Development and Implementation of the Data Science Learning Platform for Research Physician.

Data analysis and their application are the unavoidable factors in the activities analyses in health care. Unfortunately, the acquisition of data from large available medical databases is a complex process and requires deep knowledge of computer science and especially knowledge of tools for data management. According to the European General Data Protection Regulation, the problem becomes much more complex. Recognizing these problems and difficulties, we have developed a Data Science Learning Platform (DSLP) that primarily targets practitioners and researchers but also the computer science students. Using our proposed tool chain together with the developed graphical user interface, data scientists and research physicians will be able to use available medical databases, apply and analyze different anonymization methods, analyze data according to the patient's risk and quickly formulate new studies to target a disease in a complex data model. This article presents a clinical research discovery toolbox that implements and demonstrates tools for data anonymization, patient data visualization, NLP-tools for guideline search and data science learning tools.

Toward a digital decision- and workflow-support system for initiation and control of long-term non-invasive ventilation in stable hypercapnic COPD patients.

Introduction: Due to an increasing demand for the initiation and control of non-invasive ventilation (NIV), digital algorithms are suggested to support therapeutic decisions and workflows in an ambulatory setting. The DIGIVENT project established and implemented such algorithms for patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease (COPD) by a predefined process. Methods: Based on long-term clinical experience and guideline recommendations as provided by the German Respiratory Society, detailed graphical descriptions of how to perform NIV in stable COPD patients were created. Subsequently, these clinical workflows were implemented in the Business Process Model and Notation (BPMN) as one tool to formalize these workflows serving as input for an executable digital implementation. Results: We succeeded in creating an executable digital implementation that reflects clinical decision-making and workflows in digital algorithms. Furthermore, we built a user-friendly graphical interface that allows easy interaction with the DIGIVENT support algorithms. Conclusion: The DIGIVENT project established digital treatment algorithms and implemented a decision- and workflow-support system for NIV whose validation in a clinical cohort is planned.

Application of Cell Impedance as a Screening Tool to Discover Modulators of Intraocular Pressure.

Purpose: To identify new targets and compounds involved in mediating cellular contractility or relaxation in trabecular meshwork (TM) cells and test their efficacy in an ex vivo model measuring outflow facility. Methods: A low-molecular weight compound library composed of 3,957 compounds was screened for cytoskeletal changes using the Acea xCelligence impedance platform in immortalized human NTM5 TM cells. Hits were confirmed by 8-point concentration response and were subsequently evaluated for impedance changes in 2 primary human TM strains, as well as cross-reactivity in bovine primary cells. A recently described bovine whole eye perfusion system was used to evaluate effects of compounds on aqueous outflow facility. Results: The primary screen conducted was robust, with Z' values >0.5. Fifty-two compounds were identified in the primary screen and confirmed to have concentration-dependent effects on impedance in NTM5 cells. Of these, 9 compounds representing distinct drug classes were confirmed to modulate impedance in both human primary TM cells and bovine cells. One of these compounds, wortmannin, an inhibitor of phosphoinositide 3-kinase, increased outflow facility by 11%. Conclusions: A robust phenotypic assay was developed that enabled identification of contractility modulators in immortalized TM cells. The screening hits were translatable to primary TM cells and modulated outflow facility in an ex vivo perfusion assay.

Object-oriented modeling of thoracic fluid balance to study cardiogenic pulmonary congestion in humans.

BACKGROUND AND OBJECTIVE: We hypothesized that a biophysical computational model implemented in an object-oriented modeling language (OOML) would provide physiological information and simulative data to study the development and treatment of cardiogenic pulmonary congestion. METHODS: This work is based on the object-oriented cardiopulmonary interaction introduced in [1]. This paper describes the novel model components required to study cardiogenic pulmonary congestion: i) interstitial fluid exchange related to the Starling equation, ii) the lymphatic pump, and iii) the interconnection of these elements with the original cardiopulmonary model. The presented model succeeds in i) describing lymphatic flow at the capillary artery and venous end, ii) activation of the lymphatic pump at elevated pulmonary pressures, and iii) the simulation of the different safety factors related to lung tissue, osmotic gradient, and the lymphatic system during the development of lung congestion. RESULTS: Simulations show a qualitative correlation between model behavior and physiological data from literature. The model also demonstrates the beneficial effect of continuous positive airway pressure therapy on fluid clearance and respiratory mechanics. CONCLUSION: This study demonstrates the successful use of OOML to describe the development of cardiogenic congestion by introducing a model of the lymphatic system and the thoracic fluid balance system, as well as connecting them to the existing cardiopulmonary model.

An object-oriented computational model to study cardiopulmonary hemodynamic interactions in humans.

BACKGROUND AND OBJECTIVE: This work introduces an object-oriented computational model to study cardiopulmonary interactions in humans. METHODS: Modeling was performed in object-oriented programing language Matlab Simscape, where model components are connected with each other through physical connections. Constitutive and phenomenological equations of model elements are implemented based on their non-linear pressure-volume or pressure-flow relationship. The model includes more than 30 physiological compartments, which belong either to the cardiovascular or respiratory system. The model considers non-linear behaviors of veins, pulmonary capillaries, collapsible airways, alveoli, and the chest wall. Model parameters were derisved based on literature values. Model validation was performed by comparing simulation results with clinical and animal data reported in literature. RESULTS: The model is able to provide quantitative values of alveolar, pleural, interstitial, aortic and ventricular pressures, as well as heart and lung volumes during spontaneous breathing and mechanical ventilation. Results of baseline simulation demonstrate the consistency of the assigned parameters. Simulation results during mechanical ventilation with PEEP trials can be directly compared with animal and clinical data given in literature. CONCLUSIONS: Object-oriented programming languages can be used to model interconnected systems including model non-linearities. The model provides a useful tool to investigate cardiopulmonary activity during spontaneous breathing and mechanical ventilation.

Assessing regional lung mechanics by combining electrical impedance tomography and forced oscillation technique.

There is a lack of noninvasive pulmonary function tests which can assess regional information of the lungs. Electrical impedance tomography (EIT) is a radiation-free, non-invasive real-time imaging that provides regional information of ventilation volume regarding the measurement of electrical impedance distribution. Forced oscillation technique (FOT) is a pulmonary function test which is based on the measurement of respiratory mechanical impedance over a frequency range. In this article, we introduce a new measurement approach by combining FOT and EIT, named the oscillatory electrical impedance tomography (oEIT). Our oEIT measurement system consists of a valve-based FOT device, an EIT device, pressure and flow sensors, and a computer fusing the data streams. Measurements were performed on five healthy volunteers at the frequencies 3, 4, 5, 6, 7, 8, 10, 15, and 20 Hz. The measurements suggest that the combination of FOT and EIT is a promising approach. High frequency responses are visible in the derivative of the global impedance index ΔZeit(t,fos). $\Delta {Z_{{\text{eit}}}}(t,{f_{{\text{os}}}}).$ The oEIT signals consist of three main components: forced oscillation, spontaneous breathing, and heart activity. The amplitude of the oscillation component decreases with increasing frequency. The band-pass filtered oEIT signal might be a new tool in regional lung function diagnostics, since local responses to high frequency perturbation could be distinguished between different lung regions.

Effects of the nasal passage on forced oscillation lung function measurements.

The forced oscillation technique (FOT) is a non-invasive pulmonary function test which is based on the measurement of respiratory impedance. Recently, promising results were obtained by the application of FOT on patients with respiratory failure and obstructive sleep apnea (OSA). By using a nasal mask instead of a mouthpiece, the influences of the nasal passage and upper shunt alter the measured mechanical impedance. In this paper, we investigated the effects of the nasal passage and mask on FOT measurements from eight healthy subjects. A method for flow correction has been developed, which contains a pressure-flow characteristics compensation of the undetermined flow leakage at the face-mask interface. Impedance calculation and parameter estimation were performed in the frequency domain using fast Fourier transform (FFT). Average nasal parameters were Rnaw=4.07 cmH2O/l/s for resistance and Lnaw=0.0183 cmH2O/l/s2 for inertance. On average, the nasal resistance corresponds to 65.85% of the total resistance.

Linearity of electrical impedance tomography during maximum effort breathing and forced expiration maneuvers.

Electrical impedance tomography (EIT) provides global and regional information about ventilation by means of relative changes in electrical impedance measured with electrodes placed around the thorax. In combination with lung function tests, e.g. spirometry and body plethysmography, regional information about lung ventilation can be achieved. Impedance changes strictly correlate with lung volume during tidal breathing and mechanical ventilation. Initial studies presumed a correlation also during forced expiration maneuvers. To quantify the validity of this correlation in extreme lung volume changes during forced breathing, a measurement system was set up and applied on seven lung-healthy volunteers. Simultaneous measurements of changes in lung volume using EIT imaging and pneumotachography were obtained with different breathing patterns. Data was divided into a synchronizing phase (spontaneous breathing) and a test phase (maximum effort breathing and forced maneuvers). The EIT impedance changes correlate strictly with spirometric data during slow breathing with increasing and maximum effort ([Formula: see text]) and during forced expiration maneuvers ([Formula: see text]). Strong correlations in spirometric volume parameters [Formula: see text] ([Formula: see text]), [Formula: see text]/FVC ([Formula: see text]), and flow parameters PEF, [Formula: see text], [Formula: see text], [Formula: see text] ([Formula: see text]) were observed. According to the linearity during forced expiration maneuvers, EIT can be used during pulmonary function testing in combination with spirometry for visualisation of regional lung ventilation.

An object-oriented model of the cardiopulmonary system with emphasis on the gravity effect.

We introduce a novel comprehensive model of the cardiopulmonary system with emphasis on perfusion and ventilation distribution along the vertical thorax axis under the gravity effect. By using an object-oriented environment, the complex physiological system can be represented by a network of electrical, lumped-element compartments. The lungs are divided into three zones: upper, middle, and lower zone. Blood flow increases with the distance from the apex to the base of the lungs. The upper zone is characterized by a complete collapse of the pulmonary capillary vasculature; thus, there is no flow in this zone. The second zone has a "waterfall effect" where the blood flow is determined by the difference between the pulmonary-arterial and alveolar pressures. At resting position, the upper lobes of the lungs are more expanded than the middle and lower lobes. However, during spontaneous breathing, ventilation is nonuniform with more air entering the lower lobes than the middle and upper lobes. A simulative model of the complete system is developed which shows results in good agreement with the literature.

Regulation of Endothelin-1-Induced Trabecular Meshwork Cell Contractility by Latanoprostene Bunod.

PURPOSE: Previous in vivo studies demonstrated that latanoprostene bunod (LBN), a nitric oxide (NO)-donating prostaglandin F2α receptor agonist, results in greater intraocular pressure (IOP) lowering than latanoprost. The present series of investigations compared the effects of LBN and latanoprost on primary human trabecular meshwork cell (HTMC) contractility and underlying signaling pathways to determine whether LBN might mediate this additional IOP lowering via the conventional outflow pathway. METHODS: The effect of LBN (1-100 µM) on HTMC cGMP levels was determined by ELISA with or without the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Endothelin-1 (ET-1) was used to induce HTMC contractility. To determine the effect of LBN on myosin light chain-2 (MLC-2) phosphorylation, HTMCs were pretreated with 10 to 60 µM LBN for 1 hour and then ET-1 for 5 minutes. MLC-2 phosphorylation was determined by Western blotting. Effects of LBN (30 and 45 µM) on ET-1-induced filamentous (F)-actin cytoskeletal stress fibers and the focal adhesion associated protein vinculin were determined by confocal microscopy. ET-1-induced HTMC monolayer resistance in the presence of LBN (45 µM) was determined by electrical cell substrate impedance sensing, as an indicator of cell contractility. Latanoprost and SE 175 (an NO donor which releases NO on reductive transformation within the cells) were used as comparators in all studies. RESULTS: LBN (1-100 µM) significantly increased cGMP levels in a dose-dependent manner, with a half maximal effective concentration (EC50) of 1.5 ± 1.3 µM, and with maximal effect similar to that of 100 µM SE 175. In contrast, latanoprost caused a minimal increase in cGMP levels at 100 µM only. The cGMP elevation induced by LBN or SE 175 was abolished by ODQ and was therefore sGC-dependent. The two NO donors SE 175 and LBN elicited a reduction in ET-1-induced MLC-2 phosphorylation that was significantly greater than that mediated by latanoprost in HTMCs. SE 175 (100 µM) and LBN (30 or 45 µM) caused a dramatic reduction in ET-1-induced actin stress fibers and vinculin localization at focal adhesions, whereas 45 µM latanoprost was without observable effect. SE 175 reduced ET-1-induced increases in HTMC resistance in a dose-dependent manner. A synergistic effect on reduction of HTMC resistance was observed when latanoprost and SE 175 doses were given together. LBN significantly reduced ET-1-induced HTMC monolayer resistance increases to a greater extent than latanoprost, indicating a greater reduction in cell contractility with LBN. CONCLUSIONS: LBN, SE 175, and latanoprost caused relaxation of ET-1-contracted HTMCs. The effect on HTMC relaxation observed with LBN was significantly greater in magnitude than that observed with latanoprost or SE 175. Data indicate that the NO-donating moiety of LBN mediates HTMC relaxation through activation of the cGMP signaling pathway and a subsequent reduction in MLC-2 phosphorylation. These findings suggest that increased conventional outflow facility may mediate the additional IOP-lowering effects of LBN over that of latanoprost observed in in vivo studies.

Bioelectrical impedance spectroscopy as a fluid management system in heart failure.

Episodes of hospitalization for heart failure patients are frequent and are often accompanied by fluid accumulations. The change of the body impedance, measured by bioimpendace spectroscopy, is an indicator of the water content. The hypothesis was that it is possible to detect edema from the impedance data. First, a finite integration technique was applied to test the feasibility and allowed a theoretical analysis of current flows through the body. Based on the results of the simulations, a clinical study was designed and conducted. The segmental impedances of 25 patients suffering from heart failure were monitored over their recompensation process. The mean age of the patients was 73.8 and their mean body mass index was 28.6. From these raw data the model parameters from the Cole model were deduced by an automatic fitting algorithm. These model data were used to classify the edema status of the patient. The baseline values of the regression lines of the extra- and intracellular resistance from the transthoracic measurement and the baseline value of the regression line of the extracellular resistance from the foot-to-foot measurement were identified as important parameters for the detection of peripheral edema. The rate of change of the imaginary impedance at the characteristic frequency and the mean intracellular resistance from the foot-to-foot measurement were identified as important parameters for the detection of pulmonary edema. To classify the data, two decision trees were considered: One should detect pulmonary edema (n(pulmonary) = 13, n(none) = 12) and the other peripheral edema (n(peripheral) = 12, n(none) = 13). Peripheral edema could be detected with a sensitivity of 100% and a specificity of 90%. The detection of pulmonary edema showed a sensitivity of 92.31% and a specificity of 100%. The leave-one-out cross-validation-error for the peripheral edema detection was 12% and 8% for the detection of pulmonary edema. This enables the application of BIS as an early warning system for cardiac decompensation with the potential to optimize patient care.

Individualized biomonitoring in heart failure--Biomon-HF "Keep an eye on heart failure--especially at night".

In the project "Individualized Biomonitoring in Heart Failure (Biomon-HF)," innovative sensors and algorithms for measuring vital signs, i.e., during the nocturnal sleep period, have been developed and successfully tested in five clinical feasibility studies involving 115 patients. The Biomon-HF sensor concepts are an important step toward future patient-customized telemonitoring and sensor-guided therapy management in chronic heart failure, including early detection of upcoming HF exacerbation and comorbidities at home. The resulting preventable disease complications and emergencies and reduction of consequences of disease are very important advantages for the patients, causing relief for medical staff and, thus, offer an enormous potential for improvements and cost savings in healthcare systems.

Anti-inflammatory effects of mapracorat, a novel selective glucocorticoid receptor agonist, is partially mediated by MAP kinase phosphatase-1 (MKP-1).

Mapracorat is a novel selective glucocorticoid receptor agonist (SEGRA), structurally distinct from corticosteroids. In preclinical studies, mapracorat potently inhibits the production of a variety of inflammatory mediators including cytokines and prostaglandin E2 (PGE(2)), with limited side effects associated with traditional corticosteroids. The objective of this study was to delineate the mechanisms underlying the anti-inflammatory properties of mapracorat. We found that mapracorat potently inhibited the production of GM-CSF and TNF-α in LPS-stimulated Raw 264.7 macrophages. Mapracorat also substantially attenuated the expression of COX-2 and the production of PGE(2). The inhibition of mapracorat on the inflammatory response was dose-dependent, and substantially inhibitory effects were observed at concentrations in the 10-100 nm range. Examination of the activation kinetics of p38 and its downstream target MAPK-activated protein kinase-2 (MK-2) revealed a shortened activation course after LPS stimulation in cells pretreated with mapracorat. Supporting the notion that mapracorat augments a feedback control mechanism restraining the p38 pathway, we found that mapracorat enhanced the expression of MAPK phosphatase-1 (MKP-1), a critical negative regulator of MAPKs that drive the production of cytokines and other inflammatory mediators. While mapracorat alone did not stimulate MKP-1 expression, it markedly enhanced the expression of MKP-1 in cells stimulated by LPS, in a similar manner and potency to the augmenting effect of dexamethasone. Blocking MKP-1 expression by triptolide also abolished the accelerating effects of mapracorat on p38 and MK-2 deactivation, further supporting a role of MKP-1 in the anti-inflammatory mechanism of mapracorat. Taken together, these results indicate that mapracorat exerts its anti-inflammatory effects, at least in part, by augmenting MKP-1 expression.

Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells.

PURPOSE: To determine the anti-inflammatory and anti-oxidant effects of epigallocatechin gallate (EGCG), the major polyphenol component of green tea, in human corneal epithelial cells (HCEpiC). METHODS: HCEpiC were challenged with interleukin-1ß (IL-1ß) for 18 h or hyperosmolarity (440 mOsm) for 24 h. Luminex technology was used to determine the effects of EGCG (0.3-30 µM) on IL-1ß- or hyperosmolar-induced cytokine release into the medium. Cell metabolic activity was measured using the alamarBlue assay. Effects of EGCG on mitogen-activated protein kinase (MAPK) phosphorylation were determined by cell-based enzyme-linked immunosorbent assay (ELISA) and western blotting. Effects of EGCG on nuclear factor kappa B (NFκB) and activator protein-1 (AP-1) transcriptional activity were assessed by reporter gene assay. The effects of EGCG on glucose oxidase (GO)-induced reactive oxygen species (ROS) production was determined using the ROS probe CM-H2DCFDA. RESULTS: Treatment of HCEpiC with 1 ng/ml IL-1ß for 18 h significantly increased release of the cytokines/chemokines granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1), while hyperosmolarity-induced release of IL-6 and MCP-1. When cells were treated with IL-1ß and EGCG or hyperosmolarity and EGCG there was a dose-dependent reduction in release of these cytokines/chemokines, with significant inhibition observed at 3-30 µM. There was no effect of EGCG on cell metabolic activity at any of the doses tested (0.3-30 µM). EGCG significantly inhibited phosphorylation of the MAPKs p38 and c-Jun N-terminal kinase (JNK), and NFκB and AP-1 transcriptional activities. There was a significant dose-dependent decrease in GO-induced ROS levels after treatment of HCEpiC with EGCG. CONCLUSIONS: EGCG acts as an anti-inflammatory and anti-oxidant agent in HCEpiC and therefore may have therapeutic potential for ocular inflammatory conditions such as dry eye.