Spinal Cord Injury Clinical Registries: Improving Care across the SCI Care Continuum by Identifying Knowledge Gaps.

Timely access and ongoing delivery of care and therapeutic interventions is needed to maximize recovery and function after traumatic spinal cord injury (tSCI). To ensure these decisions are evidence-based, access to consistent, reliable, and valid sources of clinical data is required. The Access to Care and Timing Model used data from the Rick Hansen SCI Registry (RHSCIR) to generate a simulation of healthcare delivery for persons after tSCI and to test scenarios aimed at improving outcomes and reducing the economic burden of SCI. Through model development, we identified knowledge gaps and challenges in the literature and current health outcomes data collection throughout the continuum of SCI care. The objectives of this article were to describe these gaps and to provide recommendations for bridging them. Accurate information on injury severity after tSCI was hindered by difficulties in conducting neurological assessments and classifications of SCI (e.g., timing), variations in reporting, and the lack of a validated SCI-specific measure of associated injuries. There was also limited availability of reliable data on patient factors such as multi-morbidity and patient-reported measures. Knowledge gaps related to structures (e.g., protocols) and processes (e.g., costs) at each phase of care have prevented comprehensive evaluation of system performance. Addressing these knowledge gaps will enhance comparative and cost-effectiveness evaluations to inform decision-making and standards of care. Recommendations to do so were: standardize data element collection and facilitate database linkages, validate and adopt more outcome measures for SCI, and increase opportunities for collaborations with stakeholders from diverse backgrounds.

Forecasting Financial Resources for Future Traumatic Spinal Cord Injury Care Using Simulation Modeling.

Survivors of traumatic spinal cord injury (tSCI) have intense healthcare needs during acute and rehabilitation care and often through the rest of life. To prepare for a growing and aging population, simulation modeling was used to forecast the change in healthcare financial resources and long-term patient outcomes between 2012 and 2032. The model was developed with data from acute and rehabilitation care facilities across Canada participating in the Access to Care and Timing project. Future population and tSCI incidence for 2012 and 2032 were predicted with data from Statistics Canada and the Canadian Institute for Health Information. The projected tSCI incidence for 2012 was validated with actual data from the Rick Hansen SCI Registry of the participating facilities. Using a medium growth scenario, in 2032, the projected median age of persons with tSCI is 57 and persons 61 and older will account for 46% of injuries. Admissions to acute and rehabilitation facilities in 2032 were projected to increase by 31% and 25%, respectively. Because of the demographic shift to an older population, an increase in total population life expectancy with tSCI of 13% was observed despite a 22% increase in total life years lost to tSCI between 2012 and 2032. Care cost increased 54%, and rest of life cost increased 37% in 2032, translating to an additional CAD $16.4 million. With the demographics and management of tSCI changing with an aging population, accurate projections for the increased demand on resources will be critical for decision makers when planning the delivery of healthcare after tSCI.

Methodology of the Access to Care and Timing Simulation Model for Traumatic Spinal Cord Injury Care.

Despite the relatively low incidence of traumatic spinal cord injury (tSCI), the management and care of persons with tSCI can be resource intensive and complex, spanning multiple phases of care and disciplines. Using a simulation model built with a system level view of the healthcare system allows for prediction of the impact of interventions on patient and system outcomes from injury through to community reintegration after tSCI. As has been previously described, the Access to Care and Timing (ACT) project developed a simulation model for tSCI care using techniques from operations research. The objective of this article is to briefly describe the methodology and the application of the ACT Model, as it was used in several of the articles in this focus issue. The approaches employed in this model provide a framework to look into the complexity of interactions both within and among the different SCI programs, sites, and phases of care.

Understanding Length of Stay after Spinal Cord Injury: Insights and Limitations from the Access to Care and Timing Project.

Costs associated with initial hospitalization following spinal cord injury (SCI) are substantial, and a major driver of costs is the length of stay (LOS); that is, the time that the injured individual remains hospitalized prior to community reintegration. Our aim was to study the factors and variables that contribute to LOS following traumatic SCI. Modeling (process mapping of the SCI healthcare delivery system in Canada and discrete event simulation) and regression analysis using a national registry of individuals with acute traumatic SCI in Canada, existing databases, and peer-reviewed literature were used to examine the driver of LOS following traumatic SCI. In different jurisdictions, there is considerable variation in the definitions and methods used to determine LOS following SCI. System LOS can be subdivided into subcomponents, and progression through these is not unidirectional. Modeling reveals that healthcare organization and processes are important contributors to differences in LOS independent of patient demographics and injury characteristics. Future research is required to identify and improve understanding of contributors to LOS following traumatic SCI. This will help enhance system performance. Work in this area will be facilitated by the adoption of common terminology and definitions, as well as by the use of simulations and modeling.

Optimizing Clinical Decision Making in Acute Traumatic Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating event causing lifelong disability that results in a significant decrease in quality of life and immense cost to the health care system, individuals and their families. Providing specialized and timely care can improve recovery and reduce costs, but to make this a reality requires understanding of the current care delivery processes and the care journey. The objective of this focus issue is to examine the current state of health care delivery and discover opportunities to improve access and timing to specialized care for individuals with tSCI. This issue provides an overview of care throughout the SCI continuum and its impact on individuals with tSCI using pan-Canadian data. The issue also presents findings from the RHI Access to Care and Timing (ACT) Project, a multi-center research study involving a multi-disciplinary team of Canadian researchers and clinicians. The initial articles describe the current state of the tSCI care journey including a comparison of environmental barriers, health status, and quality-of-life outcomes between patients living in rural and urban settings. The issue concludes with an article describing the national knowledge translation efforts of using the evidence from the articles published here to inform practice and policy change. Overall, this focus issue will be an excellent reference to guide and optimize evidence informed decision-making in the care of those with tSCI. The evidence can be transferred to care in non-traumatic SCI and other conditions that benefit from timely access to specialized care such as stroke and traumatic brain injury.

The utility of the in vitro micronucleus test for evaluating the genotoxicity of natural and manmade nano-scale fibres.

A range of fibrous materials, including several types of asbestos and carbon fibres with nano scale diameters that had reported positive genotoxicity data (predominantly clastogenicity), were tested in the in vitro micronucleus test (OECD 487) in GLP-compliant studies in Chinese Hamster Ovary cells. Out of eight materials tested, only one (crocidolite, an asbestos fibre) gave a positive response either in the presence or absence of metabolic activation (S9) and at short (3h) or extended (24h) exposure times (p≤0.001). Our data suggest that the commonly used tests for clastogenicity in mammalian cells require extensive modification before fibrous materials are detected as positive, raising questions about the validity of these tests for detecting clastogenic and aneugenic fibrous materials.

Modeling the patient journey from injury to community reintegration for persons with acute traumatic spinal cord injury in a Canadian centre.

BACKGROUND: A patient's journey through the health care system is influenced by clinical and system processes across the continuum of care. METHODS: To inform optimized access to care and patient flow for individuals with traumatic spinal cord injury (tSCI), we developed a simulation model that can examine the full impact of therapeutic or systems interventions across the care continuum for patients with traumatic spinal cord injuries. The objective of this paper is to describe the detailed development of this simulation model for a major trauma and a rehabilitation centre in British Columbia (BC), Canada, as part of the Access to Care and Timing (ACT) project and is referred to as the BC ACT Model V1.0. FINDINGS: To demonstrate the utility of the simulation model in clinical and administrative decision-making we present three typical scenarios that illustrate how an investigator can track the indirect impact(s) of medical and administrative interventions, both upstream and downstream along the continuum of care. For example, the model was used to estimate the theoretical impact of a practice that reduced the incidence of pressure ulcers by 70%. This led to a decrease in acute and rehabilitation length of stay of 4 and 2 days, respectively and a decrease in bed utilization of 9% and 3% in acute and rehabilitation. CONCLUSION: The scenario analysis using the BC ACT Model V1.0 demonstrates the flexibility and value of the simulation model as a decision-making tool by providing estimates of the effects of different interventions and allowing them to be objectively compared. Future work will involve developing a generalizable national Canadian ACT Model to examine differences in care delivery and identify the ideal attributes of SCI care delivery.

Using operations research to plan improvement of the transport of critically ill patients.

OBJECTIVE: Operations research is the application of mathematical modeling, statistical analysis, and mathematical optimization to understand and improve processes in organizations. The objective of this study was to illustrate how the methods of operations research can be used to identify opportunities to reduce the absolute value and variability of interfacility transport intervals for critically ill patients. METHODS: After linking data from two patient transport organizations in British Columbia, Canada, for all critical care transports during the calendar year 2006, the steps for transfer of critically ill patients were tabulated into a series of time intervals. Statistical modeling, root-cause analysis, Monte Carlo simulation, and sensitivity analysis were used to test the effect of changes in component intervals on overall duration and variation of transport times. Based on quality improvement principles, we focused on reducing the 75th percentile and standard deviation of these intervals. RESULTS: We analyzed a total of 3808 ground and air transports. Constraining time spent by transport personnel at sending and receiving hospitals was projected to reduce the total time taken by 33 minutes with as much as a 20% reduction in standard deviation of these transport intervals in 75% of ground transfers. Enforcing a policy of requiring acceptance of patients who have life- or limb-threatening conditions or organ failure was projected to reduce the standard deviation of air transport time by 63 minutes and the standard deviation of ground transport time by 68 minutes. CONCLUSIONS: Based on findings from our analyses, we developed recommendations for technology renovation, personnel training, system improvement, and policy enforcement. Use of the tools of operations research identifies opportunities for improvement in a complex system of critical care transport.

The application of operations research methodologies to the delivery of care model for traumatic spinal cord injury: the access to care and timing project.

The long-term impact of spinal cord injury (SCI) on the health care system imposes a need for greater efficiency in the use of resources and the management of care. The Access to Care and Timing (ACT) project was developed to model the health care delivery system in Canada for patients with traumatic SCI. Techniques from Operations Research, such as simulation modeling, were used to predict the impact of best practices and policy initiatives on outcomes related to both the system and patients. These methods have been used to solve similar problems in business and engineering and may offer a unique solution to the complexities encountered in SCI care delivery. Findings from various simulated scenarios, from the patients' point of injury to community re-integration, can be used to inform decisions on optimizing practice across the care continuum. This article describes specifically the methodology and implications of producing such simulations for the care of traumatic SCI in Canada. Future publications will report on specific practices pertaining to the access to specialized services and the timing of interventions evaluated using the ACT model. Results from this type of research will provide the evidence required to support clinical decision making, inform standards of care, and provide an opportunity to engage policymakers.

Interaction of tea polyphenols and food constituents with model gut epithelia: the protective role of the mucus gel layer.

The luminal surface of the gastrointestinal tract is covered by a mucus gel layer that acts to protect gut epithelial cells from the harsh luminal environment. This study investigated the use of two human colonic adenocarcinoma cell lines, HT29-MTX-E12 and HT29, as a model to mimic gut epithelium with and without a mucus gel layer. The effect of adding the tea polyphenols epigallocatechin gallate (EGCG) and epicatechin (EC) to the cells with subsequent examination of cell morphology and viability was assessed. EGCG, at the concentrations tested, was very toxic to the HT29 cells, but less toxic to the HT29-MTX-E12 cells, suggesting that the mucus gel layer on the HT29-MTX-E12 cells can protect the cells against EGCG toxicity. In contrast, EC had no effect on the viability of either the HT29 or HT29-MTX-E12 cells, suggesting that proteins within the mucus gel layer on the apical surface of gut epithelial cells may bind to the galloyl ring of EGCG. The effect of adding food-related ingredients with the ability to complex with EGCG, ß-casein and maltodextrin, on cell viability was also examined. The presence of ß-casein was very effective in protecting the cells against the toxicity effect of EGCG, but maltodextrin, at the concentration tested, was less effective in protecting against this toxicity. In conclusion, the results demonstrate that the mucus gel layer on HT29 human colonic adenocarcinoma cells may protect these cells against EGCG toxicity. In addition, the data showing reduced toxicity of EC compared to that of EGCG suggest that the cytotoxic effects of high polyphenol levels may be associated with the ability of polyphenols to interact with cellular proteins and mucins.

Secondary Complications in SCI Across the Continuum: Using Operations Research to Predict the Impact and Optimize Management Strategies.

Secondary complications following traumatic spinal cord injury (tSCI) have a tremendous impact on quality of life and health care costs. Although some complications result from the injury itself, many originate from the care provided; complications arising early in the tSCI journey can predispose an individual to recurrence later. To measure the total impact of secondary complications on patient outcomes and health care costs, all the stages of care, from first response to life in the community, must be spanned. Interventions to ameliorate secondary complications need to consider the effects on the whole system and not just individual phases of care; however, such an approach is not common in the literature. To measure the impact of complications as well as the effect of proposed interventions, a partnership between clinical researchers and operations research professionals was formed to develop a discrete-event simulation model of the entire continuum of tSCI care. In this article, we focus on the part of the model concerning common secondary complications (eg, pressure ulcers, pneumonia). We first describe early results from the model, discuss how the effects from the complications impact care throughout the tSCI continuum, and review assumptions of the model. The article concludes with a discussion as to the possible uses of the model, their strengths/limitations, and future directions.

Residential long-term care capacity planning: the shortcomings of ratio-based forecasts.

This paper uses observations from two British Columbia studies to illustrate the shortcomings of widely used ratio-based approaches for residential long-term care capacity planning. It shows that capacity plans based on a fixed ratio of beds per population over age 75 may result in either excess capacity or long wait times for admission. It then investigates the use of linear regression models to obtain a "best" ratio by relating optimal plans derived by rigorous analytical methods to population characteristics and shows that no single ratio applies broadly. While the use of regression is promising, finding these "best" ratios is too analytically complex for general practice. The paper concludes by providing and evaluating an easy-to-use planning method, which we call the average flow model (AFM). The AFM combines demand forecasts with length-of-stay estimates to produce enhanced capacity plans. The AFM is transparent, easily implemented in a spreadsheet and well suited for "what if?" analyses.

Cet article porte sur les observations de deux études britanno-colombiennes afin de dégager les lacunes des démarches de planification de la capacité fondée sur les ratios, grandement utilisées dans les centres d'hébergement et de soins de longue durée. L'article montre que la planification fondée sur un ratio fixe de lits par habitant âgé de plus de 75 ans peut donner lieu soit à un excès de capacité, soit à de longs temps d'attente pour l'admission. L'article examine aussi l'utilisation de modèles de régression linéaire afin d'obtenir le «meilleur¼ ratio en associant des planifications optimales, dérivées de méthodes analytiques rigoureuses, aux caractéristiques de la population et démontre qu'aucun ratio unique ne peut s'appliquer à toutes les situations. Bien que l'emploi de la régression soit prometteur, la recherche des «meilleurs¼ ratios est trop complexe du point de vue analytique. L'article conclut en fournissant et en évaluant une méthode de planification facile à utiliser, que nous nommons le modèle du débit moyen (MDM). Le MDM combine les prévisions de la demande aux estimations des durées de séjour afin de produire une meilleure planification de la capacité. Le MDM est transparent, facile à utiliser dans un tableur et adéquat pour les analyses de simulation.

Systematic comparative protein expression profiling of clear cell renal cell carcinoma: a pilot study based on the separation of tissue specimens by two-dimensional gel electrophoresis.

Proteome-based technologies represent powerful tools for the analysis of protein expression profiles, including the identification of potential cancer candidate biomarkers. Thus, here we provide a comprehensive protein expression map for clear cell renal cell carcinoma established by systematic comparative two-dimensional gel electrophoresis-based protein expression profiling of 16 paired tissue systems comprising clear cell renal cell carcinoma lesions and corresponding tumor-adjacent renal epithelium using overlapping narrow pH gradients. This approach led to the mapping of 348 distinct spots corresponding to 248 different protein identities. By implementing restriction criteria concerning their detection frequency and overall regulation mode, 28 up- and 56 down-regulated single target spots were considered as potential candidate biomarkers. Based on their gene ontology information, these differentially expressed proteins were classified into distinct functional groups and according to their cellular distribution. Moreover, three representative members of this group, namely calbindin, gelsolin, and heart fatty acid-binding protein, were selected, and their expression pattern was analyzed by immunohistochemistry using tissue microarrays. Thus, this pilot study provides a significant update of the current renal cell carcinoma map and defines a number of differentially expressed proteins, but both their potential as candidate biomarkers and clinical relevance has to be further explored in tissues and for body fluids like serum and urine.

Combined analysis of transcriptome and proteome data as a tool for the identification of candidate biomarkers in renal cell carcinoma.

Results obtained from expression profilings of renal cell carcinoma using different "ome"-based approaches and comprehensive data analysis demonstrated that proteome-based technologies and cDNA microarray analyses complement each other during the discovery phase for disease-related candidate biomarkers. The integration of the respective data revealed the uniqueness and complementarities of the different technologies. While comparative cDNA microarray analyses though restricted to up-regulated targets largely revealed genes involved in controlling gene/protein expression (19%) and signal transduction processes (13%), proteomics/PROTEOMEX-defined candidate biomarkers include enzymes of the cellular metabolism (36%), transport proteins (12%), and cell motility/structural molecules (10%). Candidate biomarkers defined by proteomics and PROTEOMEX are frequently shared, whereas the sharing rate between cDNA microarray and proteome-based profilings is limited. Putative candidate biomarkers provide insights into their cellular (dys)function and their diagnostic/prognostic value but still warrant further validation in larger patient numbers. Based on the fact that merely three candidate biomarkers were shared by all applied technologies, namely annexin A4, tubulin alpha-1A chain, and ubiquitin carboxyl-terminal hydrolase L1, the analysis at a single hierarchical level of biological regulation seems to provide only limited results thus emphasizing the importance and benefit of performing rather combinatorial screenings which can complement the standard clinical predictors.

Vesicles from peptidic side-chain polymers synthesized by atom transfer radical polymerization.

Block copolymers can adopt a wide range of morphologies in dilute aqueous solution. There is a significant amount of interest in the use of block copolymer vesicles for a number of applications. We show that a series of oligo(valine) and oligo(phenylalanine) peptides coupled to a methacrylic group can be prepared by conventional peptide coupling techniques. These can be successfully polymerized by atom transfer radical polymerization (ATRP) in hexafluoroisopropanol (HFIP) giving access to poly(ethylene oxide)- b-poly(side-chain peptides). Many of these polymers self-assemble to form vesicles using an organic to aqueous solvent exchange. One example with a divaline hydrophobic block gives a mixture of toroids and vesicles. Circular dichroism demonstrates that secondary structuring is observed in the hydrophobic region of the vesicle walls for the valine side-chain containing polymers.

Impact of mechanism of formation on encapsulation in block copolymer vesicles.

Vesicles prepared from block copolymers have been mooted for the encapsulation of water-soluble molecules. This is because the membranes of polymer vesicles have been shown to be more stable than those in vesicles formed from lipids, with the membrane properties being tuned by the length and nature of the hydrophobic block in the polymer. The generally accepted mechanisms of vesicle formation involve either wrap-up of a lamellar sheet or formation via a sequence of micelle to worm to disks to vesicles. These should lead to efficient encapsulation. Alternatively, a method involving phase separation followed by re-structuring has been recently suggested. Here, we show that this final mechanism holds for vesicles formed from a PEO-b-PDEAMA copolymer by a pH switch and that this mechanism leads to highly inefficient encapsulation on vesicle formation.

Surgical block scheduling in a system of hospitals: an application to resource and wait list management in a British Columbia health authority.

Scheduling surgical specialties in a medical facility is a very complex process. The choice of schedules and resource availability impact directly on the number of patients treated by specialty, cancellations, wait times, and the overall performance of the system. In this paper we present a system-wide model developed to allow management to explore tradeoffs between OR availability, bed capacity, surgeons' booking privileges, and wait lists. We developed a mixed integer programming model to schedule surgical blocks for each specialty into ORs and applied it to the hospitals in a British Columbia Health Authority, considering OR time availability and post-surgical resource constraints. The results offer promising insights into resource optimization and wait list management, showing that without increasing post-surgical resources hospitals could handle more cases by scheduling specialties differently.

Dimerization region of soluble guanylate cyclase characterized by bimolecular fluorescence complementation in vivo.

The ubiquitously expressed nitric oxide (NO) receptor soluble guanylate cyclase (sGC) plays a key role in signal transduction. Binding of NO to the N-terminal prosthetic heme moiety of sGC results in approximately 200-fold activation of the enzyme and an increased conversion of GTP into the second messenger cGMP. sGC exists as a heterodimer the dimerization of which is mediated mainly by the central region of the enzyme. In the present work, we constructed deletion mutants within the predicted dimerization region of the sGC alpha(1)- and beta(1)-subunit to precisely map the sequence segments crucial for subunit dimerization. To track mutation-induced alterations of sGC dimerization, we used a bimolecular fluorescence complementation approach that allows visualizing sGC heterodimerization in a noninvasive manner in living cells. Our study suggests that segments spanning amino acids alpha(1)363-372, alpha(1)403-422, alpha(1)440-459, beta(1)212-222, beta(1)304-333, beta(1)344-363, and beta(1)381-400 within the predicted dimerization region are involved in the process of heterodimerization and therefore in the expression of functional sGC.

Ubiquitin COOH-terminal hydrolase 1: a biomarker of renal cell carcinoma associated with enhanced tumor cell proliferation and migration.

PURPOSE: Renal cell carcinoma (RCC) accounts for 2% to 3% of all malignancies. It represents one of the most radiation- and chemotherapy-resistant tumors and surgical resections are only effective in organ-defined disease. However, RCC is an immunogenic tumor with response rates to immunotherapies between 10% and 20% of the treated patients. Due to the currently inefficient therapies and the low 5-year survival rates of RCC patients, novel diagnostic, prognostic, and therapeutic markers are urgently needed for this disease. EXPERIMENTAL DESIGN: Proteome-based approaches were used to identify (a) differentially expressed proteins in RCC compared with normal kidney epithelium and (b) proteins that are able to induce an antibody response in RCC patients. Based on these experiments, a promising candidate was subsequently validated by reverse transcription-PCR, Western blot analyses, and immunohistochemistry. In addition, functional assays were done in generated transfectants. RESULTS: The ubiquitin COOH-terminal hydrolase L1 (UCHL1) was found to be differentially expressed in both RCC lesions and RCC cell lines and immunoreactive using patients' sera. UCHL1 expression was often down-regulated in primary RCC when compared with normal kidney epithelium but dependent on the RCC subtype, the von Hippel-Lindau phenotype, and the tumor grading. Moreover, the frequency and the level of UCHL1 expression were higher in metastases when compared with primary RCC lesions. Gain-of-function transfectants exhibited a significant higher proliferation and migration rate than UCHL1-negative RCC cells. CONCLUSIONS: UCHL1 expression seems to be associated with the metastatic phenotype of RCC and therefore might serve as potential biomarker for the diagnosis and prognosis of RCC patients.

Frequent loss of HLA-A2 expression in metastasizing ovarian carcinomas associated with genomic haplotype loss and HLA-A2-restricted HER-2/neu-specific immunity.

Defective expression of HLA class I molecules is common in tumor cells and may allow escape from CTL-mediated immunity. We here investigate alterations in expression of HLA class I and their underlying molecular mechanisms in ovarian cancer patients. The HLA class I and HLA-A2 expression levels on noncultured tumor cells of 12 patients diagnosed with ovarian carcinoma were investigated by flow cytometry. Molecular analyses of antigen-processing machinery (APM) components were done in metastatic cancer cells, and the HLA genotype was determined in both these and the primary tumor. HER-2/neu-specific immunity was evaluated by enzyme-linked immunospot assays. The metastatic tumor cells from all patients expressed low levels of HLA class I surface antigens. In six of nine HLA-A2+ patients, HLA-A2 expression was heterogeneous with a subpopulation of tumor cells exhibiting decreased or absent HLA-A2 expression. One patient-derived tumor cell line completely lacked HLA-A2 but exhibited constitutive expression of APM components and high HLA class I expression that was further inducible by IFN-gamma treatment. Genotyping showed a haplotype loss in the metastatic tumor cells, whereas tumor tissue microdissected from the primary tumor exhibited an intact HLA gene complex. Interestingly, HLA-A2-restricted HER-2/neu-specific T-cell responses were evident among the lymphocytes of this patient. Abnormalities in HLA class I antigen expression are common features during the progression of ovarian cancer, and haplotype loss was, for the first time, described as an underlying mechanism.