The two tryptophans of ß2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure.

BACKGROUND: We have recently discovered that the two tryptophans of human ß2-microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of ß2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI). We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter-balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of ß2-microglobulin with respect to these residues. RESULTS: Having defined the ß2-microglobulin protein family, we performed multiple sequence alignments and analysed the residue conservation in homologous proteins to generate a phylogenetic tree. Our results indicate that Trp60 is highly conserved, whereas some species have a Leu in position 95; the replacement of Trp95 with Leu destabilizes ß2-microglobulin by 1 kcal/mol and accelerates the kinetics of unfolding. Both thermodynamic and kinetic data fit with the crystallographic structure of the Trp95Leu variant, which shows how the hydrophobic cavity of the wild-type protein is completely occupied by Trp95, but is only half filled by Leu95. CONCLUSIONS: We have established that the functional Trp60 has been present within the sequence of ß2-microglobulin since the evolutionary appearance of proteins responsible for acquired immunity, whereas the structural Trp95 was selected and stabilized, most likely, for its capacity to fully occupy an internal cavity of the protein thereby creating a better stabilization of its folded state.

Data mining techniques for analyzing stroke care processes.

Controlled randomized clinical trials and meta-analyses show that stroke patients benefit from access to specialized Stroke Units, in terms of mortality, disability and dependency. However, many issues relating to stroke diagnosis and therapy and to the organization of stroke care remain to be solved and little is known about what interventions make Stroke Units more effective. It is also agreed that compliance with clinical practice guidelines improves health outcomes for these patients, but little is known about the relative weight of the different guideline recommendations. Over the last decade, many hospital- or population-based stroke registers have been set up with the aim of identifying specific key indicators able to monitor the quality and adequacy of acute stroke care. Registers seem to be adequate tools for collecting the data needed to analyze care processes, providing data useful for both national healthcare planning and scientific research. In this paper we applied data mining techniques to data collected within the stroke register of the Lombardia region in Italy. From our analyses both expected and unexpected results have been found: not always compliance to recommendations is related to a good patients' outcome.

An automated reasoning framework for translational research.

In this paper we propose a novel approach to the design and implementation of knowledge-based decision support systems for translational research, specifically tailored to the analysis and interpretation of data from high-throughput experiments. Our approach is based on a general epistemological model of the scientific discovery process that provides a well-founded framework for integrating experimental data with preexisting knowledge and with automated inference tools. In order to demonstrate the usefulness and power of the proposed framework, we present its application to Genome-Wide Association Studies, and we use it to reproduce a portion of the initial analysis performed on the well-known WTCCC dataset. Finally, we describe a computational system we are developing, aimed at assisting translational research. The system, based on the proposed model, will be able to automatically plan and perform knowledge discovery steps, to keep track of the inferences performed, and to explain the obtained results.

Oct-4 regulates the expression of Stella and Foxj2 at the Nanog locus: implications for the developmental competence of mouse oocytes.

BACKGROUND: Our knowledge of what determines the mammalian oocyte developmental competence is meagre. By comparing the transcriptional profiles of developmentally competent surrounded nucleolus (SN) and incompetent not surrounded nucleolus (NSN) mouse MII oocytes, we recently demonstrated that Oct-4 and Stella are key factors in the establishment of the oocytes' developmental competence. METHODS: Using RT-PCR, microarray and immunocytochemistry assays, we analysed expression of genes and proteins in oocytes isolated throughout folliculogenesis and classified based on their SN- or NSN-type of chromatin organization. RESULTS: We show that: (1) Oct-4 and Stella are expressed concurrently at the beginning of oocytes' growth and only in SN oocytes; (2) Germ Cell Nuclear Factor is a putative regulator of Oct-4 expression in MII oocytes; (3) the function of Oct-4 is directed at the Nanog locus, regulating the expression of Stella and Foxj2. CONCLUSIONS: (1) A number of factors that act upstream and downstream of Oct-4 emerge as candidate players in the acquisition of the oocyte's developmental competence; (2) we define molecular markers that identify a specific group of ovarian oocytes (SN) that have a potential to acquire developmental competence; (3) the presence of SN and NSN oocytes in human ovaries extends the interest of these results to the field of human reproduction.

Matching incomplete time series with dynamic time warping: an algorithm and an application to post-stroke rehabilitation.

OBJECTIVE: The purpose of this study was to assess the performance of a real-time ("open-end") version of the dynamic time warping (DTW) algorithm for the recognition of motor exercises. Given a possibly incomplete input stream of data and a reference time series, the open-end DTW algorithm computes both the size of the prefix of reference which is best matched by the input, and the dissimilarity between the matched portions. The algorithm was used to provide real-time feedback to neurological patients undergoing motor rehabilitation. METHODS AND MATERIALS: We acquired a dataset of multivariate time series from a sensorized long-sleeve shirt which contains 29 strain sensors distributed on the upper limb. Seven typical rehabilitation exercises were recorded in several variations, both correctly and incorrectly executed, and at various speeds, totaling a data set of 840 time series. Nearest-neighbour classifiers were built according to the outputs of open-end DTW alignments and their global counterparts on exercise pairs. The classifiers were also tested on well-known public datasets from heterogeneous domains. RESULTS: Nonparametric tests show that (1) on full time series the two algorithms achieve the same classification accuracy (p-value =0.32); (2) on partial time series, classifiers based on open-end DTW have a far higher accuracy (kappa=0.898 versus kappa=0.447;p<10(-5)); and (3) the prediction of the matched fraction follows closely the ground truth (root mean square <10%). The results hold for the motor rehabilitation and the other datasets tested, as well. CONCLUSIONS: The open-end variant of the DTW algorithm is suitable for the classification of truncated quantitative time series, even in the presence of noise. Early recognition and accurate class prediction can be achieved, provided that enough variance is available over the time span of the reference. Therefore, the proposed technique expands the use of DTW to a wider range of applications, such as real-time biofeedback systems.

The coming of age of artificial intelligence in medicine.

This paper is based on a panel discussion held at the Artificial Intelligence in Medicine Europe (AIME) conference in Amsterdam, The Netherlands, in July 2007. It had been more than 15 years since Edward Shortliffe gave a talk at AIME in which he characterized artificial intelligence (AI) in medicine as being in its "adolescence" (Shortliffe EH. The adolescence of AI in medicine: will the field come of age in the '90s? Artificial Intelligence in Medicine 1993;5:93-106). In this article, the discussants reflect on medical AI research during the subsequent years and characterize the maturity and influence that has been achieved to date. Participants focus on their personal areas of expertise, ranging from clinical decision-making, reasoning under uncertainty, and knowledge representation to systems integration, translational bioinformatics, and cognitive issues in both the modeling of expertise and the creation of acceptable systems.

Temporal data mining for the assessment of the costs related to diabetes mellitus pharmacological treatment.

Diabetes care and chronic disease management represent data-intensive contexts which allow Local Healthcare Agencies (ASL) to collect a huge amount of information. Time is often an essential component of such information, given the strong importance of the temporal evolution of the considered disease and of its treatment. In this paper we show the application of a temporal data mining technique to extract temporal association rules over an integrated repository including both administrative and clinical data related to a sample of diabetic patients. We will show how the method can be used to highlight cases and conditions which lead to the highest pharmaceutical costs. Considering the perspective of a Regional Healthcare Agency, this method could be properly exploited to assess the overall standards and quality of care, while lowering costs.

Maternal Oct-4 is a potential key regulator of the developmental competence of mouse oocytes.

BACKGROUND: The maternal contribution of transcripts and proteins supplied to the zygote is crucial for the progression from a gametic to an embryonic control of preimplantation development. Here we compared the transcriptional profiles of two types of mouse MII oocytes, one which is developmentally competent (MIISN oocyte), the other that ceases development at the 2-cell stage (MIINSN oocyte), with the aim of identifying genes and gene expression networks whose misregulated expression would contribute to a reduced developmental competence. RESULTS: We report that: 1) the transcription factor Oct-4 is absent in MIINSN oocytes, accounting for 2) the down-regulation of Stella, a maternal-effect factor required for the oocyte-to-embryo transition and of which Oct-4 is a positive regulator; 3) eighteen Oct-4-regulated genes are up-regulated in MIINSN oocytes and are part of gene expression networks implicated in the activation of adverse biochemical pathways such as oxidative phosphorylation, mitochondrial dysfunction and apoptosis. CONCLUSION: The down-regulation of Oct-4 plays a crucial function in a sequence of molecular processes that leads to the developmental arrest of MIINSN oocytes. The use of a model study in which the MII oocyte ceases development consistently at the 2-cell stage has allowed to attribute a role to the maternal Oct-4 that has never been described before. Oct-4 emerges as a key regulator of the molecular events that govern the establishment of the developmental competence of mouse oocytes.

Improving compliance to guidelines through workflow technology: implementation and results in a stroke unit.

This work describes the results of the implementation of a workflow management system integrated into the electronic clinical chart of a Stroke Unit. The workflow logic is based on the rules provided by the SPREAD guidelines for stroke management. In this way, the already existing clinical chart has been transformed into an evidence-based, real-time decision support system, meanwhile maintaining the same look the users were familiar with. Since the final aim of the work was to improve evidence-based behavior and detect possible organizational bottlenecks, non-compliance to the clinical practice guidelines, before and after the system introduction, have been analyzed, as well as the accuracy of the clinical chart compilation, some care process variables, and system usability. Results show that the system enhances the clinical practice without boring users. Moreover, non-compliance analysis gives rise to ideas for further improvement.

Interacting agents through a web-based health serviceflow management system.

The management of chronic and out-patients is a complex process which requires the cooperation of different agents belonging to several organizational units. Patients have to move to different locations to access the necessary services and to communicate their health status data. From their point of view there should be only one organization (Virtual Health-Care Organization) which provides both virtual and face-to-face encounters. In this paper we propose the Serviceflow Management System as a solution to handle these information and the communication requirements. The system consists of: (a) the model of the care process represented as a Serviceflow and developed using the Workflow Management System YAWL; (b) an organizational ontology representing the VHCO; and (c) agreements and commitments between the parties defined in a contract (represented as an XML document). On the basis of a general architecture we present an implementation in the area of Diabetes management.

Workflow technology to enrich a computerized clinical chart with decision support facilities.

Literature results and personal experience show that intrusive modalities of presenting suggestions of computerized clinical practice guidelines are detrimental to the routine use of an information system. This paper describes a solution for smoothly integrating a guideline-based decision support system into an existing computerized clinical chart for patients admitted to a Stroke Unit. Since many years, the healthcare personnel were using a commercial product for the ordinary patients' data management, and they were satisfied with it. Thus, the decision support system has been integrated keeping attention to minimize changes and preserve existing human-computer interaction. Our decision support system is based on workflow technology. The paper illustrates the middleware layer developed to allow communication between the workflow management system and the clinical chart. At the same time, the consequent modification of the graphical users' interface is illustrated.

Architectures and tools for innovative Health Information Systems: the Guide Project.

This paper describes the architecture of the Guide Project, a proposal for innovation of Health Information Systems, putting together medical and organizational issues through the Separation of Concerns paradigm. In particular, we focus on one building block of the architecture: the Guideline Management System handling the whole life cycle of computerized Clinical Practice Guidelines. The communication between the Guideline Management System and the other components of the project architecture is message-based, according to specific contracts that allow an easy integration of the components developed by different parties and, in particular, with legacy systems (i.e. existing electronic patient records). In turn, the Guideline Management System components are organized in a distributed architecture: an editor to formalize guidelines, a repository to store and publish them, an enactment system to implement guidelines instances in a multi-user environment and a reporting system able to completely trace any individual physician's guideline-based decision process. The repository is organized in different levels that can be international, national, regional, down to the specific health care organization, according to the healthcare delivery policy of a country. Different organizations can get Clinical Practice Guidelines from the repository, adapt and introduce them in clinical practice.

Automated spoken dialogue system for hypertensive patient home management.

Recent advances in automatic speech recognition and related technologies allow computers to carry on conversations by telephone. We developed an intelligent dialogue system that interacts with hypertensive patients to collect data about their health status. Patients thus avoid the inconvenience of traveling for frequent face to face visits to monitor the clinical variables they can easily measure at home; the physician is facilitated in acquiring patient information and cardiovascular risk, which is evaluated from the data according to noted guidelines. Controlled trials to assess the clinical efficacy are under way.

Cardiovascular risk calculators: understanding differences and realising economic implications.

In recent years, the concept of "global cardiovascular risk assessment" has grown in interest for its role in primary prevention of cardiovascular diseases. Interventions for reducing the risk of relapse for persons with cardiovascular past history are well agreed-on. But for persons without such a history, the risk of a first attack varies greatly and this variability implies a range in the intensity of interventions. In several countries, guidelines for general practitioners have been diffused about pharmaceutical prescriptions in the different risk classes. In particular, in Italy, a governmental drug management commission has established that Statins, the most used cholesterol lowering medicines, can be refunded by the National Healthcare System only if they are prescribed to hyper-cholesterol patients with a global risk greater than 20%. The question is: how to calculate the risk? We performed a review of both the web and the literature and we found a lot of different "risk calculators". By means of a simulation study, we showed that these tools, when used for the same person, may lead to very different results. We estimated the economic impact of using one or another calculator.

A guideline management system.

This paper describes the architecture of NewGuide, a guide-line management system for handling the whole life cycle of a computerized clinical practice guideline. NewGuide components are organized in a distributed architecture: an editor to formalize guidelines, a repository to store them, an inference engine to implement guidelines instances in a multi-user environment, and a reporting system storing the guidelines logs in order to be able to completely trace any individual physician guideline-based decision process. There is a system "central level" that maintains official versions of the guidelines, and local Healthcare Organizations may download and implement them according to their needs. The architecture has been implemented using the Java 2 Enterprise Edition (J2EE) platform. Simple Object Access Protocol (SOAP) and a set of con-tracts are the key factors for the integration of NewGuide with healthcare legacy systems. They allow maintaining unchanged legacy user interfaces and connecting the system with what-ever electronic patient record. The system functionality will be illustrated in three different contexts: homecare-based pressure ulcer prevention, acute ischemic stroke treatment and heart failure management by general practitioners.

A careflow management system for chronic patients.

The management of chronic patients is a complex process, which requires the cooperation of all primary care professionals and their interaction with specialists, laboratories and personnel of different organizations. In this paper we show how a Careflow Management System (CfMS) may represent an essential component of an innovative Health Information System (HIS) able to handle the information and communication needs underlying chronic diseases management. On the basis of a general architecture designed for chronic diseases, we describe a CfMS implementation in the area of diabetes management; such a system embeds EPR and telemedicine functionalities as end-users applications as well as a module for inter-organizational communication based on contracts and on XML messages.

Cognitive human factors for telemedicine systems.

The recent integration of telephony systems with information and communication technology (ICT) enables the development of innovative tools for telemedicine. The dissemination and widespread acceptance of telephone-based care monitoring systems challenge the researcher to deal with the cognitive factors involved in the patient-physician interaction, and the way they should be to shape up the technological solutions. This paper proposes a model that describes the impact of socio-cognitive factors in the complex process of health care management. The model has been used to design and develop a telephone system for the management of hypertensive patient within the EU funded Homey project. The knowledge existed in a widely accepted guideline for the care of hypertension has been represented and augmented through the proposed cognitive model. The final product is an intelligent system able to manage an adaptive dialogue. It monitors patients' adherence and increases their involvement by promoting self-care through frequent virtual visits, which is complementary to the traditional face-to-face encounters with their primary care physicians.

An ontological framework for the implementation of clinical guidelines in health care organizations.

The paper presents the outlines of an ontology of plans and guidelines, which is then used as the basis for a framework for implementing guideline-based systems for the management of workflow in health care organizations. The framework has a number of special features, above all in that it enables us to represent in formal terms assignments of work-items both to individuals and to teams and to tailor guideline to specific contexts of application in health care organizations. It is designed also to enable implementations to do justice to the fact that the processes carried out in health care organizations may deviate in different ways from the norms set forth in corresponding guideline definitions. This means that implementations built in conformity with the framework will be marked by a type of flexibility that might make them more likely to be accepted by healthcare professionals than are standard guideline-based management systems.

Management of patients with diabetes through information technology: tools for monitoring and control of the patients' metabolic behavior.

BACKGROUND: The junction of telemedicine home monitoring with multifaceted disease management programs seems nowadays a promising direction to combine the need for an intensive approach to deal with diabetes and the pressure to contain the costs of the interventions. Several projects in the European Union and the United States are implementing information technology-based services for diabetes management using a comprehensive approach. Within these systems, the role of tools for data analysis and automatic reminder generation seems crucial to deal with the information overload that may result from large home monitoring programs. The objective of this study was to describe the automatic reminder generation system and the summary indicators used in a clinical center within the telemedicine project M2DM, funded by the European Commission, and to show their usage during a 7-month on-field testing period. METHODS: M2DM is a multi-access service for management of patients with diabetes. The basic functionality of the technical service includes a Web-based electronic medical record and messaging system, a computer telephony integration service, a smart-modem located at home, and a set of specialized software modules for automated data analysis. The information flow is regulated by a software scheduler, called the Organizer, that, on the basis of the knowledge on the health care organization, is able to automatically send e-mails and alerts notifications as well as to commit activities to software agents, such as data analysis. Thanks to this system, it was possible to define an automatic reminder system, which relies on a data analysis tool and on a number of technologies for communication. Within the M2DM system, we have also defined and implemented a number of indexes able to summarize the patients' day-by-day metabolic control. In particular, we have defined the global risk index (GRI) of developing microangiopathic complications. RESULTS: The system for generating automatic alarms and reminders coupled with the indexes for evaluating the patients' metabolic control has been used for 7 months at the Fondazione Salvatore Maugeri (FSM) in Pavia, Italy. Twenty-two patients (43 +/- 16 years old, 12 men and 10 women) have been involved; six dropped out from the study. The average number of monthly automatic messages was 29.44 +/- 9.83, i.e., about 1.8 messages per patient per month. The number of monthly alarm reminders generated by the system was 16.44 +/- 4.39, so that the number of alarms per patient was about 1. The number of messages sent by patients and physicians during the project was about 13 per month. The GRI analysis shows, during the last trimester, a slight improvement of the performance of the FSM clinic, with a decrease in the percentage of badly controlled values from 33% to 27%. Finally, we found the presence of a linear increasing correlation between the mean GRI values and the number of alarms generated by the system. CONCLUSIONS: A telemedicine system may incorporate features that make it a suitable technological backbone for implementing a disease management program. The availability of data analysis tools, automated messaging system, and summary indicators of the effectiveness of the health care program may help in defining efficient clinical interventions.