A Monte-Carlo based model of the AX-PET demonstrator and its experimental validation.

AX-PET is a novel PET detector based on axially oriented crystals and orthogonal wavelength shifter (WLS) strips, both individually read out by silicon photo-multipliers. Its design decouples sensitivity and spatial resolution, by reducing the parallax error due to the layered arrangement of the crystals. Additionally the granularity of AX-PET enhances the capability to track photons within the detector yielding a large fraction of inter-crystal scatter events. These events, if properly processed, can be included in the reconstruction stage further increasing the sensitivity. Its unique features require dedicated Monte-Carlo simulations, enabling the development of the device, interpreting data and allowing the development of reconstruction codes. At the same time the non-conventional design of AX-PET poses several challenges to the simulation and modeling tasks, mostly related to the light transport and distribution within the crystals and WLS strips, as well as the electronics readout. In this work we present a hybrid simulation tool based on an analytical model and a Monte-Carlo based description of the AX-PET demonstrator. It was extensively validated against experimental data, providing excellent agreement.

Physiological modelling of agitation-sedation dynamics including endogenous agitation reduction.

Sedation administration and agitation management are fundamental activities in any intensive care unit. A lack of objective measures of agitation and sedation, as well as poor understanding of the underlying dynamics, contribute to inefficient outcomes and expensive healthcare. Recent models of agitation-sedation pharmacodynamics have enhanced understanding of the underlying dynamics and enable development of advanced protocols for semi-automated sedation administration. However, these initial models do not capture all observed dynamics, particularly periods of low sedative infusion. A physiologically representative model that incorporates endogenous agitation reduction (EAR) dynamics is presented and validated using data from 37 critical care patients. High median relative average normalised density (RAND) values of 0.77 and 0.78 support and minimum RAND values of 0.51 and 0.55 for models without and with EAR dynamics respectively show that both models are valid representations of the fundamental agitation-sedation dynamics present in a broad spectrum of intensive care unit (ICU) patients. While the addition of the EAR dynamic increases the ability of the model to capture the observed dynamics of the agitation-sedation system, the improvement is relatively small and the sensitivity of the model to the EAR dynamic is low. Although this may represent a limitation of the model, the inclusion of EAR is shown to be important for accurately capturing periods of low, or no, sedative infusion, such as during weaning prior to extubation.

Physiological modelling of agitation-sedation dynamics.

Agitation-sedation cycling in critically ill patients, characterized by oscillations between states of agitation and over-sedation, damages patient health and increases length of stay and cost. A model that captures the essential dynamics of the agitation-sedation system and is physiologically representative is developed, and validated using data from 37 critical care patients. It is more physiologically representative than a previously published agitation-sedation model, and captures more realistic and complex dynamics. The median time in the 90% probability band is 90%, and the total drug dose, relative to recorded drug dose data, is a near ideal 101%. These statistical model validation metrics are 5-13% better than a previously validated model. Hence, this research provides a platform to develop and test semi-automated sedation management controllers that offer the significant clinical potential of improved agitation management and reduced length of stay in critical care.

Automated agitation management accounting for saturation dynamics.

Agitation-sedation cycling in critically ill is damaging to patient health and increases length of and cost. A physiologically representative model of the agitation-sedation system is used as a platform to evaluate feedback controllers offering improved agitation management. A heavy-derivative controller with upper and infusion rate bounds maintains minimum plasma concentrations through a low constant infusion, and minimizes outbursts of agitation through strong, timely boluses. controller provides improved agitation management using from 37 critically ill patients, given the saturation of effect at high concentration. Approval was obtained the Canterbury Ethics Board for this research.

Physiologically-based minimal model of agitation-sedation dynamics.

Agitation-sedation cycling in critically ill patients, characterized by oscillations between states of agitation and over-sedation, damages patient health and increases length of stay and cost. The model presented captures the essential dynamics of the agitation-sedation system, is physiologically representative, and is validated by accurately simulating patient response for 37 critical care patients. The model provides a platform to develop and test controllers that offer the potential of improved agitation management.

Rethinking sedation and agitation management in critical illness.

OBJECTIVE: To examine difficulties in sedation management in the critically ill patient and explore how a semi automated sedation controller can improve agitation control. To present recent work on measurements of agitation, dynamic systems modelling and control of patient agitation response. DATA SOURCES: Articles and peer-reviewed studies identified through a PUBMED search and selected original works from the biomedical engineering literature of relevance to agitation control and management. SUMMARY OF REVIEW: Over-sedation has an adverse impact on intensive care resources. Interventions to constrain sedation delivery through development of protocols or regular cessation of infusions result in reduction in resource utilisation, but have not significantly addressed existing difficulties in agitation control. We develop a paradigm in which control of agitation in critically ill patients becomes the primary objective of sedation management. This principle is central to the function of a nurse-managed semi-automated sedation delivery device. The clinical application of this device using subjective assessments of agitation is presented. A framework for the development of improved automated sedation delivery systems using objective measurements of agitation and control, based on agitation feedback, is described. Using dynamic systems modelling and a simulated nurse, a bolus-driven approach significantly reduced agitation and minimised drug utilisation. This result challenges the current practice of sedating patients using continuous infusions. CONCLUSIONS: A simple computerised interface with an algorithm that continually reduces the infusion rate in the absence of agitation has successfully been introduced into clinical practice. Nursing staff reported high levels of satisfaction with this device and it has enabled detailed data on patterns of sedation administration to be extracted for analysis. This data has been used to validate a model of the fundamental agitation-sedation dynamics.

Carbocyclic frenolicin analogues: novel anticoccidial agents.

Carbocyclic analogues of the antibacterial natural product frenolicin B have been synthesised. These analogues were active against parasitic protozoa of the genus Eimeria and represent a new series of anticoccidial agents. The synthesis of simplified analogues helped to define a possible pharmacophore for frenolicin.

Molecular basis of hereditary C3 deficiency.

Hereditary deficiency of complement component C3 in a 10-yr-old boy was studied. C3 could not be detected by RIA of serum from the patient. Segregation of C3 S and C3 F allotypes within the family confirmed the presence of a null gene for C3, for which the patient was homozygous. 30 exons have been characterized, spanning the entire beta chain of C3 and the alpha chain as far as the C3d region. Sequence analysis of the exons derived from the C3 null gene showed no abnormalities in the coding sequences. A GT-AT mutation at the 5' donor splice site of the intervening sequence 18 was found in the C3 null gene. Exons 17-21 were amplified by the polymerase chain reaction (PCR) from first-strand cDNA synthesized from mRNA obtained from peripheral blood monocytes stimulated with LPS. This revealed a 61-bp deletion in exon 18, resulting from splicing of a cryptic 5' donor splice site in exon 18 with the normal 3' splice site in exon 19. This deletion leads to a disturbance of the reading frame of the mRNA with a stop codon 17 bp downstream from the abnormal splice in exon 18. His parents had both the normal and abnormal C3 mRNA and were shown to be heterozygous for this mutation by sequence analysis of genomic DNA amplified by PCR. Similar splice mutants have previously been reported in the beta-globin, phenylalanine hydroxylase, and porphobilinogen deaminase genes. This mutation is sufficient to cause the deficiency of C3 in the patient.

Reduced numbers of complement receptor type 1 on erythrocytes are associated with increased levels of anticardiolipin antibodies. Findings in patients with systemic lupus erythematosus and the antiphospholipid syndrome.

In several diseases, including systemic lupus erythematosus (SLE) and autoimmune hemolytic anemias, the numbers of complement receptor type 1 (CR1) expressed on erythrocytes of patients are reduced. In patients with SLE, anticardiolipin antibodies (aCL) have been associated with positive results on direct antiglobulin tests. Because of these findings, we investigated whether the reduced expression of erythrocyte CR1 in 61 patients (53 with SLE and 8 with the antiphospholipid syndrome) might be associated with the presence of aCL. A negative correlation was observed between aCL levels and mean numbers of CR1 (rs = -0.43, P = 0.001), and a positive correlation was observed between aCL levels and the levels of erythrocyte C4d and C3d (rs = 0.33 and 0.41, P = 0.01 and 0.001, respectively), but no correlation of aCL levels with serum C4 levels was found. When the results were further analyzed according to the IgG or IgM class of aCL, levels of antibodies of both classes were negatively correlated with CR1 numbers, but only IgM aCL levels were correlated with erythrocyte C4d and C3d numbers. The levels of anti-double-stranded DNA antibodies showed no correlation with erythrocyte CR1, C4d, or C3d numbers but were negatively correlated with serum C4 levels (rs = -0.43, P = 0.002). These data suggest that aCL, or a closely related antibody specificity, may bind to erythrocytes and may be directly involved in the mechanism for reduction of erythrocyte CR1 expression in SLE patients.

Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results.

We describe the development of a simple and highly sensitive double antibody sandwich enzyme-linked immunosorbent assay (ELISA) for measuring IgG and IgM anticardiolipin antibodies (ACA). Microtitre plates were coated with cardiolipin at a concentration of 45 micrograms/ml by evaporation under nitrogen. Non-specific binding of diluted sera was eliminated by blocking of plates with 10% fetal calf serum in phosphate buffered saline (PBS/FCS) for 2 h. Then sera (100 microliters) at a dilution of 1:100 were incubated in the wells for 1 h. Affinity purified goat anti-human IgG or IgM (100 microliters) at a concentration of 1 microgram/ml was subsequently added and allowed to incubate for 1 h; detection of ACA was achieved using an alkaline phosphatase conjugated rabbit anti-goat IgG reagent by reading the colorimetric yield at 405 nm after incubation with substrate. Reference serum pools were established to study reproducibility of the assay throughout its sensitivity range, and Standard curves were established. The quantitative normal range was 0-9.0 Anticardiolipin ELISA Units (AEU) for IgG and 0-8.0 (AEU) for IgM-ACA. A strong correlation was found between the ELISA and radioimmunoassay methods for measuring ACA of both IgG and IgM classes. Results from 65 patients with systemic lupus erythematosus (SLE) and 45 patients with seropositive rheumatoid arthritis are also reported. The advantages of the ELISA method for quantitative determination of ACA levels, should make it a useful and reliable method for clinical and experimental monitoring of patients with SLE and associated autoimmune disorders.