Strategy in developing cell based therapy for large bone

Regeneration of osseous defects by tissue-engineering approach provides a novel means of treatment utilizing cell biology, materials science, and molecular biology. The concept of in vitro cultured osteoblasts having an ability to induce new bone formation has been demonstrated in the critical size defects using small animal models. The bone derived cells can be incorporated into bioengineered scaffolds and synthesize bone matrix, which on implantation can induce new bone formation. In search of optimal cell delivery materials, the extracellular matrix as cell carriers for the repair and regeneration of tissues is receiving increased attention. We have investigated extracellular matrix formed by osteoblasts in vitro as a scaffold for osteoblasts transplantation and found a mineralized matrix, formed by human osteoblasts in vitro, can initiate bone formation by activating endogenous mesenchymal cells. To repair the large bone defects, osteogenic or stem cells need to be prefabricated in a large three dimensional scaffold usually made of synthetic biomaterials, which have inadequate interaction with cells and lead to in vivo foreign body reactions. The interstitial extracellular matrix has been applied to modify biomaterials surface and identified vitronectin, which binds the heparin domain and RGD (Arg-Gly-Asp) sequence can modulate cell spreading, migration and matrix formation on biomaterials. We also synthesized a tri-block copolymer, methoxy-terminated poly(ethylene glycol)(MPEG)-polyL-lactide(PLLA)-polylysine(PLL) for human osteoblasts delivery. We identified osteogenic activity can be regulated by the molecular weight and composition of the triblock copolymers. Due to the sequential loss of lineage differentiation potential during the culture of bone marrow stromal cells that hinderers their potential clinical application, we have developed a clonal culture system and established several stem cell clones with fast growing and multi-differentiation properties. Using proteomics and subtractive immunization, several differential proteins have been identified and verified their potential application in stem cell characterization and tissue regeneration

A grouping model for distributed pipeline assets maintenance decision

Distributed pipeline assets systems are crucial to society. The deterioration of these assets and the optimal allocation of limited budget for their maintenance correspond to crucial challenges for water utility managers. Decision makers should be assisted with optimal solutions to select the best maintenance plan concerning available resources and management strategies. Much research effort has been dedicated to the development of optimal strategies for maintenance of water pipes. Most of the maintenance strategies are intended for scheduling individual water pipe. Consideration of optimal group scheduling replacement jobs for groups of pipes or other linear assets has so far not received much attention in literature. It is a common practice that replacement planners select two or three pipes manually with ambiguous criteria to group into one replacement job. This is obviously not the best solution for job grouping and may not be cost effective, especially when total cost can be up to multiple million dollars. In this paper, an optimal group scheduling scheme with three decision criteria for distributed pipeline assets maintenance decision is proposed. A Maintenance Grouping Optimization (MGO) model with multiple criteria is developed. An immediate challenge of such modeling is to deal with scalability of vast combinatorial solution space. To address this issue, a modified genetic algorithm is developed together with a Judgment Matrix. This Judgment Matrix is corresponding to various combinations of pipe replacement schedules. An industrial case study based on a section of a real water distribution network was conducted to test the new model. The results of the case study show that new schedule generated a significant cost reduction compared with the schedule without grouping pipes.

Evaluation of financial incentives as a quality improvement strategy in the public hospital context : clinician attitudes, design variables, and economic costs

In 2008, a three-year pilot ‘pay for performance’ (P4P) program, known as ‘Clinical Practice Improvement Payment’ (CPIP) was introduced into Queensland Health (QHealth). QHealth is a large public health sector provider of acute, community, and public health services in Queensland, Australia. The organisation has recently embarked on a significant reform agenda including a review of existing funding arrangements (Duckett et al., 2008). Partly in response to this reform agenda, a casemix funding model has been implemented to reconnect health care funding with outcomes. CPIP was conceptualised as a performance-based scheme that rewarded quality with financial incentives. This is the first time such a scheme has been implemented into the public health sector in Australia with a focus on rewarding quality, and it is unique in that it has a large state-wide focus and includes 15 Districts. CPIP initially targeted five acute and community clinical areas including Mental Health, Discharge Medication, Emergency Department, Chronic Obstructive Pulmonary Disease, and Stroke. The CPIP scheme was designed around key concepts including the identification of clinical indicators that met the set criteria of: high disease burden, a well defined single diagnostic group or intervention, significant variations in clinical outcomes and/or practices, a good evidence, and clinician control and support (Ward, Daniels, Walker & Duckett, 2007). This evaluative research targeted Phase One of implementation of the CPIP scheme from January 2008 to March 2009. A formative evaluation utilising a mixed methodology and complementarity analysis was undertaken. The research involved three research questions and aimed to determine the knowledge, understanding, and attitudes of clinicians; identify improvements to the design, administration, and monitoring of CPIP; and determine the financial and economic costs of the scheme. Three key studies were undertaken to ascertain responses to the key research questions. Firstly, a survey of clinicians was undertaken to examine levels of knowledge and understanding and their attitudes to the scheme. Secondly, the study sought to apply Statistical Process Control (SPC) to the process indicators to assess if this enhanced the scheme and a third study examined a simple economic cost analysis. The CPIP Survey of clinicians elicited 192 clinician respondents. Over 70% of these respondents were supportive of the continuation of the CPIP scheme. This finding was also supported by the results of a quantitative altitude survey that identified positive attitudes in 6 of the 7 domains-including impact, awareness and understanding and clinical relevance, all being scored positive across the combined respondent group. SPC as a trending tool may play an important role in the early identification of indicator weakness for the CPIP scheme. This evaluative research study supports a previously identified need in the literature for a phased introduction of Pay for Performance (P4P) type programs. It further highlights the value of undertaking a formal risk assessment of clinician, management, and systemic levels of literacy and competency with measurement and monitoring of quality prior to a phased implementation. This phasing can then be guided by a P4P Design Variable Matrix which provides a selection of program design options such as indicator target and payment mechanisms. It became evident that a clear process is required to standardise how clinical indicators evolve over time and direct movement towards more rigorous ‘pay for performance’ targets and the development of an optimal funding model. Use of this matrix will enable the scheme to mature and build the literacy and competency of clinicians and the organisation as implementation progresses. Furthermore, the research identified that CPIP created a spotlight on clinical indicators and incentive payments of over five million from a potential ten million was secured across the five clinical areas in the first 15 months of the scheme. This indicates that quality was rewarded in the new QHealth funding model, and despite issues being identified with the payment mechanism, funding was distributed. The economic model used identified a relative low cost of reporting (under $8,000) as opposed to funds secured of over $300,000 for mental health as an example. Movement to a full cost effectiveness study of CPIP is supported. Overall the introduction of the CPIP scheme into QHealth has been a positive and effective strategy for engaging clinicians in quality and has been the catalyst for the identification and monitoring of valuable clinical process indicators. This research has highlighted that clinicians are supportive of the scheme in general; however, there are some significant risks that include the functioning of the CPIP payment mechanism. Given clinician support for the use of a pay–for-performance methodology in QHealth, the CPIP scheme has the potential to be a powerful addition to a multi-faceted suite of quality improvement initiatives within QHealth.

A Stochastic View of Optimal Regret through Minimax Duality

We study the regret of optimal strategies for online convex optimization games. Using von Neumann's minimax theorem, we show that the optimal regret in this adversarial setting is closely related to the behavior of the empirical minimization algorithm in a stochastic process setting: it is equal to the maximum, over joint distributions of the adversary's action sequence, of the difference between a sum of minimal expected losses and the minimal empirical loss. We show that the optimal regret has a natural geometric interpretation, since it can be viewed as the gap in Jensen's inequality for a concave functional--the minimizer over the player's actions of expected loss--defined on a set of probability distributions. We use this expression to obtain upper and lower bounds on the regret of an optimal strategy for a variety of online learning problems. Our method provides upper bounds without the need to construct a learning algorithm; the lower bounds provide explicit optimal strategies for the adversary. Peter L. Bartlett, Alexander Rakhlin

Optimal sitting and sizing of distributed generators considering plug-in electric vehicles

Some uncertainties such as the stochastic input/output power of a plug-in electric vehicle due to its stochastic charging and discharging schedule, that of a wind unit and that of a photovoltaic generation source, volatile fuel prices and future uncertain load growth, all together could lead to some risks in determining the optimal siting and sizing of distributed generators (DGs) in distributed systems. Given this background, under the chance constrained programming (CCP) framework, a new method is presented to handle these uncertainties in the optimal sitting and sizing problem of DGs. First, a mathematical model of CCP is developed with the minimization of DGs investment cost, operational cost and maintenance cost as well as the network loss cost as the objective, security limitations as constraints, the sitting and sizing of DGs as optimization variables. Then, a Monte Carolo simulation embedded genetic algorithm approach is developed to solve the developed CCP model. Finally, the IEEE 37-node test feeder is employed to verify the feasibility and effectiveness of the developed model and method. This work is supported by an Australian Commonwealth Scientific and Industrial Research Organisation (CSIRO) Project on Intelligent Grids Under the Energy Transformed Flagship, and Project from Jiangxi Power Company.

The scalability and the strategy for EMR database encryption techniques

EMR (Electronic Medical Record) is an emerging technology that is highly-blended between non-IT and IT area. One methodology is to link the non-IT and IT area is to construct databases. Nowadays, it supports before and after-treatment for patients and should satisfy all stakeholders such as practitioners, nurses, researchers, administrators and financial departments and so on. In accordance with the database maintenance, DAS (Data as Service) model is one solution for outsourcing. However, there are some scalability and strategy issues when we need to plan to use DAS model properly. We constructed three kinds of databases such as plan-text, MS built-in encryption which is in-house model and custom AES (Advanced Encryption Standard) - DAS model scaling from 5K to 2560K records. To perform custom AES-DAS better, we also devised Bucket Index using Bloom Filter. The simulation showed the response times arithmetically increased in the beginning but after a certain threshold, exponentially increased in the end. In conclusion, if the database model is close to in-house model, then vendor technology is a good way to perform and get query response times in a consistent manner. If the model is DAS model, it is easy to outsource the database, however, some techniques like Bucket Index enhances its utilization. To get faster query response times, designing database such as consideration of the field type is also important. This study suggests cloud computing would be a next DAS model to satisfy the scalability and the security issues.

Optimal image sample size for corneal nerve morphometry

Purpose Arbitrary numbers of corneal confocal microscopy images have been used for analysis of corneal subbasal nerve parameters under the implicit assumption that these are a representative sample of the central corneal nerve plexus. The purpose of this study is to present a technique for quantifying the number of random central corneal images required to achieve an acceptable level of accuracy in the measurement of corneal nerve fiber length and branch density. Methods Every possible combination of 2 to 16 images (where 16 was deemed the true mean) of the central corneal subbasal nerve plexus, not overlapping by more than 20%, were assessed for nerve fiber length and branch density in 20 subjects with type 2 diabetes and varying degrees of functional nerve deficit. Mean ratios were calculated to allow comparisons between and within subjects. Results In assessing nerve branch density, eight randomly chosen images not overlapping by more than 20% produced an average that was within 30% of the true mean 95% of the time. A similar sampling strategy of five images was 13% within the true mean 80% of the time for corneal nerve fiber length. Conclusions The “sample combination analysis” presented here can be used to determine the sample size required for a desired level of accuracy of quantification of corneal subbasal nerve parameters. This technique may have applications in other biological sampling studies.

A new technique for optimal allocation and sizing of capacitors and setting of LTC

An iterative based strategy is proposed for finding the optimal rating and location of fixed and switched capacitors in distribution networks. The substation Load Tap Changer tap is also set during this procedure. A Modified Discrete Particle Swarm Optimization is employed in the proposed strategy. The objective function is composed of the distribution line loss cost and the capacitors investment cost. The line loss is calculated using estimation of the load duration curve to multiple levels. The constraints are the bus voltage and the feeder current which should be maintained within their standard range. For validation of the proposed method, two case studies are tested. The first case study is the semi-urban 37-bus distribution system which is connected at bus 2 of the Roy Billinton Test System which is located in the secondary side of a 33/11 kV distribution substation. The second case is a 33 kV distribution network based on the modification of the 18-bus IEEE distribution system. The results are compared with prior publications to illustrate the accuracy of the proposed strategy.

Cartilage regeneration using zonal chondrocyte subpopulations : a promising approach or an overcomplicated strategy?

Cartilage defects heal imperfectly and osteoarthritic changes develop frequently as a result. Although the existence of specific behaviours of chondrocytes derived from various depth-related zones in vitro has been known for over 20 years, only a relatively small body of in vitro studies has been performed with zonal chondrocytes and current clinical treatment strategies do not reflect these native depth-dependent (zonal) differences. This is surprising since mimicking the zonal organization of articular cartilage in neo-tissue by the use of zonal chondrocyte subpopulations could enhance the functionality of the graft. Although some research groups including our own have made considerable progress in tailoring culture conditions using specific growth factors and biomechanical loading protocols, we conclude that an optimal regime has not yet been determined. Other unmet challenges include the lack of specific zonal cell sorting protocols and limited amounts of cells harvested per zone. As a result, the engineering of functional tissue has not yet been realized and no long-term in vivo studies using zonal chondrocytes have been described. This paper critically reviews the research performed to date and outlines our view of the potential future significance of zonal chondrocyte populations in regenerative approaches for the treatment of cartilage defects. Secondly, we briefly discuss the capabilities of additive manufacturing technologies that can not only create patient-specific grafts directly from medical imaging data sets but could also more accurately reproduce the complex 3D zonal extracellular matrix architecture using techniques such as hydrogel-based cell printing.

A flexible asset maintenance decision-making process model

Optimal Asset Maintenance decisions are imperative for efficient asset management. Decision Support Systems are often used to help asset managers make maintenance decisions, but high quality decision support must be based on sound decision-making principles. For long-lived assets, a successful Asset Maintenance decision-making process must effectively handle multiple time scales. For example, high-level strategic plans are normally made for periods of years, while daily operational decisions may need to be made within a space of mere minutes. When making strategic decisions, one usually has the luxury of time to explore alternatives, whereas routine operational decisions must often be made with no time for contemplation. In this paper, we present an innovative, flexible decision-making process model which distinguishes meta-level decision making, i.e., deciding how to make decisions, from the information gathering and analysis steps required to make the decisions themselves. The new model can accommodate various decision types. Three industrial case studies are given to demonstrate its applicability.

An evidence-informed strategy to prevent osteoporosis in Australia

Osteoporosis imposes a tremendous burden on Australia : 1.2 million Australians have osteoporosis and 6.3 million have Osteopenia. In the 2007-08 financial year, 82000 Australians suffered fragility fractures, of Which >17000 were hip fractures. In the 2000-01 financial year, direct costs were estimated at $1.9 billion per year and an additional $5.6 billion on indirect costs. Osteoporosis was designated a National Health Priority Area in 2002; however, implementation of national plans has not yet matched the rhetoric in terms of urgency. Building healthy bones throughout life, the Osteoporosis Australia strategy to prevent osteoporosis throughout the life cycle, presents an evidence-informed set of recommendations for consumers, health care professionals and policymakers. The strategy was adopted by consensus at the Osteoporosis Australia Summit in Sydney, 20 October 2011. Primary objectives throughout the life cycle are: to maximise peak bone mass during childhood and adolescence to prevent premature bone loss and improve or maintain muscle mass, strength and functional capacity in healthy adults to prevent and treat osteoporosis in order to minimise the risk of suffering fragility fractures, and reduce falls risk, in older people. The recommendations focus on three affordable and important interventions to ensure people have adequate calcium intake, vitamin D levels and appropriate, physical activity throughout their lives. Recommendations relevant to all stages of life include: daily dietary calcium intakes should be consistent with Australian and New Zealand guidelines serum levels of vitamin D in the general population should be above 50 nmol/L in winter or early spring for optimal bone health regular weight-bearing physical activity, Muscle strengthening exercises and challenging balance/ mobility activities should be conducted in a safe environment.

Numerical solution of an optimal control model of dendritic cell treatment of a growing tumour

A new optimal control model of the interactions between a growing tumour and the host immune system along with an immunotherapy treatment strategy is presented. The model is based on an ordinary differential equation model of interactions between the growing tu- mour and the natural killer, cytotoxic T lymphocyte and dendritic cells of the host immune system, extended through the addition of a control function representing the application of a dendritic cell treat- ment to the system. The numerical solution of this model, obtained from a multi species Runge–Kutta forward-backward sweep scheme, is described. We investigate the effects of varying the maximum al- lowed amount of dendritic cell vaccine administered to the system and find that control of the tumour cell population is best effected via a high initial vaccine level, followed by reduced treatment and finally cessation of treatment. We also found that increasing the strength of the dendritic cell vaccine causes an increase in the number of natural killer cells and lymphocytes, which in turn reduces the growth of the tumour.

Two-stage power network reconfiguration strategy considering node importance and restored generation capacity

Network reconfiguration after complete blackout of a power system is an essential step for power system restoration. A new node importance evaluation method is presented based on the concept of regret, and maximisation of the average importance of a path is employed as the objective of finding the optimal restoration path. Then, a two-stage method is presented to optimise the network reconfiguration strategy. Specifically, the restoration sequence of generating units is first optimised so as to maximise the restored generation capacity, then the optimal restoration path is selected to restore the generating nodes concerned and the issues of selecting a serial or parallel restoration mode and the reconnecting failure of a transmission line are next considered. Both the restoration path selection and skeleton-network determination are implemented together in the proposed method, which overcomes the shortcoming of separate decision-making in the existing methods. Finally, the New England 10-unit 39-bus power system and the Guangzhou power system in South China are employed to demonstrate the basic features of the proposed method.

Go with the flow : optimal AUV path planning in coastal environments

This paper describes a novel optimum path planning strategy for long duration AUV operations in environments with time-varying ocean currents. These currents can exceed the maximum achievable speed of the AUV, as well as temporally expose obstacles. In contrast to most other path planning strategies, paths have to be defined in time as well as space. The solution described here exploits ocean currents to achieve mission goals with minimal energy expenditure, or a tradeoff between mission time and required energy. The proposed algorithm uses a parallel swarm search as a means to reduce the susceptibility to large local minima on the complex cost surface. The performance of the optimisation algorithms is evaluated in simulation and experimentally with the Starbug AUV using a validated ocean model of Brisbane’s Moreton Bay.

Output feedback optimal control with contraints

In Chapters 1 through 9 of the book (with the exception of a brief discussion on observers and integral action in Section 5.5 of Chapter 5) we considered constrained optimal control problems for systems without uncertainty, that is, with no unmodelled dynamics or disturbances, and where the full state was available for measurement. More realistically, however, it is necessary to consider control problems for systems with uncertainty. This chapter addresses some of the issues that arise in this situation. As in Chapter 9, we adopt a stochastic description of uncertainty, which associates probability distributions to the uncertain elements, that is, disturbances and initial conditions. (See Section 12.6 for references to alternative approaches to model uncertainty.) When incomplete state information exists, a popular observer-based control strategy in the presence of stochastic disturbances is to use the certainty equivalence [CE] principle, introduced in Section 5.5 of Chapter 5 for deterministic systems. In the stochastic framework, CE consists of estimating the state and then using these estimates as if they were the true state in the control law that results if the problem were formulated as a deterministic problem (that is, without uncertainty). This strategy is motivated by the unconstrained problem with a quadratic objective function, for which CE is indeed the optimal solution (˚Astr¨om 1970, Bertsekas 1976). One of the aims of this chapter is to explore the issues that arise from the use of CE in RHC in the presence of constraints. We then turn to the obvious question about the optimality of the CE principle. We show that CE is, indeed, not optimal in general. We also analyse the possibility of obtaining truly optimal solutions for single input linear systems with input constraints and uncertainty related to output feedback and stochastic disturbances.We first find the optimal solution for the case of horizon N = 1, and then we indicate the complications that arise in the case of horizon N = 2. Our conclusion is that, for the case of linear constrained systems, the extra effort involved in the optimal feedback policy is probably not justified in practice. Indeed, we show by example that CE can give near optimal performance. We thus advocate this approach in real applications.