Federated electronic data capture (fEDC): Architecture and prototype.

In clinical research as well as patient care, structured documentation of findings is an important task. In many cases, this is achieved by means of electronic case report forms (eCRF) using corresponding information technology systems. To avoid double data entry, eCRF systems can be integrated with electronic health records (EHR). However, when researchers from different institutions collaborate in collecting data, they often use a single joint eCRF system on the Internet. In this case, integration with EHR systems is not possible in most cases due to information security and data protection restrictions. To overcome this shortcoming, we propose a novel architecture for a federated electronic data capture system (fEDC). Four key requirements were identified for fEDC: Definitions of forms have to be available in a reliable and controlled fashion, integration with electronic health record systems must be possible, patient data should be under full local control until they are explicitly transferred for joint analysis, and the system must support data sharing principles accepted by the scientific community for both data model and data captured. With our approach, sites participating in a joint study can run their own instance of an fEDC system that complies with local standards (such as being behind a network firewall) while also being able to benefit from using identical form definitions by sharing metadata in the Operational Data Model (ODM) format published by the Clinical Data Interchange Standards Consortium (CDISC) throughout the collaboration. The fEDC architecture was validated with a working open-source prototype at five German university hospitals. The fEDC architecture provides a novel approach with the potential to significantly improve collaborative data capture: Efforts for data entry are reduced and at the same time, data quality is increased since barriers for integrating with local electronic health record systems are lowered. Further, metadata are shared and patient privacy is ensured at a high level.

Editor's Choice - Association Between Peri-OPerative Aspirin ResisTance and CardioVascular Outcome (POPART-CVO): a Prospective Non-Interventional Cohort Study.

OBJECTIVE: New onset aspirin resistance during surgery, known as peri-operative aspirin resistance, is observed in up to 30% of vascular surgery patients and is associated with post-operative myocardial damage; questioning aspirin effectiveness towards peri-operative cardiovascular events. The objective of this study was to prospectively evaluate whether peri-operative aspirin resistance in vascular surgery is associated with an adverse cardiovascular outcome. METHODS: Based on a sample size calculation, 194 adult elective vascular or endovascular surgery patients receiving aspirin were analysed in this prospective, single centred, non-interventional cohort study. Platelet function was measured before surgery, one hour after incision, four hours post-operatively, and on the morning of the first and second post-operative days using the Multiplate analyser. The primary outcome was myocardial injury after non-cardiac surgery (MINS). Secondary outcomes included major bleeding, admission to intensive care unit, length of hospital stay, and major adverse cardiac and cerebrovascular events. Subgroup analyses were performed for patients with different cardiovascular risk and for patients who underwent endovascular surgery. RESULTS: Peri-operative aspirin resistance was observed in 27.8% of patients but was not associated with MINS (27.8% vs. 32.1%, aspirin resistance vs. no aspirin resistance, OR 0.812, 95% CI 0.406 - 1.624, p = .56) or with any of the secondary endpoints (all p > .050). In nine of the 10 subgroup analyses, aspirin resistance was not associated with a difference in MINS rate. However, in patients with a low cardiovascular risk profile (RCRI 0-2), MINS occurred more frequently in patients without aspirin resistance (p = .049). CONCLUSION: This study confirmed previous reports demonstrating that peri-operative aspirin resistance is common in patients undergoing vascular or endovascular surgery. However, in patients who continue aspirin throughout the peri-operative period, aspirin resistance is a phenomenon, which does not appear to be related to MINS. Measuring peri-operative platelet function using the Multiplate analyser with the intention to identify and potentially prevent or treat peri-operative aspirin resistance seems to be dispensable.

Ventilation strategies for front of neck airway rescue: an in silico study.

BACKGROUND: During induction of general anaesthesia a 'cannot intubate, cannot oxygenate' (CICO) situation can arise, leading to severe hypoxaemia. Evidence is scarce to guide ventilation strategies for small-bore emergency front of neck airways that ensure effective oxygenation without risking lung damage and cardiovascular depression. METHODS: Fifty virtual subjects were configured using a high-fidelity computational model of the cardiovascular and pulmonary systems. Each subject breathed 100% oxygen for 3 min and then became apnoeic, with an obstructed upper airway. When arterial haemoglobin oxygen saturation reached 40%, front of neck airway access was simulated with various configurations. We examined the effect of several ventilation strategies on re-oxygenation, pulmonary pressures, cardiovascular function, and oxygen delivery. RESULTS: Re-oxygenation was achieved in all ventilation strategies. Smaller airway configurations led to dynamic hyperinflation for a wide range of ventilation strategies. This effect was absent in airways with larger internal diameter (≥3 mm). Intrapulmonary pressures increased quickly to supra-physiological values with the smallest airways, resulting in pronounced cardio-circulatory depression (cardiac output <3 L min-1 and mean arterial pressure <60 mm Hg), impeding oxygen delivery (<600 ml min-1). Limiting tidal volume (≤200 ml) and ventilatory frequency (≤8 bpm) for smaller diameter cannulas reduced dynamic hyperinflation and gas trapping, preventing cardiovascular depression. CONCLUSIONS: Dynamic hyperinflation can be demonstrated for a wide range of front of neck airway cannulae when the upper airway is obstructed. When using small-bore cannulae in a CICO situation, ventilation strategies should be chosen that prevent gas trapping to prevent severe adverse events including cardio-circulatory depression.

A Short Review of Cavity-Enhanced Raman Spectroscopy for Gas Analysis.

The market of gas sensors is mainly governed by electrochemical, semiconductor, and non-dispersive infrared absorption (NDIR)-based optical sensors. Despite offering a wide range of detectable gases, unknown gas mixtures can be challenging to these sensor types, as appropriate combinations of sensors need to be chosen beforehand, also reducing cross-talk between them. As an optical alternative, Raman spectroscopy can be used, as, in principle, no prior knowledge is needed, covering nearly all gas compounds. Yet, it has the disadvantage of a low quantum yield through a low scattering cross section for gases. There have been various efforts to circumvent this issue by enhancing the Raman yield through different methods. For gases, in particular, cavity-enhanced Raman spectroscopy shows promising results. Here, cavities can be used to enhance the laser beam power, allowing higher laser beam-analyte interaction lengths, while also providing the opportunity to utilize lower cost equipment. In this work, we review cavity-enhanced Raman spectroscopy, particularly the general research interest into this topic, common setups, and already achieved resolutions.

Effect of oxygen fraction on airway rescue: a computational modelling study.

BACKGROUND: During induction of general anaesthesia, patients frequently experience apnoea, which can lead to dangerous hypoxaemia. An obstructed upper airway can impede attempts to provide ventilation. Although unrelieved apnoea is rare, it continues to cause deaths. Clinical investigation of management strategies for such scenarios is effectively impossible because of ethical and practical considerations. METHODS: A population-representative cohort of 100 virtual (in silico) subjects was configured using a high-fidelity computational model of the pulmonary and cardiovascular systems. Each subject breathed 100% oxygen for 3 min and then became apnoeic, with an obstructed upper airway, during induction of general anaesthesia. Apnoea continued throughout the protocol. When arterial oxygen saturation (Sao2) reached 20%, 40%, or 60%, airway obstruction was relieved. We examined the effect of varying supraglottic oxygen fraction (Fo2) on the degree of passive re-oxygenation occurring without tidal ventilation. RESULTS: Relief of airway obstruction during apnoea produced a single, passive inhalation (caused by intrathoracic hypobaric pressure) in all cases. The degree of re-oxygenation after airway opening was markedly influenced by the supraglottic Fo2, with a supraglottic Fo2 of 100% providing significant and sustained re-oxygenation (post-rescue Pao2 42.3 [4.4] kPa, when the airway rescue occurred after desaturation to Sao2 60%). CONCLUSIONS: Supraglottic oxygen supplementation before relieving upper airway obstruction improves the effectiveness of simulated airway rescue. Management strategies should be implemented to assure a substantially increased pharyngeal Fo2 during difficult airway management.

The bile acid receptor TGR5 does not interact with ß-arrestins or traffic to endosomes but transmits sustained signals from plasma membrane rafts.

TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of ß-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with ß-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with ß-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-ß-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with ß-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists.

Europe's Largest Research Infrastructure for Curated Medical Data Models with Semantic Annotations.

BACKGROUND: Structural metadata from the majority of clinical studies and routine health care systems is currently not yet available to the scientific community. OBJECTIVE: To provide an overview of available contents in the Portal of Medical Data Models (MDM Portal). METHODS: The MDM Portal is a registered European information infrastructure for research and health care, and its contents are curated and semantically annotated by medical experts. It enables users to search, view, discuss, and download existing medical data models. RESULTS: The most frequent keyword is "clinical trial" (n = 18,777), and the most frequent disease-specific keyword is "breast neoplasms" (n = 1,943). Most data items are available in English (n = 545,749) and German (n = 109,267). Manually curated semantic annotations are available for 805,308 elements (554,352 items, 58,101 item groups, and 192,855 code list items), which were derived from 25,257 data models. In total, 1,609,225 Unified Medical Language System (UMLS) codes have been assigned, with 66,373 unique UMLS codes. CONCLUSION: To our knowledge, the MDM Portal constitutes Europe's largest collection of medical data models with semantically annotated elements. As such, it can be used to increase compatibility of medical datasets and can be utilized as a large expert-annotated medical text corpus for natural language processing.

Next-generation study databases require FAIR, EHR-integrated, and scalable Electronic Data Capture for medical documentation and decision support.

Structured patient data play a key role in all types of clinical research. They are often collected in study databases for research purposes. In order to describe characteristics of a next-generation study database and assess the feasibility of its implementation a proof-of-concept study in a German university hospital was performed. Key characteristics identified include FAIR access to electronic case report forms (eCRF), regulatory compliant Electronic Data Capture (EDC), an EDC with electronic health record (EHR) integration, scalable EDC for medical documentation, patient generated data, and clinical decision support. In a local case study, we then successfully implemented a next-generation study database for 19 EDC systems (n = 2217 patients) that linked to i.s.h.med (Oracle Cerner) with the local EDC system called OpenEDC. Desiderata of next-generation study databases for patient data were identified from ongoing local clinical study projects in 11 clinical departments at Heidelberg University Hospital, Germany, a major tertiary referral hospital. We compiled and analyzed feature and functionality requests submitted to the OpenEDC team between May 2021 and July 2023. Next-generation study databases are technically and clinically feasible. Further research is needed to evaluate if our approach is feasible in a multi-center setting as well.

Exploring Use Cases for CovidGraph.

HealthECCO is the driving force behind the COVID-19 knowledge graph spanning multiple biomedical data domains. One way to access CovidGraph is SemSpect, an interface designed for data exploration in graphs. To showcase the possibilities that arise from integrating a variety of COVID-19 related data sources over the last three years, we present three use cases from the (bio-)medical domain. Availability: The project is open source and freely available from: https://healthecco.org/covidgraph/. The source code and documentation are available on GitHub: https://github.com/covidgraph.

Portal of Medical Data Models: Application in Federated Data Capture.

So far, the portal for medical data models allows its users to download medical forms in a standardized format. Importing data models into electronic data capture software involved a manual step of downloading and importing the files. Now, the portal was enhanced with a web services interface to allow electronic data capture systems to automatically download the forms. This mechanism can be used in federated studies to ensure that all partners are working with identical definitions of study forms.

Prostaglandin E2 stimulates the epithelial sodium channel (ENaC) in cultured mouse cortical collecting duct cells in an autocrine manner.

Prostaglandin E2 (PGE2) is the most abundant prostanoid in the kidney, affecting a wide range of renal functions. Conflicting data have been reported regarding the effects of PGE2 on tubular water and ion transport. The amiloride-sensitive epithelial sodium channel (ENaC) is rate limiting for transepithelial sodium transport in the aldosterone-sensitive distal nephron. The aim of the present study was to explore a potential role of PGE2 in regulating ENaC in cortical collecting duct (CCD) cells. Short-circuit current (ISC) measurements were performed using the murine mCCDcl1 cell line known to express characteristic properties of CCD principal cells and to be responsive to physiological concentrations of aldosterone and vasopressin. PGE2 stimulated amiloride-sensitive ISC via basolateral prostaglandin E receptors type 4 (EP4) with an EC50 of ∼7.1 nM. The rapid stimulatory effect of PGE2 on ISC resembled that of vasopressin. A maximum response was reached within minutes, coinciding with an increased abundance of ß-ENaC at the apical plasma membrane and elevated cytosolic cAMP levels. The effects of PGE2 and vasopressin were nonadditive, indicating similar signaling cascades. Exposing mCCDcl1 cells to aldosterone caused a much slower (∼2 h) increase of the amiloride-sensitive ISC. Interestingly, the rapid effect of PGE2 was preserved even after aldosterone stimulation. Furthermore, application of arachidonic acid also increased the amiloride-sensitive ISC involving basolateral EP4 receptors. Exposure to arachidonic acid resulted in elevated PGE2 in the basolateral medium in a cyclooxygenase 1 (COX-1)-dependent manner. These data suggest that in the cortical collecting duct, locally produced and secreted PGE2 can stimulate ENaC-mediated transepithelial sodium transport.

High oxygen fraction during airway opening is key to effective airway rescue in obese subjects.

Apnea is common after induction of anesthesia and may produce dangerous hypoxemia, particularly in obese subjects. Optimal management of airway emergencies in obese, apneic subjects is complex and controversial, and clinical studies of rescue strategies are inherently difficult and ethically-challenging to perform. We investigated rescue strategies in various degrees of obesity, using a highly-integrated, computational model of the pulmonary and cardiovascular systems, configured against data from 8 virtual subjects (body mass index [BMI] 24-57 kg m-2). Each subject received pre-oxygenation with 100% oxygen for 3 min, and then apnea with an obstructed airway was simulated until SaO2 reached 40%. At that time, airway rescue was simulated, opening of the airway with the provision of various patterns of tidal ventilation with 100% oxygen. Rescue using tidal ventilation with 100% oxygen provided rapid re-oxygenation in all subjects, even with small tidal volumes in subjects with large BMI. Overall, subjects with larger BMI pre-oxygenated faster and, after airway obstruction, developed hypoxemia more quickly. Our results indicate that attempts to achieve substantial tidal volumes during airway rescues are probably not worthwhile (and may be counter-productive); rather, it is the assurance of a high-inspired oxygen fraction that will prevent critical hypoxemia.