysis revealed no significant difference in referral rates (relative risk = 1.02; 95% confidence interval = 0.911–1.141; p = .74). Secondary analyses accounting for sociodemographic and practice characteristics but omitting county pairing resulted in significant differences of referral rates between intervention practices and control practices. Matched county pair, general practitioner age, patient age, and patient sex distribution in the practices were significantly related to referral rates.
Conclusions
While a store-and-forward teleconsultation system was successfully implemented in the German primary health care setting, the intervention's effect was superimposed by regional factors. Such regional factors should be considered in future teledermatology research.
One of the key challenges for automatic assistance is the support of actors in the operating room depending on the status of the procedure. Therefore, context information collected in the operating room is used to gain knowledge about the current situation. In literature, solutions already exist for specific use cases, but it is doubtful to what extent these approaches can be transferred to other conditions. We conducted a comprehensive literature research on existing situation recognition systems for the intraoperative area, covering 274 articles and 95 cross-references published between 2010 and 2019. We contrasted and compared 58 identified approaches based on defined aspects such as used sensor data or application area. In addition, we discussed applicability and transferability. Most of the papers focus on video data for recognizing situations within laparoscopic and cataract surgeries. Not all of the approaches can be used online for real-time recognition. Using different methods, good results with recognition accuracies above 90% could be achieved. Overall, transferability is less addressed. The applicability of approaches to other circumstances seems to be possible to a limited extent. Future research should place a stronger focus on adaptability. The literature review shows differences within existing approaches for situation recognition and outlines research trends. Applicability and transferability to other conditions are less addressed in current work.
The scoring of sleep stages is an essential part of sleep studies. The main objective of this research is to provide an algorithm for the automatic classification of sleep stages using signals that may be obtained in a non-obtrusive way. After reviewing the relevant research, the authors selected a multinomial logistic regression as the basis for their approach. Several parameters were derived from movement and breathing signals, and their combinations were investigated to develop an accurate and stable algorithm. The algorithm was implemented to produce successful results: the accuracy of the recognition of Wake/NREM/REM stages is equal to 73%, with Cohen's kappa of 0.44 for the analyzed 19324 sleep epochs of 30 seconds each. This approach has the advantage of using the only movement and breathing signals, which can be recorded with less effort than heart or brainwave signals, and requiring only four derived parameters for the calculations. Therefore, the new system is a significant improvement for non-obtrusive sleep stage identification compared to existing approaches.
Context-aware systems to support actors in the operating room depending on the status of the intervention require knowledge about the current situation in the intra-operative area. In literature, solutions to achieve situation awareness already exist for specific use cases, but applicability and transferability to other conditions are less addressed. It is assumed that a unified solution that can be adapted to different processes and sensors would allow for greater flexibility, applicability, and thus transferability to different applications. To enable a flexible and intervention-independent system, this work proposes a concept for an adaptable situation recognition system. The system consists of four layers with several modular components for different functionalities. The feasibility is demonstrated via prototypical implementation and functional evaluation of a first basic framework prototype. Further development goal is the stepwise extension of the prototype.
In the era of precision medicine, digital technologies and artificial intelligence, drug discovery and development face unprecedented opportunities for product and business model innovation, fundamentally changing the traditional approach of how drugs are discovered, developed and marketed. Critical to this transformation is the adoption of new technologies in the drug development process, catalyzing the transition from serendipity-driven to data-driven medicine. This paradigm shift comes with a need for both translation and precision, leading to a modern Translational Precision Medicine approach to drug discovery and development. Key components of Translational Precision Medicine are multi-omics profiling, digital biomarkers, model-based data integration, artificial intelligence, biomarker-guided trial designs and patient-centric companion diagnostics. In this review, we summarize and critically discuss the potential and challenges of Translational Precision Medicine from a cross-industry perspective.
Background/Aim: The aim of this study was the conception, production, material analysis and cytocompatibility analysis of a new collagen foam for medical applications. Materials and Methods: After the innovative production of various collagen sponges from bovine sources, the foams were analyzed ex vivo in terms of their structure (including pore size) and in vitro in terms of cytocompatibility according to EN ISO 10993-5/-12. In vitro, the collagen foams were compared with the established soft and hard tissue materials cerabone and Jason membrane (both botiss biomaterials GmbH, Zossen, Germany). Results: Collagen foams with different compositions were successfully produced from bovine sources. Ex vivo, the foams showed a stable and long-lasting primary structure quality with a bubble area of 1,000 to 2,000 μm2. In vitro, all foams showed sufficient cytocompatibility. Conclusion: Collagen sponges represent a promising material for hard and soft tissue regeneration. Future studies could focus on integrating and investigating different additives in the foams.
Programmable nano-bio interfaces driven by tuneable vertically configured nanostructures have recently emerged as a powerful tool for cellular manipulations and interrogations. Such interfaces have strong potential for ground-breaking advances, particularly in cellular nanobiotechnology and mechanobiology. However, the opaque nature of many nanostructured surfaces makes non-destructive, live-cell characterization of cellular behavior on vertically aligned nanostructures challenging to observe. Here, a new nanofabrication route is proposed that enables harvesting of vertically aligned silicon (Si) nanowires and their subsequent transfer onto an optically transparent substrate, with high efficiency and without artefacts. We demonstrate the potential of this route for efficient live-cell phase contrast imaging and subsequent characterization of cells growing on vertically aligned Si nanowires. This approach provides the first opportunity to understand dynamic cellular responses to a cell-nanowire interface, and thus has the potential to inform the design of future nanoscale cellular manipulation technologies.
Die Corona-Pandemie hat zu einer Einschränkung des Alltags der medizinischen Versorgung geführt. Das zeigt sich u.a. in zum Teil erheblichen Zugangsbeschränkungen zu Krankenhäusern und Praxen mit stark reduzierter Einbestellung von Patienten, der Einhaltung von gesteigerten Hygienemaßnahmen mit entsprechend längeren Wartezeiten, dem Zugangsverbot für Begleitpersonen und nicht zuletzt der Angst vieler Patienten vor einer Ansteckung bei einem Aufenthalt in medizinischen Bereichen. Folge dessen war und ist, dass ein deutlich wahrnehmbarer Rückgang der Patientenzahlen in den Krankenhausambulanzen und Praxen zu verzeichnen war. Davon war die Augenheilkunde als Fachdisziplin mit einem hohen Anteil an ambulanten und geplanten, chirurgischen Eingriffen in besonderem Maße betroffen.
Purpose
Injury or inflammation of the middle ear often results in the persistent tympanic membrane (TM) perforations, leading to conductive hearing loss (HL). However, in some cases the magnitude of HL exceeds that attributable by the TM perforation alone. The aim of the study is to better understand the effects of location and size of TM perforations on the sound transmission properties of the middle ear.
Methods
The middle ear transfer functions (METF) of six human temporal bones (TB) were compared before and after perforating the TM at different locations (anterior or posterior lower quadrant) and to different degrees (1 mm, ¼ of the TM, ½ of the TM, and full ablation). The sound-induced velocity of the stapes footplate was measured using single-point laser-Doppler-vibrometry (LDV). The METF were correlated with a Finite Element (FE) model of the middle ear, in which similar alterations were simulated.
Results
The measured and calculated METF showed frequency and perforation size dependent losses at all perforation locations. Starting at low frequencies, the loss expanded to higher frequencies with increased perforation size. In direct comparison, posterior TM perforations affected the transmission properties to a larger degree than anterior perforations. The asymmetry of the TM causes the malleus-incus complex to rotate and results in larger deflections in the posterior TM quadrants than in the anterior TM quadrants. Simulations in the FE model with a sealed cavity show that small perforations lead to a decrease in TM rigidity and thus to an increase in oscillation amplitude of the TM mainly above 1 kHz.
Conclusion
Size and location of TM perforations have a characteristic influence on the METF. The correlation of the experimental LDV measurements with an FE model contributes to a better understanding of the pathologic mechanisms of middle-ear diseases. If small perforations with significant HL are observed in daily clinical practice, additional middle ear pathologies should be considered. Further investigations on the loss of TM pretension due to perforations may be informative.
Background: One of the most promising health care development areas is introducing telemedicine services and creating solutions based on blockchain technology. The study of systems combining both these domains indicates the ongoing expansion of digital technologies in this market segment.
Objective: This paper aims to review the feasibility of blockchain technology for telemedicine.
Methods: The authors identified relevant studies via systematic searches of databases including PubMed, Scopus, Web of Science, IEEE Xplore, and Google Scholar. The suitability of each for inclusion in this review was assessed independently. Owing to the lack of publications, available blockchain-based tokens were discovered via conventional web search engines (Google, Yahoo, and Yandex).
Results: Of the 40 discovered projects, only 18 met the selection criteria. The 5 most prevalent features of the available solutions (N=18) were medical data access (14/18, 78%), medical service processing (14/18, 78%), diagnostic support (10/18, 56%), payment transactions (10/18, 56%), and fundraising for telemedical instrument development (5/18, 28%).
Conclusions: These different features (eg, medical data access, medical service processing, epidemiology reporting, diagnostic support, and treatment support) allow us to discuss the possibilities for integration of blockchain technology into telemedicine and health care on different levels. In this area, a wide range of tasks can be identified that could be accomplished based on digital technologies using blockchains.
The present work proposes the use of modern ICT technologies such as smartphones, NFCs, internet, and web technologies, to help patients in carrying out their therapies. The implemented system provides a calendar with a reminder of the assumptions, ensures the drug identification through NFC, allows remote assistance from healthcare staff and family members to check and manage the therapy in real-time. The system also provides centralized information on the patient's therapeutic situation, helpful in choosing new compatible therapies.
We investigated the state of artificial intelligence (AI) in pharmaceutical research and development (R&D) and outline here a risk and reward perspective regarding digital R&D. Given the novelty of the research area, a combined qualitative and quantitative research method was chosen, including the analysis of annual company reports, investor relations information, patent applications, and scientific publications of 21 pharmaceutical companies for the years 2014 to 2019. As a result, we can confirm that the industry is in an ‘early mature’ phase of using AI in R&D. Furthermore, we can demonstrate that, despite the efforts that need to be managed, recent developments in the industry indicate that it is worthwhile to invest to become a ‘digital pharma player’.
It has been widely shown that biomaterial surface topography can modulate host immune response, but a fundamental understanding of how different topographies contribute to pro-inflammatory or anti-inflammatory responses is still lacking. To investigate the impact of surface topography on immune response, we undertook a systematic approach by analyzing immune response to eight grades of medical grade polyurethane of increasing surface roughness in three in vitro models of the human immune system. Polyurethane specimens were produced with defined roughness values by injection molding according to the VDI 3400 industrial standard. Specimens ranged from 0.1 μm to 18 μm in average roughness (Ra), which was confirmed by confocal scanning microscopy. Immunological responses were assessed with THP-1-derived macrophages, human peripheral blood mononuclear cells (PBMCs), and whole blood following culture on polyurethane specimens. As shown by the release of pro-inflammatory and anti-inflammatory cytokines in all three models, a mild immune response to polyurethane was observed, however, this was not associated with the degree of surface roughness. Likewise, the cell morphology (cell spreading, circularity, and elongation) in THP-1-derived macrophages and the expression of CD molecules in the PBMC model on T cells (HLA-DR and CD16), NK cells (HLA-DR), and monocytes (HLA-DR, CD16, CD86, and CD163) showed no influence of surface roughness. In summary, this study shows that modifying surface roughness in the micrometer range on polyurethane has no impact on the pro-inflammatory immune response. Therefore, we propose that such modifications do not affect the immunocompatibility of polyurethane, thereby supporting the notion of polyurethane as a biocompatible material.
Artificial intelligence (AI) technologies, such as machine learning or deep learning, have been predicted to highly impact future organizations and radically change the way how projects are managed. The Project Management Institute (PMI), the network of around 1.1 million certified project managers, ranked AI as one of the top three disruptors of their profession. In an own study on the effect of AI, 37% of the project management processes can be executed by machine learning and other AI technologies. In addition, Gartner recently postulated that 80% of the work of today's project managers may be eliminated by AI in 2030.
This editorial aims to outline today's project and portfolio management in context of pharmaceutical research and development (R&D), followed by an AI-vision and a more tangible mission, and illustrate what the consequences of an AI-enabled project and portfolio management could be for pharmaceutical R&D.
The aim of this work was to investigate the mean fill weight control of a continuous capsule-filling process, whether it is possible to derive controller settings from an appendant process model. To that end, a system composed out of fully automated capsule filler and an online gravimetric scale was used to control the filled weight. This setup allows to examine challenges associated with continuous manufacturing processes, such as variations in the amount of active pharmaceutical ingredient (API) in the mixture due to fluctuations of the feeders or due to altered excipient batch qualities. Two types of controllers were investigated: a feedback control and a combination of feedback and feedforward control. Although both of those are common in the industry, determining the optimal parameter settings remains an issue. In this study, we developed a method to derive the control parameters based on process models in order to obtain optimal control for each filled product. Determined via rapid automated process development (RAPD), this method is an effective and fast way of determining control parameters. The method allowed us to optimize the weight control for three pharmaceutical excipients. By conducting experiments, we verified the feasibility of the proposed method and studied the dynamics of the controlled system. Our work provides important basic data on how capsule filler can be implemented into continuous manufacturing systems.
Intraoperative brain deformation, so called brain shift, affects the applicability of preoperative magnetic resonance imaging (MRI) data to assist the procedures of intraoperative ultrasound (iUS) guidance during neurosurgery. This paper proposes a deep learning-based approach for fast and accurate deformable registration of preoperative MRI to iUS images to correct brain shift. Based on the architecture of 3D convolutional neural networks, the proposed deep MRI-iUS registration method has been successfully tested and evaluated on the retrospective evaluation of cerebral tumors (RESECT) dataset. This study showed that our proposed method outperforms other registration methods in previous studies with an average mean squared error (MSE) of 85. Moreover, this method can register three 3D MRI-US pair in less than a second, improving the expected outcomes of brain surgery.
Checklists are a valuable tool to ensure process quality and quality of care. To ensure proper integration in clinical processes, it would be desirable to generate checklists directly from formal process descriptions. Those checklists could also be used for user interaction in context-aware surgical assist systems. We built a tool to automatically convert Business Process Model and Notation (BPMN) process models to checklists displayed as HTML websites. Gateways representing decisions are mapped to checklist items that trigger dynamic content loading based on the placed checkmark. The usability of the resulting system was positively evaluated regarding comprehensibility and end-user friendliness.
Pharmaceutical companies are among the top investors into research and development (R&D) globally, as product innovation is still the main growth driver for the industry and because the related complexities necessitate enormous R&D investments. The market demand for new medicines to be more efficacious or to provide better safety than existing drugs and the regulatory need to prove superiority in clinical trials are reasons why drug R&D is increasingly expensive and pharmaceutical companies need to manage extraordinarily high costs per approved new compound.
Purpose: Gliomas are the most common and aggressive type of brain tumors due to their infiltrative nature and rapid progression. The process of distinguishing tumor boundaries from healthy cells is still a challenging task in the clinical routine. Fluid attenuated inversion recovery (FLAIR) MRI modality can provide the physician with information about tumor infiltration. Therefore, this paper proposes a new generic deep learning architecture, namely DeepSeg, for fully automated detection and segmentation of the brain lesion using FLAIR MRI data.
Methods: The developed DeepSeg is a modular decoupling framework. It consists of two connected core parts based on an encoding and decoding relationship. The encoder part is a convolutional neural network (CNN) responsible for spatial information extraction. The resulting semantic map is inserted into the decoder part to get the full-resolution probability map. Based on modified U-Net architecture, different CNN models such as residual neural network (ResNet), dense convolutional network (DenseNet), and NASNet have been utilized in this study.
Results: The proposed deep learning architectures have been successfully tested and evaluated on-line based on MRI datasets of brain tumor segmentation (BraTS 2019) challenge, including s336 cases as training data and 125 cases for validation data. The dice and Hausdorff distance scores of obtained segmentation results are about 0.81 to 0.84 and 9.8 to 19.7 correspondingly.
Conclusion: This study showed successful feasibility and comparative performance of applying different deep learning models in a new DeepSeg framework for automated brain tumor segmentation in FLAIR MR images. The proposed DeepSeg is open source and freely available at https://github.com/razeineldin/DeepSeg/.
Size and function of bioartificial tissue models are still limited due to the lack of blood vessels and dynamic perfusion for nutrient supply. In this study, we evaluated the use of cytocompatible methacryl-modified gelatin for the fabrication of a hydrogel-based tube by dip-coating and subsequent photo-initiated cross-linking. The wall thickness of the tubes and the diameter were tuned by the degree of gelatin methacryl-modification and the number of dipping cycles. The dipping temperature of the gelatin solution was adjusted to achieve low viscous fluids of approximately 0.1 Pa s and was different for gelatin derivatives with different modification degrees. A versatile perfusion bioreactor for the supply of surrounding tissue models was developed, which can be adaped to several geometries and sizes of blood-vessel mimicking tubes. The manufactured bendable gelatin tubes were permeable for water and dissolved substances, like Nile Blue and serum albumin. As a proof of concept, human fibroblasts in a three-dimensional collagen tissue model were sucessfully supplied with nutrients via the central gelatin tube under dynamic conditions for 2 days. Moreover, the tubes could be used as scaffolds to build-up a functional and viable endothelial layer. Hence, the presented tools can contribute to solving current challenges in tissue engineering.
Background/Aim: The aim of this study was the development of a new osteoconductivity index to determine the bone healing capacities of bone substitute materials (BSM) on the basis of 3D microcomputed tomographic (μ-CT) data. Materials and Methods: Sinus biopsies were used for the comparative analysis of the integration behavior of two xenogeneic BSM (cerabone® and Bio Oss®). 3D μ-CT and data sets from histomorphometrical measurements based on 2D histological slices were used to measure the bone-material-contact and the tissue distribution within the biopsies. The tissue reactions to both BSM were microscopically analyzed. Results: The 3D and 2D results of the osteoconductivity measurements showed comparable material-bone contacts for both BSM, but the 2D data were significantly lower. The same results were found when tissue distribution was measured in both groups. The histopathological analysis showed comparative tissue reactions in both BSM. Conclusion: Osteoconductivity index is a reliable measurement parameter for determining the healing capacities of BSM. The observed differences between both measurement methods could be assigned to the resolution capacity of μ-CT data that did not allow for a precise interface distinction between both BSM and bone tissue. Histomorphometrical data based on histological slides still allow for a more exact evaluation.
Artefaktkorrektur und verfeinerte Metriken für ein EEG-basiertes System zur Müdigkeitserkennung
(2019)
Fragestellung: Müdigkeit ist ein oft unterschätztes, aber dennoch großes Problem im Straßenverkehr. Von rund 2,5 Mio. Verkehrsunfällen 2015 in Deutschland, waren 2898 Unfälle, mit insgesamt 59 Toten (~1,7 % der Todesfälle), auf Übermüdung zurückzuführen. Schätzungen gehen von einer Dunkelziffer von bis zu 20 % aus. In einer ersten eigenen Studie wurde überprüft, ob ein mobiles EEG in einem Fahrsimulator Müdigkeitszustände zuverlässig erkennen kann. Die Erkennungsrate lag lediglich bei 61 %. Ziel dieser Arbeit ist, das verwendete Messsystem zu verbessern. Dazu wird die Genauigkeit durch eine Artefaktkorrektur und mit Hilfe von verfeinerten Qualitätsmetriken erhöht. Eine erkannte Übermüdung wird dem Fahrer dann in angemessener Weise angezeigt, so dass er entsprechend reagieren kann.
Patienten und Methoden: Die Independent Component Analysis (ICA) ist ein multivariates Verfahren, um mehrere Zufallsvariablen zu analysieren. Für die Entscheidung, ob ein Fahrer gerade müde oder wach ist, wird der erstellte Merkmalsvektor für jede Sequenz mit ICA klassifiziert. Dafür wird ein trainierter Machine-Learning-Algorithmus eingesetzt, der in der Lage ist, auch unbekannte Datensätze in Klassen einzuteilen. Um die benötigten Frequenzwerte zu erhalten, wurde für jeden EEG-Kanal eine Fourier Transformation durchgeführt. Der erstellte Merkmalsvektor wird im nächsten Schritt durch ein Künstliches Neuronales Netz klassifiziert. Für das Training werden vorab erstellte Merkmalsvektoren mit den Klassen „Wach“ und „Müde“ versehen. Diese Daten werden zufällig gemischt und im Verhältnis 2:1 in eine Trainings- und Testmenge geteilt. Das Experiment wurde mit acht Personen mit jeweils zweimal 45 min Testfahrt durchgeführt.
Ergebnisse: Der komplette Datensatz besteht aus 150.000 Signalwerten, welche zu ca. 7000 Sequenzen zusammengefasst werden. Durch die Anwendung der Qualitätsmetrik bleiben 4370 Sequenzen für das Training übrig. Bei invaliden Sequenzen aufgrund von EEG-Artefakten gibt es deutliche Unterschiede. Im „Wach“ Zustand werden dreimal so viele Sequenzen verworfen als im „Müde“ Zustand. Insgesamt werden bei wachen Probanden im Schnitt ca. 50 % der Sequenzen verworfen, bei Müden lediglich 25 %. Im Durchschnitt erreicht das System eine Erkennungsrate von 73 % für beide Zustände. Vergleicht man nun das Verhältnis von „Wach“ und „Müde“ und lässt „Leichte Müdigkeit“ außen vor, liegen die Ergebnisse bei über 90 %.
Schlussfolgerungen: Die Ergebnisse zeigen, dass die Aufmerksamkeit während des Experiments abnimmt bzw. die Müdigkeit zunimmt. Dies verdeutlichen zum einen subjektive und objektive Beobachtungen von Müdigkeitsanzeichen. Zum anderen lassen sich messbare und klassifizierbare Unterschiede im EEG Signal nachweisen. Die als Merkmale eingesetzten Theta-Wellen zeigten eine niedrigere Amplitude gegen Ende des Experiments. Die Erweiterung der binären Klassifizierung führt zu einer weiteren Stabilisierung der Ergebnisse. Artefaktkorrektur und Qualitätsmetriken steigern die Güte der Daten weiter. Die entwickelte Anwendung zur Müdigkeitserkennung ermittelt messbare Zeichen von Müdigkeit und kann eine gute Entscheidung über die Fahrtauglichkeit treffen.
Today, virtualizing pharma R&D is increasingly related with data analytics and artificial intelligence (AI), technologies that have been developed by software companies outside the healthcare sector. The process of virtualizing pharma R&D is closely related to the technological advancements that result in the generation of large data sets ranging from genomics, proteomics, metabolomics, medical imaging, IoT wearables and large clinical trials, making it necessary for pharma companies to find new ways to store and ultimately analyze information. As a consequence, pharma companies are experimenting with AI in R&D ranging from in-silico drug design to clinical trail participants identification or dosage error reduction.
New approaches to respiratory assist: bioengineering an ambulatory, miniaturized bioartificial lung
(2019)
Although state-of-the-art treatments of respiratory failure clearly have made some progress in terms of survival in patients suffering from severe respiratory system disorders, such as acute respiratory distress syndrome (ARDS), they failed to significantly improve the quality of life in patients with acute or chronic lung failure, including severe acute exacerbations of chronic obstructive pulmonary disease or ARDS as well. Limitations of standard treatment modalities, which largely rely on conventional mechanical ventilation, emphasize the urgent, unmet clinical need for developing novel(bio)artificial respiratory assist devices that provide extracorporeal gas exchange with a focus on direct extracorporeal CO2 removal from the blood. In this review, we discuss some of the novel concepts and critical prerequisites for such respiratory lung assist devices that can be used with an adequate safety profile, in the intensive care setting, as well as for long-term domiciliary therapy in patients with chronic ventilatory failure. Specifically, we describe some of the pivotal steps, such as device miniaturization, passivation of the blood-contacting surfaces by chemical surface modifications, or endothelial cell seeding, all of which are required for converting current lung assist devices into ambulatory lung assist device for long-term use in critically ill patients. Finally, we also discuss some of the risks and challenges for the long-term use of ambulatory miniaturized bioartificial lungs.
Completely defined co-culture of adipogenic differentiated ASCs and microvascular endothelial cells
(2018)
Vascularized adipose tissue models are in high demand as alternatives to animal models to elucidate the mechanisms of widespread diseases, screen for new drugs or assess drug safety levels. Animal-derived sera such as fetal bovine serum (FBS), which are commonly used in these models, are associated with ethical concerns, risk of contaminations and inconsistencies of their composition and impact on cells. In this study, we developed a serum-free, defined co culture medium and implemented it in an adipocyte/endothelial cell (EC) co culture model.
Human adipose-derived stem cells were differentiated under defined conditions (diffASCs) and, like human microvascular ECs (mvECs), cultured in a defined co culture medium in mono-, indirect or direct co-culture for 14 days. The defined co-culture medium was superior when compared to mono-culture media and facilitated the functional maintenance and maturation of diffASCs including perilipin A expression, lipid accumulation, and also glycerol and leptin release. The medium also allowed mvEC maintenance, confirmed by the expression of CD31 and von Willebrand factor (vWF), and by acetylated low density lipoprotein (acLDL) uptake. Thereby, mvECs showed strong dependence on EC-specific factors. Additionally, mvECs formed vascular structures in direct co-culture with diffASCs.
The completely defined co-culture system allows for the serum-free culture of adipocyte/EC co-cultures and thereby represents a valuable and ethically acceptable tool for the culture and study of vascularized adipose tissue models.
Background aims: In vitro engineered adipose tissue is in great demand to treat lost or damaged soft tissue or to screen for new drugs, among other applications.However, today most attempts depend on the use of animal-derived sera. To pave the way for the application of adipose tissue-engineered
products in clinical trials or as reliable and robust in vitro test systems, sera should be completely excluded from the production process. In this study, we aimed to develop an in vitro adipose tissue model in the absence of sera and maintain its function long-term.
Methods: Human adipose tissue-derived stem cells were expanded and characterized in a xeno- and serum-free environment. Adipogenic differentiation was induced using a completely defined medium. Developed adipocytes were maintained in a completely defined maturation medium for additional 28 days. In addition to cell-viability and adherence, adipocyte-specific markers such as perilipin A expression of leptin release were evaluated.
Results: The defined differentiation medium enhanced cell adherence and lipid
accumulation at a significant level compared with the corresponding negative control. The defined maturation medium also significantly supported cell adherence and functional adipocyte maturation during the long-term culture period.
Conclusions: The process described here enables functional adipocyte generation and maintenance without the addition fo unknown or unimal-derived constituents, achieving an important milestone in the introduction of adipose tissue engineered products into clinical trials or in vitro screening.
Bone remodeling can be mimicked in vitro by co-culture models. Based on bone cells, such co-cultures help to study synergistic morphological changes and the impact of materials and applied substances. Hence, we examined the formation of osteoclasts on bovine bone materials to prove the bone resorption functionality of the osteoclasts in three different co-culture set-ups using human monocytes (hMCs) and (I) human mesenchymal stem cells (hMSCs), (II) osteogenic differentiated hMSCs (hOBs), and (III) hOBs in addition of soluble monocyte-colony stimulating factor (M CSF) and cytokine receptor activator of NFkB ligand (RANKL).We detected osteoclast-specific actin morphology, as well as the expression of cathepsin K and CD51/61 in single cells in set-up II and in numerous cells in set-up III. Resorption pits on bone material as characteristic proof of functional osteoclasts were not found in set-up I and II, but we detected such resorption pits in set–up III. We conclude in co culture models without M-CSF and RANKL that monocytes can differentiate into osteoclasts that show the characteristic actin structures and protein expression. However, to receive functional bone resorbing osteoclasts in vitro, the addition of M-CSF and RANKL is needed. Moreover, we suggest the use of bone or bone-like materials for future studies evaluating osteoclastogenesis.
Background: Internationally, teledermatology has proven to be a viable alternative to conventional physical referrals. Travel cost and referral times are reduced while patient safety is preserved. Especially patients from rural areas benefit from this healthcare innovation. Despite these established facts and positive experiences from EU neighboring countries like the Netherlands or the United Kingdom, Germany has not yet implemented store-and-forward teledermatology in routine care.
Methods: The TeleDerm study will implement and evaluate store-and-forward teledermatology in 50 general practitioner (GP) practices as an alternative to conventional referrals. TeleDerm aims to confirm that the possibility of store-and-forward teledermatology in GP practices is going to lead to a 15% (n = 260) reduction in referrals in the intervention arm. The study uses a cluster-randomized controlled trial design. Randomization is planned for the cluster “county”. The main observational unit is the GP practice. Poisson distribution of referrals is assumed. The evaluation of secondary outcomes like acceptance, enablers and barriers uses a mixed methods design with questionnaires and interviews.
Discussion: Due to the heterogeneity of GP practice organization, patient management software, information technology service providers, GP personal technical affinity and training, we expect several challenges in implementing teledermatology in German GP routine care. Therefore, we plan to recruit 30% more GPs than required by the power calculation. The implementation design and accompanying evaluation is expected to deliver vital insights into the specifics of implementing telemedicine in German routine care.
The focus of the developed maturity model was set on processes. The concept of the widespread CMM and its practices has been transferred to the perioperative domain and the concept of the new maturity model. Additional optimization goals and technological as well as networking-specific aspects enable a process- and object-focused view of the maturity model in order to ensure broad coverage of different subareas. The evaluation showed that the model is applicable to the perioperative field. Adjustments and extensions of the maturity model are future steps to improve the rating and classification of the new maturity model.
Perivascular stromal cells, including mesenchymal stem/stromal cells (MSCs), secrete paracrine factor in response to exercise training that can facilitate improvements in muscle remodeling. This study was designed to test the capacity for muscle-resident MSCs (mMSCs) isolated from young mice to release regenerative proteins in response to mechanical strain in vitro, and subsequently determine the extent to which strain-stimulated mMSCs can enhance skeletal muscle and cognitive performance in a mouse model of uncomplicated aging. Protein arrays confirmed a robust increase in protein release at 24 h following an acute bout of mechanical strain in vitro (10%, 1 Hz, 5 h) compared to non-strain controls. Aged (24 month old), C57BL/6 mice were provided bilateral intramuscular injection of saline, non strain control mMSCs, or mMSCs subjected to a single bout of mechanical strain in vitro (4 ×104). No significant changes were observed in muscle weight, myofiber size, maximal force, or satellite cell quantity at 1 or 4 wks between groups. Peripheral perfusion was significantly increased in muscle at 4 wks post-mMSC injection (p < 0.05), yet no difference was noted between control and preconditioned mMSCs. Intramuscular injection of preconditioned mMSCs increased the number of new neurons and astrocytes in the dentate gyrus of the hippocampus compared to both control groups (p < 0.05), with a trend toward an increase in water maze performance noted (p=0.07). Results from this study demonstrate that acute injection of exogenously stimulated muscle-resident stromal cells do not robustly impact aged muscle structure and function, yet increase the survival of new neurons in the hippocampus.
Perceptual integration of kinematic components in the recognition of emotional facial expressions
(2018)
According to a long-standing hypothesis in motor control, complex body motion is organized in terms of movement primitives, reducing massively the dimensionality of the underlying control problems. For body movements, this low dimensional organization has been convincingly demonstrated by the learning of low-dimensional representations from kinematic and EMG data. In contrast, the effective dimensionality of dynamic facial expressions is unknown, and dominant analysis approaches have been based on heuristically defined facial ‘‘action units,’’ which reflect contributions of individual face muscles. We determined the effective dimensionality of dynamic facial expressions by learning of a low dimensional model from 11 facial expressions. We found an amazingly low dimensionality with only two movement primitives being sufficient to simulate these dynamic expressions with high accuracy. This low dimensionality is confirmed statistically, by Bayesian model comparison of models with different numbers of primitives, and by a psychophysical experiment that demonstrates that expressions, simulated with only two primitives, are indistinguishable from natural ones.
In addition, we find statistically optimal integration of the emotion information specified by these primitives in visual perception. Taken together, our results indicate that facial expressions might be controlled by a very small number of independent control units, permitting very low dimensional parametrization of the associated facial expression.