Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain.

BACKGROUND: Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients. METHODS: Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools. RESULTS: The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools. CONCLUSIONS: Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.

Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically.

Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of NF-kappaB ligand (RANKL), which is a pivotal molecule required for osteoclast formation. In vitro OPG inhibits osteoclast formation and in vivo (administered as Fc-OPG) it reduces hypercalcemia and the establishment of osteolytic lesions in mouse models of tumor cell growth in bone. Osteolysis can be induced by parathyroid hormone-related protein (PTHrP) produced by breast cancer cells that results in an increased osteoblastic RANKL/OPG ratio. We examined the effect of local tumor production of OPG on the ability of breast cancer cells to establish and grow in bone and mammary fat pad. MCF-7 cells or MCF-7 cells overexpressing PTHrP were transfected with full-length OPG and inoculated into the proximal tibiae of athymic nude mice. Mice injected with cells overexpressing PTHrP and OPG showed enhanced tumor growth, increased osteolysis (2-fold compared with MCF-7 cells overexpressing PTHrP), and altered histology that was reflective of a less differentiated (more aggressive) phenotype compared with MCF-7 cells. In contrast, administration of recombinant Fc-OPG reduced tumor growth and limited osteolysis even in mice inoculated with OPG overexpressing cells. Similarly, OPG overexpression by breast cancer cells enhanced tumor growth following orthotopic inoculation. These results indicate that OPG overexpression by breast cancer cells increases tumor growth in vivo and that there are strikingly different responses between therapeutically administered Fc-OPG and full-length OPG produced by tumor cells.

The effects of coal tar based pavement sealer on amphibian development and metamorphosis.

Coal tar based pavement sealers are applied regularly to parking lots and contain significant levels of polycyclic aromatic hydrocarbons (PAHs). Recently a connection between elevated levels of PAHs in streams and storm water runoff from parking lots has been identified. We tested the hypothesis that coal tar based pavement sealers could alter the survival, growth, and development of amphibians using a model species, Xenopus laevis. Ten fertilized individuals were placed singly into containers containing one of four treatment groups: control, low, medium, and high (respective nominal concentrations 0, 3, 30, and 300 ppm TPAH). All of the individuals in the high exposure group died by the sixth day of exposure. By day 14 there were significant patterns of stunted growth (p<0.0001) and slower development (p=0.006) in the medium and high exposure groups relative to the control and low treatment groups. When the experiment ended on day 52 the control and low-dose individuals had achieved more advanced developmental stages than the medium group (p=0.0007). These data indicate that these commonly used coal tar based pavement sealers may potentially affect the amphibian taxa living in areas that receive storm water runoff.

Isolation of a human homolog of osteoclast inhibitory lectin that inhibits the formation and function of osteoclasts.

UNLABELLED: Osteoclast inhibitory lectin (OCIL) is a newly recognized inhibitor of osteoclast formation. We identified a human homolog of OCIL and its gene, determined its regulation in human osteoblast cell lines, and established that it can inhibit murine and human osteoclast formation and resorption. OCIL shows promise as a new antiresorptive. INTRODUCTION: Murine and rat osteoclast inhibitory lectins (mOCIL and rOCIL, respectively) are type II membrane C-type lectins expressed by osteoblasts and other extraskeletal tissues, with the extracellular domain of each, expressed as a recombinant protein, able to inhibit in vitro osteoclast formation. MATERIALS AND METHODS: We isolated the human homolog of OCIL (hOCIL) from a human fetal cDNA library that predicts a 191 amino acid type II membrane protein, with the 112 amino acid C-type lectin region in the extracellular domain having 53% identity with the C-type lectin sequences of rOCIL and mOCIL. The extracellular domain of hOCIL was expressed as a soluble recombinant protein in E. coli, and its biological effects were determined. RESULTS AND CONCLUSIONS: The hOCIL gene is 25 kb in length, comprised of five exons, and is a member of a superfamily of natural killer (NK) cell receptors encoded by the NK gene complex located on chromosome 12. Human OCIL mRNA expression is upregulated by interleukin (IL)-1alpha and prostaglandin E2 (PGE2) in a time-dependent manner in human osteogenic sarcoma MG63 cells, but not by dexamethasone or 1,25 dihydroxyvitamin D3. Soluble recombinant hOCIL had biological effects comparable with recombinant mOCIL on human and murine osteoclastogenesis. In addition to its capacity to limit osteoclast formation, OCIL was also able to inhibit bone resorption by mature, giant-cell tumor-derived osteoclasts. Thus, a human homolog of OCIL exists that is highly conserved with mOCIL in its primary amino acid sequence (C-lectin domain), genomic structure, and activity to inhibit osteoclastogenesis.

T-cells mediate an inhibitory effect of interleukin-4 on osteoclastogenesis.

IL-4 is an important cytokine that can influence bone. We identified two distinct actions of IL-4 to inhibit osteoclast formation: one direct on osteoclast progenitors and the second through the production of a novel T-cell surface-associated molecule(s). These data show a new link between the immune system and bone. The Th2 cytokine interleukin (IL)-4 inhibits osteoclast formation in vitro but also acts on other cell types found in bone, including T-cells and macrophages. Because some osteoclastogenesis inhibitors (e.g., IL-12) act indirectly through T-cells, we investigated IL-4 action on osteoclastogenesis in the presence of T-cells. Osteoclast formation from murine spleen cells treated with RANKL and macrophage colony-stimulating factor (M-CSF) was blocked by IL-4 even when spleen cells were depleted of T-cells (Thy 1.2+) and/or B-cells (B220+). Also, IL-4 inhibited osteoclastogenesis in RANKL/M-CSF-stimulated adherent spleen cells, Rag1 -/- (lymphocyte-deficient) spleen cells, and bone marrow macrophages, indicating an action on myelomonocytic cells to block osteoclastogenesis. In contrast, IL-4 did not inhibit osteoclastogenesis in cells from IL-4 receptor null mice (IL-4R -/-). However, when wildtype T-cells were added to IL-4R -/- spleen cell cultures, IL-4 inhibited osteoclast formation, indicating a T-cell-dependent action. Osteoclast formation in RANKL-stimulated RAW 264.7 cells was not inhibited by IL-4 unless T-cells were added to the culture. Separation of RAW 264.7 cells and T-cells by semipermeable membrane ablated this action of IL-4, suggesting the induction of a membrane-associated osteoclastogenesis inhibitor. However, membrane-bound inhibitors thymic shared antigen-1 (TSA-1) and osteoclast inhibitory lectin (OCIL) were not regulated by IL-4. In summary, at least two mechanisms of IL-4 -mediated osteoclastogenesis inhibition exist, including a direct action on myelomonocytic progenitors (from which osteoclasts derive) and an indirect action through T-cells that may involve novel anti-osteoclastic factors.