Eric F. Swart

In vitro analysis of a hepatic device with intrinsic microvascular-based channels

A novel microfluidics-based bilayer device with a discrete parenchymal chamber modeled upon hepatic organ architecture is described. The microfluidics network was designed using computational models to provide appropriate flow behavior based on physiological data from human microvasculature. Patterned silicon wafer molds were used to generate films with the vascular-based microfluidics network design and parenchymal chamber by soft lithography. The assembled device harbors hepatocytes behind a nanoporous membrane that permits transport of metabolites and small proteins while protecting them from the effects of shear stress. The device can sustain both human hepatoma cells and primary rat hepatocytes by continuous in vitro perfusion of medium, allowing proliferation and maintaining hepatic functions such as serum protein synthesis and metabolism. The design and fabrication processes are scalable, enabling the device concept to serve as both a platform technology for drug discovery and toxicity, and for the continuing development of an improved liver-assist device.

Noninvasive imaging of pancreatic inflammation and its reversal in type 1 diabetes

A major stumbling block for research on and treatment of type 1 diabetes is the inability to directly, but noninvasively, visualize the lymphocytic/inflammatory lesions in the pancreatic islets. One potential approach to surmounting this impediment is to exploit MRI of magnetic nanoparticles (MNP) to visualize changes in the microvasculature that invariably accompany inflammation. MNP-MRI did indeed detect vascular leakage in association with insulitis in murine models of type 1 diabetes, permitting noninvasive visualization of the inflammatory lesions in vivo in real time. We demonstrate, in proof-of-principle experiments, that this strategy allows one to predict, within 3 days of completing treatment with an anti-CD3 monoclonal antibody, which NOD mice with recent-onset diabetes are responding to therapy and may eventually be cured. Importantly, an essentially identical MNP-MRI strategy has previously been used with great success to image lymph node metastases in prostate cancer patients. This success strongly argues for rapid translation of these preclinical observations to prediction and/or stratification of type 1 diabetes and treatment of individuals with the disease; this would provide a crucially needed early predictor of response to therapy.

Murine B16 melanomas expressing high levels of the chemokine stromal-derived factor-1/CXCL12 induce tumor-specific T cell chemorepulsion and escape from immune control.

The chemokine, stromal-derived factor-1/CXCL12, is expressed by normal and neoplastic tissues and is involved in tumor growth, metastasis, and modulation of tumor immunity. T cell-mediated tumor immunity depends on the migration and colocalization of CTL with tumor cells, a process regulated by chemokines and adhesion molecules. It has been demonstrated that T cells are repelled by high concentrations of the chemokine CXCL12 via a concentration-dependent and CXCR4 receptor-mediated mechanism, termed chemorepulsion or fugetaxis. We proposed that repulsion of tumor Ag-specific T cells from a tumor expressing high levels of CXCL12 allows the tumor to evade immune control. Murine B16/OVA melanoma cells (H2b) were engineered to constitutively express CXCL12. Immunization of C57BL/6 mice with B16/OVA cells lead to destruction of B16/OVA tumors expressing no or low levels of CXCL12 but not tumors expressing high levels of the chemokine. Early recruitment of adoptively transferred OVA-specific CTL into B16/OVA tumors expressing high levels of CXCL12 was significantly reduced in comparison to B16/OVA tumors, and this reduction was reversed when tumor-specific CTLs were pretreated with the specific CXCR4 antagonist, AMD3100. Memory OVA-specific CD8+ T cells demonstrated antitumor activity against B16/OVA tumors but not B16/OVA.CXCL12-high tumors. Expression of high levels of CXCL12 by B16/OVA cells significantly reduced CTL colocalization with and killing of target cells in vitro in a CXCR4-dependent manner. The repulsion of tumor Ag-specific T cells away from melanomas expressing CXCL12 confirms the chemorepellent activity of high concentrations of CXCL12 and may represent a novel mechanism by which certain tumors evade the immune system.

Prevention and screening programs for anterior cruciate ligament injuries in young athletes: a cost-effectiveness analysis.

BACKGROUND Anterior cruciate ligament (ACL) injuries are common among young athletes. Biomechanical studies have led to the development of training programs to improve neuromuscular control and reduce ACL injury rates as well as screening tools to identify athletes at higher risk for ACL injury. The purpose of this study was to evaluate the cost-effectiveness of these training methods and screening strategies for preventing ACL injuries. METHODS A decision-analysis model was created to evaluate three strategies for a population of young athletes participating in organized sports: (1) no training or screening, (2) universal neuromuscular training, and (3) universal screening, with neuromuscular training for identified high-risk athletes only. Risk of injury, risk reduction from training, and sensitivity and specificity of screening were based on published data from clinical trials. Costs of training and screening programs were estimated on the basis of the literature. Sensitivity analyses were performed on key model parameters to evaluate their effect on base case conclusions. RESULTS Universal neuromuscular training of all athletes was the dominant strategy, with better outcomes and lower costs compared with screening. On average, the implementation of a universal training program would save

Dedicated Perioperative Hip Fracture Comanagement Programs are Cost-effective in High-volume Centers: An Economic Analysis

100 per player per season, and would reduce the incidence of ACL injury from 3% to 1.1% per season. Screening was not cost-effective within the range of reported sensitivity and specificity values. CONCLUSIONS AND CLINICAL RELEVANCE Given its low cost and ease of implementation, neuromuscular training of all young athletes represents a cost-effective strategy for reducing costs and morbidity from ACL injuries. While continued innovations on inexpensive and accurate screening methods to identify high-risk athletes remain of interest, improving existing training protocols and implementing neuromuscular training into routine training for all young athletes is warranted.

The Effects of Pain, Supination, and Grip Strength on Patient-Rated Disability After Operatively Treated Distal Radius Fractures

BackgroundOsteoporotic hip fractures are common injuries typically occurring in patients who are older and medically frail. Studies have suggested that creation of a multidisciplinary team including orthopaedic surgeons, internal medicine physicians, social workers, and specialized physical therapists, to comanage these patients can decrease complication rates, improve time to surgery, and reduce hospital length of stay; however, they have yet to achieve widespread implementation, partly owing to concerns regarding resource requirements necessary for a comanagement program.Questions/PurposesWe performed an economic analysis to determine whether implementation of a comanagement model of care for geriatric patients with osteoporotic hip fractures would be a cost-effective intervention at hospitals with moderate volume. We also calculated what annual volume of cases would be needed for a comanagement program to “break even”, and finally we evaluated whether universal or risk-stratified comanagement was more cost effective.MethodsDecision analysis techniques were used to model the effect of implementing a systems-based strategy to improve inpatient perioperative care. Costs were obtained from best-available literature and included salary to support personnel and resources to expedite time to the operating room. The major economic benefit was decreased initial hospital length of stay, which was determined via literature review and meta-analysis, and a health benefit was improvement in perioperative mortality owing to expedited preoperative evaluation based on previously conducted meta-analyses. A break-even analysis was conducted to determine the annual case volume necessary for comanagement to be either (1) cost effective (improve health-related quality of life enough to be worth additional expenses) or (2) result in cost savings (actually result in decreased total expenses). This calculation assumed the scenario in which a hospital could hire only one hospitalist (and therapist and social worker) on a full-time basis. Additionally, we evaluated the scenario where the necessary staff was already employed at the hospital and could be dedicated to a comanagement service on a part-time basis, and explored the effect of triaging only patients considered high risk to a comanagement service versus comanaging all geriatric patients. Finally, probabilistic sensitivity analysis was conducted on all critical variables, with broad ranges used for values around which there was higher uncertainty.ResultsFor the base case, universal comanagement was more cost effective than traditional care and risk-stratified comanagement (incremental cost effectiveness ratios of USD 41,100 per quality-adjusted life-year and USD 81,900 per quality-adjusted life-year, respectively). Comanagement was more cost effective than traditional management as long as the case volume was more than 54 patients annually (range, 41–68 patients based on sensitivity analysis) and resulted in cost savings when there were more than 318 patients annually (range, 238–397 patients). In a scenario where staff could be partially dedicated to a comanagement service, universal comanagement was more cost effective than risk-stratified comanagement (incremental cost effectiveness of USD 2300 per quality-adjusted life-year), and both comanagement programs had lower costs and better outcomes compared with traditional management. Sensitivity analysis was conducted and showed that the level of uncertainty in key variables was not high enough to change the core conclusions of the model.ConclusionsImplementation of a systems-based comanagement strategy using a dedicated team to improve perioperative medical care and expedite preoperative evaluation is cost effective in hospitals with moderate volume and can result in cost savings at higher-volume centers. The optimum patient population for a comanagement strategy is still being defined.Level of EvidenceLevel 1, Economic and Decision Analysis.

Diagnosis of Occult Scaphoid Fractures: A Cost-Effectiveness Analysis.

PURPOSE The correlation between physician-observed parameters and patient-rated disability in distal radius fractures is complex and poorly understood. Anecdotal clinical experience suggests that supination is an important factor in the return of functional status after distal radius fracture. To explore this relationship, we conducted a retrospective multivariate linear regression analysis of an existing patient database to evaluate the hypothesis that range of motion and other objective parameters are important determinants of patient-rated disability. METHODS We analyzed a prospectively gathered registry of patients undergoing operative fixation of distal radius fractures using physical examination parameters measured at each follow-up visit and patient-based outcomes including Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and visual analog scale for pain. We constructed a multivariate linear regression model to evaluate the association of range of motion, grip strength, and visual analog scale score with the DASH score. RESULTS We analyzed data from 190 patients and 611 total clinic visits. Pain, grip strength, and supination were significantly correlated with DASH scores, controlling for all other factors. These 3 variables were able to predict 56% of the variability of the DASH score. Flexion-extension, radial-ulnar deviation, and pronation had no significant correlation to DASH score. CONCLUSIONS Pain, strength, and supination appear to be important determinants of patient-rated outcomes after distal radius fracture. Pain and strength continuously improve over time up to 2 years after surgery, whereas supination plateaus more quickly, usually within the first 3 to 6 months. TYPE OF STUDY/LEVEL OF EVIDENCE Diagnostic II.

How long should patients be kept non-weight bearing after ankle fracture fixation? A survey of OTA and AOFAS members

BACKGROUND Scaphoid fractures are common but may be missed on initial radiographs. Advanced imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) have improved diagnostic accuracy, but at an increased initial cost. The purpose of this study was to evaluate the cost-effectiveness of immediate advanced imaging for suspected occult scaphoid fractures. METHODS A decision analysis model was created to evaluate three diagnostic strategies for patients with concerning history and examination but negative radiographs: (1) empiric cast immobilization with orthopaedic follow-up and repeat radiography at two weeks post-injury, (2) immediate CT scanning, or (3) immediate MRI. Prevalence of occult scaphoid fracture, sensitivity and specificity of CT and MRI, and risks and outcomes of a missed fracture were derived from published clinical trials. Costs of imaging, lost worker productivity, and surgical costs of nonunion surgery were estimated on the basis of the literature. RESULTS Advanced imaging was dominant over empiric cast immobilization; advanced imaging had lower costs and its health outcomes were projected to be better than those of empiric cast immobilization. MRI was slightly more cost-effective than CT on the basis of the mean published diagnostic performance, but was highly sensitive to test performance characteristics. Advanced imaging would have to increase in cost to more than

Operative Treatment of Rib Fractures in Flail Chest Injuries: A Meta-analysis and Cost-effectiveness Analysis

2000 or decrease in sensitivity to <25% for CT or <32% for MRI for empiric cast immobilization to be cost-effective. CONCLUSIONS Given its relatively low cost and high diagnostic accuracy, advanced imaging for suspected scaphoid fractures in the setting of negative radiographs represents a cost-effective strategy for reducing both costs and morbidity. The decision to use CT compared with MRI is a function of individual institutional costs and local test performance characteristics.

ORIF or arthroplasty for displaced femoral neck fractures in patients younger than 65 years old an economic decision analysis

BACKGROUND Ankle fractures are common injuries treated routinely by orthopaedic surgeons. A variety of different post-operative protocols have been described with differing periods of non-weight bearing after surgery. The aim of this study was to identify how patient injury characteristics and medical comorbidities contribute to the period of non-weight bearing chosen by orthopaedic surgeons after open reduction and internal fixation of rotational ankle fractures. METHODS A cross sectional expert opinion survey was administered to members of the AOFAS as well as OTA to determine how long they would instruct patients to be non-weight bearing after open reduction and internal fixation of ankle fractures. Three different injury characteristics were described: supination external rotation type 4 equivalents, bimalleolar, and trimalleolar patterns. These patterns were combined with three different medical statuses: young and healthy, older and healthy, and older with significant medical comorbidity. Respondents selected how long they would keep the patient non-weight bearing after surgery for each of the potential scenarios. Finally, they were directly asked which factors they felt affected their decision about length of time to keep patients non-weight bearing. RESULTS Seven hundred and two surgeons (31%) responded to the survey. The average time of non-weight bearing selected varied from 4.9 (± 3.1) weeks for in young, healthy patients with SER4 equivalent injuries to 7.6 (± 6.0) weeks for older patients with medical comorbidities with trimalleolar fractures. Responses had a high degree of heterogeneity, but both injury pattern and medical status were significant predictors of non-weight bearing period (p<0.01), with medical status the stronger determinant. CONCLUSIONS There is significant variation among orthopaedic surgeons when selecting period of non-weight bearing after fixation of ankle fractures, with both injury pattern and medical comorbidity playing a role in decision of time to keep patient non-weight bearing. Further research further evaluating the relationship between these factors and safe periods of non-weight bearing could help identify patients that may benefit from earlier mobilization, and improve surgeons comfort with early mobilization. LEVEL OF EVIDENCE Therapeutic Level V.