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Dermal capillary clearance: physiology and modeling.

Substances applied to the skin surface may permeate deeper tissue layers and pass into the body's systemic circulation by entering blood or lymphatic vessels in the dermis. The purpose of this review is an in-depth analysis of the dermal clearance/exchange process and its constituents: transport through the interstitium, permeability of the microvascular barrier and removal via the circulation. We adapt an 'engineering' viewpoint with emphasis on quantifying the dermal microcirculatory physiology, providing the theoretical framework for the physics of key transport processes and reviewing the available computational clearance models in a comparative manner. Selected experimental data which may serve as valuable input to modeling attempts are also reported.

Administration, Cutaneous↗

Review of Expert System (ES), Geographic Information System (GIS), Decision Support System (DSS), and their applications in landfill design and management.

This paper provides the reader with a brief discussion on Expert System (ES), Geographic Information System (GIS), and Environmental Decision Support System (EDSS) technologies and their applications in environmental engineering in general and in landfill design and management in specific. It also brings into attention the benefits of integrating ESs and GISs together with simulation models (SM) in a decision support systems (DSS) framework to solve complex environmental problems, facilitated by the new advancements of computer technologies (both in hardware and software). Examples of such integration are provided to reflect how such a system can improve landfill design and management. Finally, the discussion concludes with the fact that although solving landfill design problems could greatly benefit from such a combination of technologies, there have been no attempts to combine ES, GIS, and SM for the comprehensive evaluation of landfill design and performance.

Decision Support Techniques↗

A generic approach to the management of time-related signals and images in medicine.

A framework concept for design and implementation of medical workstations is described by (a) its underlying principles, (b) the handlers provided by the concept, (c) the available data structures and (d) the graphical user interface (GUI). The design principle takes care of a modular approach both for the framework and for the applications. The GUI provides a coherent look and feel for applications based on toolkits for displaying data objects and application control. The data handler allows management of n-dimensional data matrices in a multi-vendor environment, whereas the parameter handler takes care of the data object description. An implementation of a medical workstation exploiting the framework concept is presented.

Computer Graphics↗

Transformation of flow in rehabilitation: the role of advanced communication technologies.

Authentic rehabilitation requires the active participation of patients and their involvement with opportunities for action and development. Within this framework, in this article we outline the possibility of using two emerging computing and communication technologies-ambient intelligence (AmI) and virtual reality (VR)--for a new breed of rehabilitative and clinical applications based on a strategy defined as transformation of flow. Transformation of flow is a person's ability to exploit an optimal (flow) experience to identify and use new and unexpected psychological resources as sources of involvement. We identify the feeling of presence--the feeling of being in a world that exists outside oneself--as the theoretical link between the technology and rehabilitation. AmI and VR are used to trigger broad empowerment processes induced by a strong sense of presence, leading to greater agency and control over one's actions and environment.

Aged↗

Current and future R&D activities of the EC-IST programme in eHealth.

The EU support to R&D in eHealth over the last few years has addressed citizens, patients and health professionals needs in their activities. The societal challenges based on the principle of citizen-centred care have found solutions in the many projects financed through the IST programme. Major paradigm shifts have emerged e.g. from "hospital centred healthcare" to "patient/citizen centred health" and from "treatment" to "prevention". Information technologies became one of the major driving forces for healthcare evolution, receiving acceptance by an increasing number of health professionals. In addition, a new industrial sector was clearly identified; the "Health Telematics Industry". This paper present the main research and development activities carried out in eHealth during the 5th R&D Framework Programme and the future research and development activities in the 6th R&D Framework Programme.

Computer Communication Networks↗

Large medical datasets on the Grid.

OBJECTIVE: This paper shows the use of the emerging Grid technology for gathering underused resources that are distributed among a corporate network. The work of these resources is coordinated for facing tasks which are not affordable by the individual usage of each of them. METHODS: This paper shows an application for the projection, using Volume Rendering techniques, of huge medical volumes obtained from CTs and RMIs, adapted to Grid computing. RESULTS: As a result the article shows the feasibility of the creation of an application based up on Grid technology, which solves problems that cannot be addressed by using common techniques. As an example, the article describes the projection of a huge medical dataset, which exceeds the resources of most common PCs, carried out by taking profit of idle CPU cycles from the computers of an organization. CONCLUSIONS: Grid technology is emerging as a new framework which allows gathering and coordinating resources distributed among a network (LAN or WAN), for addressing problems which cannot be solved through the single use of any of these resources. Medical Imaging is a clear application area for this technology.

Algorithms↗

Literacy and health research in Canada: where have we been and where should we go?

This article reviews current literature and research on literacy and health and identifies priorities for research on this topic in Canada. Information sources included documents found through an environmental scan, the Alpha Plus collection and a computer search of recent documents. The information was analyzed using a conceptual framework. The review found that low literacy has direct and indirect impacts on health. Families are at risk due to difficulty reading medication prescriptions, baby formula instructions and health and safety education materials. People with lower levels of literacy tend to live and work in less healthy environments. They have more difficulties obtaining employment and income security. Determinants of literacy include: education, early childhood development, aging, living and working conditions, personal capacity/genetics, gender and culture. Action is needed to improve literacy and health through a combination of health communication, education and training, community development, organizational development, and policy development. There is some evidence that such interventions can have a positive effect on health, particularly when combined with one another. Further program and policy development requires greater evidence and evaluation of existing initiatives, more cost/benefit analyses, more culturally specific studies, and greater attention to current social trends and needs.

Adolescent↗

[Characteristics of pregnant women, labor, and the newborn at the Skopje Clinic from 1978 to 1979].

An analysis was made of the first computer data received from the IFRP (International Fertility Research Program) within the framework of the International Study "Maternity Record" -- "Maternity Monitoring Care'. The main findings are the following: The women who were confined at the Skopje University Hospital during 1978--1979 were young, in their twenties. Women over thirty were confined very rarely. Most of the women surveyed had about 12 years of education. Pregnant women had artificial abortions very rarely (1:5.7 in favor of terminating pregnancy). Preventive work on contraception should include women at the time of delivery. Pregnant women in Skopje come to the Consulting Centers for a check-up mostly five times. The higher the parity, the less frequent the visits. More than half of pregnant women during the antenatal period had no complaints. Younger pregnant women had fewer difficulties and complications. The values of haemoglobin under 10 g% were very often in primiparas and over 12 g% in multiparas. The birthweight of women smoker's babies proved lower than that of women non-smokers' babies. In two thirds of women the delivery was induced by drugs and amniotomy. The delivery mostly lasted between 7--12 h, regardless of parity. Prolonged deliveries were the more frequent the younger the women. Primiparas gave birth to babies with a lower birthweight than multiparas. Almost all women (92.4%) were previously using no contraceptive devices. The main method of protection was coitus interruptus.

Adult↗

Engineered anti-CD38 monoclonal antibodies for immunotherapy of multiple myeloma.

Multiple myeloma is a malignancy of plasma cells for which there is no effective treatment. To develop an immunotherapeutic agent, we have raised a high affinity mAb (AT13/5) against CD38, one of the few well-characterized surface Ags present on myeloma cells. Since murine monoclonals have many disadvantages as human therapeutics, we prepared two engineered forms of the Ab: a CDR-grafted humanized IgG1 and a chimeric FabFc2 (mouse Fab cross-linked to two human gamma 1 Fc). To retain affinity in the humanized Ab, a number of changes were required to the human framework regions of the heavy chain. In particular, through systematic mutagenesis and computer modeling, we identified a critical interaction between the side chains of residues 29 and 78, which may be important for the humanization of other Abs. The properties of the humanized IgG1 and FabFc2 constructs were compared in a series of in vitro tests. Both constructs efficiently directed Ab-dependent cellular cytotoxicity against CD38-positive cell lines, but C was activated only poorly. Neither construct caused down-modulation of CD38, nor did they affect the NADase activity of CD38. Despite their differing structures, both Abs showed similar activity in most assays, although the humanized IgG1 was more potent at inducing monocyte cytotoxicity. These data represent the first direct comparison of CDR-grafted and chimeric FabFc2 forms of the same Ab, and offer no support for the perceived advantages of the FabFc2. These Abs show promise for therapy of multiple myeloma and other diseases involving CD38-positive cells.

ADP-ribosyl Cyclase↗

[Computer-assisted neuropsychological training in neurological rehabilitation].

Using computer-assisted cognitive training to treat patients with cognitive disorders has proved a useful tool in neurological rehabilitation. This has been shown by positive experience in many rehabilitation clinics but also in numerous control studies investigating the efficiency of such training. Patients with attention deficits show the most pronounced improvements as the computer with its technical possibilities is an ideal training instrument because of stimulus representation and reaction time measures. In other areas, computer training has become an essential therapeutic means complementing other therapies. In a clinical environment it seems that computer training is essential because it enables attaining the necessary therapeutic density. However, training must be integrated and become part of a global therapeutic framework.

Brain Damage, Chronic↗

The object technology framework: an object-oriented interface to molecular data and its application to collagen.

We describe the Object Technology Framework (OTF) software system developed at the University of California, San Francisco Computer Graphics Laboratory for creating C+2 classes that facilitate rapid biomolecular application development and the application of the OTF to collagen modeling. C+2 class libraries for accessing and manipulating data from standard scientific data sources can be generated using the program genlib and its class library toolkit Molecule, thereby facilitating development of new applications. Use of the OTF for generating ideal collagen structural models (gencollagen) is described. The source code for the OTF is freely available at http:/(/)www.cgl.ucsf.edu/off/ to interested application developers.

Collagen↗

An automated geometric modeling framework in GATE for the design and optimization of high-sensitivity converging-beam SPECT collimators.

Objective.The trade-off between detection sensitivity and spatial resolution is a fundamental challenge in designing organ-dedicated Single-photon emission computed tomography (SPECT) collimators. While converging-hole geometries offer a solution, their optimization is often hindered by the lack of flexible computational tools capable of modeling large-scale, non-parallel hole arrays. This study aims to develop an automated geometric modeling framework to facilitate the design and evaluation of complex converging- and diverging-hole collimators within standard Monte Carlo environments.Approach.We developed a specialized modeling framework by implementing custom C++ classes and a vector-based alignment algorithm within GATE. This platform enables automated, orientation-consistent construction of large-scale converging arrays not natively supported by standard implementations. A high-sensitivity pure cone-beam collimator (CBC) was designed using this framework. The evaluation used hot-rod, disc, and Jaszczak phantoms for physical characterization, while XCAT and dedicated brain models were employed for clinical tasks, including cardiac, brain perfusion, and DaTscan SPECT simulations.Main results.The CBC achieved a nearly fourfold sensitivity increase compared to a conventional low-energy high-resolution parallel-hole collimator at a 20 cm radius of rotation, while maintaining comparable spatial resolution. Despite a 52.3% field of view reduction, the CBC yielded a 2.2-fold noise reduction (CV: 11.7% vs 25.9%) and mitigated partial volume effects via geometric magnification. XCAT and brain phantom simulations confirmed enhanced anatomical definition and contrast recovery in cardiac, perfusion, and DaTscan tasks.Significance.This work provides an efficient computational tool for rapid design space exploration of advanced collimator geometries. The results demonstrate that the proposed CBC design offers a significant sensitivity advantage, making it highly suitable for high-performance, small-volume clinical applications such as brain and cardiac molecular imaging.

Tomography, Emission-Computed, Single-Photon↗

A uniform framework for ordered restriction map problems.

Optical Mapping is an emerging technology for constructing ordered restriction maps of DNA molecules. The underlying computational problems for this technology have been studied and several models have been proposed in recent literature. Most of these propose combinatorial models; some of them also present statistical approaches. However, it is not a priori clear as to how these models relate to one another and to the underlying problem. We present a uniform framework for the restriction map problems where each of these various models is a specific instance of the basic framework. We achieve this by identifying two "signature" functions f() and g() that characterize the models. We identify the constraints these two functions must satisfy, thus opening up the possibility of exploring other plausible models. We show that for all of the combinatorial models proposed in literature, the signature functions are semi-algebraic. We also analyze a proposed statistical method in this framework and show that the signature functions are transcendental for this model. We also believe that this framework would provide useful guidelines for dealing with other inferencing problems arising in practice. Finally, we indicate the open problems by including a survey of the best known results for these problems.

Algorithms↗

Dynamic Fusion of Genomics and Functional Network Connectivity in UK Biobank Reveals Schizophrenia-Related SNP Manifolds.

Many mental disorders show strong genetic influence. In parallel, dynamic functional network connectivity (dFNC) has shown high sensitivity to brain changes related to mental disorders. However, previous studies linking dFNC to genetics largely follow a paradigm to identify associations between one set of genetic factors and multiple sets of connectivity features from different dFNC states, ignoring the potential variability in genetic correlates across states. We propose a novel joint ICA (jICA)-based "dynamic fusion" framework to identify dynamically tuned genetic manifolds. A sliding window approach was utilized to estimate four dFNC states and compute subject-level state-average dFNC (sa-dFNC) features. The sa-dFNC features of each state were combined with schizophrenia risk single nucleotide polymorphisms (SNPs) within a jICA fusion framework, resulting in four parallel fusions in 32,861 individuals of the UK Biobank cohort. The extracted four sets of joint SNP-dFNC components were further validated for clinical relevance in a combined schizophrenia cohort of 820 individuals (348 patients). The similarity of SNP-dFNC components across four parallel fusions was evaluated as a measure of state variability. We observed a mixture of "state-invariant" and "state-variant" components for SNP and dFNC modalities. Particularly, the schizophrenia-related state-variant SNP components, or manifolds, complemented each other by capturing different SNPs involved in the same biological functions, revealing a partition of genomic risk particularly elicited by the dynamics of brain function. By augmenting the SNP factors to state-variant manifolds, this dynamic fusion framework promises additional insights into the underlying genetic risk of disease-related alterations in dynamic brain function.

Humans↗

Computing power in case-control association studies through the use of quadratic approximations: application to meta-statistics.

In the framework of case-control studies many different test statistics are available to measure the association of a marker with a given disease. Nevertheless, choosing one particular statistic can lead to very different conclusions. In the absence of a consensus for this choice, a tempting option is to evaluate the power of these different statistics prior to make any decision. We review the available methods dedicated to power computation and assess their respective reliability in treating a wide range of tests on a wide range of alternative models. Considering Monte-Carlo, non-central chi-square and Delta-Method estimates, we evaluate empirical, asymptotic and numerical approaches. Additionally we introduce the use of the Delta-Method, extended to order 2, intended to provide better results than the traditional order-1 Delta-Method. Supplementary data can be found at: http://stat.genopole.cnrs.fr/software/dm2.

Alleles↗

The cognitive neuroscience paradigm: a unifying metatheoretical framework for the science and practice of clinical psychology.

The emerging discipline of cognitive neuroscience (CN) enjoins the efforts of cognitive psychologists, neuroscientists, computer scientists, clinical neurologists, neurophilosophers, and many others working collaboratively across traditional disciplinary boundaries to elucidate the manner in which the physical operations of the brain give rise to the vast panoply of human mental and behavioral events. The present article describes the foundational tenets of the CN metatheoretical framework and contends that the CN framework is capable of providing a coherent, unifying scientific paradigm for the discipline of clinical psychology. Clinical psychology's adoption of the CN paradigm would facilitate (a) its consilient linkage with the natural sciences, (b) resolution of long-standing internecine theoretical schisms, and (c) enhanced understanding and treatment of numerous forms of psychopathology. Nevertheless, psychology's historically influential radical behavioral (RB) perspective is not easily reconciled with the CN paradigm. However, unlike CN, RB (a) is not fully consilient with the natural sciences, (b) fails to articulate the proximal causal mechanisms that mediate environment-behavior relations, and (c) engages in "greedy reductionism" in its disavowal of informational levels of complexity in the patterning of neural activity. The article concludes with a discussion of the possibility of theoretical rapprochement between CN and RB.

Behaviorism↗

BALL--rapid software prototyping in computational molecular biology. Biochemicals Algorithms Library.

MOTIVATION: Rapid software prototyping can significantly reduce development times in the field of computational molecular biology and molecular modeling. Biochemical Algorithms Library (BALL) is an application framework in C++ that has been specifically designed for this purpose. RESULTS: BALL provides an extensive set of data structures as well as classes for molecular mechanics, advanced solvation methods, comparison and analysis of protein structures, file import/export, and visualization. BALL has been carefully designed to be robust, easy to use, and open to extensions. Especially its extensibility which results from an object-oriented and generic programming approach distinguishes it from other software packages. BALL is well suited to serve as a public repository for reliable data structures and algorithms. We show in an example that the implementation of complex methods is greatly simplified when using the data structures and functionality provided by BALL.

Algorithms↗

Humanization of a murine monoclonal antibody by simultaneous optimization of framework and CDR residues.

Optimal protein function often depends on co-operative interactions between amino acid residues distant in the protein primary sequence yet spatially near one another following protein folding. For example, antibody affinity is influenced by interactions of framework residues with complementarity-determining region (CDR) residues. However, despite the abundance of antibody structural information and computational tools the humanization of rodent antibodies for clinical use often results in a significant loss of affinity. To date, antibody engineering efforts have focused either on optimizing CDR residues involved in antigen binding or on optimizing antibody framework residues that serve critical roles in preserving the conformation of CDRs. In the present study a new approach which permits the rapid identification of co-operatively interacting framework and CDR residues was used to simultaneously humanize and optimize a murine antibody directed against CD40. Specifically, a combinatorial library that examined eight potentially important framework positions concomitantly with focused CDR libraries consisting of variants containing random single amino acid mutations in the third CDR of the heavy and light chains was expressed. Multiple anti-CD40 Fab variants containing as few as one murine framework residue and displaying up to approximately 500-fold higher affinity than the initial chimeric Fab were identified. The higher affinity humanized variants demonstrated a co-operative interaction between light chain framework residue Y49 and heavy chain CDR3 residue R/K101 (coupling energy, DeltaGI=0.9 kcal/mol). Screening of combinatorial framework-CDR libraries permits identification of monoclonal antibodies (mAb) with structures optimized for function, including instances in which the antigen induces conformational changes in the mAb. Moreover, the enhanced humanized variants contain fewer murine framework residues and could not be identified by sequential in vitro humanization and affinity muturation strategies. This approach to identifying co-operatively interacting residues is not restricted to antibody-antigen interactions and consequently, may be used broadly to gain insight into protein structure-function relationships, including proteins that serve as catalysts.

Amino Acid Sequence↗