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Pandemic influenza has been an important public health concern with several historical outbreaks in 1918, 1957, and 1968. During an influenza pandemic outbreak, hospitals are often overwhelmed by the surge demand of influenza patients. It is important to prepare response plans to react to a pandemic influenza outbreak. Because of the widespread effect of the disease and the increased demand on limited medical resources, collaboration among hospitals both in planning and in response is necessary. This paper focuses on patient and resource allocation among hospitals in a healthcare network. Mathematical models are built to optimize the patient allocation considering two objectives related to patients' cost of access to healthcare services: (1) minimization of the total travel distance by patients to hospitals; and (2) minimizing the maximum distance a patient travels to a hospital. Moreover, the models help to predict a resource shortage during an outbreak; this prediction will alert decision makers to consider increasing the medical capacity or requesting additional capacity from state or national agencies. In addition, the model aids in the determination of the optimal allocation of the additional resources, when available, among hospitals by considering the above two objectives related to patients' cost of access to services. A case study from Metro Louisville, Kentucky, is presented to demonstrate how the models would aid in patient allocation during a pandemic influenza outbreak.

The Kentucky Cabinet for Health and Family Services' main office in Louisville, Kentucky deals with hundreds of clients with various needs each day. The office provides food stamps, child care assistance, and financial support among other services. A simulation model of the intake process was developed and analyzed in order to investigate various alternatives concerning process flow, staffing, and layout. The simulation model shows long wait times for clients coming into the system to receive benefits. Working with a state budget during variable economic times leaves no room for hiring new workers, so changes must come from within. The flexibility of the simulation model allows for experiments on the system to be created and observed. This paper describes the simulation model, the analysis of alternatives with the model, and the changes implemented in the system as a result of the analysis.

Proper planning and execution of mass vaccination at the onset of a pandemic outbreak is important for local health departments. Mass vaccination clinics are required to be setup and run for naturally occurring pandemic outbreaks or even in response to terrorist attacks, e.g., anthrax attack. Walk-in clinics have often been used to administer vaccines. When a large percentage of a population must be vaccinated to mitigate the ill-effects of an attack or pandemic, drive-through clinics appear to be more effective because a much higher throughput can be achieved when compared to walk-in clinics. There are other benefits as well. For example, the spread of the disease can be minimized because infected patients are not exposed to uninfected patients. This research extends the simulation modeling work that was done for a mass vaccination drive-through clinic in the city of Louisville in November 2009. This clinic is one of the largest clinics ever set up with more than 19,000 patients served, over two-thirds via ten drive-through lanes. The intent of the model in this paper is to illustrate a general tool that can be customized for a community of any size. The simulation–optimization tool will allow decision makers to investigate several interacting control variables in a simultaneous fashion; any of several criterion models in which various performance measures are either optimized or constrained, can be investigated. The model helps the decision maker determine the required number of Points of Dispense (POD) lanes, number and length of the lanes for consent hand outs and fill in, staff needed at the consent handout stations and PODs, and average user waiting time in the system.

Reverse logistics, induced by various forms of return, has received growing attention throughout this decade. Reverse logistics network design is a major strategic issue. This paper addresses the analysis of reverse logistic networks that deal with the returns requiring repair service. A problem involving a manufacturer outsourcing to a third-party logistics (3PLs) provider for its post-sale services is proposed. First, a bi-objective optimization model is developed. Two objectives, minimization of the overall costs and minimization of the total tardiness of cycle time, are addressed. The facility capacity option at each potential location is treated as a discrete parameter. The purpose is to find a set of non-dominated solutions to the facility capacity arrangement among the potential facility locations, as well as the associated transportation flows between customer areas and service facilities. Then, a solution approach is designed for solving this bi-objective optimization model. The solution approach consists of a combination of three algorithms: scatter search, the dual simplex method and the constraint method. Finally, computational analyses are performed on trial examples. Numerical results present the trade-off relationship between the two objectives. The numerical results also show that the optimization for the first objective function leads to a centralized network structure; the optimization for the second objective function results in a decentralized network structure.

In light of growing concerns of bacterial resistance to fluoroquinolones, the province of Ontario instituted a fluoroquinolone restriction policy in March of 2001. The objective of this study was to examine the immediate impact of this policy on the rates of antibiotic prescription use and infectious disease-related hospitalizations among elderly individuals who are dispensed antibiotics.An interrupted time series analysis was conducted from January 1, 1994, to March 31, 2002, using administrative health care databases covering more than 1.4 million residents of Ontario, Canada, aged 65 years and older. Population rates of antibiotic use and infectious disease-related hospitalizations within 4 weeks after an antibiotic prescription were examined using interventional autoregressive integrated moving average models.Immediately after the introduction of the fluoroquinolone policy, fluoroquinolone prescription rates decreased to approximately 70% of expected rates (P.01). Approximately 30% higher than expected use of sulfonamide (P=.01) and urinary anti-infectives (primarily nitrofurantoin and trimethoprim; P.01) were observed within 1 year after policy implementation. No significant changes in the use of any other groups of antibiotics were observed. Although no significant changes in the rates of overall infection-related hospital admissions among antibiotic users were observed, the rate of hospital admission for gastrointestinal infections was 32% lower than expected in the 1 year after the policy change (P.01). The hospital admission rate for urinary tract infections was approximately 8% higher than expected (P.01).These findings suggest that formulary restrictions to fluoroquinolones can be implemented effectively to decrease use among an elderly population without adverse impact on hospital admission rates.

Problem structuring heuristics and creative thinking techniques have been advanced as useful approaches for solving ill-structured problems. Unfortunately, little controlled experimentation has been done to test the effectiveness of these techniques. This paper describes an experiment in which the effects of training in the use of a problem-structuring heuristic and creative thinking on the quality and quantity of problem statements are investigated. The experiment illustrates that such training does have a positive impact on problem formulation quality and quantity.

Today's competitive business environment has resulted in increasing cooperation among individual companies as members of a supply chain. Accordingly, third party logistics providers (3PLs) must operate supply chains for a number of different clients who want to improve their logistics operations for both forward and reverse flows. As a result of the dynamic environment in which these supply chains must operate, 3PLs must make a sequence of inter-related decisions over time. However, in the past, the design of distribution networks has been independently conducted with respect to forward and reverse flows. Thus, this paper presents a mixed integer nonlinear programming model for the design of a dynamic integrated distribution network to account for the integrated aspect of optimizing the forward and return network simultaneously. Since such network design problems belong to a class of NP hard problems, a genetic algorithm-based heuristic with associated numerical results is presented and tested in a set of problems by an exact algorithm. Finally, a solution of a network plan would help in the determination of various resource plans for capacities of material handling equipments and human resources.

An integrated formulation and solution approach to Quality Function Deployment (QFD) is presented. Various models are developed by defining the major model components (namely, system parameters, objectives, and constraints) in a crisp or fuzzy way using multiattribute value theory combined with fuzzy regression and fuzzy optimization theory. The proposed approach would allow a design team to reconcile tradeoffs among the various performance characteristics representing customer satisfaction as well as the inherent fuzziness in the system. In addition, the modeling approach presented makes it possible to assess separately the effects of possibility and flexibility inherent or permitted in the design process on the overall design. Knowledge of the impact of the possibility and flexibility on customer satisfaction can also serve as a guideline for acquiring additional information to reduce fuzziness in the system parameters as well as determine how much flexibility is warranted or possible to improve a design. The proposed modeling approach would be applicable to a wide spectrum of design problems where multiple design criteria and functional design relationships are interacting and/or conflicting in an uncertain, qualitative, and fuzzy way.

The number and configuration of franchise outlets in a market defines the distribution strategy of a franchise company. The introduction of new franchise outlets contributes to conflict between the franchisee and franchisor over the degree of market penetration. The selection of sites for new franchises is an important factor in the long-term profitability of many types of franchises. This selection process requires consideration of objectives of the franchisee and franchisor which are often conflicting in nature. This paper deals with the problem of locating new franchises in an existing franchise network using multiple objective integer programming models and methods.

Here we report the expression of a fork head domain protein in human T helper cells. We cloned and characterized a fork head cDNA from human T helper cell mRNA using differential display RT-PCR. The cDNA contains a 546-nucleotide (nt) open reading frame (ORF) that codes for the carboxyl-terminal 180 amino acids (aa) of the recently identified fkhrl1 gene. This ORF does not contain the characteristic DNA-binding domain found in members of the forkhead protein family. In-vitro transcription/translation of this cDNA expressed a protein of approximately 20 kDa. We have generated antibodies that specifically immunoprecipitated the in-vitro-translated 20-kDa protein. This antibody also recognizes in human T lymphocytes a 70-kDa protein corresponding in size to that predicted for the fkhrl1 gene product. The mRNA levels for fkhrl1 is elevated in T helper-induced lymphocytes in comparison to PHA-stimulated T lymphocytes. Further characterization of FKHRL1 and its related family members should shed light on the transcriptional mechanisms of this fork head gene subfamily and their role in T helper cell differentiation and regulation of cell growth.

The interleukin (IL)-2 receptor system has previously been shown to signal through the association and tyrosine phosphorylation of Shc. This study demonstrates that the IL-2 receptor beta (IL-2R beta) chain is the critical receptor component required to mediate this effect. The use of IL-2R beta chain deletion mutants transfected into a Ba/F3 murine cell model describes a requirement for the IL-2R beta "acid-rich" domain between amino acids 315 and 384 for Shc tyrosine phosphorylation and receptor association. COS cell co-transfection studies of IL-2R beta chain constructs containing point mutations of tyrosine to phenylalanine along with the tyrosine kinase Jak-1 and a hemagglutinin-tagged Shc revealed that the motif surrounding phosphorylated tyrosine 338 within the acid-rich domain of the IL-2R beta is a binding site for Shc. Deletion of this domain has previously been shown to abrogate the ability of IL-2 to activate Ras but does not affect IL-2-dependent mitogenesis in the presence of serum. Proliferation assays of Ba/F3 cells containing IL-2R beta chain deletion mutants in serum-free medium with or without insulin shows that deletion of the acid-rich domain does not affect IL-2-driven mitogenesis regardless of the culture conditions. This study thus defines the critical domain within the IL-2R beta chain required to mediate Shc binding and Shc tyrosine phosphorylation and further shows that Shc binding and phosphorylation are not required for IL-2-dependent mitogenesis. Neither serum nor insulin is required to supplement the loss of induction of the Shc adapter or Ras pathways, which therefore suggests a novel mechanism for mitogenic signal transduction mediated by this hematopoietin receptor.

A four phase model is presented in which problem generation and problem formulation precede problem solving and solution implementation. A relatively new heuristic for formulating ill-structured problems is described. The methodology is a systematic thinking process which combines analytical precision with structured imagination, and is called the ‘why-what's stopping’ analysis. Current techniques for defining problems are positioned as inadequate because they do not always fit the problems faced in day to day work and because they ignore human behavioral deficiencies. Deferral of judgment, active divergence and active convergence are identified as three behavioral skills which underly the successful application of the ‘why-what's stopping’ analysis. Several examples of the application of this process in real world situations are provided. Directions for future research are discussed.

In this paper we have extended previous results on interleukin-2 receptor (IL2-R) signal transduction and focused on the interleukin-2 (IL-2)-stimulated tyrosine phosphorylation of a 116-kDa protein (p116) observed in IL-2 responsive cells. This protein exhibited rapid and transient phosphorylation kinetics in both human T-lymphocytes and the YT cell line, attaining maximum tyrosine phosphorylation within 5 min of stimulation with IL-2. Tyrosine phosphorylated p116 co-purified with activated IL-2 receptor beta-chain (IL2-R beta) when IL2-R complexes were covalently stabilized with the membrane-permeable cleavable cross-linking agent dithiobis(succimidyl propionate) prior to detergent cell lysis and immunoprecipitation with monoclonal anti-IL2-R beta antibodies. Under these conditions comparable amounts of tyrosine-phosphorylated p116 were immunoprecipitated with either anti-IL2-R beta antibodies or anti-phosphotyrosine antibodies, suggesting that a major portion of tyrosine phosphorylated p116 is associated with the IL2-R beta subunit. Furthermore, unphosphorylated p116 was also associated with unactivated IL2-R beta, based on the observation that p116 from unstimulated YT cells underwent tyrosine phosphorylation in IL2-R beta immune-complex tyrosine kinase assay as demonstrated by anti-phosphotyrosine immunoblotting. The presence of tyrosine kinase activity in affinity-purified IL2-R beta complexes supports the notion of a preformed receptor-kinase complex. The co-association of both p116 and tyrosine kinase activity with the IL2-R beta supports the critical role of the beta-chain in IL2-R signal transduction and suggests that p116 may have a role in the dynamics of IL2-R activation.

Distribution management is concerned with the location of facilities, routing, and scheduling of vehicles and crews between the facilities to meet given objectives. Decision problems arising in distribution management are spatial in nature. This paper presents a method for the development of decision support systems based on geographic information systems for solving facility location and logistics problems.

We have examined the signal transduction pathways of a number of cytokines that interact with receptors that are members of the hematopoietin receptor superfamily. A 97-kDa protein was phosphorylated on tyrosine in response to stimulation of appropriate target cells with interleukin (IL)-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, or erythropoietin. These data suggest that a 97-kDa phosphotyrosylprotein represents a point of convergence for signal transduction by a number of growth factor receptors that do not have homology with any known protein tyrosine kinase. To address the possibility that p97 may represent a tyrosine kinase involved in multiple signal transduction pathways, we tested the capacity of this protein to bind a tyrosine kinase substrate or ATP. Indeed, a 97-kDa phosphotyrosylprotein purified from IL-2-stimulated lymphoid cells as well as granulocyte-macrophage-CSF-stimulated myeloid cells bound to a polymer of glutamic acid and tyrosine which is a tyrosine kinase substrate. Further, a 97-kDa phosphotyrosylprotein present in both lineages also bound 8-azido-ATP. These data indicate that a 97-kDa phosphotyrosylprotein with properties consistent with those of a protein tyrosine kinase is involved in the signal transduction pathways of certain members of the newly identified hematopoietin receptor superfamily and may represent an early point of convergence in the stimulus-response coupling of multiple cytokine receptors.

The intracellular events which are involved in controlling the G1 to S phase transition during the eucaryotic cell cycle are important to define in order to understand the mechanisms by which mitogenic and growth arrest-inducing agents control cell growth. Because a change in protein kinase activity is associated with the initial response of cells to mitogenic stimulants and growth factors, we used a kinase renaturation assay to identify specific protein kinases which are modulated as human T cells make the G1 to S phase transition after mitogenic stimulation with lectin. We identified four protein serine/threonine kinases of 180, 97, 85, and 38 kilodaltons which are increased in activity as these cells enter S phase. A-55 kDa serine/threonine kinase (PK55) was shown to have maximal activity during G0 and its activity was reduced by 95% upon movement into S phase. PK55 is inducible in human T cells by removal of interleukin 2 and low serum incubation which arrests cells in G1 phase, indicating that it is closely associated with G1 phase growth arrest. Furthermore, a similar PK55 activity was induced upon growth arrest in HL-60 cells treated with dimethyl sulfoxide and in Daudi cells treated with interferon alpha. Because the cAMP-dependent protein kinase (PK-A) family has been shown to be antiproliferative to lectin stimulated T cells, we were interested in determining whether PK55 was in fact an isozyme of PK-A. Comparative analysis using a specific peptide inhibitor of PK-A activity revealed that PK55 is catalytically distinct from PK-A. This data suggest that increases in PK55 may be associated with the growth-arrested state and further that PK55 is distinct from PK-A.

In this paper, we develop a bicriterion approach to the design of process control charts through the use of a multi-attribute utility function. This approach accounts for both the multi-objective aspect (involving minimization of expected administrative cost and maximization of outgoing quality) and the uncertainty/risk aspect (involving uncertainty in the process output) of the problem. As such, the approach allows for several advantages over current design methodologies, including the elimination of a dichotomous view of quality. To illustrate the new methodology, we present a specific model for the joint design of an X chart and an R chart. Results are given for a hypothetical situation involving various utility functions. The results concerning the optimal design for the control charts are robust with respect to the forms (e.g., linear, concave, or convex) of the individual attribute utility functions over the cost and quality attributes. However, the respective weights attached to these individual attribute utility functions within the overall utility function have a significant impact on the optimal design.

Interleukin 2 (IL-2) has been shown to stimulate tyrosine phosphorylation of a number of proteins requiring only the p75 β chain of the IL-2 receptor. Unlike the receptors for epidermal growth factor, insulin, and other growth factors, the p55-α and p75-β chains of the IL-2 receptor have no tyrosine protein kinase domain suggesting that the IL-2 receptor complex activates protein kinases by a unique mechanism. The activation of tyrosine kinases by IL-2 in situ was studied and using a novel methodology has shown tyrosine kinase activity associated with the purified IL-2R complex in vitro. IL-2 stimulated the in situ tyrosine phosphorylation of 97 kDa and 58 kDa proteins which bound to poly(Glu,Tyr)4:1, a substrate for tyrosine protein kinases, suggesting these proteins had characteristics found in almost all tyrosine kinases. IL-2 was found to stimulate tyrosine protein kinase activity in receptor extracts partially purified from human T lymphocytes and the YT cell line. Biotinylated IL-2 was used to precipitate the high-affinity-receptor complex and phosphoproteins associated with it. The data indicated that the 97-kDa and 58-kDa phosphotyrosyl proteins were tightly associated with the IL-2 receptor complex. These proteins were phosphorylated on tyrosine residues by IL-2 stimulation of intact cells and ligand treatment of in vitro receptor extracts. Furthermore, the 97-kDa and 58-kDa proteins were found in streptavidin-agarose/biotinylated IL-2 purified receptor preparations and showed high affinity for tyrosine kinase substrate support matrixes. The experiments suggest that these two proteins are potential candidates for tyrosine kinases involved in the IL-2R complex signal transduction process.

An increasing number of organizations are implementing Flexible Manufacturing Systems (FMSs) to achieve competitive advantage. The implementation process can be viewed in a hierarchical perspective: ranging from design problems at the top level to scheduling and control problems at the lower level. In recent years, researchers have focused a significant amount of attention on FMS scheduling problems. However, the major share of those studies considered FMS scheduling in the context of a single performance criterion. Though several researchers have synthesized the literature involving single criteria, the literature with multi-criterion approaches has not been consolidated and reviewed. Therefore, the purpose of this paper is to explore the applicability of multi-criterion approaches to the production scheduling problems of an FMS and review the pertinent literature on FMS scheduling involving multiple objectives. Some areas for future research are also identified.

Layout design is a complex problem involving multiple, conflicting objectives as well as inputs that can be either qualitative or quantitative in nature. This paper describes and illustrates an approach to the layout design problem which considers both of these difficulties. The approach involves the use of several layout design algorithms as well as manual methods to generate candidate layouts. These candidate layouts are then used as input to Saaty's Analytic Hierarchy Process in order to allow the consideration of the problem's multiple objectives. The approach is illustrated on a problem involving the layout of a commercial printing and binding facility.

In this paper, we discuss the importance of models in manufacturing system design, and the difficulties associated with the optimization of these models. An example problem, involving the global optimization of a simulation model of a discrete-parts manufacturing system, is presented.

A case of fulminant myocarditis in a young man is described. Bedside hand-held focused cardiac ultrasound demonstrated severe systolic dysfunction with hypertrophied myocardium. Echocardiogram showed a speckled texture of the myocardium and a "velvet-like" appearance. Unfortunately, the patient developed cardiogenic shock and despite aggressive management, he died. The autopsy showed multifocal lymphohistiocytic infiltration and myocyte injury. We propose that the "velvet" myocardial ultrasonic appearance with ventricular hypertrophy is an indicator of rapid clinical demise.

This paper describes a new procedure for optimizing multi-response simulation models. This method is based on the gradient projection technique and the use of a value function.

In this paper, equations which relate the estimated duration of a resource-constrained project to functions of various, easily computed, network characteristics are developed and tested. Results are given for a total of 7978 single and multi-resource problems. These results indicate that in many cases a simple, easy-to-use equation could be employed in place of a sophisticated scheduling heuristic for estimating project duration.

The effects of liquid protein diet (LPD) on the collagen metabolism of developing skin tissue was examined in young rats fed a 20% liquid protein diet starting at day 23 after birth. Other rats were pair-fed, but with a 20% casein diet, and another group of rats were fed a 20% casein diet ad libitum. The LPD rats rapidly lost their hair, and they were smaller and weighed less than the pair-fed and ad libitum rats. None of the LPD-fed rats survived beyond day 53 of the study. Collagen contents of the skin continuously increased in all age groups, while hexosamine content decreased from day 23 to 35. From day 23 to 35, noncollagenous protein content in the ad libitum group decreased about 40% and in the LPD and pair-fed groups, about 50%; from day 35 to 48, the decrease was about 35% in the ad libitum group and only about 14% in both the LPD and pair-fed groups. The ratio of Type III to I collagen in the LPD group at days 35 and 48 was greater than that of the ad libitum group. Current observations suggest that LPD alters biochemical composition of the skin on young, growing rats.

A survey of senior managers from 18 firms comprising 20 different operational divisions was conducted to determine the perceived difference between hardware and software companies. The survey questions addressed the structural, managerial, financial, product, and personnel distinctions between hardware oriented and software oriented companies. The results indicated that there are sizable factor and cultural differences between computer hardware and software firms. Software firms are smaller, more intellectually diverse, and more vulnerable than hardware firms. Hardware companies have considerable economic inertia and continuing revenue streams. These differences require unique management approaches and styles.

A group of subjects with arteriosclerotic heart disease who had previously been in congestive heart failure were studied at rest and exercise before and after vasodilation with phentolamine, a direct arteriole dilator. Studies showed a significant rise in exercise cardiac output after vasodilation with an associated fall in peripheral resistance. Evidence that this was not the result of altered venous return is presented. Subjects without evidence of heart disease showed a similar response. These findings indicate that the heart itself is not the sole factor in determining the cardiac output response to exercise and that peripheral resistance plays a significant role.

The basic circulatory response to pulmonary embolism is obstruction to blood flow through the lung. No circulatory changes occur until the cross-sectional area of the pulmonary vasculature is reduced by over 50 per cent. The roles of mechanical obstruction, vasoconstriction and humoral agents in this disorder are reviewed. In response to increased precapillary resistance to blood flow occasioned by embolism, pulmonary arterial and right ventricular systolic pressures rise; if this is severe enough, the right ventricle dilates, its enddiastolic pressure rises, and its coronary flow increases. In contrast to man, in whom embolism is commonly associated with manifestations of left ventricular failure, in the experimental animal the left ventricle is spared. Its output and systolic pressure fall, its work load is reduced, its end-diastolic pressure remains normal until terminally, and its coronary flow is unaltered or increases until terminally, when, with overall disruption of the cardiovascular system, it falls. It has been postulated by some that the fall of systemic arterial pressure cannot be entirely explained by the fall of cardiac output and that it represents in part a reflex hypotension. Heart rate and rhythm remain stable, except with massive embolism or in association with hypotension or apnea, when bradycardia and arrhythmias may occur.