Avascular Necrosis of the Foot and Ankle in a Patient with Systemic Sclerosis: A Case Based Review

This review describes a case of atraumatic avascular necrosis in the foot and ankle in a patient with systemic sclerosis who did not receive corticosteroid therapy. Both avascular necrosis and systemic sclerosis are uncommon disease entities. This case demonstrates that vasculitis and secondary vasoconstriction in the pathogenesis of systemic sclerosis are important risk factors for the development of avascular necrosis of the foot and ankle. Therefore, if these patients develop chronic foot and ankle pain, avascular necrosis should be included in the differential diagnosis, even if they do not receive corticosteroids. For the diagnosis and follow-up of avascular necrosis MRI remains the gold standard. Thus, MRI should be used to diagnose avascular necrosis in an early stage. Level of Clinical Evidence: 4.This review describes a case of atraumatic avascular necrosis in the foot and ankle in a patient with systemic sclerosis who did not receive corticosteroid therapy. Both avascular necrosis and systemic sclerosis are uncommon disease entities. This case demonstrates that vasculitis and secondary vasoconstriction in the pathogenesis of systemic sclerosis are important risk factors for the development of avascular necrosis of the foot and ankle. Therefore, if these patients develop chronic foot and ankle pain, avascular necrosis should be included in the differential diagnosis, even if they do not receive corticosteroids. For the diagnosis and follow-up of avascular necrosis MRI remains the gold standard. Thus, MRI should be used to diagnose avascular necrosis in an early stage. Level of Clinical Evidence: 4

A response surface model approach for continuous measures of hypnotic and analgesic effect during sevoflurane-remifentanil interaction: quantifying the pharmacodynamic shift evoked by stimulation

Background: The authors studied the interaction between sevoflurane and remifentanil on bispectral index (BIS), state entropy (SE), response entropy (RE), Composite Variability Index, and Surgical Pleth Index, by using a response surface methodology. The authors also studied the influence of stimulation on this interaction. Methods: Forty patients received combined concentrations of remifentanil (0 to 12 ng/ml) and sevoflurane (0.5 to 3.5 vol%) according to a crisscross design (160 concentration pairs). During pseudo–steady-state anesthesia, the pharmacodynamic measures were obtained before and after a series of noxious and nonnoxious stimulations. For the “prestimulation” and “poststimulation” BIS, SE, RE, Composite Variability Index, and Surgical Pleth Index, interaction models were applied to find the best fit, by using NONMEM 7.2.0. (Icon Development Solutions, Hanover, MD). Results: The authors found an additive interaction between sevoflurane and remifentanil on BIS, SE, and RE. For Composite Variability Index, a moderate synergism was found. The comparison of pre- and poststimulation data revealed a shift of C50SEVO for BIS, SE, and RE, with a consistent increase of 0.3 vol%. The Surgical Pleth Index data did not result in plausible parameter estimates, neither before nor after stimulation. Conclusions: By combining pre- and poststimulation data, interaction models for BIS, SE, and RE demonstrate a consistent influence of “stimulation” on the pharmacodynamic relationship between sevoflurane and remifentanil. Significant population variability exists for Composite Variability Index and Surgical Pleth Index

Frontal electroencephalogram based drug, sex, and age independent sedation level prediction using non-linear machine learning algorithms

Brain monitors which track quantitative electroencephalogram (EEG) signatures to monitor sedation levels are drug and patient specific. There is a need for robust sedation level monitoring systems to accurately track sedation levels across all drug classes, sex and age groups. Forty-four quantitative features estimated from a pooled dataset of 204 EEG recordings from 66 healthy adult volunteers who received either propofol, dexmedetomidine, or sevoflurane (all with and without remifentanil) were used in a machine learning based automated system to estimate the depth of sedation. Model training and evaluation were performed using leave-one-out cross validation methodology. We trained four machine learning models to predict sedation levels and evaluated the influence of remifentanil, age, and sex on the prediction performance. The area under the receiver-operator characteristic curve (AUC) was used to assess the performance of the prediction model. The ensemble tree with bagging outperformed other machine learning models and predicted sedation levels with an AUC = 0.88 (0.81-0.90). There were significant differences in the prediction probability of the automated systems when trained and tested across different age groups and sex. The performance of the EEG based sedation level prediction system is drug, sex, and age specific. Nonlinear machine-learning models using quantitative EEG features can accurately predict sedation levels. The results obtained in this study may provide a useful reference for developing next generation EEG based sedation level prediction systems using advanced machine learning algorithms

Utility of the SmartPilot® View advisory screen to improve anaesthetic drug titration and postoperative outcomes in clinical practice: a two-centre prospective observational trial.

BACKGROUND The advisory system SmartPilot® View (Drägerwerk AG, Lübeck, Germany) provides real-time, demographically adjusted pharmacodynamic information throughout anaesthesia, including time course of effect-site concentrations of administered drugs and a measure of potency of the combined drug effect termed the "'Noxious Stimulation Response Index' (NSRI). This dual-centre, prospective, observational study assesses whether the availability of SmartPilot® View alters the behaviour of anaesthetic drug titration of anaesthetists and improves the Anaesthesia Quality Score (AQS; percentage of time spent with MAP 60-80 mm Hg and Bispectral Index [BIS] 40-60 [blinded]). METHODS We recruited 493 patients scheduled for elective surgery in two university centres. A control group (CONTROL; n=170) was enrolled to observe drug titration in current practice. Thereafter, an intervention group was enrolled, for which SmartPilot® View was made available to optimise drug titration (SPV; n=188). The AQS, haemodynamic and hypnotic effects, recovery times, pain scores, and other parameters were compared between groups. RESULTS There were 358 patients eligible for analysis. Anaesthesia quality score was similar between CONTROL and SPV (median AQS [Q1-Q3]) 25.3% [7.4-41.5%] and 22.2% [8.0-44.4%], respectively; P=0.898). Compared with CONTROL, SPV patients had less severe hypotension and hypertension, less BIS <40, faster tracheal extubation, and lower early postoperative pain scores. CONCLUSIONS Adding SmartPilot® View information did not affect average drug titration behaviour. However, small improvements in control of MAP and BIS and early recovery suggest improved titration for some patients without increasing the risk of overdosing or underdosing. CLINICAL TRIAL REGISTRATION NCT01467167

Electron Beam Charging of Insulators with Surface Layer and Leakage Currents

International audienceThe electron beam induced selfconsistent charge transport in layered insulators is described by means of an electron-hole fight-drift model FDM and an iterative computer simulation. Ballistic secondary electrons and holes, their attenuation and drift, as well as their recombination, trapping, and detrapping are included. Thermal and field-enhanced detrapping are described by the Poole-Frenkel effect. Furthermore, an additional surface layer with a modified electric surface conductivity is included which describes the surface leakage currents and will lead to particular charge incorporation at the interface between the surface layer and the bulk substrate

Dexmedetomidine pharmacokineticpharmacodynamic modelling in healthy volunteers:1. Influence of arousal on bispectral index and sedation

Background. Dexmedetomidine, a selective alpha(2)-adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. Methods. In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokineticpharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG. Results. We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise. Conclusions. The new pharmacokinetic-pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation

Cerebral state index during propofol anesthesia:A Comparison with the Bispectral Index and the A-Line ARX Index

Background: The objective of this study was to prospectively test the Cerebral State Index designed for measuring the depth of anesthesia. The Cerebral State Index is calculated using a fuzzy logic combination of four subparameters of the electroencephalographic signal. The performance of the Cerebral State index was compared with that of the Bispectral Index and the A-Line ARX Index. Methods: This study applied raw data from two previously published clinical protocols. The patients in protocol 1 were given a continuous propofol infusion, 300 ml/h, until 80% of burst suppression occurred. In protocol 2, a stepwise increased target-controlled infusion of propofol was administered to patients until loss of response to noxious stimuli while the Observer's Assessment of Alertness and Sedation was registered every 4 min. The Cerebral State index was calculated off-line from the recorded electroencephalographic data. The Spearman rank correlation coefficient between electronic indices and the effect site concentration of propofol was calculated along with the prediction probability of each index to predict the Observer's Assessment of Alertness and Sedation level. Results: The Spearman rank correlation coefficients between the Cerebral State Index, Bispectral Index, and A-Line ARX Index and the propofol effect site concentration were -0.94, -0.89, and -0.82, respectively, in protocol 1, whereas the prediction probability values between the Cerebral State Index, Bispectral Index, and A-Line ARX Index and the Observer's Assessment of Alertness and Sedation score in protocol 2 were 0.92, 0.93, and 0.91, respectively. Conclusion: The Cerebral State Index detects well the graduated levels of propofol anesthesia when compared with the propofol effect site concentration and the Observer's Assessment of Alertness and Sedation score

Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90%

This prospective study evaluates haemodynamic and electroencephalographic effects observed when administering four combinations of effect-site concentrations of propofol (Ce-PROP) and remifentanil (Ce-REMI), all yielding a single predicted probability of tolerance of laryngoscopy of 90% (P-TOL = 90%) according to the Bouillon interaction model. We aimed to identify combinations of Ce-PROP and Ce-REMI along a single isobole of P-TOL that result in favourable hypnotic and haemodynamic conditions. This knowledge could be of advantage in the development of drug advisory monitoring technology. 80 patients (18-90 years of age, ASA I-III) were randomized into four groups and titrated towards Ce-PROP (Schnider model, ug.ml(-1)) and Ce-REMI (Minto model, ng.ml(-1)) of respectively 8.6 and 1, 5.9 and 2, 3.6 and 4 and 2.0 and 8. After eleven minutes of equilibration, baseline measurements of haemodynamic endpoints and bispectral index were compared with three minutes of responsiveness measurements after laryngoscopy. Before laryngoscopy, bispectral index differed significantly (p < 0.0001) between groups in concordance with Ce-PROP. Heart rate decreased with increasing Ce-REMI (p = 0.001). The haemodynamic and arousal responses evoked by laryngoscopy were not significantly different between groups, but Ce-PROP = 3.6 mu g.ml(-1) and Ce-REMI = 4 ng.ml(-1) evoked the lowest median value for increment HR and increment SAP after laryngoscopy. This study provides clinical insight on the haemodynamic and hypnotic consequences, when a model based predicted P-TOL is used as a target for combined effect-site controlled target- controlled infusion of propofol and remifentanil. Heart rate and bispectral index were significantly different between groups despite a theoretical equipotency for P-TOL, suggesting that each component of the anaesthetic state (immobility, analgesia, and hypnotic drug effect) should be considered as independent neurophysiological and pharmacological phenomena. However, claims of (in)accuracy of the predicted P-TOL must be considered preliminary because larger numbers of observations are required for that goal

Musculoskeletal models of a human and bonobo finger: parameter identification and comparison to in vitro experiments

Introduction: Knowledge of internal finger loading during human and non-human primate activities such as tool use or knuckle-walking has become increasingly important to reconstruct the behaviour of fossil hominins based on bone morphology. Musculoskeletal models have proven useful for predicting these internal loads during human activities, but load predictions for non-human primate activities are missing due to a lack of suitable finger models. The main goal of this study was to implement both a human and a representative non-human primate finger model to facilitate comparative studies on metacarpal bone loading. To ensure that the model predictions are sufficiently accurate, the specific goals were: (1) to identify species-specific model parameters based on in vitro measured fingertip forces resulting from single tendon loading and (2) to evaluate the model accuracy of predicted fingertip forces and net metacarpal bone loading in a different loading scenario. Materials & Methods: Three human and one bonobo (Pan paniscus) fingers were tested in vitro using a previously developed experimental setup. The cadaveric fingers were positioned in four static postures and load was applied by attaching weights to the tendons of the finger muscles. For parameter identification, fingertip forces were measured by loading each tendon individually in each posture. For the evaluation of model accuracy, the extrinsic flexor muscles were loaded simultaneously and both the fingertip force and net metacarpal bone force were measured. The finger models were implemented using custom Python scripts. Initial parameters were taken from literature for the human model and own dissection data for the bonobo model. Optimized model parameters were identified by minimizing the error between predicted and experimentally measured fingertip forces. Fingertip forces and net metacarpal bone loading in the combined loading scenario were predicted using the optimized models and the remaining error with respect to the experimental data was evaluated. Results. The parameter identification procedure led to minor model adjustments but considerably reduced the error in the predicted fingertip forces (root mean square error reduced from 0.53/0.69 N to 0.11/0.20 N for the human/bonobo model). Both models remained physiologically plausible after the parameter identification. In the combined loading scenario, fingertip and net metacarpal forces were predicted with average directional errors below 6◦ and magnitude errors below 12%. Conclusions. This study presents the first attempt to implement both a human and nonhuman primate finger model for comparative palaeoanthropological studies. The good agreement between predicted and experimental forces involving the action of extrinsic flexors—which are most relevant for forceful grasping—shows that the models are likely sufficiently accurate for comparisons of internal loads occurring during human and non-human primate manual activities

A20 (Tnfaip3) Deficiency in Myeloid Cells Protects against Influenza A Virus Infection

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections