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Type-1 (insulin-dependent) diabetes is a chronic disease characterized by persistent excessive concentration of glucose in blood due to lack or insufficient secretion of the insulin hormone, which needs to be administered exogenously, possibly with automatic control techniques. In this work, we present a novel approach to glucose regulation for patients with type-1 diabetes, based on optimal impulsive control strategies, in the framework of the so-called multiple daily injections (MDI). In more detail, the optimal (periodic) glucose trajectory is first computed offline in ideal conditions and is then optimally tracked in real-time, with reduced computational effort, based on sparse measurements, so that possible nonidealities can be properly accounted for. The theoretical framework is able to preserve the nonlinear and continuous-time nature of the glucose–insulin model while realistically managing quantization in the actuation and assuming sporadic output measurements, from which the state of the system is estimated online. A preclinical in silico validation campaign based on a different, extended model of the glucose–insulin system shows the effectiveness of the proposed approach.

Observational studies suggest that bariatric–metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial.

ObjectiveClinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis.DesignThis multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16−monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis.ResultsThe algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography.ConclusionsThe proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers.Clinical trialsDiscovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

OBJECTIVE--Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed [...]

OBJECTIVE--The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We [...]

Several hypotheses have been proposed to explain the nutritional deficiencies seen in Crohn disease patients, including inadequate food intake, decreased assimilation and increased loss of nutrients, and increased energy expenditure. To assess the effect of steroid therapy on body composition, energy expenditure, and fuel selection in Crohn disease, we compared 12 patients (6 men and 6 women) with biopsy-proven ileal Crohn disease with 11 healthy volunteers (6 men and 5 women). Five patients [Crohn's disease activity index (CDAI) = 98.4 [+ or -] 3.78] took no medication and seven patients (CDAI = 283.9 [+ or -] 22.5) were administered 29 [+ or -] 18 mg prednisone/d. Body composition was evaluated by isotopic dilution and bioelectrical impedance analysis, and 24-h energy expenditure and basal metabolic rate were measured in a respiratory chamber. Fat-free mass was not significantly different among groups, whereas fat mass was lower in patients than in control subjects. Energy intake was higher in treated patients than in both untreated patients (P = 0.004) and control subjects (P = 0.005). Fecal losses were not significantly different between untreated patients and control subjects, but were higher (and proportional to the CDAI) in treated patients than in control subjects (P = 0.001). Metabolizable energy was not significantly different among groups, whereas energy balance was significantly higher in treated patients than in both control subjects (P = 0.0057) and untreated patients (P = 0.018). Nitrogen balance was mildly negative in treated patients compared with both control subjects and untreated patients, but not significantly so. In conclusion, prednisone treatment in Crohn disease patients stimulates food intake, promoting an overall positive energy balance despite large fecal nutrient losses. Am J Clin Nutr 1998;67:118-23.

We evaluated the metabolic response to a standard (75-g) oral-glucose-tolerance test (OGTT) in eight post-obese women (PO) who underwent biliopancreatic diversion and in eight healthy control women (C). All subjects had been weight-stable for [greater than or equal to] 2 y. Blood samples for glucose, insulin, C-peptide, and nonesterified free fatty acids were taken at baseline and during 180 min after the glucose load. Plasma glucose and insulin concentrations at baseline and during the OGTT were similar in the two groups, suggesting the absence of an insulin-resistant state in the PO. Continuous indirect calorimetry was performed throughout the test. Glucose-induced thermogenesis (GIT) was higher in PO than in C (8.6 [+ or -] 2.6 vs 4.3 [+ or -] 1.9%; P < 0.01). These data indicate that GIT and insulin-glucose metabolism are not impaired in postobese patients when a near ideal body weight is reached and maintained after weight loss; this suggests that thermogenic deficiencies and hyperinsulinemia - insulin resistance are alterations secondary to obesity.

No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes.

Background: The incidence of celiac disease has been on the rise in both Europe and the United States. Celiac disease patients are at high risk of undernutrition because of nutrient malabsorption. Objective: The aim of the present study was to evaluate changes in body composition and energy metabolism in a group of patients with celiac disease before and after consumption of a gluten-free diet (GFD). Design: Body composition (by anthropometry and isotopic dilution), resting metabolic rate (RMR), and substrate oxidation rates (by indirect calorimetry) were assessed in 39 adult celiac disease patients (16 men and 23 women) with a mean ([+ or -]SD) age of 29.9 [+ or -] 7.6 y, weight of 58.3 [+ or -] 6.6 kg, and percentage body fat of 20.1 [+ or -] 6.7%, and in 63 (29 men and 34 women) age- and height-matched control subjects (age: 33.2 [+ or -] 8.1 y; weight: 66.8 [+ or -] 6.6 kg; and percentage body fat: 25.4 [+ or -] 3.7%). Celiac disease patients were studied twice, at diagnosis and 1 y after treatment with a GFD. Results: Before treatment, celiac disease patients had a lower body weight (P [is less than] 0.05) and a higher carbohydrate oxidation rate (P [is less than] 0.01) than did control subjects. Carbohydrate oxidation rates correlated positively with fecal lipid loss in untreated celiac disease patients (r = 0.80, P [is less than] 0.0001). After the GFD, percentage body fat was higher in celiac disease patients than in control subjects (P [is less than] 0.01), and lipid intakes tended to be higher than before treatment. Conclusions: This longitudinal study showed that the GFD treatment significantly increased body fat stores. Untreated patients preferentially utilized carbohydrates as a fuel substrate, probably as a consequence of both lipid malabsorption and a high carbohydrate intake, and lipid utilization increased with the restoration of the intestinal mucosa. Am J Clin Nutr 2000;72:76-81. KEY WORDS Celiac disease, fat mass, fat-free mass, resting metabolic rate, substrate oxidation, body composition, gluten-free diet

Little information is available in the literature about the effect of L-Carnitine in improving glucose disposal in both healthy controls and type 2 diabetic patients, while no data are achievable [...]

We found that reactive hypoglycemia is no less common after SG than after RYGB, but RYGB is associated with more severe hypoglycemic episodes.

Type-2 Diabetes Mellitus (T2DM) is a metabolic syndrome characterized by low insulin sensitivity, so that higher amounts of insulin are required in order to keep glycemia in a safe range (approximately, 60 ~ 110 mg/dl or, equivalently, 3.33 ~ 6.11 mM). Although insulin resistance and T2DM are often treated without exogenous insulin administration, the possibility to early treat pre-diabetic states or T2DM patients with insulin administration could be envisaged if the clinical need exists (e.g. surgical stress, infection). The present work introduces a possible new therapeutic insulin administration dosing approach for T2DM patients. The IVGTT glycemia and insulinemia profiles of a diseased patient are collected and, successively, its metabolic parameters are obtained by fitting a compact delay model to those data. Then a controller is designed exploiting the previous model as a tool. Finally, the tuned controller is applied to the patient as an artificial pancreas supplying external insulin administration. The results are shown on a virtual patient, whose behavior is described by a comprehensive, validated extensive model.

Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients.

Background: Although malnutrition is frequently observed in Crohn disease (CD), its cause is not clear. Regulation of energy metabolism and diet-induced thermogenesis (DIT) have not been adequately studied in CD. Objective: The aim was to study DIT and substrate oxidation in patients with inactive ileal CD. Design: After a test meal providing 50.2 kJ/kg body wt, DIT was assessed by indirect calorimetry performed over 360 min in 18 CD patients and 12 healthy volunteers matched for age, sex, weight, and height. Body composition was evaluated with the labeled-water-bolus injection technique. Results: Fat-free mass did not differ significantly between groups, but CD patients had markedly lower fat mass than control subjects (13.8 [+ or -] 5.63 compared with 19.0 [+ or -] 3.49 kg; P [is less than] 0.001). Nonprotein respiratory quotient was lower in CD patients than control subjects (0.80 [+ or -] 0.04 compared with 0.86 [+ or -] 0.03; P [is less than] 0.001). Average respiratory quotient between 75 and 150 min after the test meal was 0.85 [+ or -] 0.03 in CD patients and 0.91 [+ or -] 0.02 in control subjects (P [is less than] 0.001). Lipid oxidation rate was higher in CD patients than in control subjects (2.26 [+ or -] 1.13 compared with 1.50 + 0.75 kJ/min; P [is less than] 0.05). DIT was higher in CD patients than in control subjects (9.89 [+ or -] 1.93% compared with 5.67 [+ or -] 0.91% of energy intake; P [is less than] 0.001). Conclusions: Patients with inactive ileal CD had significantly higher DIT and lipid oxidation rate than do healthy volunteers. These results may explain why CD patients have difficulty maintaining adequate nutritional status, and the findings also suggest that a diet relatively rich in fat may attain better energy balance. Am J Clin Nutr 1999;69:325-30. KEY WORDS Body composition, Crohn disease, diet-induced thermogenesis, substrate oxidation rates, lipid oxidation, carbohydrate oxidation, indirect calorimetry, labeled-waterbolus injection technique, resting energy expenditure, basal metabolic rate, respiratory quotient, fat mass, fat-free mass

The problem of tracking a desired plasma glucose evolution is considered, for cases of basal hyperglycemia. A time-delay model is used to describe the glucose–insulin regulatory system, aiming to detail the endogenous pancreatic insulin release, which is not negligible in Type 2 diabetic patients. Insulin is assumed to be administered by means of intra-venous infusions. Only measurements of glycemia are considered: to this aim a nonlinear observer for time-delay systems is used to estimate the plasma insulin concentration. In the spirit of the separation theorem, a nonlinear control law is proposed, based on the exact input/output feedback linearization, which makes use of the observer estimates instead of the full state measurements. The local convergence of the tracking error to zero is theoretically proved. Simulations are performed in a virtual environment, taking into account the standard technology concerning blood glucose sensors and insulin delivery devices. Numerical results show the robustness of the proposed approach with respect to the uncertainties of the model parameters, as well as to the glucose measurement errors and insulin pump malfunctioning.

Abstract: The Euglycemic Hyperinsulinemic Clamp (EHC) is the most widely used experimental procedure for the determination of insulin sensitivity. In the present study, 16 subjects with BMI between 18.5 and 63.6 kg/m2 have been studied with a long-duration (5 hours) EHC. In order to explain the oscillations of glycemia occurring in response to the hyperinsulinization and to the continuous glucose infusion at varying speeds, we first hypothesized a system of ordinary differential equations (ODEs), with limited success. We then extended the model and represented the experiment using a system of stochastic differential equations (SDEs). The latter allow for distinction between (i) random variation imputable to observation error and (ii) system noise (intrinsic variability of the metabolic system), due to a variety of influences which change over time. The stochastic model of the EHC was fitted to data and the system noise was estimated by means of a (simulated) maximum likelihood procedure, for a series of different hypothetical measurement error values. We showed that, for the whole range of reasonable measurement error values: (i) the system noise estimates are non-negligible; and (ii) these estimates are robust to changes in the likely value of the measurement error. Explicit expression of system noise is physiologically relevant in this case, since glucose uptake rate is known to be affected by a host of additive influences, usually neglected when modeling metabolism. While in some of the studied subjects system noise appeared to only marginally affect the dynamics, in others the system appeared to be driven more by the erratic oscillations in tissue glucose transport rather than by the overall glucose-insulin control system. It is possible that the quantitative relevance of the unexpressed effects (system noise) should be considered in other physiological situations, represented so far only with deterministic models.

Current studies are investigating new E-cadherin gene (CDH1)mutations that may be responsible for diffuse gastric cancer susceptibility. Recently, a novel CDH1germline variant presenting a G/A nucleotide change at cDNA position 2494 has been found in Japanese patients with familial diffuse gastric cancer. The consequent amino acid variation (Val/Met) may alter the binding activity to beta-catenin and the adhesive function of the E-cadherin protein. We have investigated its frequency in Italian cases of sporadic diffuse gastric cancer a well as in healthy controls. Peripheral blood samples were collected from consecutive patients with sporadic, diffuse gastric cancer and from healthy controls in the District of Urbino, Marche Region, Central Italy. After DNA extraction, standard techniques for molecular analyses were used to investigate the 2494 G/A germline nucleotide change in CDH1cDNA. None of the 48 patients and 48 controls showed the G/A 2494 nucleotide change. Assuming a binomial distribution of the mutation among individuals and the absence of mutations in the 48 patients, the 95% upper bound for the underlying mutation frequency was 7.4%. The novel CDH1nucleotide change is uncommon in Italian patients with sporadic diffuse gastric cancer. Given these results, further analyses in large population-based studies are not advisable.

Abstract.:  Several attempts at building a satisfactory model of the glucose-insulin system are recorded in the literature. The minimal model, which is the model currently mostly used in physiological research on the metabolism of glucose, was proposed in the early eighties for the interpretation of the glucose and insulin plasma concentrations following the intravenous glucose tolerance test. It is composed of two parts: the first consists of two differential equations and describes the glucose plasma concentration time-course treating insulin plasma concentration as a known forcing function; the second consists of a single equation and describes the time course of plasma insulin concentration treating glucose plasma concentration as a known forcing function. The two parts are to be separately estimated on the available data. In order to study glucose-insulin homeostasis as a single dynamical system, a unified model would be desirable. To this end, the simple coupling of the original two parts of the minimal model is not appropriate, since it can be shown that, for commonly observed combinations of parameter values, the coupled model would not admit an equilibrium and the concentration of active insulin in the “distant” compartment would be predicted to increase without bounds. For comparison, a simple delay-differential model is introduced, is demonstrated to be globally asymptotically stable around a unique equilibrium point corresponding to the pre-bolus conditions, and is shown to have positive and bounded solutions for all times. The results of fitting the delay-differential model to experimental data from ten healthy volunteers are also shown. It is concluded that a global unified model is both theoretically desirable and practically usable, and that any such model ought to undergo formal analysis to establish its appropriateness and to exclude conflicts with accepted physiological notions.

Insulin resistance is a common feature in obese patients. To evaluate the modifications in insulin sensitivity after a bariatric operation such as Bilio-pancreatic diversion (BPD), three groups of subjects (14 normal controls (N); seven eX-obese patients (X) with at least 2 years at weight-stable conditions after BPD surgery; and eight morbidly obese patients (O)) were studied with intravenous (IVGTT) and oral (OGTT) glucose tolerance tests. The ratio of the area under the curve (AUC) for glucose over that of insulin was used as a measure of insulin sensitivity. All the following tests were conducted as Bonferroni-corrected pairwise t-tests, in case overall ANOVA was significant. No significant difference was found between N and X subjects, while obese patients showed a reduced AUCg/AUCi ratio with respect to the normal controls (O vs N: 0.01164 � 0.00039 vs 0.02392 � 0.0039, p < 0.05). IVGTT, AUCs: significant differences were found in each case: N vs X: 0.0591 � 0.0075 vs 0.1402 � 0.0399, p < 0.05; N vs O: 0.0591 � 0.0075 vs 0.0223 � 0.0031, p < 0.01; X vs O: 0.1402 � 0.0399 vs 0.0223 � 0.0031, p < 0.05. IVGTT-derived data were also analyzed using the minimal model of glucose kinetics; with this method, glucose effectiveness was significantly different between normal subject and obese subjects (0.0248 � 0.00288 vs 0.00905 � 0.00135 per min, p < 0.001). The insulin sensitivity index was not significantly different between normal and ex-obese subjects, while both of these groups were significantly different from obese patients (N vs O: 12.04 � 10−5 � 2.61 � 10−5 vs 3.29 � 10−5 � 0.61 � 10−5, p < 0.066; X vs O: 16.42 � 10−5 � 4.23 � 10−5 vs 3.29 � 10−5 � 0.61 � 10−5 per min per pM, p < 0.02). In conclusion, the present study indicates that, after a body weight reduction operation capable of almost re-establishing ideal body weight like BPD, obese individuals with a family history of obesity show a normalization of insulin response to glucose load.

Abstract: The object of clinical computing is to support the making of clinical decisions. This takes place in an integrated context of care that involves processes of three different kinds: (1) the physiologic processes in the patient, (2) the processes of physiologic data as stored in, and moved within, a distributed computing system, and (3) the therapeutic and decision-making processes of the clinical staff. The clinical computing system is complex, and as we press it further to work as a partner in the complete care context, it tends to become unmanageably so. In this article, we try to suggest how one might begin using a formal mathematical theory, called ‘computational logic,’ to give theoretical analyses that might help one to understand the computing system and thereby to try to increase its ability to meet demands on it, and might help one to understand the care context as a whole. We examine the three levels, one at a time, looking for structural analogies between them, and trying to identify the ways that they are linked together. Computational logic provides us with a common set of notions for doing so.

Summary: A PC-based minimisation software written in C-language is described, which solves numerically both simple non-linear regression problems and problems expressed as systems of (unsolved) initial-value ordinary or partial differential equations. The software uses second-order iterated Runge-Kutta algorithm to approximate numerically the solution curves. It uses a quasi-Newton algorithm to minimize either sums of squares (weighted or unweighed) or NONMEM loss functions. Inverse Hessian approximation to the parameter dispersion and Monte Carlo generation of artificial samples are offered to test the robustness of the parameter values obtained. A real test problem is described, involving the hydrolysation of plasma Medium Chain Triglycerides to Free Fatty Acids and the uptake of these from plasma. Two competing models were evaluated, one involving linear terms for each transfer and one involving carrier-mediated, rate-limited hydrolysis and tissue absorption steps. The simpler linear model was found to be more robust and eventually used to describe the experimental data.

Abstract: This paper describes work to develop a model-based system to support clinical decision-making. In previous articles, we have developed (from 695 measurement sets obtained from 148 patients) a physiologic state classification based on a set of 11 cardiovascular and metabolic measurements. There is an R or reference state, for stable ICU patients. Patients under (operative, traumatic, or compensated septic) stress, or with (septic or hepatic) metabolic, respiratory, or cardiac insufficiency are in the A, B, C or D states, respectively. We wished to make the state easier to measure and eventually available continuously, automatically, and noninvasively, as well as reflecting a wider group of bodily systems. The 5 centers define a 4 dimensional affine subspace, designated thecardiovascular state space. Using eigenvector analysis, we have found four new derived physiologic variables CV1, CV2, CV3 and CV4 that span the state space. We have fit sets of linear regression equations that allow the patient's position in the state space, and therefore his state, to be determined from more easily obtainable sets of measurements. Further, we selected 1966 measurement sets from 512 patients at two hospitals. We used the data from 250 of these patients to define 13 prototypical types, namely survivors and deaths from various combinations of sepsis, cardiogenic decompensation, cirrhosis, and pneumonitis, following trauma or general surgery. For any future patient, the statistical theory of Bayesian inference allows one to infer back from the measurements observed to the probability of his being of any of these types and of surviving or dying. We used this method to predict the outcome of the other 262 patients, prospectively. Statistically, the predictions of survival or death were not significantly different from the actual. For individual patients, the method predicts a clinical course that closely follows the actual episodes in their history. These results confirm and explain the validity of the concept of the patient state and make the state easier to compute. The patient state and the probability plot together help to stage, select, and evaluate therapy. They do not replace the clinician's judgement, but rather are tools that help the clinician to exercise judgement.

Background: The goal of the present work is to present an effective surgical approach for the treatment of a medically-resisitant form of hyperlipidemia. Methods: Two siblings with familial lipoprotein-lipase deficiency and subsequent hyperchylomicronemia, widespread skin xanthomas and severe insulin-resistant diabetes mellitus came to our observation after several unsuccessful attempts at medical treatment. In order to lower plasma lipids through lipid malabsorption, a modified bilio-pancreatic diversion operation was employed. The rationale in deciding to use this surgical approach was based also on the likely hypothesis that diabetes, in these subjects, was secondary to high circulating and tissue levels of lipids. Insulin sensitivity in the two treated subjects, as well as in 24 healthy volunteers constituting the control group, was assessed by euglycemic hyperinsulinemic clamp and indirect calorimetry, obtaining total end-clamp glucose uptake (M) and end-clamp glucose oxidation (ECGO) rates. Results: Within 3 weeks of surgery, plasma triglycerides and cholesterol levels had decreased from 4500 and 500 mg/dl (with dietary restrictions) to lower than 450 and 150 mg/dl (on a free, lipid-rich diet) respectively. Fasting plasma glucose levels had decreased from above 300 (under daily repeated subcutaneous injections of insulin) to 80-100 mg/dl (without administration of insulin or oral hypoglycemic agents). Body weight and fat free mass were maintained in both subjects after surgery. In both patients, before surgery M and ECGO were significantly lower than in normal subjects, while after surgery they were not significantly different from normal subjects, confirming the positive metabolic effect of the operation. Conclusion: The surgical option used in these patients may represent an interesting and effective new possibility for treatment of those severe cases of hyperlipemia leading otherwise to metabolic complications and a low quality of life.

A PC-based minimisation software written in C-language is described, which solves numerically both simple non-linear regression problems and problems expressed as systems of (unsolved) initial-value ordinary or partial differential equations. The software uses second-order iterated Runge-Kutta algorithm to approximate numerically the solution curves. It uses a quasi-Newton algorithm to minimize either sums of squares (weighted or unweighed) or NONMEM loss functions. Inverse Hessian approximation to the parameter dispersion and Monte Carlo generation of artificial samples are offered to test the robustness of the parameter values obtained.

The object of clinical computing is to support the making of clinical decisions. This takes place in an integrated context of care that involves processes of three different kinds: (1) the physiologic processes in the patient, (2) the processes of physiologic data as stored in, and moved within, a distributed computing system, and (3) the therapeutic and decision-making processes of the clinical staff. The clinical computing system is complex, and as we press it further to work as a partner in the complete care context, it tends to become unmanageably so.

This paper describes work to develop a model-based system to support clinical decision-making. In previous articles, we have developed (from 695 measurement sets obtained from 148 patients) a physiologic state classification based on a set of 11 cardiovascular and metabolic measurements. There is an R or reference state, for stable ICU patients. Patients under (operative, traumatic, or compensated septic) stress, or with (septic or hepatic) metabolic, respiratory, or cardiac insufficiency are in the A, B, C or D states, respectively. We wished to make the state easier to measure and eventually available continuously, automatically, and noninvasively, as well as reflecting a wider group of bodily systems. The 5 centers define a 4 dimensional affine subspace, designated thecardiovascular state space. Using eigenvector analysis, we have found four new derived physiologic variables CV1, CV2, CV3 and CV4 that span the state space. We have fit sets of linear regression equations that allow the patient's position in the state space, and therefore his state, to be determined from more easily obtainable sets of measurements.

When a subject is at rest and meals have not been eaten for a relatively long time (e.g. during the night), presumably near-constant, zero-order glucose production occurs in the liver. Glucose elimination from the bloodstream may be proportional to glycemia, with an apparently first-order, linear elimination rate. Besides glycemia itself, unobserved factors (insulinemia, other hormones) may exert second and higher order effects. Random events (sleep pattern variations, hormonal cycles) may also affect glycemia. The time-course of transcutaneously, continuously measured glycemia (CGM) thus reflects the superposition of different orders of control, together with random system error. The problem may be formalized as a fractional random walk, or fractional Brownian motion. In the present work, the order of this fractional stochastic process is estimated on night-time CGM data from one subject. • We propose a novel order estimation method for fractional stochastic models (FSDE). • We apply the method to a FSDE glucose model fitted from real CGM data. • A scheme for the approximate FSDE integration via finite increments is proposed. • Stochastic correctness of our algorithm in terms of increment covariance is proved. • The accuracy is comparable to other fractional noise integration algorithms. [ABSTRACT FROM AUTHOR]

Highlights: [•] We review mathematical modeling of the glucose–insulin feedback system. [•] Pancreatic insulin production, ranging over cellular and subcellular scales. [•] Short-term organ/tissue models focused on important clinical/experimental tests. [•] Intra-venous and oral glucose tolerance tests and euglycemic hyperinsulinemic clamp. [•] Total-body, long-term diabetes models of disease progression over a period of years. [Copyright &y& Elsevier]