A quantitative framework for analyzing epicardial activation patterns during ventricular fibrillation

Few techniques have been developed for deriving quantitative measures of activation patterns during ventricular fibrillation (VF). Such measures have many potential applications, for example, assessing the effects of time, drugs, or electrical interventions. We have developed a new framework for quantifying VF patterns as mapped from an array of ≈500 unipolar electrodes. Individual activation wavefronts are isolated from one another using an algorithm that groups together adjacent active electrogram samples (dV/dt <−0.5 V/sec). Contacts between wavefronts are detected; these include fractionations, in which a single wavefront breaks into multiple wavefronts, and collisions, in which multiple wavefronts coalesce to form a new wavefront. The timing and contact relationships between wavefronts are summarized as a directed graph. From this model of the VF episode, we derive several parameters: number of wavefronts number of fractionations, number of collisions, mean wavefront size, mean area swept out, and mean duration. As an example of this analysis, we computed these parameters in six open-chest pigs at 5, 10, 15, and 20 sec after electrical induction of VF. The number of wavefronts and the number of collisions decreased, whereas the mean wavefront size and mean area swept out increased during this period. These results are consistent with previous studies showing a recovery of organization during the first minute of VF.     

A new method for quantifying the complexity of muscle attachment sites

Muscle attachment site morphology may have valuable use for reconstructing activity patterns in individuals from historic populations or extinct species. The skeletal locations where muscles and tendons attach are morphologically very complex, and variations in this morphology may reflect stresses experienced by these attachment sites as a result of muscular contractions. However, existing methods for assessing attachment site complexity are qualitative and subjective. This article describes a new method for quantifying attachment site complexity in which attachment sites are scanned with a 3D laser scanner and the morphological complexities of their surfaces are quantified using fractal analysis. The method described here documents the complexity at specific transects along six limb attachment sites in adult female sheep (Ovis aries), and variations in complexity within attachment sites are explored. Overall trends indicate that most of the attachment sites examined here are more complex at their peripheries than at their centers, indicating that these sites experience more varied loads at the peripheries of the tendon attachments. Exceptions to this trend are noted and all functional implications are discussed. This method provides the first opportunity to explore variations in morphological complexity within attachment sites. Assuming a relationship between tensile strains and bony morphology exists, this method provides a new tool to explore the strain environments of muscle attachment sites.     

Evaluation of an automatic cardiac activation detector for bipolar electrograms

The identification of local activation events in bipolar cardiac electrograms, the first step of isochronal map construction, is a time-consuming and difficult process. Owing to the variability among bipolar activation complexes and the lack of practical knowledge concerning the relationship of the bipolar waveform to action potential characteristics, a set of empirical rules to guide the assignment of local activation times have been adopted. A computer program, called AP, has been designed, which implements these rules in the form of a syntactic analyser. Canine epicardial recordings were used to evaluate AP by comparing local activation times, assigned by AP, with times assigned independently by three investigators. The Hermes-Cox model for detector evaluation and a bootstrap statistical method were used in conjunction with ROC analysis to evaluate the ability of AP to detect events. Analysis of discrepancies among investigator-assigned times showed that the reliabilities of AP event detection and AP-assigned times were comparable to those of the investigators. The methods used in system design and evaluation are applicable to a broad range of problems in the detection and localisation of waveform components.     

A method for the classification of corrective activity in context dependent postural controlling tasks

Difficulties in maintaining postural stability are not common among young healthy people. However, with increasing age problems start to emerge. Deficits in the postural control system may also originate from a working environment where noise and solvents are present. Some diseases, for instance Menière's disease, can cause instability in walking and standing. Regardless of the origin of the problem in the balance system, it has to be detected in a meaningful, easily interpretable way. When detected, a suitable rehabilitation method can be proposed. In this paper we present a method which extracts a scalar feature from a stabilogram signal, which well describes the differences between young and elderly people's swaying processes. When our feature is applied to the K nearest neighbour algorithm the correct recognition accuracy is over 70% in cases where the purpose is to predict whether an unknown test feature is measured from a young or an elderly subject.     

A hybrid algorithm for solving the EEG inverse problem from spatio-temporal EEG data

Epilepsy is a neurological disorder caused by intense electrical activity in the brain. The electrical activity, which can be modelled through the superposition of several electrical dipoles, can be determined in a non-invasive way by analysing the electro-encephalogram. This source localization requires the solution of an inverse problem. Locally convergent optimization algorithms may be trapped in local solutions and when using global optimization techniques, the computational effort can become expensive. Fast recovery of the electrical sources becomes difficult that way. Therefore, there is a need to solve the inverse problem in an accurate and fast way. This paper performs the localization of multiple dipoles using a global-local hybrid algorithm. Global convergence is guaranteed by using space mapping techniques and independent component analysis in a computationally efficient way. The accuracy is locally obtained by using the Recursively Applied and Projected-MUltiple Signal Classification (RAP-MUSIC) algorithm. When using this hybrid algorithm, a four times faster solution is obtained.     

A non-parametric method for the analysis of experimental tumour growth data

Analysis of tumour growth is required to investigate the biology of tumours and to determine the effects of new anti-tumour therapies. A non-parametric mathematical method for the analysis of a set of experimental tumour growth data is described. The method is based on the similarity between time series of tumour size measurements (e.g. tumour volume), similarity being defined as the Euclidean distance between data measured for each tumour at the same time. Subsets of similar time series are found for a given population of tumours. A biologically meaningful parameter H has been derived which is a measure of the scattering of experimental volume samples. The method has been applied to the analysis of the growth of (i) untreated multicellular tumour spheroids obtained with different cell lines and (ii) spheroids, treated with cytotoxic drugs (immunotoxins). Results are compared with those previously obtained by applying the classical Gompertz growth model to the analysis of treated and untreated spheroids.     

A non-parametric method for the analysis of experimental tumour growth data

Analysis of tumour growth is required to investigate the biology of tumours and to determine the effects of new anti-tumour therapies. A non-parametric mathematical method for the analysis of a set of experimental tumour growth data is described. The method is based on the similarity between time series of tumour size measurements (e.g. tumour volume), similarity being defined as the Euclidean distance between data measured for each tumour at the same time. Subsets of similar time series are found for a given population of tumours. A biologically meaningful parameter H has been derived which is a measure of the scattering of experimental volume samples. The method has been applied to the analysis of the growth of (i) untreated multicellular tumour spheroids obtained with different cell lines and (ii) spheroids treated with cytotoxic drugs (immunotoxins). Results are compared with those previously obtained by applying the classical Gompertz growth model to the analysis of treated and untreated spheroids.     

An interactive graphical user interface for comprehensive analysis of human and swine cardiac monophasic action potential

This research describes a novel monophasic action potential (MAP) annotation algorithm coupled with an interactive graphical user interface (GUI). This algorithm incorporates a number of features to reduce error. Additionally, the GUI has several convenient features to view and manipulate the annotation visually. We analyzed data from swine and human hearts in normal sinus rhythm, during myocardial ischemia, and while eliciting high rates. Validation results indicate correlation >90% between human and computer measurements. This analysis system has several clinical applications in electrophysiological interventions, pharmacodynamic therapies, ischemia detection, and/or in assessment of the time course of electrical activation.     

The impact of noise on the reliability of heart-rate variability and complexity analysis in trauma patients

This study focused on the impact of noise on the reliability of heart-rate variability and complexity (HRV, HRC) to discriminate between different trauma patients and to monitor individual patients. Life-saving interventions (LSIs) were chosen as an endpoint because performance of LSIs is a critical aspect of trauma patient care. Noise was modeled and simulated by modifying original R–R interval (RRI) sequences via decimation, concatenation, and division of RRIs, as well as R-wave detection using the electrocardiogram. Results showed that under increasing simulated noise, entropy and autocorrelation measures can still effectively discriminate between LSI and non-LSI patients and monitor individuals over time.     

On processing of Doppler returns from the foetal heart: An electronic processing method for extraction of valvular timing information

An electronic processing scheme intended for use in conjunction with a multicrystal ultrasonic array to measure cardiac intervals in the human foetus is described. This new processing method possesses sufficient signal extraction capability to allow the time of opening of the aortic valve to be determined and tracked. Application of this method to a pulsed Doppler and continuous wave Doppler system is discussed. Features include amplitude independent detection, rapid response time and excellent frequency selectivity. Laboratory and clinical test results are presented that demonstrate the viability of an instrument based on this principle.     

Time and frequency domain methods for heart rate variability analysis: A methodological comparison

The purpose of this paper is to analytically evaluate and compare two of the most common methods for measuring respiration-related heart rate fluctuations: linear detrended heart rate power spectral analysis and the Porges technique of filtered variance. Low-frequency power was removed from instantaneous 4-Hz R-R interval signals using either a first-order linear (linear/spectral technique) or a third-order polynomial (MPF-var technique). The signals were band-pass filtered and analyzed in both the time and frequency domains. Although in most cases the two techniques yielded substantially similar results, the MPF-var technique resulted in signal amplification at a few specific frequencies. The frequency range and effect of amplification of the MPF-var technique were dependent upon the polynomial size, sampling frequency, and frequency content of the signal.     

A method for quantifying adrenocortical nodular hyperplasia at autopsy: some use of the method in illuminating hypertension and atherosclerosis

Quantifying the severity of adrenocortical nodular hyperplasia at autopsy or surgery has much potential practical value. For instance, this inquiry explores the correlation of adrenal nodularity with features of atherosclerosis in coronary arteries and microvascular features of hypertension in the renal cortex. Tissue retrieved from forensic autopsies in 96 men and women ages 16 to 88 years were evaluated for adrenal nodularity, coronary atheroma, and hypertensive renal microvasculopathies. Formalin-fixed adrenal glands were cut into 0.5-cm thick slices and fixed to plastic sheets with SuperGlue (Ross Products, Inc, Columbus, OH). After ranking the specimens on increasing nodularity, they were judged to fall into 10 distinguishable grades of increasing severity; photographs of a representative in each grade were arranged onto a panel. Each gland was then assigned the grade of the photograph it most resembled. Coronaries and kidneys were evaluated in paraffin sections. Weight and nodularity of adrenal glands increased with age. Men with at least one instance of atheroma in the coronary sample had heavier and more nodular glands (age-adjusted) than in men without atheroma. The differences held stronger statistical significance for nodularity than for weight because nodularity continued to show significance even within age groups sometimes represented by few cases. Hypertensive renal microvasculopathies failed to correlate with any of the adrenal features. Women were too few for the analysis. Findings made with the panel of photographs now available for grading adrenocortical nodular hyperplasia showed interesting correlations with coronary atherosclerosis in this data set, suggesting that use of this method might offer some insight into cardiovascular disease.     

Changes in linear and nonlinear EEG measures as a function of task complexity: evidence for local and distant signal synchronization

The purpose of the present study was threefold: First, to replicate previous findings of changes in local gamma band power as a function of the complexity of a visuo-semantic processing task, second, to extend these findings in tasks delivered in the auditory modality, and third to explore the use of non-linear algorithms as indices of complexity and distant synchronization in the EEG signal. EEG was recorded from 28 scalp locations as participants performed three visual discrimination tasks designed to tap into increasingly more complex operations regularly involved in the recognition of living animate objects. Two auditory processing tasks involving the same stimuli, but requiring no semantic processing, served as controls. The degree of complexity of the semantic decision was associated with the predicted changes in local gamma power, as well as with broadband changes in the non-linear predictability of the signal (an index derived using an artificial neural network algorithm). These changes were observed at all scalp regions, a finding consistent with the wide cortical distribution of component processes involved in the tasks. In addition, the synchronization between temporal and parieto-occipital electrodes and the remaining recording sites was highest in the gamma bands and lowest in the alpha bands for the task that required the most complex visuo-semantic decision. This trend reversed with reduced task complexity, consistent with the view that multidimensional semantic decisions require the involvement of distributed cortical networks in auditory and visual association areas and in the frontal lobes.     

New method for the assessment of neonatal respiratory sinus arrhythmia

Respiratory sinus arrhythmia (RSA) is sometimes hard to identify in neonates, in particular when the respiratory rate approaches half the mean heart rate. It is shown that the analysis of the cardiac event series may reveal RSA in cases where traditional heart rate variability analysis methods fail. A signal analysis approach to event series processing is reviewed. The validation of the spectral analysis of event series is illustrated with the help of simulation results. In accordance with this approach, the event series spectrum of a neonate shows a RSA component at 0·9 Hz, which was in agreement with the frequency of the simultaneously measured respiration. The possible implications for research into the causes of sudden infant death syndrome (SIDS) are discussed.     

A microcomputer-based method for physiologically interpretable measurement of the rewarding efficacy of brain stimulation

Determination of the function relating rate of pressing to the number of pulses in a train of fixed duration (the rate-frequency function) yields a physiologically interpretable measure of changes in the rewarding efficacy of the stimulation, because the number of action potentials in the reward-relevant first stage axons is directly proportional to the number of pulses in the train. We describe a system, based on a low cost microcomputer, which permits determination of 16-data-point rate-frequency functions in 4-6 animals simultaneously in less than 10 minutes. We give an empirical and theoretical justification for using the curve-shift measurement procedure in drug and lesion work, where the experimental treatments must be presumed to have substantial effects on performance factors.     

MKP-1: A critical phosphatase in the biology of macrophages controlling the switch between proliferation and activation

Macrophages play a central role in the immune response. These cells either proliferate in response to, for example, growth factors or become activated in response to, for example, LPS and develop functional activities. Experiments carried out in mice showed that macrophage proliferation requires a short period of ERK phosphorylation, while an extended period is required for macrophage activation. The length of phosphorylation is controlled by the MAPK phosphatase-1 (MKP-1), a nuclear-localized dual-specificity phosphatase that dephosphorylates the MAPKs ERK, p38, and c-Jun NH(2) -terminal kinase (JNK). MKP-1 is induced in macrophages by growth factors, as well as by activators such as LPS, but with different kinetics; to achieve the different functional outcomes (proliferation versus activation), the inhibition of MKP-1 by cytokines such as IFN-γ blocks macrophage proliferation and induces activation. The data presented in this review show that this phosphatase is the switch between macrophage proliferation and activation.     

A novel method for the production of antibodies against ACTH: their characterization and use in epitope mapping

Our earlier attempts at immunization with human adrenocorticotropin hormone (ACTH) were unsuccessful and we therefore developed a new strategy including the chemical modification of the hormone by succinic anhydride in order to increase its immunogenicity. This process allowed us to obtain antisera with titers of up to 1/1000 and yielded 39 anti-succinylated ACTH (sACTH)-secreting hybridomas. Subsequently, the epitopes of sACTH were mapped by testing monoclonal antibodies two by two for simultaneous binding to sACTH and for their capacity to recognize its succinylated fragments 1–13, 1–17 and 1–24. The results, obtained with the use of radioactive tracers, were confirmed by and complemented with experiments conducted with biosensor technology. Seven groups of antibodies were defined on the basis of their pattern of reactivity and it was shown that four monoclonal antibodies could bind simultaneously to sACTH. Their dissociation constants (K_d) for sACTH were calculated and ranged from 10⁻⁸ M to 10⁻¹¹ M. In order to obtain a fast and sensitive immunoassay for the hormone, we developed a protocol for the chemical modification of ACTH in serum and the most efficient monoclonal antibodies were selected on the basis of the epitope map and of their dissociation constants.     

Optimizing the user interface of a data entry module for an electronic patient record for cardiac rehabilitation: A mixed method usability approach

IntroductionCumbersome electronic patient record (EPR) interfaces may complicate data-entry in clinical practice. Completeness of data entered in the EPR determines, among other things, the value of computerized clinical decision support (CCDS). Quantitative usability evaluations can provide insight into mismatches between the system design model of data entry and users’ data entry behavior, but not into the underlying causes for these mismatches. Mixed method usability evaluation studies may provide these insights, and thus support generating redesign recommendations for improving an EPR system’s data entry interface.AimTo improve the usability of the data entry interface of an EPR system with CCDS in the field of cardiac rehabilitation (CR), and additionally, to assess the value of a mixed method usability approach in this context.MethodsSeven CR professionals performed a think-aloud usability evaluation both before (beta-version) and after the redesign of the system. Observed usability problems from both evaluations were analyzed and categorized using Zhang et al.’s heuristic principles of good interface design. We combined the think-aloud usability evaluation of the system’s beta-version with the measurement of a new usability construct: users’ deviations in action sequence from the system’s predefined data entry order sequence. Recommendations for redesign were implemented. We assessed whether the redesign improved CR professionals’ (1) task efficacy (with respect to the completeness of data they collected), and (2) task efficiency (with respect to the average number of mouse clicks they needed to complete data entry subtasks).ResultsWith the system’s beta version, 40% of health care professionals’ navigation actions through the system deviated from the predefined next system action. The causes for these deviations as revealed by the think-aloud method mostly concerned mismatches between the system design model for data entry action sequences and users expectations of these action sequences, based on their paper-based daily routines. This caused non completion of data entry tasks (31% of main tasks completed), and more navigation actions than minimally required (146% of the minimum required). In the redesigned system the data entry navigational structure was organized in a flexible way around an overview screen to better mimic users’ paper-based daily routines of collecting patient data. This redesign resulted in an increased number of completed main tasks (70%) and a decrease in navigation actions (133% of the minimum required). The think-aloud usability evaluation of the redesigned system showed that remaining problems concerned flexibility (e.g., lack of customization options) and consistency (mainly with layout and position of items on the screen).ConclusionThe mixed method usability evaluation was supportive in revealing the magnitude and causes of mismatches between the system design model of data-entry with users’ data entry behavior. However, as both task efficacy and efficiency were still not optimal with the redesigned EPR, we advise to perform a cognitive analysis on end users’ mental processes and behavior patterns in daily work processes specifically during the requirements analysis phase of development of interactive healthcare information systems.