Improving IV insulin administration in a community hospital

Diabetes mellitus is a major independent risk factor for increased morbidity and mortality in the hospitalized patient, and elevated blood glucose concentrations, even in non-diabetic patients, predicts poor outcomes. The 2008 consensus statement by the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) states that "hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes." It is important to recognize that hyperglycemia occurs in patients with known or undiagnosed diabetes as well as during acute illness in those with previously normal glucose tolerance. The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study involved over six thousand adult intensive care unit (ICU) patients who were randomized to intensive glucose control or conventional glucose control. Surprisingly, this trial found that intensive glucose control increased the risk of mortality by 14% (odds ratio, 1.14; p = 0.02). In addition, there was an increased prevalence of severe hypoglycemia in the intensive control group compared with the conventional control group (6.8% vs. 0.5%, respectively; p < 0.001). From this pivotal trial and two others, Wyoming Medical Center (WMC) realized the importance of controlling hyperglycemia in the hospitalized patient while avoiding the negative impact of resultant hypoglycemia. Despite multiple revisions of an IV insulin paper protocol, analysis of data from usage of the paper protocol at WMC shows that in terms of achieving normoglycemia while minimizing hypoglycemia, results were suboptimal. Therefore, through a systematical implementation plan, monitoring of patient blood glucose levels was switched from using a paper IV insulin protocol to a computerized glucose management system. By comparing blood glucose levels using the paper protocol to that of the computerized system, it was determined, that overall, the computerized glucose management system resulted in more rapid and tighter glucose control than the traditional paper protocol. Specifically, a substantial increase in the time spent within the target blood glucose concentration range, as well as a decrease in the prevalence of severe hypoglycemia (BG < 40 mg/dL), clinical hypoglycemia (BG < 70 mg/dL), and hyperglycemia (BG > 180 mg/dL), was witnessed in the first five months after implementation of the computerized glucose management system. The computerized system achieved target concentrations in greater than 75% of all readings while minimizing the risk of hypoglycemia. The prevalence of hypoglycemia (BG < 70 mg/dL) with the use of the computer glucose management system was well under 1%.     

Postprandial blood glucose control using a hybrid adaptive PD controller with insulin-on-board limitation

This paper addresses the design of blood glucose control during the postprandial period for Type 1 diabetes patients. An artificial pancreas for ambulatory purposes has to deal with the delays inherent to the subcutaneous route, the carbohydrate intakes, the metabolic changes, the glucose sensor errors and noise, and the insulin pump constraints. A time response typically obtained in closed-loop insulin delivery shows hyperglycemia in the early postprandial period caused by the lag in the insulin absorbtion, followed by hypoglycemia caused by control over-reaction. A hybrid control system is proposed in this paper to overcome these problems. An insulin bolus is administered prior to the meals like in open-loop control, whereas a PD controller is used for robust glucose regulation. The controller gain is progressively increased after the bolus from zero up to its nominal value as function of the insulin on board, so that the PD controller becomes fully operational just when the insulin on board falls below a prescribed value. An excessive accumulation of active insulin is avoided in this way, drastically reducing the risk of hypoglycemia. The controller gain is adapted by means of a variable structure algorithm, allowing a very simple software implementation. The robust performance of the control algorithm is intensively assessed in silico on a cohort of virtual patients under challenging realistic scenarios considering mixed meals, circadian variations, time-varying uncertainties, discrete measurement and actuation, sensor errors and other disturbances.     

Developing a Hybrid Programmable Logic Controller Platform for a Flexible Manufacturing System

In this article, we present the design and implementation of a flexible manufacturing system (FMS) control platform based on a programmable logic controller (PLC) and a personal computer (PC)-based visual man-machine interface (MMI) and data acquisition (DAS) unit. The key aspect of an FMS is its flexibility to adapt to changes in a demanding process operation. The PLC provides feasible solutions to FMS applications, using PC-based MMI/DAS, whereby PLCs are optimized for executing rapid sequential control strategies. PCs running MMI/DAS front-ends make intuitive operation interfaces, full of powerful graphics and reporting tools. Information from the PC can be distributed through a company's local area network or web using client-server technologies. Currently, with the convergence of underlying microprocessor technology and software programming techniques, many users find that PLCs provide a cost-effective solution to real-time control in small- to medium-sized process plants, especially when combined with supervisory PCs using hybrid systems. The major work of this article demonstrates that PLCs are responsive to rapid and repetitious control tasks, using PCs that present the flow of information automation and accept operator instructions, thereby providing the user a tool to modify and monitor the process as the requirements change.     

Continuous glucose monitoring and control in a rotating wall perfused bioreactor

A glucose control system consisting of a single in-line glucose sensor, concentrated glucose solution, and computer hardware and software were developed. The system was applied to continuously control glucose concentrations of a perfusion medium in a rotating wall perfused vessel (RWPV) bioreactor culturing BHK-21 cells. The custom-made glucose sensor was based on a hydrogen peroxide electrode. The sensor continuously and accurately measured the glucose concentration of GTSF-2 medium in the RWPV bioreactor during cell culture. Three sets of two-point calibrations were applied to the glucose sensor during the 55-day cell culture. The system first controlled the glucose concentration in perfusing medium between 4.2 and 5.6 mM for 36 days and then at different glucose levels for 19 days. A stock solution with a high glucose concentration (266 mM) was used as the glucose injection solution. The standard error of prediction (SEP) for glucose measurement by the sensor, compared to measurement by the Beckman glucose analyzer, was +/-0.4 mM for 55 days.     

Inline noninvasive Raman monitoring and feedback control of glucose concentration during ethanol fermentation

Raman spectroscopy as a process analytical technology tool was implemented for the monitoring and control of ethanol fermentation carried out with Saccharomyces cerevisiae. The need for the optimization of bioprocesses such as ethanol production, to increase product yield, enhanced the development of control strategies. The control system developed by the authors utilized noninvasive Raman measurements to avoid possible sterilization problems. Real-time data analysis was applied using partial least squares regression (PLS) method. With the aid of spectral pretreatment and multivariate data analysis, the monitoring of glucose and ethanol concentration was successful during yeast fermentation with the prediction error of 4.42 g/L for glucose and 2.40 g/L for ethanol. By Raman spectroscopy-based feedback control, the glucose concentration was maintained at 100 g/L by the automatic feeding of concentrated glucose solution. The control of glucose concentration during fed-batch fermentation resulted in increased ethanol production. Ethanol yield of 86% was achieved compared to the batch fermentation when 75 % yield was obtained. The results show that the use of Raman spectroscopy for the monitoring and control of yeast fermentation is a promising way to enhance process understanding and achieve consistently high production yield.     

Viola: A New Visual Programming Language Designed for the Rapid Development of Interacting Agent Systems

The construction of complex simulation models and the application of new computer hardware to ecological problems has resulted in the need for many ecologists to rely on computer programmers to develop their modelling software. However, this can lead to a lack of flexibility and understanding in model implementation and in resource problems for researchers. This paper presents a new programming language, Viola, based on a simple organisational concept which can be used by most researchers to develop complex simulations much more easily than could be achieved with standard programming languages such as C++. The language is object oriented and implemented through a visual interface. It is specifically designed to cope with complicated individual based behavioural simulations and comes with embedded concurrency handling abilities.     

Cardiac metabolism in mice: tracer method developments and in vivo application revealing profound metabolic inflexibility in diabetes

Studies of cardiac fuel metabolism in mice have been almost exclusively conducted ex vivo. The major aim of this study was to assess in vivo plasma FFA and glucose utilization by the hearts of healthy control (db/+) and diabetic (db/db) mice, based on cardiac uptake of (R)-2-[9,10-(3)H]bromopalmitate ([3H]R-BrP) and 2-deoxy-D-[U-14C]glucose tracers. To obtain quantitative information about the evaluation of cardiac FFA utilization with [3H]R-BrP, simultaneous comparisons of [3H]R-BrP and [14C]palmitate ([14C]P) uptake were first made in isolated perfused working hearts from db/+ mice. It was found that [3H]R-BrP uptake was closely correlated with [14C]P oxidation (r2 = 0.94, P < 0.001). Then, methods for in vivo application of [3H]R-BrP and [14C]2-DG previously developed for application in the rat were specially adapted for use in the mouse. The method yields indexes of cardiac FFA utilization (R(f)*) and clearance (K(f)*), as well as glucose utilization (R(g)'). Finally, in the main part of the study, the ability of the heart to switch between FFA and glucose fuels (metabolic flexibility) was investigated by studying anesthetized, 8-h-fasted control and db/db mice in either the basal state or during glucose infusion. In control mice, glucose infusion raised plasma levels of glucose and insulin, raised R(g)' (+58%), and lowered plasma FFA level (-48%), K(f)* (-45%), and R(f)* (-70%). This apparent reciprocal regulation of glucose and FFA utilization by control hearts illustrates metabolic flexibility for substrate use. By contrast, in the db/db mice, glucose infusion raised glucose levels with no apparent influence on cardiac FFA or glucose utilization. In conclusion, tracer methodology for assessing in vivo tissue-specific plasma FFA and glucose utilization has been adapted for use in mice and reveals a profound loss of metabolic flexibility in the diabetic db/db heart, suggesting a fixed level of FFA oxidation in fasted and glucose-infused states.     

Effectiveness of flexible routing control

Flexibility in part process representation and in highly adaptive routing algorithms are two major sources for improvement in the control of flexible manufacturing systems (FMSs). This article reports the investigation of the impact of these two kinds of flexibilities on the performance of the system. We argue that, when feasible, the choices of operations and sequencing of the part process plans should be deferred until detailed knowledge about the real-time factory state is available. To test our ideas, a flexible routing control simulation system (FRCS) was constructed and a programming language for modeling FMS part process plans, control strategies, and environments of the FMS was designed and implemented. In addition, a scheme for implementing flexible process routing called data flow dispatching rule (DFDR) was derived. The simulation results indicate that flexible processing can reduce mean flow time while increasing system throughput and machine utilization. We observed that this form of flexibility makes automatic load balancing of the machines possible. On the other hand, it also makes the control and scheduling process more complicated and calls for new control algorithms.     

A robust feeding strategy to maintain set‐point glucose in mammalian fed‐batch cultures when input parameters have a large error

Industrial CHO cell cultures run under fed‐batch conditions are required to be controlled in particular ranges of glucose, while glucose is constantly consumed and must be replenished by a feed. The most appropriate feeding rate is ideally stoichiometric and adaptive in nature to balance the dynamically changing rate of glucose consumption. However, high errors in biomass and glucose estimation as well as limited knowledge of the true metabolic state challenge the control strategy. In this contribution, we take these errors into account and simulate the output with uncertainty trajectories in silico in order to control glucose concentration. Other than many control strategies, which require parameter estimation, our assumptions are founded on two pillars: (i) first principles and (ii) prior knowledge about the variability of fed‐batch CHO cell culture. The algorithm was exposed to an in‐silico Design of Experiments (DoE), in which variations of parameters were changed simultaneously, such as clone‐specific behavior, precision of equipment and desired control range used. The results demonstrate that our method achieved the target of holding the glucose concentration within an acceptable range. A robust and sufficient level of control could be demonstrated even with high errors for biomass or metabolic state estimation. In a time where blockbuster drugs are queuing up for time slots of their production, this transferable control strategy that is independent of tedious establishment runs may be a decisive advantage for rapid implementation during technology transfer and scale up and decrease in campaign change over time. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:317–336, 2017     

Adaptive fuzzy control of nutrients concentration in fed-batch culture of mammalian cells

An adaptive fuzzy controller was developed to control the glucose and glutamine concentrations in the reactor constant at the desired level. The parameter values of the controller change during the cultivation according to the culture phase which was detected by the lactate concentration. Cultivations with different glucose and glutamine set point concentrations of a recombinant BHK anchorage-dependent cell line were performed in a fed-batch reactor on-line connected with an HPLC system. Glucose and glutamine concentrations were satisfactorily controlled at each set point during all cultivation periods. Ammonia had a determining effect on productivity since it inhibited cell growth and protein specific production. Ammonia production increased with an increase of glutamine or a decrease of glucose set point concentrations, indicating the importance of glucose to glutamine ratio for the optimization of productivity in mammalian cell cultures. This revised version was published online in June 2006 with corrections to the Cover Date.     

An audio frequency magnetic tape programmer for cryopreservation equipment

The application of a magnetic cassette recorder and a simple solid state circuit as a programmer for cryopreservation equipment is described.Advantages of this system include: (1) ease and flexibility in programming complex time/temperature relationships; (2) incorporation of many experimental variations into single programs.     

基于酶电极系统的葡萄糖浓度在线控制

补料分批技术在发酵工业中被广泛应用,其物料流加方式有3类,其中恒流速和指数补料属无反馈控制操作,靠经验或预设的数学模型决定补料速度,但由于发酵过程的复杂性,实际过程往往偏离预设的模型;恒底物浓度流加属反馈控制,通过对特定参数的检测,根据参数的变化情况反馈控制物料的流加,可控制菌生长在最佳条件下,从而获得高浓度的目的产物。反馈控制分直接控制和间接控制。间接     

Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies

Brain cells are metabolically flexible because they can derive energy from both glucose and ketone bodies (acetoacetate and beta-hydroxybutyrate). Metabolic control theory applies principles of bioenergetics and genome flexibility to the management of complex phenotypic traits. Epilepsy is a complex brain disorder involving excessive, synchronous, abnormal electrical firing patterns of neurons. We propose that many epilepsies with varied etiologies may ultimately involve disruptions of brain energy homeostasis and are potentially manageable through principles of metabolic control theory. This control involves moderate shifts in the availability of brain energy metabolites (glucose and ketone bodies) that alter energy metabolism through glycolysis and the tricarboxylic acid cycle, respectively. These shifts produce adjustments in gene-linked metabolic networks that manage or control the seizure disorder despite the continued presence of the inherited or acquired factors responsible for the epilepsy. This hypothesis is supported by information on the management of seizures with diets including fasting, the ketogenic diet and caloric restriction. A better understanding of the compensatory genetic and neurochemical networks of brain energy metabolism may produce novel antiepileptic therapies that are more effective and biologically friendly than those currently available.     

Implementation of an Electronic Dashboard with A Remote Management System to Improve Glycemic Management Among Hospitalized Adults

Objective: Better glycemic control for hospitalized diabetic patients significantly reduces health expenditures and improves disease outcomes. We developed a dynamic dashboard with a remote management system and evaluated its impact on inpatient glycemic control.Methods: This was an observational institution-wide study; study participants were enrolled from a 1,500-bed public medical center from 2016 to 2018. We evaluated the impact of a dynamic dashboard system, which analyzed and monitored all glucose data with virtual glycemic management recommendation by a team of endocrinologists, over 3 × 1-year periods: 2016 (pre-implementation), 2017 (development), and 2018 (implementation).Results: A total of 51,641 discharges with 878,159 blood glucose measurements were obtained during the 3-year period. After implementation of the dashboard system, the proportion of patients with poor glycemic control (hyperglycemia or hypoglycemia) was reduced by 31% (from 10.2 to 7.0 per day per 100 patients with glucose monitoring; P<.001); hyperglycemia decreased by 25% (from 6.1 to 4.6 per day per 100 patients with glucose monitoring; P<.001), and hypoglycemia decreased by 45% (from 4.2 to 2.3 per day per 100 patients with glucose monitoring; P<.001). Furthermore, the trend in the proportion of patients within the treat-to-target range showed significant improvement (P<.001) during the development period, with effectiveness maintained throughout the implementation period.Conclusion: We successfully installed a dynamic, electronic medical records-based dashboard monitoring system to improve inpatient glycemic control. The system, supported by a team of endocrinologists via remote recommendations, could efficiently fill an important need for improved glycemic management among hospitalized adults.Abbreviations: CDE = certified diabetes educator; DM = diabetes mellitus; EMR = electronic medical record; POC = point-of-care; TCVGH = Taichung Veterans General Hospital; UCSF = University of California, San Francisco; U.S. = United States; vGMS = virtual glucose management service     

Implementation of a field programmable gate array based transcranial Doppler ultrasound system using pulse compression techniques

A field programmable gate array (FPGA) based hardware platform that is used to implement a digital, multi-gate pulsed Doppler ultrasound system for transcranial Doppler (TCD) use is described. The Doppler audio signal is extracted from the digitised radio-frequency signal by matched filtering and suitable sampling. The system was configured to acquire Doppler signals from 16 depth locations and to display Doppler signal power versus depth as well as a sonogram from a user specified depth. The signal-to-noise performance of the system was comparable with that of a commercially available TCD unit for equivalent pulse repetition frequency and sample volume settings.The flexibility of the platform was used to demonstrate the feasibility of using coded transducer excitation and pulse compression techniques to improve axial resolution compared to a non-coded implementation. The axial resolution improvement was demonstrated using a flow phantom and measured using a vibrating wire phantom. The measured resolutions were 9.1 and 2.4 mm for the conventional and coded implementations, respectively. The reduction in signal-to-noise ratio of approximately 5 dB associated with the configuration using coded excitation was attributable to the frequency response characteristics of the transducer rather than the processing technique used. This work demonstrates both the flexibility associated with an FPGA implementation of a Doppler ultrasound system and the potential for coded excitation to improve axial resolution in TCD systems.     

A novel galactosyl-binding lectin from the plasma of the blood clam,Anadara granosa (L) and a study of its combining site

Control Analysis has been carried out in the first steps of a rat liver glycolytic system. Attention has been focused on the effect of several glucose concentrations on the control, particularly regarding the role of glucokinase. From kinetic studies of the whole metabolic system we have obtained information on the flux variation under different glucose concentrations. This information together with the kinetics of glucokinase has allowed us to calculate Flux Control and Elasticity Coefficients for glucokinase and the Response Coefficient of the system with respect to glucose. The changes in of the value of Flux Control Coefficients demonstrates that in conditions of low glucose concentration, glucokinase is the main enzyme in controlling the flux through the pathway, but at high glucose concentration the control moves to phosphofructokinase. Next, we have compared our results with those obtained with the shortening and titration method, previously described (Torres, N.V., Mateo, F., Mélendez-Hevia, E. and Kacser, H., (1986) Biochem. J. 234, 169–174; Torres, N.V. and Meléndez-Hevia, E. 1991. Molec. Cell. Biochem. 101, 1–10). Furthermore, from knowledge of the enzyme kinetics of the system we have been able to build a model of the pathway that allows us computer similation of its behavior and calculation of the Flux Control Coefficient profile at different glucose concentrations. By the three methods the results correlate, supporting the use of the pathway substrate as external modulator of the metabolic system as a tool for practical application of Control Analysis.     

Blood glucose control algorithms for type 1 diabetic patients: A methodological review

A method for optimal continuous insulin therapy for diabetes patients has been sought since the early 1970s. Although technical and medical advances have been made, a fully automated artificial pancreas to replace the functions of the natural organ is still a research aim. This review compares recent control algorithms for type 1 diabetic patients which automatically connect continuous glucose monitoring and insulin injection, without patient intervention. Black-box model and gray-box model based control strategies are described and their performances are evaluated, with a focus on their feasibility of implementation in a real-life situation. In conclusion, a satisfactory control strategy has not yet been proposed, mainly because most control algorithms rely on continuous blood glucose measurement which is not yet available. Modeling the effect of glucose ingestion as an external disturbance on the time evolution of blood glucose concentration, is now the norm for the control community. In contrast, the effects of physical activity on the metabolic system is not yet fully understood and remain an open issue. Moreover, clinical studies on evaluation of control performance are scarce. Therefore, research on blood glucose control needs to concentrate on advanced patient modeling, control optimization and control performance evaluation under realistic patient-oriented conditions.     

Development of a direct digital-controlled fermentor using a microminicomputer hierarchical system

A computerized fermentation system was developed for use in a research environment. Major goals in the design and construction of the system were flexibility and versatility. Direct digital control is employed for all low-level and high-level control loops. A microminicomputer hierarchical configuration is used to implement this control structure. The microcomputer is also utilized to simplify the interface with the fermentor, both at the hardware and minicomputer software levels. This computerized fermentation system provides accurate data acquisition, excellent control, and flexibility in the fermentation operation.     

Distributed Electronic Commerce cluster for small enterprise

The Electronic Commerce System should provide prompt responses for user requests and continuous services despite partial failures of its sub systems. In addition, scalability and flexibility should be supported as the number of customers increases. Because Electronic Commerce is beyond the national border, the system should be implemented across different subnets for its efficiency and business needs. This paper proposes the design and implementation of a distributed system infrastructure across different subnets for Electronic Commerce. When the Electronic Commerce system is owned and managed by a small enterprise, the cost should be considered as well as fault tolerance, high availability and scalability. The proposed infrastructure was evaluated and discussed in the aspect of economics such as implementation and management cost, performance and overhead.     

Closed-loop control of fed-batch cultures of recombinant Escherichia coli using on-line HPLC

This article describes a fully automated system for the on-line monitoring and closed-loop control of a fed-batch fermentation of recombinant Escherichia coli, and presents two case studies of its used in limiting production of unwanted byproducts such as acetic in fed-batch fermentations. The system had two components. The first components, on-line monitoring, comprised an aseptic sampling device, a microcentrifuge, and HPLC System. These instruments removed a Sample from a fermentor, spun it at high speed to separate solid and liquid components, and then automatically injected the supernatant onto an HPLC column for analysis. The second component consisted of control algorithms programmed using the LabView visual programming environment in a control computer that was linked via a remote components were linked so that results from the on-line HPLC were captured and used by the control algorithm was designed to demonstrate coarse feedback control to confirm the operability of the controller. The second case study showed how the system could be used in a more sophisticated feedings strategy providing fine control and limiting acetate concentration to a low level throughout the fermentation. (c) 1994 John Wiley & Sons, Inc.