MINMOD: a computer program to calculate insulin sensitivity and pancreatic responsivity from the frequently sampled intravenous glucose tolerance test

Insulin sensitivity and pancreatic responsivity are the two main factors controlling glucose tolerance. We have proposed a method for measuring these two factors, using computer analysis of a frequently-sampled intravenous glucose tolerance test (FSIGT). This 'minimal modelling approach' fits two mathematical models with FSIGT glucose and insulin data: one of glucose disappearance and one of insulin kinetics. MINMOD is the computer program which identifies the model parameters for each individual. A nonlinear least squares estimation technique is used, employing a gradient-type of estimation algorithm, and the first derivatives (not known analytically) are computed according to the 'sensitivity approach'. The program yields the parameter estimates and the precision of their estimation. From the model parameters, it is possible to extract four indices: SG, the ability of glucose per se to enhance its own disappearance at basal insulin, SI, the tissue insulin sensitivity index, phi 1, first phase pancreatic responsivity, and phi 2, second phase pancreatic responsivity. These four characteristic parameters have been shown to represent an integrated metabolic portrait of a single individual.     

Monte Carlo analysis of a new model-based method for insulin sensitivity testing

Insulin resistance (IR), or low insulin sensitivity, is a major risk factor in the pathogenesis of type 2 diabetes and cardiovascular disease. A simple, high resolution assessment of IR would enable earlier diagnosis and more accurate monitoring of intervention effects. Current assessments are either too intensive for clinical settings (Euglycaemic Clamp, IVGTT) or have too low resolution (HOMA, fasting glucose/insulin). Based on high correlation of a model-based measure of insulin sensitivity and the clamp, a novel, clinically useful test protocol is designed with: physiological dosing, short duration (<1 h), simple protocol, low cost and high repeatability. Accuracy and repeatability are assessed with Monte Carlo analysis on a virtual clamp cohort (N=146). Insulin sensitivity as measured by this test has a coefficient of variation (CV) of CV(SI)=4.5% (90% CI: 3.8-5.7%), slightly higher than clamp ISI (CV(ISI)=3.3% (90% CI: 3.0-4.0%)) and significantly lower than HOMA (CV(HOMA)=10.0% (90% CI: 9.1-10.8%)). Correlation to glucose and unit normalised ISI is r=0.98 (90% CI: 0.97-0.98). The proposed protocol is simple, cost effective, repeatable and highly correlated to the gold-standard clamp.     

Impact of fluid replacement on heat storage while wearing protective clothing

This study used partitional calorimetry to determine the influence of fluid replacement on heat storage during uncompensable heat stress. Eight males performed either light (L; level treadmill walking at 0.97 m x s(-1) (3.5 km x h(-1)) or heavy (H; 1.33 m x s(-1) (4.8 km x h(-1)) at a 4% grade) exercise at 40 degrees C and 30% relative humidity while wearing nuclear, biological and chemical (NBC) protective clothing. Subjects received either no fluid (NF), or 200 or 250 ml of fluid (F) as warm water at approximately 35 degrees C immediately before and every 15 min during the L and H trials respectively. Similar reductions in heart rate were observed at both metabolic rates with F but rectal temperature responses were not different between F and NF. Tolerance time was extended during L/F (106.5 +/- 22.1 min) compared with L/NF (93.1 +/- 20.8 min) but fluid replacement had no influence during H (59.8 +/- 9.5 min and 58.3 +/- 11.1 min for F and NF respectively). Fluid replacement also had no effect on the rate of heat storage during L (108.2 +/- 20.6 W x m(-2) and 111.0 +/- 22.6 W x m(-2) for F and NF respectively) and H (172.5 +/- 11.5 W x m(-2) and 182.1 +/- 15.8 W x m(-2) for F and NF respectively). However, heat storage expressed per unit of mass was significantly increased during L/F (18.5 +/- 4.0 kJ x kg(-1) ) compared with the other trials (16.3 +/- 4.8 kJ x kg(-1), 16.6 +/- 3.0 kJ x kg(-1) and 16.7 +/- 4.0 kJ x kg(-1) for L/NF, H/F and H/NF respectively). It was concluded that fluid replacement does not alter the rate of heat storage during uncompensable heat stress but does increase the heat storage capacity during light exercise when tolerance times are > 60 min.     

Controlled multicenter study on the effect of computer assistance in intensive insulin therapy of type 1 diabetics

This paper describes the results of a controlled multicenter study on the effect of the computer assistance in the intensive insulin therapy. The patient collective consisted of 50 diabetics, randomly divided in two groups with 25 patients per group. The Multiple Subcutaneous Injection (MSI) group was treated with the usually intensive regimen. The treatment in the Computer Assisted Meal Related Insulin Therapy (CAMIT) group was performed with the aid of a specialized pocket computer. Only in the CAMIT group during the study we observed a significant decrease: in the mean blood glucose (BG) with 1.6+/-0.4 mmol/l (P<0.05), in the BG amplitudes by 1.0+/-0.3 mmol/l (P<0.05), and in the hypoglycemia frequency-from 2.0+/-0.4 to 1.2+/-0.3 (P<0.01) hypoglycemic episodes weekly. The HbA(1) values fell in the MSI group by 3.7+/-3.7% and in the CAMIT group significantly by 15.6+/-2.2% (P<0.05). Consequently, the computer-assisted intensive insulin therapy resulted in an improved metabolic control.     

A recursive algorithm for finding HDMR terms for sensitivity analysis

High Dimensional Model Representation (HDMR) is an efficient technique which decomposes a multivariate function into a constant, univariate, bivariate functions and so on. These functions are forced to be mutually orthogonal by means of an orthogonality condition. The technique which is generally used for high-dimensional input-output systems can be applied to various disciplines including sensitivity analysis, differential equations, inversion of data and so on. In this article we present a computer program that computes individual components of HDMR resolution of a given multivariate function. The program also calculates the global sensitivity indices. Lastly the results of the numerical experiments for different set of functions are introduced.     

Intermittent microclimate cooling during exercise-heat stress in US army chemical protective clothing

The effectiveness of intermittent, microclimate cooling for men who worked in US Army chemical protective clothing (modified mission-oriented protective posture level 3; MOPP 3) was examined. The hypothesis was that intermittent cooling on a 2 min on-off schedule using a liquid cooling garment (LCG) covering 72% of the body surface area would reduce heat strain comparably to constant cooling. Four male subjects completed three experiments at 30 degrees C, 30% relative humidity wearing the LCG under the MOPP 3 during 80 min of treadmill walking at 224 +/- 5 W . m(-2). Water temperature to the LCG was held constant at 21 degrees C. The experiments were; 1) constant cooling (CC); 2) intermittent cooling at 2-min intervals (IC); 3) no cooling (NC). Core temperature increased (1.6 +/- 0.2 degrees C) in NC, which was greater than IC (0.5 +/- 0.2 degrees C) and CC (0.5 +/- 0.3 degrees C) ( p < 0.05). Mean skin temperature was higher during NC (36.1 +/- 0.4 degrees C) than IC (33.7 +/- 0.6 degrees C) and CC (32.6 +/- 0.6 degrees C) and mean skin temperature was higher during IC than CC ( p < 0.05). Mean heart rate during NC (139 +/- 9 b . min(-1)) was greater than IC (110 +/- 10 b . min(-1)) and CC (107 +/- 9 b . min(-1)) ( p < 0.05). Cooling by conduction (K) during NC (94 +/- 4 W . m(-2)) was lower than IC (142 +/- 7 W . m(-2)) and CC (146 +/- 4 W . m(-2)) ( p < 0.05). These findings suggest that IC provided a favourable skin to LCG gradient for heat dissipation by conduction and reduced heat strain comparable to CC during exercise-heat stress in chemical protective clothing.     

Pharmacokinetics of insulin lispro in type 2 diabetes during closed-loop insulin delivery

Insulin pharmacokinetics is not well understood during continuous subcutaneous insulin infusion in type 2 diabetes (T2D). We analyzed data collected in 11 subjects with T2D [6 male, 9 white European and two of Indian ethnicity; age 59.7(12.1) years, BMI 30.1(3.9) kg/m², fasting C-peptide 1002.2(365.8) pmol/l, fasting plasma glucose 9.6(2.2) mmol/l, diabetes duration 8.0(6.2) years and HbA1c 8.3(0.8)%; mean(SD)] who underwent a 24-h study investigating closed-loop insulin delivery at the Wellcome Trust Clinical Research Facility, Cambridge, UK. Subcutaneous delivery of insulin lispro was modulated every 15 min according to a model predictive control algorithm. Two complementary insulin assays facilitated discrimination between exogenous (lispro) and endogenous plasma insulin concentrations measured every 15–60 min. Lispro pharmacokinetics was represented by a linear two-compartment model whilst parameters were estimated using a Bayesian approach applying a closed-form model solution. The time-to-peak of lispro absorption (t_max) was 109.6 (75.5–120.5) min [median (interquartile range)] and the metabolic clearance rate (MCR_I) 1.26 (0.87–1.56) × 10⁻² l/kg/min. MCR_I was negatively correlated with fasting C-peptide (r_s = −0.84; P = .001) and with fasting plasma insulin concentration (r_s = −0.79; P = .004). In conclusion, compartmental modelling adequately represents lispro kinetics during continuous subcutaneous insulin infusion in T2D. Fasting plasma C-peptide or fasting insulin may be predictive of lispro metabolic clearance rate in T2D but further investigations are warranted.     

Classification of metabolic and respiratory demands in fire fighting activity with extreme workloads

Fire fighting work comprises work tasks requiring an energy yield at maximal or close to maximal levels of the individual. Due to the very nature of fire fighting more complex physiological variables are difficult to measure. We measured metabolic and respiratory responses in 15 male, professional fire fighters during simulated work tasks on a test ground. Work time was on the average 22 min with individual components of work tasks lasting 2-4 min. The mean oxygen consumption for the whole exercise (22 min) was 2.75+/-0.29 l/min. The most demanding work task demanded an oxygen uptake of 3.55+/-0.27 l/min. Corresponding values for respiratory minute volumes were 82+/-14 and 102+/-14l/min, respectively. Heart rates averaged 168+/-12 for the whole test and 179+/-13 beats/min for the heaviest work task. Two new classes for classification of intensive and exhausting, short term physical work are proposed for inclusion in ISO8996 and values for relevant parameters are proposed.     

A parametric solution to the pole assignment problem using dynamicoutput-feedback

A technique is presented for pole placement of linear time-invariant systems using dynamic feedback. A previously developed method for partial pole assignment using constant feedback is generalized to the dynamic output-feedback case. Subject to a mild assumption on the number of complex conjugate poles to be assigned, it is almost always possible to arbitrarily assign all the closed-loop system poles using a compensator of order [(n-φ)/max(m,l)] using this new method. Here, n, m, and l are the order of the system, and the number of inputs and outputs, respectively, and φ Δ/=max(m,l)+[max(m,l)/2]+…+[max(m,l)/min(m,l)] where [x] denotes the nearest integer lower than or equal to x (i.e., floor (x)), and [x] denotes the nearest integer greater than or equal to x (i.e., ceiling (x)). An equivalent result is that using a compensator of order q, it is almost always possible to arbitrarily assign min(n+q,(max(m,l)+1)q+φ) closed-loop system poles. Only the normal procedures of linear algebra are required to implement the technique. Note that φ⩾l+m-1 and, therefore, the result is stronger than previous exact pole assignment results. Since it does not involve iteration or any other numerical techniques, it is possible to implement the method symbolically and, therefore, to obtain general parametric solutions to the pole assignment problem. The freedom in this design approach can also often be used to guarantee the internal stability and/or robustness of the resulting closed-loop system     

The influence of speed, grade and mass during simulated off road bicycling

The purpose of this investigation was to examine the effects of bicycle mass, speed, and grade on oxygen consumption (VO2), heart rate (HR), and ratings of perceived exertion (RPE) during a simulated off-road riding paradigm. Nine adult subjects with mean +/- SD age, mass, and VO2 max of 26.1 +/- 5.6 years, 71.7 +/- 7.5 kg, 56.6 +/- 5.2 ml x kg(-1) x min(-1) respectively, were trained to ride a fully suspended Trek Y-22 mountain bike on a treadmill with a 3.8 cm bump affixed to the belt. Riders completed a maximum of nine separate trials encompassing three different bike masses (11.6, 12.6 and 13.6 kg), 3 speeds (2.7, 3.6 and 4.5 m x s(-1)), and 3 grades (0, 2.5, and 5%). Throughout a trial, bike mass and speed remained constant while riding grade was increased every 5 min. During simulated off-road riding on a fully suspended mountain bike, increases in speed and grade significantly increased VO2, heart rate, and RPE. Increases in bike mass had no significant effects on VO2, heart rate or RPE. In addition, speed and grade changes interacted to differentially affect VO2, heart rate, and RPE at all speeds and grades.     

Genetic algorithm based NARX model identification for evaluation of insulin sensitivity

The evaluation of insulin sensitivity plays an important role in the clinical investigation of glucose related diseases. Mathematical models based on non-invasive tests provide an estimate of insulin sensitivity by solving a nonlinear optimization problem. However traditional optimization methods suffer from convergence problem and the final estimate is heavily dependent on the initial parameterization. This paper proposes a model based on the hybrid approach of nonlinear autoregressive with exogenous input (NARX) modeling and genetic algorithm (GA) for deriving an index of insulin sensitivity. The model does not need an initial parameterization and the convergence is always guaranteed. The index derived from the proposed model is found to correlate well with the widely used minimal model based insulin sensitivity, with a significantly higher accuracy of fit.     

Estimation of insulin sensitivity in diabetic Göttingen Minipigs

In patients with type 1 diabetes mellitus, insulin sensitivity is a parameter which strongly affects insulin therapy. Due to its time-dependent variation, this parameter can improve the strategy for automatic closed-loop blood glucose control. The aim of this work is to estimate the insulin sensitivity of patients with type 1 diabetes mellitus based on measured blood glucose concentrations. For this, an Extended Kalman Filter is used, based on a simplified version of the well-known Sorensen model. The compartment model of Sorensen was adapted to the glucose metabolic behaviour in diabetic Göttingen Minipigs by means of experimental data and reduced by neglecting unobservable state variables. Here, the Extended Kalman Filter is designed for simultaneous state and parameter estimation of insulin sensitivity using the insulin infusion rate and the meal size as input signals, and measurements of blood glucose concentration as output signal. The performance of the Extended Kalman Filter was tested in in silico studies using the minipig model, and is analysed by comparing the output signal of the filter with measurement data from the animal trials.     

Effect of five nights of normobaric hypoxia on cardiovascular responses to acute isocapnic hypoxia in humans: relationship to ventilatory chemosensitivity

The aim of this study was to elucidate (1) the cardiovascular responses to acute isocapnic hypoxia stimuli following five nights of normobaric poikilocapnic hypoxia, and (2) whether the changes in the cardiovascular responses to hypoxia are correlated to the change in acute hypoxic ventilatory (AHVR) chemosensitivity. Twelve male subjects [26.6 +/- 4.1 (SD) years] slept 8-9 h day(-1) overnight for five consecutive days at a simulated altitude of 4300 m (FiO2 = approximately 13.8%). Using the technique of dynamic end-tidal forcing, the AHVR was assessed twice, prior to and immediately after the hypoxic exposure. During each AHVR test, mean arterial blood pressure (MAP) and heart rate (HR) were measured continuously using finger photoplethysmography and an ECG monitor, respectively. Immediately following the exposure, AHVR and MAP sensitivities were increased by 1.80 +/- 1.30 l min(-1) %(-1) (p < 0.01) and 0.69 +/- 0.40 mmHg %(-1) (p < 0.05), respectively, and there were significant correlations between the increases in the AHVR and MAP sensitivities (r = 0.67; p < 0.05). In summary, following five nights of normobaric hypoxia, there is an enhanced MAP response to hypoxic stimuli. The relationship between the enhanced AHVR and MAP sensitivity raises the possibility of a common pathway in the regulation of peripheral chemosensitivity and MAP responses during periods of isocapnic hypoxia.     

Development of a model-based clinical sepsis biomarker for critically ill patients

Sepsis occurs frequently in the intensive care unit (ICU) and is a leading cause of admission, mortality, and cost. Treatment guidelines recommend early intervention, however positive blood culture results may take up to 48 h. Insulin sensitivity (S_I) is known to decrease with worsening condition and could thus be used to aid diagnosis. Some glycemic control protocols are able to accurately identify insulin sensitivity in real-time.Hourly model-based insulin sensitivity S_I values were calculated from glycemic control data of 36 patients with sepsis. The hourly S_I is compared to the hourly sepsis score (ss) for these patients (ss = 0-4 for increasing severity). A multivariate clinical biomarker was also developed to maximize the discrimination between different ss groups. Receiver operator characteristic (ROC) curves for severe sepsis (ss ≥ 2) are created for both S_I and the multivariate clinical biomarker.Insulin sensitivity as a sepsis biomarker for diagnosis of severe sepsis achieves a 50% sensitivity, 76% specificity, 4.8% positive predictive value (PPV), and 98.3% negative predictive value (NPV) at an S_I cut-off value of 0.00013 L/mU/min. Multivariate clinical biomarker combining S_I, temperature, heart rate, respiratory rate, blood pressure, and their respective hourly rates of change achieves 73% sensitivity, 80% specificity, 8.4% PPV, and 99.2% NPV. Thus, the multivariate clinical biomarker provides an effective real-time negative predictive diagnostic for severe sepsis. Examination of both inter- and intra-patient statistical distribution of this biomarker and sepsis score shows potential avenues to improve the positive predictive value.     

Heat stress while wearing long pants or shorts under firefighting protective clothing

It was the purpose of this study to examine whether replacing long pants (P) with shorts (S) would reduce the heat stress of wearing firefighting protective clothing during exercise in a warm environment. Twenty-four Toronto Firefighters were allocated to one of four groups that performed heavy (H, 4.8 km x h(-1), 5% grade), moderate (M, 4.5 km x h(-1), 2.5% grade), light (L, 4.5 km x h(-1)) or very light (VL, 2.5 km x h(-1)) exercise while wearing their full protective ensemble and self-contained breathing apparatus. Participants performed a familiarization trial followed by two experimental trials at 35 degrees C and 50% relative humidity wearing either P or S under their protective overpants. Replacing P with S had no impact on the rectal temperature (Tre) or heart rate response during heavy or moderate exercise where exposure times were less than 1 h (40.8 +/- 5.8 and 53.5 +/- 9.2 min for H and M, respectively while wearing P, and 43.5 +/- 5.3 and 54.2 +/- 8.4 min, respectively while wearing S). In contrast, as exposure times were extended during lighter exercise Tre was reduced by as much as 0.4 degrees C after 80 min of exercise while wearing S. Exposure times were significantly increased from 65.8 +/- 9.6 and 83.5 +/- 11.6 min during L and VL, respectively while wearing P to 73.3 +/- 8.4 and 97.0 +/- 12.5 min, respectively while wearing S. It was concluded that replacing P with S under the firefighting protective clothing reduced the heat stress associated with wearing the protective ensemble and extended exposure times approximately 10 - 15% during light exercise. However, during heavier exercise where exposure times were less than 1 h replacing P with S was of little benefit.     

Physiological responses of firefighters and performance predictors during a simulated rescue of hospital patients

There is incomplete information about how physically demanding rescue work may be. The aim therefore of this paper was to examine the physiological responses of firefighters during a simulated rescue of hospital patients and to relate the firefighters' performance to their endurance, strength and working technique. Fourteen part-time male firefighters with a maximal oxygen uptake (VO(2max)) of 4.4 +/- 0.3 l/min (mean +/- SD) served as subjects in this study. First, each firefighter ascended six floors (a 20.5 m vertical ascent) carrying tools, wearing protective clothing and a breathing apparatus, an extra mass of 37 kg. He thereafter 'rescued' six persons by dragging each person on a fire-sheet on a flat floor. The technique used was recorded and the O(2) uptake and the heart rate were measured continuously during the whole operation. The blood lactate concentration and the subjective rating of perceived exertion were measured during and just after the rescue. The VO(2max) and the muscle strength were measured in the laboratory. The whole operation was carried out in the course of 5-9 min. The operation was a virtual all-out effort and the peak blood lactate concentration was 13 +/- 3 mmol/l. The peak oxygen uptake was 3.7 +/- 0.5 l/min (84% of the VO(2max)) during the operation. Large and heavy firefighters carried out the task faster than smaller ones. The VO(2max) in absolute terms and the dragging technique used were both related to the rescue performance. Rescuing patients at a hospital was physically very demanding and the time needed to complete the task depended on the VO(2max) in absolute values and the working technique used. A minimum VO(2max) of 4 l/min for firefighters was recommended.     

Impact of sensor and measurement timing errors on model-based insulin sensitivity

A model-based insulin sensitivity parameter (SI) is often used in glucose–insulin system models to define the glycaemic response to insulin. As a parameter identified from clinical data, insulin sensitivity can be affected by blood glucose (BG) sensor error and measurement timing error, which can subsequently impact analyses or glycaemic variability during control. This study assessed the impact of both measurement timing and BG sensor errors on identified values of SI and its hour-to-hour variability within a common type of glucose–insulin system model.     

Heart rate strain in cable hauler choker setters in New Zealand logging operations.

This study examined the physical strain experienced by cable hauler choker setters, and the applicability of heart rate indices for measuring physical strain in commercial forest harvesting operations in New Zealand. The heart rate of four choker setters were recorded continuously throughout the working day and applied to heart rate indices. Based on the relative heart rate at work (%HRR), ratio of working heart rate to resting heart rate and 50% level indices, the mean working heart rate (HRw) of 106 bt. min(-1) +/- 6.9 (mean +/- SD) placed choker setting in the moderate workload category. The specific tasks of line shifts (120.3 +/- 4.8 bt. min(-1)), hooking up drags (118.8 +/- 6.6 bt. min(-1)) and uphill travel (126.1 +/- 12.9 bt. min(-1)), imposed the most severe workloads on the choker setters. This research also demonstrated that heart rate indices could be used as an effective means of determining the physiological strain of subjects working in New Zealand's commercial forest harvesting operations.     

Design sensitivity and reliability-based structural optimization by univariate decomposition

This paper presents a new univariate decomposition method for design sensitivity analysis and reliability-based design optimization of mechanical systems subject to uncertain performance functions in constraints. The method involves a novel univariate approximation of a general multivariate function in the rotated Gaussian space for reliability analysis, analytical sensitivity of failure probability with respect to design variables, and standard gradient-based optimization algorithms. In both reliability and sensitivity analyses, the proposed effort has been reduced to performing multiple one-dimensional integrations. The evaluation of these one-dimensional integrations requires calculating only conditional responses at selected deterministic input determined by sample points and Gauss–Hermite integration points. Numerical results indicate that the proposed method provides accurate and computationally efficient estimates of the sensitivity of failure probability, which leads to accurate design optimization of uncertain mechanical systems.     

Aerobic and anaerobic profiles, heart rate and match analysis in older soccer players

The aim of the present study was to provide aerobic (maximal oxygen consumption--VO2max) and anaerobic [jump tests: counter-movement jump (CMJ) and bounce jump (BJ); and running tests: 10 m sprint and 10 m dribbling the ball (10 mDB)] profiles of older soccer players (n = 12), and heart rate (HR), blood lactate accumulation (La) and match analysis (individual motor activity and team behaviour) aspects of a soccer match. The maximal aerobic test values were: HRmax, 154 +/- 14 beat min(-1); maximal power, 160 +/- 24 W; VO2peak, 36.3 +/- 11.3 ml kg(-1) min(-1); peak La, 8.2 +/- 1.8 mM. Jump test values were: CMJ, 21.2 +/- 4.5 cm; BJ, 17.3 +/- 4.8 cm. Running performances were: 10 m sprint, 2.06 +/- 0.36 s; 10 mDB, 2.17 +/- 0.21 s. Running showed similar values in the two halves (first half, 82%; second half, 88%), while walking lasted longer during the second half. Regarding the technical aspects of the match, 42% of the consecutive passes made in possession of the ball exceeded three passes, indicating that their play was structured in a cooperative manner. Older soccer players succeeded in maintaining good aerobic and anaerobic physical capability.