A systems engineering approach to validation of a pulmonary physiology simulator for clinical applications

Physiological simulators which are intended for use in clinical environments face harsh expectations from medical practitioners; they must cope with significant levels of uncertainty arising from non-measurable parameters, population heterogeneity and disease heterogeneity, and their validation must provide watertight proof of their applicability and reliability in the clinical arena. This paper describes a systems engineering framework for the validation of an in silico simulation model of pulmonary physiology. We combine explicit modelling of uncertainty/variability with advanced global optimization methods to demonstrate that the model predictions never deviate from physiologically plausible values for realistic levels of parametric uncertainty. The simulation model considered here has been designed to represent a dynamic in vivo cardiopulmonary state iterating through a mass-conserving set of equations based on established physiological principles and has been developed for a direct clinical application in an intensive-care environment. The approach to uncertainty modelling is adapted from the current best practice in the field of systems and control engineering, and a range of advanced optimization methods are employed to check the robustness of the model, including sequential quadratic programming, mesh-adaptive direct search and genetic algorithms. An overview of these methods and a comparison of their reliability and computational efficiency in comparison to statistical approaches such as Monte Carlo simulation are provided. The results of our study indicate that the simulator provides robust predictions of arterial gas pressures for all realistic ranges of model parameters, and also demonstrate the general applicability of the proposed approach to model validation for physiological simulation.     

The impact of diaphragm management on prolonged ventilator support after thoracoabdominal aortic repair

PURPOSE: The relationship of the division of the diaphragm during thoracoabdominal aortic repair to prolonged ventilator support has not been studied. The purpose of this study was (1) to determine whether preservation of diaphragm integrity has a significant effect on postoperative ventilator duration and (2) to elucidate other pulmonary risk factors related to thoracoabdominal aortic surgery and to study the relationship of these factors to the intact diaphragm technique. METHODS:Between February 1991 and January 1997, we repaired 397 descending and thoracoabdominal aortic aneurysms. Descending thoracic aneurysms were not included in the study because their repair does not include the diaphragm. A total of 256 patients participated in this study. The diaphragm was divided in 150 patients and left intact in 106 patients. Examined as potential risk factors were patient demographics, history and physical findings, aneurysm extent, urgency of the procedure, acute dissection, cross-clamp time, homologous and autologous blood product consumption, and adjunctive operative techniques. FEV1 also was considered in the 197 patients for whom preoperative spirometry was available. Prolonged mechanical ventilation was defined as ventilator support for >72 hours. Data were analyzed by univariate contingency table and multiple logistic regression methods. RESULTS: Increasing age (odds ratio [OR], 1.02/y; P <.02), current smoking (OR, 2.6; P <.0008), total cross-clamp time (OR, 1.0/min; P <.008), units packed red blood cells transfused (OR, 1.06/unit; P <.008), and division of the diaphragm (OR, 2.03; P <.02) were significant, independent predictors of prolonged ventilation. Sixty-seven percent of patients (71 of 106) whose diaphragms were preserved were extubated in <72 hours compared with 52% of patients (78 of 150) who underwent diaphragm division (OR, 0.53; P <.02). CONCLUSION: Independently of well known pulmonary risk factors, an intact diaphragm during thoracoabdominal aortic repair results in a higher probability of early ventilator weaning.     

Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study

BACKGROUND: Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition and diminished energy expenditure resembling a growth hormone deficient state. Hypothalamic dysfunction in PWS often includes decreased growth hormone (GH) secretion, suggesting a possible therapeutic role for exogenous GH treatment. OBJECTIVES AND METHODS: After 6 months of observation to determine baseline growth rate, and with the use of a 12-month randomized controlled study design, the effects of GH treatment (1 mg/m2/d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 54 children with PWS (n = 35 treatment and n = 19 control). Percent body fat and bone mineral density were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotients. RESULTS: Stimulated levels of GH in response to clonidine testing were low in all patients (peak, 2.0 ng/mL). After 12 months, GH-treated subjects showed significantly increased height velocity Z scores (mean, 1.0 1.7 to 4.6 2.9; P <.001), decreased percent body fat (mean, 46.3% 8.4% to 38.3% 10.7%; P <.001), and improved respiratory muscle function, physical strength, and agility (sit-ups, weight-lifts, running speed, and coordination). A significant decline in respiratory quotients occurred during GH therapy (0.81 to 0.77, P <.001), but total REE did not change. CONCLUSIONS: GH treatment of children with PWS accelerated growth, decreased percent body fat, and increased fat oxidation but did not significantly increase total REE. Improvements in respiratory muscle strength, physical strength, and agility also occurred, suggesting that GH treatment may have value in reducing some physical disabilities experienced by children with PWS.     

Bathymetric sidescan investigation of sedimentary features in the Tay Estuary,Scotland

A comparison of results from mapping using a swath bathymetric sonar system in the Tay Estuary, Scotland, and remote sensing data on the position of frontal systems, indicates that the frontal systems are controlling the distribution of sedimentary features in the estuary. The boundaries between zones, defined by the advancing flood fronts and exiting fresh water, are sharply defined both by the front and the bottom bedforms. Static fronts, usually axial fronts, exist at well-defined bathymetric changes and result in relatively stable bedforms. However, measurements of current velocities at migrating fronts suggest that the vertical component of velocity accelerated at the front boundary will cause erosion at the bed and migrating bed features. Predictions of sediment movement and sediment feature migration rates across areas where these fronts migrate are confirmed by the bathymetric sidescan sonar results that show asymmetry of the sedimentary dune features. The use of new high-resolution sonar, together with its repeatable precision in locating sedimentary bedforms, has significant implications for long-term modelling of sediment transport in estuaries and other similar areas.     

Conversion of 3-chlorocatechol by various catechol 2,3-dioxygenases and sequence analysis of the chlorocatechol dioxygenase region of Pseudomonas putida GJ31

Pseudomonas putida GJ31 contains an unusual catechol 2,3-dioxygenase that converts 3-chlorocatechol and 3-methylcatechol, which enables the organism to use both chloroaromatics and methylaromatics for growth. A 3.1-kb region of genomic DNA of strain GJ31 containing the gene for this chlorocatechol 2,3-dioxygenase (cbzE) was cloned and sequenced. The cbzE gene appeared to be plasmid localized and was found in a region that also harbors genes encoding a transposase, a ferredoxin that was homologous to XylT, an open reading frame with similarity to a protein of a meta-cleavage pathway with unknown function, and a 2-hydroxymuconic semialdehyde dehydrogenase. CbzE was most similar to catechol 2,3-dioxygenases of the 2.C subfamily of type 1 extradiol dioxygenases (L. D. Eltis and J. T. Bolin, J. Bacteriol. 178:5930-5937, 1996). The substrate range and turnover capacity with 3-chlorocatechol were determined for CbzE and four related catechol 2,3-dioxygenases. The results showed that CbzE was the only enzyme that could productively convert 3-chlorocatechol. Besides, CbzE was less susceptible to inactivation by methylated catechols. Hybrid enzymes that were made of CzbE and the catechol 2, 3-dioxygenase of P. putida UCC2 (TdnC) showed that the resistance of CbzE to suicide inactivation and its substrate specificity were mainly determined by the C-terminal region of the protein.