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PubMed1998

Oral health-related quality of life: a model for dental hygiene.

During the past decade, dental hygiene has been challenged to develop conceptual models to define the discipline. Such models can provide a common language and infrastructure for the discipline to define the process of care. Health-Related Quality of Life conceptual models have been adopted by many health professions to assist in planning health-related interventions and assessing outcomes to care. Based on the Natural History of Disease Schema, the Wilson & Cleary model, and Neuman's Systems Model, a new conceptual model for dental hygiene is proposed. The Oral Health-Related Quality of Life Model, composed of six primary domains: Health/Preclinical Disease, Biological/Clinical Disease, Symptom Status, Functional Status, Health Perceptions, and General Quality of Life. This model proposes a dynamic relationship among these domains and characteristics unique to individual clients or populations, and may have utility for interdisciplinary communication. As an integrated model, it may serve as a foundation for assessing, planning, implementing, and evaluating outcomes to dental hygiene care. This paper reviews possible application of the model for clinical practice, research, and education.

Dental Hygienists↗
PubMedDate not supplied

Distributed decision support using a web-based interface: prevention of sudden cardiac death.

Although decision models can provide a formal foundation for guideline development and clinical decision support, their widespread use is often limited by the lack of platform-independent software that geographically dispersed users can access and use easily without extensive training. To address these limitations the authors developed a World Wide Web-based interface for previously developed decision models. They describe the use and functionality of the interface using a decision model that evaluates the cost-effectiveness of strategies for preventing sudden cardiac death. The system allows an analyst to use a web browser to interact with the decision model and to change the values of input variables within pre-specified ranges, to specify sensitivity or threshold analyses, to evaluate the decision model, and to view the results generated dynamically. The web site also provides linkages to an explanation of the model, and evidence tables for input variables. The system demonstrates a method for providing distributed decision support to remote users such as guideline developers, decision analysts, and potentially practicing physicians. The web interface provides platform-independent and almost universal access to a decision model. This approach can make distributed decision support both practical and economical, and has the potential to increase the usefulness of decision models by enabling a broader audience to incorporate systematic analyses into both policy and clinical decisions.

Anti-Arrhythmia Agents↗
PubMed2004

Population pharmacokinetics I: background, concepts, and models.

OBJECTIVE: To present and emphasize the background, foundations, utility, and conceptual underlying theory of the population pharmacokinetic (PPK) approach with an examination of the advantages when compared with other approaches of pharmacokinetic modeling. DATA SOURCES: Information on PPK was retrieved from a MEDLINE search (1979-June 2002) of literature and a bibliographic review of review articles and books. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated and relevant information was included in this review. DATA SYNTHESIS: PPK plays a pivotal role in developing dosing strategies for direct patient care and in drug development. PPK is valuable because it targets the patient group that will eventually receive the drug of interest, quantitates pharmacokinetic variability at several levels, and seeks to explain those sources of variability. CONCLUSIONS: PPK models have great utility and the applications are many. They are very different from single-subject pharmacokinetic models and therefore require different approaches to model development.

Humans↗
PubMed2005

Computational prediction of human drug metabolism.

There is an urgent requirement within the pharmaceutical and biotechnology industries, regulatory authorities and academia to improve the success of molecules that are selected for clinical trials. Although absorption, distribution, metabolism, excretion and toxicity (ADME/Tox) properties are some of the many components that contribute to successful drug discovery and development, they represent factors for which we currently have in vitro and in vivo data that can be modelled computationally. Understanding the possible toxicity and the metabolic fate of xenobiotics in the human body is particularly important in early drug discovery. There is, therefore, a need for computational methodologies for uncovering the relationships between the structure and the biological activity of novel molecules. The convergence of numerous technologies, including high-throughput techniques, databases, ADME/Tox modelling and systems biology modelling, is leading to the foundation of systems-ADME/Tox. Results from experiments can be integrated with predictions to globally simulate and understand the likely complete effects of a molecule in humans. The development and early application of major components of MetaDrug (GeneGo, Inc.) software will be described, which includes rule-based metabolite prediction, quantitative structure-activity relationship models for major drug metabolising enzymes, and an extensive database of human protein-xenobiotic interactions. This represents a combined approach to predicting drug metabolism. MetaDrug can be readily used for visualising Phase I and II metabolic pathways, as well as interpreting high-throughput data derived from microarrays as networks of interacting objects. This will ultimately aid in hypothesis generation and the early triaging of molecules likely to have undesirable predicted properties or measured effects on key proteins and cellular functions.

Computational Biology↗
PubMed1996

Mechanistic hypotheses for the activation of G-protein-coupled receptors.

G-protein-coupled receptors (GPCR) play an important role in the functioning of the nervous and endocrine systems. Intensive efforts devoted to mutational analyses of GPCR have greatly enhanced our understanding of the receptor-G-protein signalling pathway. Nonetheless, the lack of receptor structural data mandates that the mechanism of receptor activation can only be probed indirectly through hypothesis testing. Mechanistic models at two different levels, a thermodynamic model and a structural model, are reviewed here. A general thermodynamic model can be used as a framework for analyzing macroscopic experimental data, while a probability function based on a helical-rotation model can potentially provide a link between microscopic conformational changes and macroscopic rate constants and equilibrium constants. Conformational induction and conformational selection are two inseparable consequences of the receptor-binding system. Mechanistic models based on the integration of mutational data, spectroscopic data, and model simulation will form a foundation upon which further experiments can be designed, and consideration of both thermodynamic and structural principles will provide coherent insights into the receptor-activation process.

Binding Sites↗
PubMed1999

A murine model of myocardial microvascular thrombosis.

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

Animals↗
PubMed2025

Knowledge-guided Contextual Gene Set Analysis Using Large Language Models.

Gene set analysis (GSA) is a foundational approach for interpreting genomic data of diseases by linking genes to biological processes. However, conventional GSA methods overlook clinical context of the analyses, often generating long lists of enriched pathways with redundant, nonspecific, or irrelevant results. Interpreting these requires extensive, ad-hoc manual effort, reducing both reliability and reproducibility. To address this limitation, we introduce cGSA, a novel AI-driven framework that enhances GSA by incorporating context-aware pathway prioritization. cGSA integrates gene cluster detection, enrichment analysis, and large language models to identify pathways that are not only statistically significant but also biologically meaningful. Benchmarking on 102 manually curated gene sets across 19 diseases and ten disease-related biological mechanisms shows that cGSA outperforms baseline methods by over 30%, with expert validation confirming its increased precision and interpretability. Two independent case studies in melanoma and breast cancer further demonstrate its potential to uncover context-specific insights and support targeted hypothesis generation.

Journal Article↗
PubMed2007

Striatal delivery of neurturin by CERE-120, an AAV2 vector for the treatment of dopaminergic neuron degeneration in Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) or its naturally occurring analog, neurturin (NTN), can potentially improve the function and delay the rate of degeneration of dopaminergic neurons in Parkinson's disease (PD). However, their delivery to the central nervous system has proven to be a significant challenge. Viral vector-mediated gene transfer offers a practical means to continuously supply neurotrophic factors in targeted areas of the brain. CERE-120 is an adeno-associated viral vector encoding NTN, developed for the treatment of PD. We found that the kinetics and pattern of NTN expression in the rat striatum following injection of CERE-120 is rapid, increases significantly up to 4 weeks, and exhibits a stable volume of distribution thereafter for at least 1 year, the longest time-point evaluated. Quantitative enzyme-linked immunosorbent assay confirmed that steady-state levels are maintained from 4 weeks onward. We demonstrated that NTN volume of distribution can be controlled by varying the dose of vector injected and that NTN delivered via CERE-120 was bioactive, as evidenced by the neuroprotection of DA neurons in the rat 6-hydroxydopamine lesion model. These data provided the foundation for further non-clinical development of CERE-120, leading to an ongoing clinical trial in PD patients.

Animals↗
PubMedDate not supplied

Taking the eagle's view: using Watson's conceptual model to investigate the extraordinary and transformative experiences of nurse healers.

Watson's conceptual model of a caring-healing transpersonal understanding of nursing was used to underpin a hermeneutic phenomenological study of the extraordinary and transformational experiences of nurse healers. The 5 essential themes uncovered from the analysis of interviews with 11 nurse healers--Belonging & Connecting, Opening to Spirit, Summoning, Wounding & Healing Journey, and Living as a Healer--are set out, along with the overarching theme "Walking Two Worlds." Foundational understandings of Watson's model as they relate to the findings, and theoretical aspects, are discussed, and potential contributions of this study to the ongoing evolution of Watson's conceptual model are articulated.

Empathy↗
PubMedDate not supplied

A present-day academic perspective on the Carolina nursing experience: building on the past, shaping the future.

Past, present, and future models of academic-service collaboration are described and projected from an academic perspective. The features that characterize academic-service partnerships during the history of nursing education in America, the goals that drove faculty and academic leaders to engage or disengage in earlier partnerships, and new forms of emerging partnerships are presented, along with a discussion of their importance in the context of environmental change. The foundation for building the Carolina Model between the University of North Carolina-Chapel Hill and the University of North Carolina Hospitals is a prototype for extending future academic-service initiatives.

Cooperative Behavior↗
PubMed2006

Cost-effectiveness of the treatment and prevention of osteoporosis--a review of the literature and a reference model.

OBJECTIVE: The purpose of the paper is to update and review the latest developments related to modelling and economic evaluation of osteoporosis in the period 2002-2005 and further to present a reference model for the assessment of the cost-effectiveness of the prevention and treatment of osteoporosis. DISCUSSION: The reference model is intended to be used for fracture specific interventions affecting the risk of fracture. An interface version and an extensive description of the model is available on the internet ( http://www.healtheconomics.se ) and also accessible via the International Osteoporosis Foundation ( http://www.osteofound.org ). The purpose of the reference model is to improve the quality and comparability of cost-effectiveness analysis in the osteoporosis field and to serve as a tool for validation of present and future cost-effectiveness models. The reference model allows the cost-effectiveness analysis to be carried out from a societal perspective including intervention, morbidity and mortality costs. The model has been extensively tested and calibrated, and meets the properties of good decision analytic modelling. The model is a state transition Markov cohort model, which is characterised by a 50-year time horizon divided into one year cycle lengths. The following health states are included: "healthy", "hip fracture", "spine fracture", "wrist fracture", "other fracture", and "dead". CONCLUSION: The model is flexible and allows for the estimation of the cost-effectiveness over different ranges for a selected number of variables (e.g., age, fracture risk, cost of intervention).

Aged↗
PubMed2000

A model of palliative care: the palliative medicine program of the Cleveland Clinic Foundation. A World Health Organization Demonstrations Project.

Patients with advanced diseases, both cancer and noncancer, experience high symptom prevalence and psychosocial distress. Multiple unmet needs in the physical, psychosocial and spiritual domains are common. In the United States, palliative medicine is an emerging discipline that focuses on meeting these needs to achieve optimal quality of life for the patient-family unit. The majority of palliative care programs in the U.S. are consultation based. In contrast, the Palliative Medicine Program of the Cleveland Clinic Foundation offers multidisciplinary, comprehensive care from a primary or a consultative focus. The program has clinical, research, and educational components. Established as a consultation service in 1987, the clinical component now includes inpatient and outpatient consultation services, a dedicated acute care inpatient hospital unit, outpatient palliative medicine and cancer pain clinics, palliative home care, hospice home care and hospice residential care. Over 800 new patient consultations took place in 1997. In this paper, development of the program and its structure are described. Challenges to effective communication in a large program within a tertiary care institution are discussed, and strategies designed to meet these challenges are presented.

Communication↗
PubMed1988

Early fractionation methods and the origins of the NSD concept.

The concept of the time factor in radiotherapy originated in the controversy surrounding single-dose and fractionated treatments during the first 20 years of this century. The success of Coutard's fractionated treatments of larynx tumors was an important factor in the abandonment of single-dose treatments. There was considerable research afterwards into the influence of dose rate and overall time of treatment on the responses of normal tissues. Recovery was modeled in terms of the Schwarzschild law of photochemistry, as exemplified by the analysis of Strandqvist in log dose-log time coordinates. Different conventions were followed in defining the time for a single-dose treatment. Subsequently the concept arose that the slopes of isoeffect lines relating dose and treatment time for normal tissues and tumors were different and moreover that the effects of fraction number and overall time could be separated; these developments constituted the foundation of the Ellis NSD model. It had an important influence on clinical practice and was reasonably successful in predicting isoeffective regimens for acute effects. It failed to predict severe late effects after large dose fractions. The dissociation between acute and late effects with altered fractionation led to recognition of the importance of the ratio alpha/beta in characterizing the fractionation sensitivity of tissues.

Humans↗
PubMed2004

Model-based neural decoding of reaching movements: a maximum likelihood approach.

A new paradigm for decoding reaching movements from the signals of an ensemble of individual neurons is presented. This new method not only provides a novel theoretical basis for the task, but also results in a significant decrease in the error of reconstructed hand trajectories. By using a model of movement as a foundation for the decoding system, we show that the number of neurons required for reconstruction of the trajectories of point-to-point reaching movements in two dimensions can be halved. Additionally, using the presented framework, other forms of neural information, specifically neural "plan" activity, can be integrated into the trajectory decoding process. The decoding paradigm presented is tested in simulation using a database of experimentally gathered center-out reaches and corresponding neural data generated from synthetic models.

Action Potentials↗
PubMed2004

Renal water reabsorption: a physiologic retrospective in a molecular era.

The cloning and sequencing of the aquaporin water channels has been an enormous advance in the biomedical sciences, as recognized by the award of the Nobel Prize to Peter Agre last year. Among many other examples, expression of aquaporin proteins in Xenopus oocytes and other heterologous expression systems has confirmed two important models of renal function: the increase in the water permeability of the collecting duct by antidiuretic hormone (ADH), and the mechanism of near isosmotic volume reabsorption by the proximal tubule. These mechanisms were the subjects of intensive investigation by numerous investigators, including Thomas E. Andreoli, who is being honored by this symposium, and who developed many of the key concepts in these areas. His early work with artificial lipid bilayer membranes and the pore-forming antibiotic amphotericin provided the rigorous foundation in experimental and conceptual modeling techniques that he later applied to physiologic and pathophysiologic mechanisms in the kidney, which are summarized in this retrospective. Dr. Andreoli and his colleagues proposed a water channel mechanism for the action of ADH, which has been confirmed by the cloning and heterologous expression of aquaporin-2. They also proposed that volume reabsorption by the proximal tubule depended on a very high hydraulic conductivity and the development of luminal hypotonicity produced by active solute reabsorption. This model has also been confirmed in mice in which aquaporin-1 expression is knocked out, resulting in a low proximal tubule water permeability that exaggerates the development of luminal hypotonicity.

Absorption↗
PubMed2005

Handling over-dispersion of performance indicators.

OBJECTIVES: A problem can arise when a performance indicator shows substantially more variability than would be expected by chance alone, since ignoring such "over-dispersion" could lead to a large number of institutions being inappropriately classified as "abnormal". A number of options for handling this phenomenon are investigated, ranging from improved risk stratification to fitting a statistical model that robustly estimates the degree of over-dispersion. DESIGN: Retrospective analysis of publicly available data on survival following coronary artery bypass grafts, emergency readmission rates, and teenage pregnancies. SETTING: NHS trusts in England. RESULTS: Funnel plots clearly show the influence of the method chosen for dealing with over-dispersion on the "banding" a trust receives. Both multiplicative and additive approaches are feasible and give intuitively reasonable results, but the additive random effects formulation appears to have a stronger conceptual foundation. CONCLUSION: A random effects model may offer a reasonable solution. This method has now been adopted by the UK Healthcare Commission in their derivation of star ratings.

Adolescent↗
PubMed1983

Community diagnosis. A theoretical model for prevention in primary health care.

The current trend in health policies in Sweden is based on a holistic view of health and this means an increased overall responsibility for the county councils. There will be new challenges for the primary health care services, especially concerning epidemiology and health education. The community diagnosis model, which has three levels--namely the descriptive, analytical, and health action programmes--should prove to be a useful tool in this work. This article gives a general review and outlines the theoretical background of community diagnosis as a tool in broad preventive programmes at the local level. Skaraborg is the only county in Sweden that has a broad preventive programme, or health plan. This is based on a political decision taken in 1971. Experience of cooperation between primary health care and the Community Health Unit, at the county level during the seventies has provided the practical foundation for the community diagnosis model. The knowledge made available by the community diagnosis is of great value to the district physician in his daily work. When he knows more about the highly prevalent diseases (such as diabetes and hypertension) in the local community, he can better organize the treatment of these diseases in the health care centre. A knowledge of health risks, individual or environmental can, in the same way, facilitate his participation in the dialogue with members of the community and the planning of preventive measures.

Models, Theoretical↗
PubMed2005

Distinct modes of collagen type I proteolysis by matrix metalloproteinase (MMP) 2 and membrane type I MMP during the migration of a tip endothelial cell: insights from a computational model.

Matrix metalloproteinases (MMPs) are a family of enzymes responsible for the proteolytic processing of extracellular matrix (ECM) structural proteins under physiological and pathological conditions. During sprouting angiogenesis, the MMPs expressed by a single "tip" endothelial cell exhibit proteolytic activity that allows the cells of the sprouting vessel bud to migrate into the ECM. Membrane type I matrix metalloproteinase (MT1-MMP) and the diffusible matrix metalloproteinase MMP2, in the presence of the tissue inhibitor of metalloproteinases TIMP2, constitute a system of proteins that play an important role during the proteolysis of collagen type I matrices. Here, we have formulated a computational model to investigate the proteolytic potential of such a tip endothelial cell. The cell expresses MMP2 in its proenzyme form, pro-MMP2, as well as MT1-MMP and TIMP2. The interactions of the proteins are described by a biochemically detailed reaction network. Assuming that the rate-limiting step of the migration is the ability of the tip cell to carry out proteolysis, we have estimated cell velocities for matrices of different collagen content. The estimated velocities of a few microns per hour are in agreement with experimental data. At high collagen content, proteolysis was carried out primarily by MT1-MMP and localized to the cell leading edge, whereas at lower concentrations, MT1-MMP and MMP2 were found to act in parallel, causing proteolysis in the vicinity of the leading edge. TIMP2 is a regulator of the proteolysis localization because it can shift the activity of MT1-MMP from its enzymatic toward its activatory mode, suggesting a tight mechanosensitive regulation of the enzymes and inhibitor expression. The model described here provides a foundation for quantitative studies of angiogenesis in extracellular matrices of different compositions, both in vitro and in vivo. It also identifies critical parameters whose values are not presently available and which should be determined in future experiments.

Cell Movement↗