Aspart and Glargine Low Reading After Dosage

Introduction. AIDA is an interactive educational diabetes simulator available on the Cyberspace without charge since 1996 (accessible at: http://www.2aida.org/). Since the program'southward original release, users have developed new requirements, with new operating systems coming into apply and more complex insulin direction regimens being adopted. The electric current work has aimed to design a comprehensive diabetes simulation system from both a clinical and information technology perspective. Methods. A collaborative development is taking place with a new generic model of subcutaneous insulin absorption, permitting the simulation of chop-chop-interim and very long-acting insulin analogues, as well equally insulin injections larger than 40 units. This novel, physiological insulin absorption model has been incorporated into AIDA v4. Technical work has also been undertaken to install and operate the AIDA software inside a DOSBox emulator, to ensure compatibility with Windows XP, Vista and 7 operating systems equally well as Apple Macintosh computers running Parallels PC emulation software. Results. Plasma insulin simulations are demonstrated following subcutaneous injections of a chop-chop-acting insulin analogue, a short-acting insulin preparation, intermediate-acting insulin, and a very long-acting insulin analogue for injected insulin doses upwards to 60 units of insulin. Discussion. The current work extends the useful life of the existing AIDA v4 plan.

1. Introduction

Interest in the apply of information engineering (IT) in diabetes care is increasing [1, 2]. The rationale underlying this involvement is the hope that computers may provide a way of improving the therapy offered to diabetic patients—permitting more patients to be managed more intensively—in line with the experience of the Diabetes Control and Complications Trial (DCCT) [3]. All the same, in addition to the landmark DCCT written report [3], there take been other randomised controlled trials that have highlighted the potential benefits of a more than flexible approach to diabetes care. The DAFNE (dose adjustment for normal eating) arroyo has been pioneered in Dusseldorf [4] and since the trialled in Bucharest [v] and elsewhere [half-dozen], as well as more recently in the United kingdom of great britain and northern ireland [seven]. This has shown that a structured training course designed to maintain blood glucose (BG) command while enabling dietary freedom—instruction diabetes self-direction skills to patients with insulin-dependent (blazon 1) diabetes mellitus—can be constructive in improving metabolic control [4–7]. The hypothesis underlying this approach is that more comprehensive didactics may lead to attainment of the applied goals achieved in the DCCT. Furthermore, the DAFNE educational model, which focuses on teaching patients the skills to self-adjust insulin dosages for sugar intake, seems as well to be associated with an improved sense of self-efficacy and treatment satisfaction [eight].

The working hypothesis underlying the AIDA interactive educational diabetes simulation approach is that there are not enough diabetes educators to provide the sort of intensive insulin therapy offered in the DCCT, and even DAFNE-style structured teaching sessions can exist workforce-intensive and time-consuming. Therefore, perhaps computer-assisted learning tools may exist able to assist in the transfer of knowledge from health-care professionals to patients [nine], specially if there becomes a need to offering echo education to people with diabetes over a longer period of time.

There are many unlike aspects to diabetes education; nevertheless, learning facts is only one of these [10]. The ability to gain feel is too of smashing importance. It is well recognised that it is not ideal for patients to learn about diabetes control solely from real-life experiences considering of the long fourth dimension frames involved, bated from the possible very real dangers of hypo- or hyper-glycemia [11]. For this reason, it has been suggested that an interactive simulation of a diabetic patient might offering one solution [12].

one.1. AIDA Background

AIDA is a freeware estimator program that permits the interactive simulation of plasma insulin and BG profiles for demonstration, teaching, cocky-learning, and enquiry purposes. It has been fabricated available since March/April 1996, without charge, on the Globe Wide Spider web as a noncommercial contribution to standing diabetes education. In the 14+ years since its original Cyberspace launch, over ii million visits have been logged to the AIDA Web pages at http://world wide web.2aida.org/ and http://www.2aida.net/ and over 345,000 copies of the programme take been downloaded, gratis (Figures 1(a) and 1(b)). Further copies have been made bachelor, in the past, on diskette by the system developers [thirteen–17] and from the British Diabetic Association, London, Britain [18].

(a)

(b)

When AIDA is run, a dialog box opens and asks the user to select the condition and individual characteristics of the subject for simulation, including body weight and master metabolic indices, such every bit renal threshold of glucose, creatinine clearance, and peripheral and hepatic insulin sensitivities (Figure ii(a)). These parameters serve to specify patients with different degrees of insulin resistance and diverse degrees of glycaemic impairment.

In one case all the fields are set up and new values are saved, the simulation can exist run. Simulation results are presented in a graphical format (Figure 2(b)), showing claret glucose and plasma insulin concentrations. Users tin specify most unlimited numbers of virtual diabetic patients and exam how unlike types of treatments, doses and dosing regimens, and even lifestyle (dietary) changes affect the daily BG profile (Figure two(c)). If a simulated regimen is found unable to go on glycaemia inside desired limits, users can experiment with culling management regimens to try and meliorate the daily BG design [19].

An estimate of medium-term BG control which volition be familiar to patients/software users is provided by the AIDA program via the glycosylated haemoglobin (HbA_1c level) which is estimated on the ground that if the simulated BG profile was maintained for approximately 8–12 weeks this is the expected glycaemic control (HbA_1c index) that would upshot [20, 21]. People with diabetes, ideally, would be aiming for an HbA_1c of 6.0%–6.5%.

A major benefit of using AIDA is that it offers an opportunity to attempt and use the patient's own data, in an attempt to improve their understanding of their own diabetes. The AIDA software and underlying model have been previously described in detail elsewhere in the literature [x, 22, 23].

one.2. Rationale for Revising the Current AIDA Program

Based on the large number of downloads, user comments clearly demonstrate that the AIDA educational software has so far stood the test of time [24–26]. Like other software products more than than 14 years later their original launch, however, the time is ripe to consider potential revisions to the existing AIDA program. Developments both in the clinical and computational arena clearly point to the need to revise and extend the current software. User comments have prompted the systematic revision of the description and spectrum of diabetes types, as well every bit interventions/lifestyle events, handled by the AIDA model.

From a clinical perspective the existing AIDA v4 software does not cater for the latest insulin analogue preparations which take become increasingly used in the therapy of people with insulin-dependent (blazon ane) diabetes mellitus. Furthermore, the existing program is unable to simulate either non-insulin-dependent (blazon 2) diabetic patients with endogenous insulin secretion or management regimens involving insulin infusions in addition to subcutaneous boluses of insulin. New insights into the processes involving carbohydrate metabolism should also appear in an updated version of the educational simulator in order to fully reflect the complexity of mod solar day diabetes therapy.

For instance, in clinical practice the regulation of the BG concentration is mainly achieved by the action of three control variables: insulin, meals, and oral hypoglycaemic agents, but too modified past the effects of other factors, such equally physical practice and stress. This implies a need to extend the scope of input variables included in the underlying AIDA model.

There are also a number of technical issues to be resolved most the current software. The AIDA plan, being DOS-based, is now becoming somewhat dated, and there can be bug about making use of the AIDA v4.3a downloadable software under the Microsoft Windows XP, Windows Vista, and Windows 7 operating systems. Furthermore, it is necessary to respond to some technical requests of AIDA users and resolve certain Turbo Pascal display problems that seem to manifest themselves on the latest notebook computers. The flexibility and user friendliness of the user interface could also clearly exist improved. The master features of the electric current and hereafter planned versions of the AIDA software are contrasted in Tabular array 1.

AIDA v4 current version	AIDA v4.5 (and afterward) future versions
Model building/structure	New features
(i) Interconnected insulin-glucose submodels	(i) Comprehensive insulin/glucose model built from unit processes (diabetes "lego"-land)
(2) Empirical models for insulin/glucose dynamics and control	(ii) Physiologically based model of insulin absorption (generic) and kinetics
(iii) Linear insulin disposition/emptying (superposition principle applies)	(iii) Fewer (merely necessary and realistic) assumptions
(four) Use of fictive compartment ("active" insulin)	(four) Patient specification with minimal number of identifiable parameters
(five) Over parameterisation of patients (apply of nonidentifiable parameters such as separate hepatic and peripheral insulin sensitivities)	(v) Specification of typical patient types (insulin sensitive versus resistant, etc.) parameterised appropriately
Limitations	Overcoming limitations
(i) IDDM merely	(i) Both IDDM and NIDDM
(ii) No insulin analogues	(ii) Both rapidly acting and very long-acting insulin analogues added
(iii) Insulin dose ≤40 units	(three) Insulin dose ≤sixty units
(iv) Carbohydrate intake/meal ≤lxxx thou	(iv) Carbohydrate intake/meal ≤120 one thousand
(v) Oral hypoglycaemic drugs not incorporated	(five) Different types of oral hypoglycaemic drugs included
(vi) Lifestyle events/furnishings not included (stress, physical activity, menstrual cycle, etc.)	(vi) Lifestyle events (stress, concrete activity, menstrual bike, etc.) included
Technical	New features
(i) Carte driven information entry (nongraphical)	(i) Intuitive graphical user interface

It is evident that AIDA should remain a user-friendly program that implements a novel physiological model of the glucose-insulin organization. This paper aims to present both the clinical and technical results accomplished to appointment in the current stage of the revision procedure.

2. Methods

The outset update to the AIDA v4.3a programme relies on several new methods which are related to modelling, programming, and technical issues. These novel developments will be overviewed in turn.

two.i. Modelling Methods

The underlying AIDA model consists of glucose and insulin submodels. The glucose submodel describes the temporal development of the concentration of glucose in the claret stream based on the faux patient's management regimen as well as lifestyle (dietary) data. BG levels are controlled by various glucose fluxes into and out of the claret stream. These fluxes are complex functions of glucose and insulin levels, some of which vary according to a diurnal rhythm [23]. The glucose submodel has non been revised in the first phase of the program's revision.

The insulin submodel encapsulates equations according to which insulin molecules enter the circulation from subcutaneous depots (insulin absorption) and are distributed/eliminated. Equally a outset stage to updating the AIDA simulator, a decision was taken to focus on the appearance of insulin in the plasma post-obit a subcutaneous injection—thereby incorporating more novel insulin analogues into the program. In a survey of 200 users of the AIDA v4 software this was an oft requested "wish listing" feature for a new release of the program [24–26].

Subcutaneous insulin assimilation is a complex process which is affected by many factors including tissue blood menses, injection site/depth, injected book, and concentration [27]. Following a subcutaneous injection, soluble insulin forms a subcutaneous depot, where it is present in several multimeric, primarily hexameric and dimeric, forms. The subcutaneous depot is cleared by assimilation of dimeric insulin molecules into the vasculature [28]. Although assimilation of hexameric insulin has been reported, information technology is considered not significant as compared to dimeric insulin [29, 30].

Various insulin assimilation models have been proposed which vary in their degree of complexity. Virtually all of them handle short-interim (regular) insulin preparations, while a few handle intermediate-acting insulin and novel insulin analogues [28, 31, 32].

The Berger-Rodbard model [33] adopted in AIDA v4.3a was a uncomplicated and flexible tool that enabled the estimation of plasma insulin levels for various insulin preparations. However, this model was developed at the end of the 1980s and thus insulin analogues were non included.

A more comprehensive model, which has focused more on physiology and pharmacokinetics, has been described by Mosekilde and colleagues [34]. This approach was afterward modified by Trajanoski et al. [35] and Wach et al. [36] in an attempt to let for parameter interpretation based on plasma insulin profiles. The model was also extended to back up monomeric insulin analogues. Being more than physiologically based, the model proposed past Mosekilde et al. [34] and modified by Trajanoski and colleagues [35] was chosen as the footing for the insulin absorption model of Tarín and colleagues [37, 38] and the electric current collaborative development work with AIDA v4 [39–41]. The Trajanoski model was extended to bargain with the long-interim insulin analogue glargine, thereby covering the whole range of insulin preparations currently used in medical therapy. Later works have subsequently appeared in the literature that also consider insulin glargine, but where the diffusion procedure is neglected or approximated [42–44].

The generic insulin absorption model planned for inclusion in AIDA v4 [37, 38] represents improvidence of insulin through the subcutaneous depot, transformation between the different insulin states—hexameric, dimeric, and crystallized (in the case of the insulin glargine)—and absorption through capillary walls. Due to diffusion, the model is no longer a set up of ordinary differential equations, only partial differential equations (PDEs) dependent on both time and infinite. Since the diffusion process is considered homogeneous and isotropic, the system of PDEs is unidimensional in infinite (distance from the injection site).

The generic model is based on published data from the literature. As described by Tarín and colleagues [37, 38] the parameters of the absorption model for insulin glargine were found through an iterative identification procedure, while the parameters for the remainder of formulations were obtained from the previous works of Mosekilde et al. [34], Trajanoski et al. [35], Höfig [45], and Gessler [46].

In the study past Mosekilde et al. [34] the model was adjusted to fit bachelor experimental data and to make up one's mind the effective diffusion abiding for subcutaneous insulin, the absorption rate constant for dimeric insulin, the equilibrium constant betwixt hexameric and dimeric insulin, the typical bounden capacity for insulin in the tissue, and the boilerplate lifetime for insulin in its jump state (not to be confused with the new "bound state" of insulin glargine). Typical values for insulin injection into the thigh of a fasting person with type 1 diabetes are summarized in Table 2.

Parameter	Value	Description
Q/mLtwo IU−2	0.13	Chemical equilibrium constant
B/min−1	1.3*x−2	Absorption rate abiding
D/cm² min−1	0.9*10−4	Improvidence constant for soluble insulin in water at 37°C
C/IU cm3	0.05	Binding capacity for insulin in the tissue
T/min	800	Average life time for insulin in its bound country

As reported past Trajanoski et al. [35], due to the model structure, the formal identification techniques cannot be adopted for the modified model (i.eastward., the model is theoretically unidentifiable [47]). Further model simplification like linearization or aggregation of distributed effects cannot be performed, since the essential characteristics of the model would exist lost if linearization was done. On the other hand, model decomposition is not possible, as it is impossible to measure insulin with different association states in the subcutaneous depot. Therefore, a parameter set has been chosen from published in vivo and in vitro experiments as shown in Tabular array three. (i) Values for the improvidence coefficients of insulin and insulin analogues published by Moeller et al. [48] were used (the diffusion constant was measured in water or tissue biopsies at 37°C). (ii) The assimilation charge per unit constant for monomeric insulin was calculated from the slope of the absorption curves observed by Kang et al. [47]. According to the assumptions of Trajanoski et al. [35] during the concluding stage of the assimilation just dimers are absorbed. Therefore, for the absorption rate constant for soluble insulin, the terminal slope of the absorption bend of Kang et al. [47] is adopted. (iii) In the study past Mosekilde et al. [34] it was causeless that the hexameric-dimeric rest is always almost equilibrium, and a large value was called for the parameter compared to the absorption charge per unit constant . Since even big changes of do not change the results significantly, in the study by Trajanoski et al. [35] the same value was used. (iv) For the distribution-elimination model for soluble insulin, parameters reported by Kraegen and Chisholm [49] were used for the calculations ( and ). (v) The plasma elimination rate constant for monomeric analogues was taken from the study by Robertson et al. [50].

Parameter	Value	Description
Q/mLii IU−2	76	Chemic equilibrium abiding
Bd /min−i	1.18*ten−ii	Assimilation charge per unit abiding for dimeric insulin
Bm /min−1	1.22*ten−two	Assimilation rate constant for monomeric insulin
P/min−i	0.v	Rate constant
D/cm²  min−ane	8.4*10−v	Diffusion constant for soluble insulin
Done thousand /cm² min−i	ane.66*x−iv	Diffusion constant for monomeric insulin analogues
KDue south /min−1	0.09	Plasma insulin emptying rate
5p /50	12	Book of plasma insulin compartment
MS /min−1	55	Plasma insulin elimination rate constant for monomeric insulin analogues

In the studies by Höfig [45] and Gessler [46] the parameter was modified in social club to mimic the assimilation curves measured with unlike insulin preparations such equally apace interim analogues and NPH (see the studies past Kang et al. [51] and Folder [52]). Readers are referred to the written report by Tarín et al. [37] for a detailed description of the mathematics underlying the generic insulin absorption model.

As the insulin period into the blood stream is markedly slower than the emptying of insulin from the plasma, plasma insulin kinetics are typically described as a single compartment model representing the claret pool and some extravascular space from where there is a starting time-order emptying of insulin. This is the modeling approach that has been used for the insulin model [33] incorporated within the existing AIDA v4 plan.

2.2. Programming Problems

The model of glucose-insulin interaction includes a set of differential equations, algebraic expressions, and parameters which helps to go far more case-/patient-specific. Model equations are integrated by separately computing the glucose and insulin submodels.

For simulating type one diabetic patients the insulin submodel is considered independent of the glucose part of the model. Every bit none of the parameters associated with the kinetics are assumed to exist patient-specific, the insulin concentrations can exist precomputed for whatsoever possible insulin delivery and stored prior to use by AIDA. Insulin levels resulting from any particular insulin regimen are computed by summing up the precomputed individual contributions corresponding to the preparations and doses equally used in the particular insulin regimen.

This technique allows the glucose subsystem exhibiting slower dynamics to exist simulated with a 15-infinitesimal step size. It is noted that integrating insulin equations in real time would crave a much smaller stride size (less than i minute) due to the short halftime (virtually 5 minutes) of insulin in the plasma.

Simulations start with a BG level of 100 mg/dL (five.vi mmol/L). Insulin and glycaemic responses are faux for 48 hours, and the results of the second day'southward simulation are displayed as the steady state response to the electric current therapy.

2.three. Precomputing Insulin Levels

Although insulin levels corresponding to dissimilar types and doses of subcutaneous insulin preparations need to exist determined only one time, these calculations are still time-consuming because of the complication of the generic insulin absorption model. Equally the coupled PDEs accept no airtight solution, integration should exist washed numerically. It is considered that insulin later the injection forms a spherical volume in the adipose tissue and starts to lengthened out symmetrically. Hence, a numerical implementation has been carried out by means of a spatial discretisation consisting of spherical shells with equal volume, based on the work of Trajanoski et al. [35].

In this solution, an approximation of Fick'south diffusion law as a residual of flows at each detached shell is carried out (Figure iii [35]).

Initial weather are provided by the corporeality (dose) and type of the injected insulin. For rapidly acting, brusque-acting, and intermediate-acting insulin, it is considered that all the insulin is in the inner shell in chemical equilibrium between hexameric and dimeric forms. The book of the inner trounce corresponds to the injected volume. For the outermost spherical shell it is considered that the insulin concentration is null exterior the considered spherical depot.

It was demonstrated by Tarín et al. [38] that a fixed number of fifteen shells, as considered by Trajanoski et al. [35], is not sufficient for all insulin types and doses. Thus, a varying number of shells is considered here depending on the dose and type of insulin. To calculate the required number of shells, the absorbed insulin menses is computed in two different means that become equivalent for a large enough spherical depot (Figure 4): (a) captivated insulin menses at a given time is the drove of insulin assimilation flows from each spherical shell; (b) absorbed insulin menstruum at a given time is the decrement of full insulin in the spherical depot per unit time.

(a)

(b)

In the first case (a), if the insulin concentration exterior the considered spherical depot is significant, the computed value will underestimate the actual insulin absorption flow, since this insulin will be neglected. However, in the second instance (b), the insulin concentration will be considered as captivated, yielding an overestimation. Profiles computed by each of the methods will converge equally the number of shells is increased, and thus the radius of the spherical depot increases. As computational time will increase with the number of shells considered, the solution is accepted as a compromise between efficiency and precision. The number of shells is considered adequate when the expanse under the curve of the calculated assimilation profile (i.e., the sum of absorption flows from each shell), computed every bit described in item (a) above, and the injected dose, differ past less than 1%.

One percent can be considered adequate given that these losses but occur for pocket-sized doses that are inappreciably always administered. This represents a good compromise between speed and precision.

Effigy 5 shows the number of shells required for each insulin type, and doses ranging from one to 60 IU, with a concentration of the preparation of 100 mIU/L (U100). (i) For rapidly-acting insulin analogues, twenty shells is regarded every bit enough for doses college than xx IU, simply for smaller doses the number of shells required increases dramatically, reaching 180 shells for 2 IU. Ciphering for 1 IU with a 1% target divergence was not possible due to memory constraints. (ii) For short acting insulin preparations, doses higher than x IU crave 10 shells or less; for smaller doses the number of shells increases upwards to 120 shells for a dose of 1 IU. (iii) For intermediate-acting insulin preparations and very long-acting insulin analogues, doses higher than 20 IU require only 20 shells, while for doses beneath three IU the number of shells exceeds 100, reaching 180 shells for a dose of 1 IU of insulin.

For smaller doses the injected volume is pocket-size, too. This automatically leads to rather small trounce radii. Since the book is kept constant, the further from the injection site, the thinner the beat out volition be. Furthermore, the smaller the radii the higher the diffusion speed and the higher the ratio between shell surface and volume. Therefore, for pocket-sized injection doses, the insulin diffuses very quickly from the inner to the outermost trounce and beyond, which leads to the loss if the number of shells is not sufficient. Yet equally the AIDA v4 software only handles integer insulin injection doses, less than one IU insulin injection simulations are non required for the current version of the plan. Although for time to come paediatric use such issues well-nigh fractional insulin injection dosages may potentially become of greater significance.

Table iv shows radii of the 15th sphere around the injected volume for various doses of U100 (100 mIU/L) insulin preparations. As can be seen, the radii are within a reasonable range with respect to the thickness of the subcutaneous tissue.

Injected dose/IU	Injected volume/mL	Radius of 15th sphere/mm
1	0.01	3.iv mm
ii	0.02	four.2 mm
five	0.05	5.eight mm
10	0.1	vii.3 mm
20	0.2	9.1 mm

Regarding fourth dimension discretisation, the Euler method is practical with a time stride of 0.01 minute. The computational burden to really calculate insulin absorption flows is not trivial but does not exceed the capabilities of modern personal computers either. Calculating the assimilation flow of i 18 IU injection of glargine, for example, needs roughly three seconds on a i.4 GHz Pentium class PC without whatsoever effort in the implementation. Doing the aforementioned on a portable device like a PocketPC or smart telephone, equipped with a 200 MHz StrongArm CPU, will crave more patience but can exist done in less than 10 seconds especially if a highly optimized implementation is used. This remains true for the vast majority of insulin injection doses. Information technology is only when calculating extremely low doses that much longer computational times are observed. As can be seen, the number of required shells may increase dramatically for low insulin doses (Effigy 5).

At low insulin doses computational time can become excessive, and running the simulations in "real time" may not be appropriate. For this reason, AIDA v4 relies on precomputed insulin profiles.

2.4. Technical Issues

In that location have been some reported display problems with the existing AIDA v4 software operating under Windows XP, specially with the latest laptop/notebook PCs. Besides Microsoft Windows Vista and Windows vii exercise not permit legacy Deejay Operating Organization (DOS) applications to switch to full-screen brandish mode, equally required by AIDA v4. Therefore, in order for AIDA to run optimally under Windows XP—and operate under Windows Vista and Windows 7—an alternative display approach has been investigated. Instead of trying to execute AIDA straight as a standalone application, as has been done previously, the idea has been adult to run AIDA using a DOS emulator. This emulator is a Windows awarding itself that mimics the behaviour of the xvi-flake DOS operating organisation for which AIDA was originally designed. The concept is that AIDA should and so in turn run within this emulator, hidden from the Windows XP/Vista/7 operating systems, nonetheless in a style that would be transparent to the user. This approach is similar to a method adopted previously to let AIDA v4 to operate on Apple Macintosh computers, using SoftWindows or PowerPC emulation software on Apple Macs (http://www.2aida.org/applemac/) [53]. The approach has been investigated for notebook and desktop PCs running Windows XP, Vista, and 7 to prolong the useful "shell life" of the existing AIDA v4 software and let people to continue making skillful use of the plan.

DOSBox is a lightweight DOS emulator that has gained broad acceptance in the DOS gaming customs. It is published nether a General Public Licence (GPL) and tin be used and distributed freely without charge or fee. Packed with a handy installer, it comes equally a 1.five Mb download, which is acceptable even for users with tiresome Internet connections. It is freely available from http://www.dosbox.com/.

Installing and starting DOSBox is a straightforward process. DOSBox also offers a convenient manner to configure itself. Upon running DOSBox, information technology scans the directory in which information technology is located for a file called "dosbox.conf." Inside this file, various settings can be prespecified. Amid these are the keyboard layout, the emulation speed, and all the steps to be executed automatically right after starting DOSBox. In this way, DOSBox tin be tailored to suit the hardware and software environments found on the host computer. All possible settings are documented at the DOSBox website (http://world wide web.dosbox.com/).

The possibility to configure the keyboard layout is peculiarly of import as AIDA is used internationally. Past exploiting the "autorun" department mechanism in the "dosbox.conf" file, DOSBox can besides be configured to start emulating AIDA upon invocation. Therefore, usage of the DOSBox DOS emulator can exist implemented in a way that is entirely transparent to the AIDA user.

Interestingly, the display problems, AIDA v4.3a can show on some of the latest notebook PCs are not experienced when AIDA is run within DOSBox. Every bit these problems might be related to missing UNICODE support of the compiler with which AIDA was compiled, the solution of this problem does not come up as a surprise every bit DOSBox emulates the ASCII environment for which AIDA v4 was compiled.

Installation of a combined AIDA/DOSBox awarding can likewise be streamlined. In order to emulate AIDA, not all files that the standard DOSBox installer copies to the host calculator are actually needed. As neither special audio output nor game-relevant hardware support (eastward.g., for joysticks) are required, it is sufficient to copy the DOSBox executable, the "dosbox.conf" file for the host computer, and the two Simple DirectMedia Layer (SDL) library files which provide cantankerous-platform multimedia capabilities designed to offer fast admission to the graphics frame buffer.

If the AIDA installer then updates the "dosbox.conf" file with the path to the AIDA executables and the keyboard layout autoidentified at install time and lets the created links in the outset menu folder point to the DOSBox executable instead of the AIDA executable, then AIDA can be used in a streamlined manner on whatsoever Microsoft Windows PC operating system, including Windows XP, Windows Vista and Windows seven.

The installer for AIDA has been created with the Nullsoft Scriptable Install Organization (NSIS). This is an advanced open source installation system that can be used for gratuitous. NSIS is especially suited for the AIDA installation as it allows more complex tasks to be performed than mere file unpack and copy routines (Figure half-dozen(a)). Instead, via its inherent script system, it can, for case, phone call whatever operating arrangement application programming interface (API) functions. In this way, it is possible to query, for case, the keyboard layout of the calculator on which AIDA is to be installed. Moreover, NSIS supports several handy script functions to edit text files. Thus, it can perform all the configurations of the DOSBox environment. Furthermore, being open up source software and freeware it is very compatible with the AIDA freeware ethos.

The DOSBox/NSIS approach has been extensively trialed, and a technical update to AIDA (called AIDA v4.3b) has been developed which provides a "turnkey" streamlined installation of AIDA v4 incorporating the DOSBox functionality in a user friendly format for Windows XP, Vista, and 7 users.

The new version of AIDA v4.3b has been released on the Net in April 2010. Figure vi shows AIDA v4.3b operating in this way successfully nether the (b) Windows XP, (c) Windows Vista, and (d) Windows vii operating systems.

The AIDA v4 simulator itself comes accompanied by a second application, called AIDADEMO, which provides a demonstration of what AIDA tin can exercise for users who are not sure whether to download the total programme. The AIDADEMO guides the user through a series of slides which explain usage and the theoretical background of the simulator, thereby pointing out the program's capabilities and limitations. As AIDADEMO has originally been created using a like development environment to AIDA v4 itself, it naturally may take similar operating system issues to the parent AIDA application. All the same, simply equally with AIDA, these issues accept been addressed by employ of the DOSBox arroyo bundled with the NSIS installer. Figure half dozen(e) shows a screenshot from the AIDADEMO awarding demonstrating for a different person ("Joy Wilson"), a 70 kg insulin-dependent diabetic patient, the effect of missing the usual morning time insulin injection earlier breakfast with the profound hyperglycaemia (raised blood glucose) that is predicted to occur in the afternoon. The DOSBox/NSIS packaged release of AIDADEMO is accessible at the AIDA website at the stop of viewing the spider web-based demo at http://www.2aida.org/demo/ or directly at http://www.2aida.org/aidademo/ (Figure 6(f)).

2.v. Running AIDA v4.3b on Apple tree Macintosh Computers

Since the yr 2000 the AIDA website has supported the apply of AIDA v4 under SoftWindows and PowerPC emulation software on Apple Macintosh computers [53], and see http://www.2aida.org/applemac/. Since the adoption of Intel microprocessors by Apple in 2006, Windows applications tin can be executed even more efficiently on Mac operating systems OSX. This requires the installation of Windows on the Mac motorcar, and the use of Boot Military camp (if it is intended to start the machine nether Windows), or a virtualization awarding (like Parallels or VMware Fusion). In the offset case, Windows volition have access to all the resources of the Mac machine. In the second case, a virtual Windows machine volition be created, sharing resource with Mac OSX. Virtualization is based on the creation of virtual hardware by ways of software. Although this will eat more resources since Mac OSX and Windows will be running at the same time, information technology is user-friendly if the user does not want to restart the machine every time they need to execute a Windows awarding. VMware Fusion and Parallels require an Intel Mac, a minimum of Mac OSX v10.4.vi Tiger, and 1 Gb of RAM. Boot Camp is a congenital-in part from Mac OSX v10.5 Leopard. Parallels Desktop 5 and VMware Fusion three for Mac OSX v10.vi Snowfall Leopard both offer compatibility with Windows seven.

The utilise of whatsoever of the to a higher place tools will allow the execution of AIDA v4.3b on any Intel-based Mac machine. By way of illustration, the execution of AIDA v4.3b on a Mac OSX Tiger machine with Parallels is shown in Figures half-dozen(g) and 6(h). This arroyo has been tested on a Macbook Pro and on an iMac—using Parallels to execute a virtual machine with Windows XP.

AIDA v4.3b, similar AIDA v4.3a earlier information technology, is intended for utilize on PC platforms, or Apple tree Macintosh computers running suitable PC emulation software. A farther freeware upgrade, called AIDA v4.v (currently under evolution), is planned incorporating the generic insulin model into the AIDA v4 software—allowing the interactive simulation of lispro, aspart, and glargine insulin analogues.

3. Results

Figure i shows the AIDA Website logstats for the number of visitors and AIDA v4 downloads since the software went on freeware Internet release—demonstrating the large number of site visitors and downloads that have taken place.

Figures 2 and half dozen show a case study using AIDA v4.3b—which demonstrates some of the ways in which the software can be applied as an educational/demonstration/pedagogy tool. "Penelope Vincent"—example scenario number 0033 in the AIDA database—is a young adult female, who is overweight (98 kg) and runs reasonably high claret sugars during the form of the day. At present she is simply injecting herself twice daily with two "shots" of intermediate-acting insulin. The AIDA software asks the user "How might you lot add in a brusque-acting insulin training to her regimen to tighten her glycaemic control? Alternatively, see if you can decrease her carbohydrate intake—thereby perhaps helping her to lose weight—and at the same fourth dimension improving her blood glucose control…." Various examples of ways in which Penelope's glycaemic control might be improved are simulated for educational purposes in Figures two(c) and half-dozen. The AIDA v4.3b freeware software is shown running on personal computers under the Windows XP, Windows Vista and Windows seven operating systems in a DOSBox environment (Figures 6(b)–6(d)), as well every bit under Parallels on Apple Macs (Figures 6(g) and 6(h)).

Plasma insulin simulations are too demonstrated using the novel generic model following subcutaneous injections of a rapidly interim insulin analogue (such as lispro/Humalog or aspart/NovoLog), a short-acting (regular) insulin grooming (e.g., Actrapid), intermediate-acting insulin (both Semilente and NPH types), and a very long-interim insulin analogue (such equally glargine/Lantus) for injected insulin doses upwards to 60 units of insulin (Figure 7).

4. Discussion

Interactive simulators offer users the chance to test the behaviour of the imitation object without risk. Diabetes simulators can breathing an underlying model of glucose metabolism and may assist to railroad train users to manage "virtual diabetic patients" with the possibility of changing decisions or starting again in the case of failure.

Numerous models of the human glucoregulatory system have been reported [22, 54–57] However, these models may not exist so useful for individual patients, their relatives, wellness-intendance professionals, or students without some sort of program (a "simulator") to allow easy access to, and interaction with, the model. A range of interactive simulation programs of glucose-insulin interaction in diabetes have also been described in the literature [12, 28, 33, 57–62]. A few notable simulators have been circulated on diskette for use by select health-care professional person/research users [thirteen–17, 19]. Some authors [22, 33, 63, 64] have too developed a simulation program which could be obtained upon request.

However, for the majority of simulation programs [28, 58–61], it would seem that readers have been wholly dependent on the authors' own descriptions of their prototypes in enquiry manufactures, since no versions appear to exist available for full general utilise past others.

With AIDA, the program has been made widely available, gratis, via the Internet, from its own Websites—http://world wide web.2aida.org/ and http://www.2aida.cyberspace/—as a noncommercial contribution to continuing diabetes education. This has led to a substantial feel with the plan—globally—with over 347,000 downloads of the software taking identify from more than 100 countries worldwide. Contained reviews of AIDA can be constitute on the Web at http://world wide web.mendosa.com/aida.htm and http://www.2aida.net/aida/review.htm too as in a range of publications [65–69].

The AIDA diabetes simulator provides a user-friendly manner of making use of the AIDA model in an interactive, intuitive, and freeware manner. It would assist research into the use of such applications in this area, equally well every bit peradventure do good the wider diabetes community, were more such diabetes simulation programs made available for complimentary on the Net.

4.1. Futurity Work

Table 1 shows the directions in which the AIDA software is intended to be developed. Revisions volition affect the model, coverage of disease types, and the direction and lifestyle events affecting BG levels.

The electric current hardwired mathematical model will be replaced past a modular ("lego"-like) design in which unit processes are clearly identified and interactions are formulated in a systematic and formal way. The revised/extended model aims to be physiologically based using parameters with values that are reasonable and which permit physiological interpretation. The insulin absorption model implemented in the revised diabetes simulator offers a description of what happens after the subcutaneous injection of different insulin preparations, including insulin analogues, with realistic assumptions and a minimal number of model parameters. Similar revisions of the glucose submodel are anticipated.

In due course information technology is planned to update AIDA farther to make it possible to simulate glycaemic responses in non-insulin-dependent (blazon 2) diabetic patients. The superposition principle adopted within the AIDA model [23], of course, could too utilize to insulin that has been secreted past pancreatic beta cells. Such endogenous secretion evolves over fourth dimension respective to the temporal variations in BG concentrations. The insulin levels arising from endogenous insulin sources at any time can be computed equally the sum of furnishings of all insulin that has been secreted in the preceding 4 hours (insulin levels are known to fall nearly to cypher within 4 hours following a curt intravenous bolus of insulin). For this computation the plasma and "agile" insulin levels in response to a reference constant charge per unit of insulin infusion delivered to the plasma over a short time menstruum would exist required. In each 15-minute integration step the average endogenous insulin secretion would be computed as the response to the average BG level in that catamenia. The overall upshot of endogenous insulin secretion would exist computed by adding together private contributions, in a similar fashion to that done currently with exogenous insulin injections.

Effigy 8 shows a epitome simulation using the superposition principle to calculate a plasma insulin profile based on exogenous insulin injections and estimated basal endogenous insulin secretion in a type 2 diabetes patient.

The patient takes six units of short-acting (regular) insulin and 12 units of intermediate-acting (NPH blazon) insulin in the morning with a further 4 units of short-acting (regular) insulin and eight units of intermediate-acting (NPH type) insulin in the evening. The estimated basal endogenous insulin secretion is shown—and the overall plasma insulin profile is superimposed.

It is intended to implement a similar facility inside AIDA to provide simulations and a representation for insulin-treated blazon 2 diabetic patients.

Further inputs such as carbohydrate intake/meals upwards to 120 grams in size also every bit different types of oral hypoglycaemic agents and lifestyle events (stress, concrete activity, menstrual cycle, etc.) will also be added. Finally the revised AIDA simulator should be hands used via an intuitive graphical user interface.

5. Conclusion

In this paper the development and freeware Internet launch of AIDA v4.3b has been described. This incorporates technical work ensuring the diabetes simulation software, and a runtime demonstration program, continue to operate seamlessly under the Windows Vista, Windows 7, and Apple Macintosh operating systems. Plasma insulin simulations are demonstrated following subcutaneous injections of a rapidly acting insulin analogue (such every bit lispro/Humalog or aspart/NovoLog) and a very long-acting insulin analogue (such as glargine/Lantus) for injected insulin doses up to 60 units of insulin. Farther work is planned to validate the generic model of insulin absorption in parallel with its incorporation into an updated release of the freeware AIDA software (AIDA v4.5).

5.1. Organisation Availability

AIDA v4.3b is freely available for download from http://www.2aida.org/. Following completion of further programming, validation, and bench testing work, information technology is expected that a new, improved version of AIDA (v4.five)—incorporating Humalog/lispro and Lantus/glargine insulin analogues—will become available at the same website for freeware download and educational apply. Readers who wish to be automatically informed past email when the new software is launched are welcome to join the very low volume AIDA registration/announcement listing by sending a blank e-mail notation to subscribe@2aida.org.

Please notation that "Penelope Vincent" and "Joy Wilson" are pseudonyms.

Abbreviations

BG:	Blood glucose
PC:	Personal reckoner
IU:	International units (of insulin).

Copyright

Copyright © 2011 Eldon D. Lehmann et al. This is an open admission article distributed under the Artistic Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original piece of work is properly cited.

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Source: https://www.hindawi.com/journals/jece/2011/427196/

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