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AbstractObjectivesMethodsResultsConclusionThe nociceptive flexion reflex (NFR) and its threshold are frequently used to investigate spinal nociception in humans. Since this threshold (NFRT) is a probabilistic measure, specific algorithms are used for NFRT estimation based on the stochastic occurrence of reflexes at different stimulus intensities. We used a validated simulation model of the NFR to investigate the amount of NFRT measurement variability induced by different estimation algorithms in a steady setting of reduced external influences.We simulated the behavior of different estimation algorithms in subjects with an artificially steady baseline NFRT variability (standard deviation: 0 mA) or low baseline NFRT variability (standard deviation: 0.156 mA), equaling a quiet experimental setting. The obtained data were analyzed for NFRT measurement variability caused by the algorithms compared to the baseline variability reflecting other physiological influences.The standard deviation of the NFRT estimated by the different algorithms ranged between 0.381 and 3.464 mA with 96.8% to 99.6% of the measurement variability attributed to the algorithm used. Out of the investigated algorithms the dynamic staircase algorithm was most precise.The NFRT measurement variability observed during quiet and steady experimental sessions is mostly caused by the properties of the estimation algorithms, due to the probabilistic nature of the reflex occurrence. Our results give reference for choosing the optimal estimation algorithm to improve measurement precision. [ABSTRACT FROM AUTHOR]

Background: Clinical practice guidelines are systematically developed statements intended to optimize patient care. However, a gapless implementation of guideline recommendations requires health care personnel not only to be aware of the recommendations and to support their content but also to recognize every situation in which they are applicable. To not miss situations in which recommendations should be applied, computerized clinical decision support can be provided through a system that allows an automated monitoring of adherence to clinical guideline recommendations in individual patients. Objective: This study aims to collect and analyze the requirements for a system that allows the monitoring of adherence to evidence-based clinical guideline recommendations in individual patients and, based on these requirements, to design and implement a software prototype that integrates guideline recommendations with individual patient data, and to demonstrate the prototype's utility in treatment recommendations. Methods: We performed a work process analysis with experienced intensive care clinicians to develop a conceptual model of how to support guideline adherence monitoring in clinical routine and identified which steps in the model could be supported electronically. We then identified the core requirements of a software system to support recommendation adherence monitoring in a consensus-based requirements analysis within the loosely structured focus group work of key stakeholders (clinicians, guideline developers, health data engineers, and software developers). On the basis of these requirements, we designed and implemented a modular system architecture. To demonstrate its utility, we applied the prototype to monitor adherence to a COVID-19 treatment recommendation using clinical data from a large European university hospital. Results: We designed a system that integrates guideline recommendations with real-time clinical data to evaluate individual guideline recommendation adherence and developed a functional prototype. The needs analysis with clinical staff resulted in a flowchart describing the work process of how adherence to recommendations should be monitored. Four core requirements were identified: the ability to decide whether a recommendation is applicable and implemented for a specific patient, the ability to integrate clinical data from different data formats and data structures, the ability to display raw patient data, and the use of a Fast Healthcare Interoperability Resources–based format for the representation of clinical practice guidelines to provide an interoperable, standards-based guideline recommendation exchange format. Conclusions: Our system has advantages in terms of individual patient treatment and quality management in hospitals. However, further studies are needed to measure its impact on patient outcomes and evaluate its resource effectiveness in different clinical settings. We specified a modular software architecture that allows experts from different fields to work independently and focus on their area of expertise. We have released the source code of our system under an open-source license and invite for collaborative further development of the system. [ABSTRACT FROM AUTHOR]

Background: Procedural pain is a common burden in critical care treatment and the prediction of nociceptive reactions remains challenging. Thus, we investigated the Behavioural Pain Scale (BPS), the Critical Pain Observational Tool (CPOT), the nociceptive flexion reflex (NFR), the pupillary dilation reflex (PDR) and the Richmond Agitation-Sedation Scale (RASS) as predictors of behavioural reactions to nociceptive procedures.Methods: In this monocentric, prospective, observational study, we analysed data of 128 critically ill adults unable to self-report pain to investigate the predictability of behavioural reactions to two procedures: endotracheal suctioning and turning. Next to routine clinical data, CPOT, BPS, PDR, NFR, RASS, propofol and sufentanil doses were recorded before the procedures.Results: For endotracheal suctioning, NFR, BPS, CPOT and RASS showed predictive performances significantly better than chance, but none of them performed significantly better than the sufentanil dose rate. For turning, BPS, CPOT and RASS showed predictive performances significantly better than chance, but only the RASS performed significantly better than the propofol dose rate.Conclusions: Behavioural reactions to both investigated clinical procedures can be predicted by observational scales or nociceptive reflexes. For endotracheal suctioning, none of the predictors performed superior to using the sufentanil dose rate as a predictor. As using sufentanil as a predictor requires no extra effort in contrast to the other predictors, none of the here investigated tools seem advisable for predicting behavioural reactions to endotracheal suctioning. For patient turning, the RASS predicts reactions better than any other tool.Significance: In this observational study, we demonstrate that behavioural reactions to potentially nociceptive procedures in critical care treatment can be predicted by observational scales and nociceptive reflexes. However, for endotracheal suctioning, none of the predictors is superior to using the opioid dose rate as a predictor. For patient turning, the RASS predicts reactions better than any other parameters. [ABSTRACT FROM AUTHOR]

Background: Cognitive abilities decline with aging, leading to a higher risk for the development of postoperative delirium or postoperative neurocognitive disorders after general anesthesia. Since frontal α-band power is known to be highly correlated with cognitive function in general, we hypothesized that preoperative cognitive impairment is associated with lower baseline and intraoperative frontal α-band power in older adults. Methods: Patients aged ≥65 years undergoing elective surgery were included in this prospective observational study. Cognitive function was assessed on the day before surgery using six age-sensitive cognitive tests. Scores on those tests were entered into a principal component analysis to calculate a composite "g score" of global cognitive ability. Patient groups were dichotomized into a lower cognitive group (LC) reaching the lower 1/3 of "g scores" and a normal cognitive group (NC) consisting of the upper 2/3 of "g scores." Continuous pre- and intraoperative frontal electroencephalograms (EEGs) were recorded. EEG spectra were analyzed at baseline, before start of anesthesia medication, and during a stable intraoperative period. Significant differences in band power between the NC and LC groups were computed by using a frequency domain (δ 0.5–3 Hz, θ 4–7 Hz, α 8–12 Hz, β 13–30 Hz)-based bootstrapping algorithm. Results: Of 38 included patients (mean age 72 years), 24 patients were in the NC group, and 14 patients had lower cognitive abilities (LC). Intraoperative α-band power was significantly reduced in the LC group compared to the NC group (NC –1.6 [–4.48/1.17] dB vs. LC –6.0 [–9.02/–2.64] dB), and intraoperative α-band power was positively correlated with "g score" (Spearman correlation: r = 0.381; p = 0.018). Baseline EEG power did not show any associations with "g." Conclusions: Preoperative cognitive impairment in older adults is associated with intraoperative absolute frontal α-band power, but not baseline α-band power. [ABSTRACT FROM AUTHOR]

Introduction: The term "usability" describes how effectively, efficiently, and with what level of user satisfaction an information system can be used to accomplish specific goals. Computerized critical care information systems (CCISs) with high usability increase quality of care and staff satisfaction, while reducing medication errors. Conversely, systems lacking usability can interrupt clinical workflow, facilitate errors, and increase charting time. The aim of this study was to investigate and compare usability across CCIS currently used in Germany. Methods: In this study, German intensive care unit (ICU) nurses and physicians completed a specialized, previously validated, web-based questionnaire. The questionnaire assessed CCIS usability based on three rating models: an overall rating of the systems, a model rating technical usability, and a model rating task-specific usability. Results: We analyzed results from 535 survey participants and compared eight different CCIS commonly used in Germany. Our results showed that usability strongly differs across the compared systems. The system ICUData had the best overall rating and technical usability, followed by the platforms ICM and MetaVision. The same three systems performed best in the rating of task-specific usability without significant differences between each other. Across all systems, overall ratings were more dependent on ease-of-use aspects than on aspects of utility/functionality, and the general scope of the functions offered was rated better than how well the functions are realized. Discussion: Our results suggest that manufacturers should shift some of their effort away from the development of new features and focus more on improving the ease-of-use and quality of existing features. [ABSTRACT FROM AUTHOR]

The implementation of computerized critical care information systems (CCIS) can improve the quality of clinical care and staff satisfaction, but also holds risks of disrupting the workflow with consecutive negative impacts. The usability of CCIS is one of the key factors determining their benefits and weaknesses. However, no tailored instrument exists to measure the usability of such systems. Therefore, the aim of this study was to design and validate a questionnaire that measures the usability of CCIS. Following a mixed-method design approach, we developed a questionnaire comprising two evaluation models to assess the usability of CCIS: (1) the task-specific model rates the usability individually for several tasks which CCIS could support and which we derived by analyzing work processes in the ICU; (2) the characteristic-specific model rates the different aspects of the usability, as defined by the international standard "ergonomics of human-system interaction". We tested validity and reliability of the digital version of the questionnaire in a sample population. In the sample population of 535 participants both usability evaluation models showed a strong correlation with the overall rating of the system (multiple correlation coefficients ≥0.80) as well as a very high internal consistency (Cronbach's alpha ≥0.93). The novel questionnaire is a valid and reliable instrument to measure the usability of CCIS and can be used to study the influence of the usability on their implementation benefits and weaknesses. [ABSTRACT FROM AUTHOR]

Introduction:The nociceptive flexion reflex threshold (NFRT) is a promising tool to monitor analgesia during general anaesthesia. Clinical studies have shown that the NFRT allows to predict movement responses to painful stimuli under a combined anaesthetic regime of sedative and opioid agents. Experimental studies indicated that the NFRT is also able to predict such movement responses under an exclusively sedative regime like propofol mono-anaesthesia. Therefore, we performed this study to investigate the ability of the NFRT to predict movement responses to painful stimuli in patients during a clinical propofol mono-anaesthesia. Methods:We investigated 140 cardiac surgery patients during their postoperative phase under propofol mono-anaesthesia. NFRT and bispectral index (BIS) were determined in each patient right before endotracheal suctioning or painful electrical test stimulation. Prediction probabilities were calculated to quantify how accurate each measure is able to predict movement responses to the stimuli. Results:The 124 patients included in the analysis received a median propofol dosage of 3.2 (2.5–3.9) [median (IQR)] mg/kg/h. The included patients showed 287 movement responses after a total of 725 investigated stimuli. The prediction probabilities for positive movement responses were 0.63 (95%CI: 0.59–0.67) for the NFRT and 0.69 (95%CI: 0.65–0.73) for the BIS. Conclusions:The NFRT allows the prediction of movement responses under propofol mono-anaesthesia, which confirms its utility as a monitor to predict movement responses under general anaesthesia. The BIS allows an even more accurate prediction, although it does not reflect the physiological structures of movement suppression, but correlates closely with the dose of propofol. Trial registration:German clinical trial register (DRKS00003062, Deutsches Register Klinischer Studien). [ABSTRACT FROM PUBLISHER]

Background: Immediate postoperative pain could be prevented by the administration of long-lasting analgesics before the end of the anaesthesia. However, to prevent over or underdosing of analgesics under anaesthesia, tools are required to estimate the analgesia-nociception balance.Objective: We investigated whether the pupillary dilation reflex (PDR) and the nociceptive flexion reflex (NFR) at the end of general anaesthesia correlate with immediate postoperative pain, as a sign of analgesic underdosing, and with delayed tracheal extubation as a sign of analgesic overdosing.Design: Prospective observational study.Setting: Klinikum im Friedrichshain, Berlin, Germany, from May 2013 to April 2015.Patients: A total of 110 patients scheduled for primary hip arthroplasty under general anaesthesia.Observations: Psychometric and clinical data were obtained preoperatively. The PDR and the NFR were assessed preoperatively and at the end of anaesthesia. Shortly after extubation of the trachea, patients rated their pain intensity.Endpoints: The primary endpoint was the immediate postoperative numeric rating scale pain intensity (0 to 10) and the secondary endpoint was the length of the time interval between reflex measurements and tracheal extubation.Results: PDR correlated significantly with the immediate postoperative pain intensity (Spearman's ρ = -0.28, P < 0.01). PDR and NFR correlated significantly with the time interval until extubation (ρ = 0.33/0.26, both P < 0.01). Multivariable linear regression models were able to predict 38% of the variability of immediate postoperative pain intensity and 44% of the variability of the time interval until extubation. The intraoperative nociceptive reflex thresholds were the strongest factors in both multivariable models, only exceeded by the preoperative reflex measurements in the model for postoperative pain.Conclusion: The investigated nociceptive reflexes reflected the analgesia-nociception balance under general anaesthesia. The preoperative reflexes provide additional information about individual subjective pain sensitivity.Trial Registration: Deutsches Register Klinischer Studien, DRKS (registration number DRKS00000665). [ABSTRACT FROM AUTHOR]

Precise multicolor single molecule localization-based microscopy (SMLM) requires bright probes with compatible photo-chemical and spectral properties to resolve distinct molecular species at the nanoscale. The accuracy of multicolor SMLM is further challenged by color channel crosstalk and chromatic alignment errors. These constrains limit the applicability of known reversibly switchable organic dyes for optimized multicolor SMLM. Here, we tested 28 commercially available dyes for their suitability to super-resolve a known cellular nanostructure. We identified eight novel dyes in different spectral regimes that enable high quality dSTORM imaging. Among those, the spectrally close dyes CF647 and CF680 comprise an optimal dye pair for spectral demixing-based, registration free multicolor dSTORM with low crosstalk. Combining this dye pair with the separately excited CF568 we performed 3-color dSTORM to image the relative nanoscale distribution of components of the endocytic machinery and the cytoskeleton. [ABSTRACT FROM AUTHOR]

We would like to thank for the opportunity to reply to the important questions raised by Kendall et al. and also would like to thank the authors of that letter for their kind words. Our results indeed seem contrary to previous results about opioid-induced hyperalgesia (OIH), but on a detailed look there is not necessarily a contradiction. Until now no direct link between the short-lasting OIH and long-term pain has been shown in humans. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

Clathrin-mediated endocytosis (CME) involves membrane-associated scaffolds of the bin-amphiphysin-rvs (BAR) domain protein family as well as the GTPase dynamin, and is accompanied and perhaps triggered by changes in local lipid composition. How protein recruitment, scaffold assembly and membrane deformation is spatiotemporally controlled and coupled to fission is poorly understood. We show by computational modelling and super-resolution imaging that phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] synthesis within the clathrin-coated area of endocytic intermediates triggers selective recruitment of the PX-BAR domain protein SNX9, as a result of complex interactions of endocytic proteins competing for phospholipids. The specific architecture induces positioning of SNX9 at the invagination neck where its self-assembly regulates membrane constriction, thereby providing a template for dynamin fission. These data explain how lipid conversion at endocytic pits couples local membrane constriction to fission. Our work demonstrates how computational modelling and super-resolution imaging can be combined to unravel function and mechanisms of complex cellular processes. [ABSTRACT FROM AUTHOR]

Objective A variety of algorithms is used for nociceptive flexion reflex threshold (NFRT) estimation, but their estimation accuracy is unknown. We developed a computer based simulation model of the NFRT to quantify and compare the accuracy of available estimation algorithms. Methods This simulation model is based on basic characteristics of the NFRT and specified by data collected from 60 healthy volunteers. We validated the model by comparing simulated data with data obtained independently in another volunteer population. The model was used to quantify the accuracy of previously published NFRT estimation algorithm for three NFRT variabilities representing sensory deprivation, distraction and general anaesthesia. Results The dynamic staircase algorithm obtained most accurate NFRT estimates during all NFRT variabilities. The number of stimuli applied can be chosen higher to increase estimate precision or lower to reduce measurement time. Conclusions Our simulation model is a valid tool to measure the accuracy of NFRT estimation algorithms. It can be applied to analyse and develop algorithms. The dynamic staircase algorithm shows the highest precision in NFRT estimation and is recommended for NFRT studies. Significance Using optimized NFRT estimation algorithms increases precision in clinical and experimental NFRT studies and might therefore reduce the measurement effort necessary. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has spurred large-scale, interinstitutional research efforts. To enable these efforts, researchers must agree on data set definitions that not only cover all elements relevant to the respective medical specialty but also are syntactically and semantically interoperable. Therefore, the German Corona Consensus (GECCO) data set was developed as a harmonized, interoperable collection of the most relevant data elements for COVID-19-related patient research. As the GECCO data set is a compact core data set comprising data across all medical fields, the focused research within particular medical domains demands the definition of extension modules that include data elements that are the most relevant to the research performed in those individual medical specialties. Objective: We aimed to (1) specify a workflow for the development of interoperable data set definitions that involves close collaboration between medical experts and information scientists and (2) apply the workflow to develop data set definitions that include data elements that are the most relevant to COVID-19-related patient research regarding immunization, pediatrics, and cardiology. Methods: We developed a workflow to create data set definitions that were (1) content-wise as relevant as possible to a specific field of study and (2) universally usable across computer systems, institutions, and countries (ie, interoperable). We then gathered medical experts from 3 specialties-infectious diseases (with a focus on immunization), pediatrics, and cardiology-to select data elements that were the most relevant to COVID-19-related patient research in the respective specialty. We mapped the data elements to international standardized vocabularies and created data exchange specifications, using Health Level Seven International (HL7) Fast Healthcare Interoperability Resources (FHIR). All steps were performed in close interdisciplinary collaboration with medical domain experts and medical information specialists. Profiles and vocabulary mappings were syntactically and semantically validated in a 2-stage process. Results: We created GECCO extension modules for the immunization, pediatrics, and cardiology domains according to pandemic-related requests. The data elements included in each module were selected, according to the developed consensus-based workflow, by medical experts from these specialties to ensure that the contents aligned with their research needs. We defined data set specifications for 48 immunization, 150 pediatrics, and 52 cardiology data elements that complement the GECCO core data set. We created and published implementation guides, example implementations, and data set annotations for each extension module. Conclusions: The GECCO extension modules, which contain data elements that are the most relevant to COVID-19-related patient research on infectious diseases (with a focus on immunization), pediatrics, and cardiology, were defined in an interdisciplinary, iterative, consensus-based workflow that may serve as a blueprint for developing further data set definitions. The GECCO extension modules provide standardized and harmonized definitions of specialty-related data sets that can help enable interinstitutional and cross-country COVID-19 research in these specialties.