Clinical Complexity in Medicine: A Measurement Model of Task and Patient Complexity.

BACKGROUND: Complexity in medicine needs to be reduced to simple components in a way that is comprehensible to researchers and clinicians. Few studies in the current literature propose a measurement model that addresses both task and patient complexity in medicine. OBJECTIVE: The objective of this paper is to develop an integrated approach to understand and measure clinical complexity by incorporating both task and patient complexity components focusing on the infectious disease domain. The measurement model was adapted and modified for the healthcare domain. METHODS: Three clinical infectious disease teams were observed, audio-recorded and transcribed. Each team included an infectious diseases expert, one infectious diseases fellow, one physician assistant and one pharmacy resident fellow. The transcripts were parsed and the authors independently coded complexity attributes. This baseline measurement model of clinical complexity was modified in an initial set of coding processes and further validated in a consensus-based iterative process that included several meetings and email discussions by three clinical experts from diverse backgrounds from the Department of Biomedical Informatics at the University of Utah. Inter-rater reliability was calculated using Cohen's kappa. RESULTS: The proposed clinical complexity model consists of two separate components. The first is a clinical task complexity model with 13 clinical complexity-contributing factors and 7 dimensions. The second is the patient complexity model with 11 complexity-contributing factors and 5 dimensions. CONCLUSION: The measurement model for complexity encompassing both task and patient complexity will be a valuable resource for future researchers and industry to measure and understand complexity in healthcare.

Prevalence of endometriosis in epithelial ovarian cancer. Analysis of the associated clinical features and study on molecular mechanisms involved in the possible causality.

PURPOSE OF INVESTIGATION: To determine the prevalence of endometriosis in patients with epithelial ovarian cancer and explore the differences between women with endometrioid and clear-cell histologic subtypes with and without associated endometriosis. MATERIALS AND METHODS: The medical charts of 496 patients with epithelial ovarian cancer at the Hospital Virgin de la Arrixaca (Murcia, Spain) between 1971 and 2010 were reviewed. RESULTS: Endometriosis was present in 27 (5.4%) of the 496 cases (p < 0001), and was associated with the endometrioid histotype in 13/45 cases (29%) and with the clear cell histotype in 7/22 (32%). The prevalence of an association with endometriosis according to histologic type was 28.8% (13/45) for endometrioid carcinoma and 31.8% (7/22) for clear-cell carcinoma. CONCLUSION: Both endometrioid and clear-cell ovarians tumours are associated with pelvic endometriosis. Patients with endometiosis associated ovarian cancer differ from non-endometiosis associated ovarian cancer in their clinical characteristics.

Complete pulse characterization of quantum dot mode-locked lasers suitable for optical communication up to 160 Gbit/s.

A complete characterization of pulse shape and phase of a 1.3 microm, monolithic-two-section, quantum-dot mode-locked laser (QD-MLL) at a repetition rate of 40 GHz is presented, based on frequency resolved optical gating. We show that the pulse broadening of the QD-MLL is caused by linear chirp for all values of current and voltage investigated here. The chirp increases with the current at the gain section, whereas larger bias at the absorber section leads to less chirp and therefore to shorter pulses. Pulse broadening is observed at very high bias, likely due to the quantum confined stark effect. Passive- and hybrid-QD-MLL pulses are directly compared. Improved pulse intensity profiles are found for hybrid mode locking. Via linear chirp compensation pulse widths down to 700 fs can be achieved independent of current and bias, resulting in a significantly increased overall mode-locking range of 101 MHz. The suitability of QD-MLL chirp compensated pulse combs for optical communication up to 160 Gbit/s using optical-time-division multiplexing are demonstrated by eye diagrams and autocorrelation measurements.

Submonolayer quantum dots for high speed surface emitting lasers.

We report on progress in growth and applications of submonolayer (SML) quantum dots (QDs) in high-speed vertical-cavity surface-emitting lasers (VCSELs). SML deposition enables controlled formation of high density QD arrays with good size and shape uniformity. Further increase in excitonic absorption and gain is possible with vertical stacking of SML QDs using ultrathin spacer layers. Vertically correlated, tilted or anticorrelated arrangements of the SML islands are realized and allow QD strain and wavefunction engineering. Respectively, both TE and TM polarizations of the luminescence can be achieved in the edge-emission using the same constituting materials. SML QDs provide ultrahigh modal gain, reduced temperature depletion and gain saturation effects when used in active media in laser diodes. Temperature robustness up to 100 °C for 0.98 µm range vertical-cavity surface-emitting lasers (VCSELs) is realized in the continuous wave regime. An open eye 20 Gb/s operation with bit error rates better than 10-12has been achieved in a temperature range 25-85 °Cwithout current adjustment. Relaxation oscillations up to ∼30 GHz have been realized indicating feasibility of 40 Gb/s signal transmission.

Modeling end-users' acceptance of a knowledge authoring tool.

OBJECTIVES: Knowledge bases comprise a vital component in the classic medical expert system model, yet the knowledge acquisition process by which they are created has been characterized as highly iterative and labor-intensive. The difficulty of this process underscores the importance of knowledge authoring tools that satisfy the demands of end-users. The authors hypothesize that the acceptability of a knowledge authoring tool for the creation of medical knowledge base content can be predicted by an accepted model in the information technology (IT) field, specifically the Technology Acceptance Model (TAM). METHODS: An online survey was conducted amongst knowledge base authors who had previously established experience with the authoring tool software. The Likert-based questions in the survey were patterned directly after accepted TAM constructs with minor modifications to particularize them to the software being used. The results were analyzed using structural equation modeling. RESULTS: The TAM performed well in predicting endusers' behavioral intentions to use the knowledge authoring tool. Five out of seven goodness-of-fit statistics indicate that the model represents the behavioral intentions of the authors well. All but one of the hypothesized relationships specified by the TAM were significant with p values less than 0.05. CONCLUSIONS: The TAM provides an adequate means by which development teams can anticipate and better understand what aspects of a knowledge authoring tool are most important to their target audience. Further research involving other behavioral models and an expanded user base will be necessary to better understand the scope of issues that factor into acceptability.

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma.

The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro. To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-alpha were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) - neuregulin-1, amphiregulin, HB-EGF - promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10(5) molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

"On-demand" access to a multi-purpose collection of best practice standards.

On-demand" information has been chosen by clinicians as one of their preferred modes of interaction with computers when in need of information about evidence-based practices. However, most of the clinicians' information needs remain unmet, especially due to a lack of easy access to resources that are able to satisfy these needs in a timely manner. We present three scenarios indicating opportunities for a clinical information system to present interdisciplinary standards at the point-of-care. In each scenario, we highlight the importance of context of use and the opportunities offered by the clinical workflow for providing access to relevant "on-demand" information. We also present an XML model for structuring non-physician interdisciplinary standards, in an effort to fulfill the requirements exposed by the three scenarios.

The knowledge authoring tool: an XML-based knowledge acquisition environment.

As part of an enterprise effort to develop new clinical information systems at Intermountain Health Care, we are developing a Knowledge Authoring Tool that facilitates the development of medical knowledge. At present, users of the application can compose order sets and other clinical knowledge documents based upon XML schemas. The flexible nature of the application allows for the authoring of new types of documents once an XML schema and accompanying web form have been developed and stored in a shared repository. The need for a knowledge acquisition tool stems largely from the desire for medical practitioners to be able to write their own content for clinical use. We hypothesize that knowledge content for clinical use can be successfully implemented around XML-based document frameworks containing structured and coded knowledge.

Accuracy of endometrial biopsy with the Cornier pipelle for diagnosis of endometrial cancer and atypical hyperplasia.

OBJECTIVE: To establish the accuracy of endometrial biopsy with the Cornier pipelle in the diagnosis of endometrial cancer and atypical endometrial hyperplasia in our milieu. MATERIAL AND METHOD: We reviewed 1,535 anatomopathologic reports on endometrial biopsies taken from outpatients using the Cornier pipelle between 1997 and 2000, in pre- and postmenopausal patients with abnormal vaginal bleeding. In 168 patients (10.9%), curettage and/or hysterectomy was subsequently carried out. In these cases, the anatomopathologic reports were compared to determine sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratio (LR). RESULTS: Sensitivity was 84.2%, specificity was 99.1%, accuracy was 96.9%, PPV was 94.1%, NPV was 93.7% and LR was 93.5. In 249 cases (16.09%) the material was insufficient for study. CONCLUSION: We determined that endometrial biopsy taken with the Cornier pipelle is, as we practice it, an accurate method for diagnosis of endometrial cancer and its precursor, atypical hyperplasia.

Comparison of two knowledge bases on the detection of drug-drug interactions.

This paper describes a drug ordering decision support system that helps with the prevention of adverse drug events by detecting drug-drug interactions in drug orders. The architecture of the system was devised in order to facilitate its use attached to physician order entry systems. The described model focuses in issues related to knowledge base maintenance and integration with external systems. Finally, a retrospective study was performed. Two knowledge bases, developed by different academic centers, were used to detect drug-drug interactions in a dataset with 37,237 drug prescriptions. The study concludes that the proposed knowledge base architecture enables content from other knowledge sources to be easily transferred and adapted to its structure. The study also suggests a method that can be used on the evaluation and refinement of the content of drug knowledge bases.

Design, implementation and evaluation of a clinical decision support system to prevent adverse drug events.

Adverse drug events are known to be a major health problem worldwide. It is estimated that the annual costs related to these events in the United States are greater than the total costs with cardiovascular disease care. Decision support systems that assist drug ordering have demonstrated to be a powerful tool to prevent prescription errors and adverse drug events. On the other hand, some issues related to the development, implementation, configuration, and evaluation of these decision support systems still need further research. This paper presents the development and evaluation of a decision support system prototype that helps with the prevention of adverse drug events by detecting drug-drug interactions in drug orders. The structure of the system tries to solve some of the problems described by the literature, such as integration with hospital information systems, adaptability to local needs, and knowledge base maintenance. The proposed model has shown to be an effective method for representing drug-drug interactions. The prototype was evaluated by a retrospective study using a dataset with 37.237 prescriptions. The system was able to detect 10.044 (27.0%) orders containing one or more drug-drug interactions. Among these interactions, 6.4% had high severity. In a future study, it is intended to apply the developed system in a real-time on-line environment, evaluating the benefits achieved in terms of improvement in medical practice and patient outcomes.

Extensive characterization of dendritic cells generated in serum-free conditions: regulation of soluble antigen uptake, apoptotic tumor cell phagocytosis, chemotaxis and T cell activation during maturation in vitro.

Dendritic cells (DC) play a key role in the initiation of primary immune response, and pilot clinical studies have demonstrated their ability to induce efficient antitumor immunity. However, the DC used in these clinical trials were generated with various serum sources and were poorly characterized. Obtaining fully characterized DC in controlled and reproducible culture conditions is thus of major interest. We demonstrate that X-VIVO 15 medium supplemented with 2% human albumin can be used to obtain DC. The phenotypic and functional characteristics of these clinical-grade DC were analyzed according to their differentiation stages. CD83 immature DC, obtained in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, were able to endocyte soluble antigens and internalize apoptotic tumor cells, and also expressed receptors for inflammatory chemokines. Tumor necrosis factor-alpha (TNF-alpha) induced irreversible DC maturation in association with a decreased ability to uptake antigens and an increased allostimulatory capacity. CD83+ mature DC became responsive to EBI1 ligand chemokine (ELC), a chemokine specifically expressed in secondary lymphoid organs. In addition, mature DC obtained with TNF-alpha produced IL-12 and some IL-10 in response to CD40 stimulation. In conclusion, we present well-defined culture conditions allowing the control of DC maturation for clinical or fundamental studies.

Effect of N-acetylcysteine on vascular endothelium function in aorta from oophorectomized rats.

1. Experiments were performed to examine and to compare vascular endothelial function in aortic rings from oophorectomized and from ovary-intact rats and to test the effect of thiol compound as N-acetylcysteine on endothelial function. 2. In precontracted aortic rings from oophorectomized and intact rats, vascular endothelial function was evaluated by measuring changes in isometric force in response to cumulative doses of superoxide dismutase, acetylcholine and sodium nitroprusside. 3. In studies designed to assess the tone-related release of nitric oxide from aortic rings moderately precontracted with phenylephrine, superoxide dismutase produced a lower concentration-related relaxant response in aortic rings from oophorectomized rats than from ovary intact rats. 4. Acetylcholine caused a concentration- and endothelium-dependent relaxation of less magnitude in aortic rings from oophorectomized animals compared with those from ovary-intact rats. Addition of N-omega-nitro-L-arginine methyl ester eliminated the relaxation induced by both superoxide dismutase and acetylcholine. 5. No differences between groups were noticed in the concentration-relaxation curve induced by sodium nitroprusside. 6. Preincubation with N-acetylcysteine normalized the depressed vasorelaxant response to acetylcholine in the aortic rings from oophorectomized rats, whereas the concentration-response curve for acetylcholine in aortic rings from ovary-intact rats did not alter. 7. These results suggest that the absence of ovary estrogens is associated with a vascular endothelium dysfunction that can be reverted by addition of N-acetylcysteine, a thiol-containing compound with a free radical scavenger effect.

Role of nitric oxide on the central hemodynamic response to acute volume expansion in the pregnant rat.

OBJECTIVES: Our hypothesis was that during pregnancy nitric oxide acts as mediator in the hemodynamic response to volume expansion. STUDY DESIGN: The study was performed on 12 rats on days 19 to 20 of pregnancy. Six rats were injected intravenously with hexamethonium bromide plus the inhibitor of nitric oxide synthase L-nitro-arginine methyl ester. For a control group, six rats were injected with hexamethonium bromide plus the L-nitro-arginine methyl ester vehicle. A volume expansion (1.2% body weight) was performed in both groups by intravenous infusion of bovine albumin (6%) solution. RESULTS: In the control group volume expansion induced a hyperdynamic circulation characterized by increased cardiac output, decreased total vascular resistance, and no change in arterial pressure; however, in the study group volume expansion induced a pressor response without hyperdynamic circulation. CONCLUSION: During pregnancy volume expansion induces a hyperdynamic circulatory state possibly mediated by nitric oxide release. A defect in the release of nitric oxide may be responsible for an inadequate hemodynamic response to volume expansion.

Generation of virtually pure and potentially proliferating dendritic cells from non-CD34 apheresis cells from patients with multiple myeloma.

Defects in immune response are often reported in patients with multiple myeloma (MM). Because dendritic cells (DCs) are key effectors in promoting cellular immunity and are potential vectors for immunotherapy, we have evaluated the ability of MM patients' apheresis cells to generate DCs in short-term cultures. We report here the obtaining of a virtually pure population of DCs (89.7% +/- 6%, n = 18) after culturing adherent apheresis cells for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF ) and interleukin-4 (IL-4). These cells exhibited all the phenotypic characteristics (CD1a+, HLA-DR+, CD80+, CD40+, CD14-) and the MLR stimulating capacity of mature DCs. The number of DCs reached 12. 1% of the initial apheresis cell number put into culture. As DC precursors involved in this model were CD34(-) cells, the unabsorbed cells resulting from clinical-grade CD34 purification were a reliable source of DCs, even after freezing. The proliferation of DC precursors could be increased 10-fold by adding IL-3 and tumor necrosis factor-alpha together with GM-CSF and IL-4. Thus, CD34- apheresis cells from patients with MM offer an interesting source for generating pure, functional, and potentially proliferating DCs.