Through-and-through stab wound of the cervical spinal canal with retained weapon but no neurological repercussions: an exceptionally rare injury and the case for direct withdrawal. Illustrative case.

BACKGROUND: Nonmissile penetrating spinal injuries are rare and potentially debilitating. Such injuries can sometimes be complicated by the retention of a foreign body, which is usually part of the assailant's weapon, making their management even more problematic. OBSERVATIONS: We present a unique case of stab wound to the neck with a retained ice pick, traversing the spinal canal from one intervertebral foramen to the other, yet with no ensuing neurological damage to the patient. After carefully analyzing the weapon's trajectory on computed tomography and ruling out vertebral artery injury via catheter angiography, the ice pick was successfully withdrawn under general anesthesia and intraoperative neurophysiological monitoring, averting the need for a more invasive surgical procedure. LESSONS: Stab wounds of the spinal canal with a retained foreign body can occasionally be managed by direct withdrawal. Whether this simple technique is a safe alternative to open surgical exploration should be determined on a case-by-case basis after careful review of spinal and vascular imaging. The absence of significant neurological or vascular injury is an absolute prerequisite for attempting direct withdrawal. Moreover, preparations should be made for possible conversion to open surgical exploration in the rare event of active hemorrhage, expanding hematoma, or acute neurological deterioration.

Sinking bullet syndrome: A unique case of transhemispheric migration.

BACKGROUND: Spontaneous migration of retained intracranial bullet fragments is an increasingly recognized phenomenon. However, such migration is usually limited in extent, since it occurs along the bullet tract or cerebrospinal fluid (CSF) spaces. Transhemispheric migration through an intact cerebral hemisphere has not been previously reported. OBSERVATIONS: A 20-year old man sustained a gunshot wound (GSW) to the head with a left parieto-occipital entry point, resulting in retained bullet fragments within the anterior right frontal lobe. The patient developed medically refractory intracranial hypertension, necessitating a left decompressive hemicraniectomy. He exhibited a favorable postoperative course, with gradual neurologic recovery, and was ultimately discharged to a rehabilitation facility. Notwithstanding, serial head CT scans during the first 2 weeks revealed gradual transhemispheric migration of bullet fragments from the right frontal pole to the right occipital pole, traveling through largely intact, uninjured brain tissue. LESSONS: Transhemispheric migration of bullet fragments via intact brain tissue may rarely occur. While the exact mechanisms underlying this phenomenon remain unclear, potential factors may include: bullet weight, CSF pulsations, dissection through white matter tracts, and biomechanical effects of large skull defects. Bullet migration does not necessarily delay or prevent neurologic recovery.

In situ evaluation of spatiotemporal distribution of doxorubicin from Drug-eluting Beads in a tissue mimicking phantom.

Understanding the intra-tumoral distribution of chemotherapeutic drugs is extremely important in predicting therapeutic outcome. Tissue mimicking gel phantoms are useful for studying drug distribution in vitro but quantifying distribution is laborious due to the need to section phantoms over the relevant time course and individually quantify drug elution. In this study we compare a bespoke version of the traditional phantom sectioning approach, with a novel confocal microscopy technique that enables dynamic in situ measurements of drug concentration. Release of doxorubicin from Drug-eluting Embolization Beads (DEBs) was measured in phantoms composed of alginate and agarose over comparable time intervals. Drug release from several different types of bead were measured. The non-radiopaque DC Bead™ generated a higher concentration at the boundary between the beads and the phantom and larger drug penetration distance within the release period, compared with the radiopaque DC Bead LUMI™. This is likely due to the difference of compositional and structural characteristics of the hydrogel beads interacting differently with the loaded drug. Comparison of in vitro results against historical in vivo data show good agreement in terms of drug penetration, when confounding factors such as geometry, elimination and bead chemistry were accounted for. Hence these methods have demonstrated potential for both bead and gel phantom validation, and provide opportunities for optimisation of bead design and embolization protocols through in vitro-in vivo comparison.

Safety and Tolerability of Topotecan-Eluting Radiopaque Microspheres for Hepatic Chemoembolization in a Rabbit Preclinical Model.

PURPOSE: Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan. MATERIALS AND METHODS: Topotecan was loaded into radiopaque microspheres (70-150 µm, DC Bead LUMI™, Biocompatibles UK Ltd-Boston Scientific Corporation) to the maximum capacity of 80 mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28 days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan. RESULTS: The mean bead volume and topotecan dose delivered were 0.086 mL (0.076-0.105 mL) and 1.99 mg/kg (1.51-2.55 mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10 h compared to 3 h for irinotecan-loaded microspheres. CONCLUSION: Selective embolization with ROMTOP was tolerated at a dose of 2 mg/kg (24 mg/m2) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan.

Handling and performance characteristics of a new small caliber radiopaque embolic microsphere.

The in vitro and in vivo handling and performance characteristics of a small caliber radiopaque embolic microsphere, 40-90 µm DC Bead LUMI™ (LUMI40-90), were studied. Microsphere drug loading and elution and effects on size, suspension, and microcatheter delivery were evaluated using established in vitro methodologies. In vivo evaluations of vascular penetration (rabbit renal artery embolization), long-term biocompatibility and X-ray imaging properties, pharmacokinetics and local tissue effects of both doxorubicin (Dox) and irinotecan (Iri) loaded microspheres (swine hepatic artery embolization) were conducted. Compared to 70-150 µm DC Bead LUMI (LUMI70-150), LUMI40-90 averaged 70 µm versus 100 µm, which was unchanged upon drug loading. Handling, suspension, and microsphere delivery studies were successfully performed. Dox loading was faster (20 min) and Iri equivalent (<10 min) while drug elution rates were similar. Contrast suspension times were longer with no delivery complications. Vascular penetration was statistically greater (rabbit) with no unexpected adverse safety findings (swine). Microspheres ± drug were visible under X-ray imaging (CT) at 90 days. Peak plasma drug levels and area under the curve were greater for LUMI40-90 compared to LUMI70-150 but comparable to 70-150 µm DC BeadM1™ (DC70-150). Local tissue effects showed extensive hepatic necrosis for Dox, whereas Iri displayed lower toxicity with more pronounced lobar fibrosis. LUMI40-90 remains suspended for longer and have greater vessel penetration compared to the other DC Bead LUMI sizes and are similarly highly biocompatible with long-term visibility under X-ray imaging. Drug loading is equivalent or faster with pharmacokinetics similar to DC70-150 for both Dox and Iri.

Evaluation of novel formulations for transarterial chemoembolization: combining elements of Lipiodol emulsions with Drug-eluting Beads.

There are currently two methods widely used in clinical practice to perform transarterial chemoembolization (TACE). One is based on mixing an aqueous drug with an iodized oil (Lipiodol) and creating an emulsion that is delivered intraarterially, followed by embolization with a particulate agent. The other is based on a one-step TACE using Drug-eluting Beads (DEBs) loaded with drug. It is not recommended to mix Lipiodol with DEBs due to incompatibility. For the first time, novel DEB: Lipiodol: doxorubicin (Dox) emulsions are identified using lyophilized polyvinyl alcohol (PVA) hydrogels (non-iodinated or iodinated) DEBs. METHODS: 15 DEB emulsions (50mg Dox) were assessed for stability and deliverability in vitro and in vivo in a swine model. Dox release from selected formulations was measured in vitro using a vascular flow model and in vivo in a VX2 rabbit tumor model. RESULTS: Both DEB formats were shown to be able to form emulsions, however only Iodinated DEBs consistently met defined handling criteria. Those based on the non-iodinated DEB achieved >99%+ Dox loading in <5 minutes but were generally less stable. Those prepared using iodinated DEBs, which are more hydrophobic, were able to form stable Pickering-like emulsions (separation time ≥ 20 minutes) and demonstrated handling, administration and imaging observations more akin to Lipiodol™ TACE emulsions in both embolization models. Controlled Dox release and hence beneficial in vivo pharmacokinetics associated with DEB-TACE were maintained. CONCLUSIONS: This study demonstrates that it is possible to formulate novel DEB emulsions suitable for TACE that combine positive elements of both Lipiodol™ based and DEB-TACE procedures.

Impact of Donor Hepatectomy Time During Organ Procurement in Donation After Circulatory Death Liver Transplantation: The United Kingdom Experience.

BACKGROUND: No data exist to evaluate how hepatectomy time (HT), in the context of donation after cardiac death (DCD) procurement, impacts short- and long-term outcomes after liver transplantation (LT). In this study, we analyze the impact of the time from aortic perfusion to end of hepatectomy on outcomes after DCD LT in the United Kingdom. METHODS: An analysis of 1112 DCD donor LT across all UK transplant centers between 2001 and 2015 was performed, using data from the UK Transplant Registry. Donors were all Maastricht Category III. Graft survival after transplantation was estimated using Kaplan-Meier method and logistic regression to identify risk factors for primary nonfunction (PNF) and short- and long-term graft survivals after LT. RESULTS: Incidence of PNF was 4% (40) and in multivariate analysis only cold ischemia time (CIT) longer than 8 hours (hazard ratio [HR], 2.186; 95% confidence interval [CI], 1.113-4.294; P = 0.023) and HT > 60 minutes (HR, 3.669; 95% CI, 1.363-9.873; P = 0.01) were correlated with PNF. Overall 90-day, 1-, 3-, and 5-year graft survivals in DCD LT were 91.2%, 86.5%, 80.9%, and 77.7% (compared with a donation after brain death cohort in the same period [n = 7221] 94%, 91%, 86.6%, and 82.6%, respectively [P < 0.001]). In multivariate analysis, the factors associated with graft survival were HT longer than 60 minutes, donor older than 45 years, CIT longer than 8 hours, and recipient previous abdominal surgery. CONCLUSIONS: There is a negative impact of prolonged HT on outcomes on DCD LT and although HT is 60 minutes or longer is not a contraindication for utilization, it should be part of a multifactorial assessment with established prognostic donor factors, such as age (>45 y) and CIT (>8 h) for an appropriately selected recipient.

From embracing to managing risks.

OBJECTIVE: To assess developments over time in the capture, curation and use of quality and safety information in managing hospital services. SETTING: Four acute National Health Service hospitals in England. PARTICIPANTS: 111.5 hours of observation of hospital board and directorate meetings, and 72 hours of ward observations. 86 interviews with board level and middle managers and with ward managers and staff. RESULTS: There were substantial improvements in the quantity and quality of data produced for boards and middle managers between 2013 and 2016, starting from a low base. All four hospitals deployed data warehouses, repositories where datasets from otherwise disparate departmental systems could be managed. Three of them deployed real-time ward management systems, which were used extensively by nurses and other staff. CONCLUSIONS: The findings, particularly relating to the deployment of real-time ward management systems, are a corrective to the many negative accounts of information technology implementations. The hospital information infrastructures were elements in a wider move, away from a reliance on individual professionals exercising judgements and towards team-based and data-driven approaches to the active management of risks. They were not, though, using their fine-grained data to develop ultrasafe working practices.

Mapping Drug Dose Distribution on CT Images Following Transarterial Chemoembolization with Radiopaque Drug-Eluting Beads in a Rabbit Tumor Model.

Purpose To correlate bead location and attenuation on CT images with the quantity and distribution of drug delivered to the liver following transarterial chemoembolization (TACE) with radiopaque drug-eluting beads (DEB) in a rabbit tumor model. Materials and Methods All procedures were performed with a protocol approved by the Institutional Animal Care and Use Committee. TACE was performed in rabbits (n = 4) bearing VX2 liver tumors by using radiopaque DEB (70-150 µm) loaded with doxorubicin (DOX). Livers were resected 1 hour after embolization, immediately frozen, and cut by using liver-specific three-dimensional-printed molds for colocalization of liver specimens and CT imaging. DOX penetration into tissue surrounding beads was evaluated with fluorescence microscopy. DOX levels in liver specimens were predicted by using statistical models correlating DOX content measured in tissue with bead volume and attenuation measured on CT images. Model predictions were then compared with actual measured DOX concentrations to assess the models' predictive power. Results Eluted DOX remained in close proximity (<600 µm) to beads in the liver 1 hour after TACE. Bead volume and attenuation measured on CT images demonstrated positive linear correlations (0.950 and 0.965, respectively) with DOX content in liver specimens. DOX content model predictions based on CT images were accurate compared with actual liver DOX levels at 1 hour. Conclusion CT may be used to estimate drug dose delivery and distribution in the liver following transarterial chemoembolization (TACE) with doxorubicin-loaded radiopaque drug-eluting beads (DEB). Although speculative, this informational map might be helpful in planning and understanding the spatial effects of TACE with DEB. © RSNA, 2018.

Bench-to-clinic development of imageable drug-eluting embolization beads: finding the balance.

This review describes the historical development of an imageable spherical embolic agent and focuses on work performed in collaboration between Biocompatibles UK Ltd (a BTG International group company) and the NIH to demonstrate radiopaque bead utility and bring a commercial offering to market that meets a clinical need. Various chemistries have been investigated and multiple prototypes evaluated in search of an optimized product with the right balance of handling and imaging properties. Herein, we describe the steps taken in the development of DC Bead LUMI™, the first commercially available radiopaque drug-eluting bead, ultimately leading to the first human experience of this novel embolic agent in the treatment of liver tumors.

Comparison of microsphere penetration with LC Bead LUMI™ versus other commercial microspheres.

The purpose of this study was to evaluate LC Bead LUMI™ (40-90µm and 70-150µm) in order to determine if their increased resistance to compression influences microsphere penetration and distribution compared to more compressible commercial microspheres. LC Bead LUMI™ 40-90µm and 70-150µm, LC BeadM1® 70-150µm, Embozene™ 40µm and Embozene™ 100µm size and distributions were measured using optical microscopy. Penetration in vitro was evaluated using an established 'plate model', consisting of a calibrated tapered gap between a glass plate and plastic housing to allow visual observation of microsphere penetration depth. Behaviour in vivo was assessed using a rabbit renal embolization model with histopathologic confirmation of vessel penetration depth. Penetration behaviour in vitro was reproducible and commensurate with the measured microsphere size, the smaller the microsphere the deeper the penetration. Comparison of the microsphere diameter measured on the 2D plate model versus the corresponding average microsphere size measured by histopathology in the kidney showed no significant differences (p = > 0.05 Mann-Whitney, demonstrating good in vitro - in vivo predictive capabilities of the plate model) confirming predictable performance for LC Bead LUMI™ (40-90µm and 70-150µm) based on microsphere size, their increased rigidity having no bearing on their depth of penetration and distribution. An assessment of a LC Bead LUMI™ (40-90µm and 70-150µm) has shown that despite having greater resistance to compression, these microspheres behave in a predictable manner within in vitro and in vivo models comparable with more compressible microspheres of similar sizes.

Inter-rater reliability of the McKenzie System of Mechanical Diagnosis and Therapy in the examination of the knee.

OBJECTIVE: The McKenzie System of Mechanical Diagnosis and Therapy (MDT) is a widely used method of classification and management of musculoskeletal problems. Although MDT has been investigated for its reliability and efficacy in the management of spinal pain, few studies have evaluated the system when applying it to musculoskeletal problems in the extremities, in particular the knee. The purpose of this study was to investigate the inter-rater reliability of MDT when classifying clinical vignettes describing patients with musculoskeletal knee pain. METHODS: This study was divided into two phases. First, 10 clinicians experienced in the use of MDT were recruited to write a total of 60 clinical vignettes based upon the initial assessment of their past patients with knee pain. Second, six different MDT raters were recruited to rate 53 selected vignettes and reliability was determined using Fleiss Kappa. RESULTS: There was 'substantial agreement' among six MDT raters classifying the clinical vignettes into one of four categories (κ = 0.72). There was no statistically significant difference between therapists with different levels of training. DISCUSSION: MDT demonstrated acceptable reliability among trained raters to classify clinical vignettes describing patients with musculoskeletal knee pain. To generalize the use of the system to more users, future research should continue to investigate the reliability of MDT using raters with lower levels of training and experience and assess reliability in real patients. LEVEL OF EVIDENCE: 5.

Characterization of a novel intrinsically radiopaque Drug-eluting Bead for image-guided therapy: DC Bead LUMI™.

We have developed a straightforward and efficient method of introducing radiopacity into Polyvinyl alcohol (PVA)-2-Acrylamido-2-methylpropane sulfonic acid (AMPS) hydrogel beads (DC Bead™) that are currently used in the clinic to treat liver malignancies. Coupling of 2,3,5-triiodobenzaldehyde to the PVA backbone of pre-formed beads yields a uniformly distributed level of iodine attached throughout the bead structure (~150mg/mL) which is sufficient to be imaged under standard fluoroscopy and computed tomography (CT) imaging modalities used in treatment procedures (DC Bead LUMI™). Despite the chemical modification increasing the density of the beads to ~1.3g/cm3 and the compressive modulus by two orders of magnitude, they remain easily suspended, handled and administered through standard microcatheters. As the core chemistry of DC Bead LUMI™ is the same as DC Bead™, it interacts with drugs using ion-exchange between sulfonic acid groups on the polymer and the positively charged amine groups of the drugs. Both doxorubicin (Dox) and irinotecan (Iri) elution kinetics for all bead sizes evaluated were within the parameters already investigated within the clinic for DC Bead™. Drug loading did not affect the radiopacity and there was a direct relationship between bead attenuation and Dox concentration. The ability (Dox)-loaded DC Bead LUMI™ to be visualized in vivo was demonstrated by the administration of into hepatic arteries of a VX2 tumor-bearing rabbit under fluoroscopy, followed by subsequent CT imaging.

Long-term biocompatibility, imaging appearance and tissue effects associated with delivery of a novel radiopaque embolization bead for image-guided therapy.

The objective of this study was to undertake a comprehensive long-term biocompatibility and imaging assessment of a new intrinsically radiopaque bead (LC Bead LUMI™) for use in transarterial embolization. The sterilized device and its extracts were subjected to the raft of ISO10993 biocompatibility tests that demonstrated safety with respect to cytotoxicity, mutagenicity, blood contact, irritation, sensitization, systemic toxicity and tissue reaction. Intra-arterial administration was performed in a swine model of hepatic arterial embolization in which 0.22-1 mL of sedimented bead volume was administered to the targeted lobe(s) of the liver. The beads could be visualized during the embolization procedure with fluoroscopy, DSA and single X-ray snapshot imaging modalities. CT imaging was performed before and 1 h after embolization and then again at 7, 14, 30 and 90 days. LC Bead LUMI™ could be clearly visualized in the hepatic arteries with or without administration of IV contrast and appeared more dense than soluble contrast agent. The CT density of the beads did not deteriorate during the 90 day evaluation period. The beads embolized predictably and effectively, resulting in areas devoid of contrast enhancement on CT imaging suggesting ischaemia-induced necrosis nearby the sites of occlusion. Instances of off target embolization were easily detected on imaging and confirmed pathologically. Histopathology revealed a classic foreign body response at 14 days, which resolved over time leading to fibrosis and eventual integration of the beads into the tissue, demonstrating excellent long-term tissue compatibility.

First Human Experience with Directly Image-able Iodinated Embolization Microbeads.

PURPOSE: To describe first clinical experience with a directly image-able, inherently radio-opaque microspherical embolic agent for transarterial embolization of liver tumors. METHODOLOGY: LC Bead LUMI™ is a new product based upon sulfonate-modified polyvinyl alcohol hydrogel microbeads with covalently bound iodine (~260 mg I/ml). 70-150 µ LC Bead LUMI™ iodinated microbeads were injected selectively via a 2.8 Fr microcatheter to near complete flow stasis into hepatic arteries in three patients with hepatocellular carcinoma, carcinoid, or neuroendocrine tumor. A custom imaging platform tuned for LC LUMI™ microbead conspicuity using a cone beam CT (CBCT)/angiographic C-arm system (Allura Clarity FD20, Philips) was used along with CBCT embolization treatment planning software (EmboGuide, Philips). RESULTS: LC Bead LUMI™ image-able microbeads were easily delivered and monitored during the procedure using fluoroscopy, single-shot radiography (SSD), digital subtraction angiography (DSA), dual-phase enhanced and unenhanced CBCT, and unenhanced conventional CT obtained 48 h after the procedure. Intra-procedural imaging demonstrated tumor at risk for potential under-treatment, defined as paucity of image-able microbeads within a portion of the tumor which was confirmed at 48 h CT imaging. Fusion of pre- and post-embolization CBCT identified vessels without beads that corresponded to enhancing tumor tissue in the same location on follow-up imaging (48 h post). CONCLUSION: LC Bead LUMI™ image-able microbeads provide real-time feedback and geographic localization of treatment in real time during treatment. The distribution and density of image-able beads within a tumor need further evaluation as an additional endpoint for embolization.

A Novel Inherently Radiopaque Bead for Transarterial Embolization to Treat Liver Cancer - A Pre-clinical Study.

PURPOSE: Embolotherapy using microshperes is currently performed with soluble contrast to aid in visualization. However, administered payload visibility dimishes soon after delivery due to soluble contrast washout, leaving the radiolucent bead's location unknown. The objective of our study was to characterize inherently radiopaque beads (RO Beads) in terms of physicomechanical properties, deliverability and imaging visibility in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: RO Beads, which are based on LC Bead® platform, were compared to LC Bead. Bead size (light microscopy), equilibrium water content (EWC), density, X-ray attenuation and iodine distribution (micro-CT), suspension (settling times), deliverability and in vitro penetration were investigated. Fifteen rabbits were embolized with either LC Bead or RO Beads + soluble contrast (iodixanol-320), or RO Beads+dextrose. Appearance was evaluated with fluoroscopy, X-ray single shot, cone-beam CT (CBCT). RESULTS: Both bead types had a similar size distribution. RO Beads had lower EWC (60-72%) and higher density (1.21-1.36 g/cc) with a homogeneous iodine distribution within the bead's interior. RO Beads suspension time was shorter than LC Bead, with durable suspension (>5 min) in 100% iodixanol. RO Beads ≤300 µm were deliverable through a 2.3-Fr microcatheter. Both bead types showed similar penetration. Soluble contrast could identify target and non-target embolization on fluoroscopy during administration. However, the imaging appearance vanished quickly for LC Bead as contrast washed-out. RO Beads+contrast significantly increased visibility on X-ray single shot compared to LC Bead+contrast in target and non-target arteries (P=0.0043). Similarly, RO beads demonstrated better visibility on CBCT in target arteries (P=0.0238) with a trend in non-target arteries (P=0.0519). RO Beads+dextrose were not sufficiently visible to monitor embolization using fluoroscopy. CONCLUSION: RO Beads provide better conspicuity to determine target and non-target embolization compared to LC Bead which may improve intra-procedural monitoring and post-procedural evaluation of transarterial embolization.

Patient and provider experience with a new model of care for primary hip and knee arthroplasties.

BACKGROUND: The orthopaedic program at a large academic teaching hospital introduced a quality initiative for the primary hip and knee arthroplasty population with the goal to reduce the overall length of stay (LOS) to less than 3 days while ensuring an efficient and exceptional patient experience. This article focuses on the process used to evaluate patient and provider satisfaction with the changes made to achieve a reduction in length of stay. METHOD: The initiative involved current and future process mapping, patient and staff education, a comprehensive mobility strategy, pain management pathways and an evaluation of the patient and provider experience. The goal to reduce LOS for both primary hip and knee arthroplasty surgery was achieved. CONCLUSION: The patients were satisfied with their overall experience including their LOS and preparedness for discharge home.

Preparation of Radiopaque Drug-Eluting Beads for Transcatheter Chemoembolization.

PURPOSE: To develop a simple method to produce radiopaque drug-eluting microspheres (drug-eluting beads [DEBs]) that could be incorporated into the current clinical transcatheter arterial chemoembolization workflow and evaluate their performance in vitro and in vivo. MATERIALS AND METHODS: An ethiodized oil (Lipiodol; Guerbet, Villepinte, France) and ethanol solution was added to a lyophilized 100-300 µm bead before loading with doxorubicin. These radiopaque drug-eluting beads (DEBs; Biocompatibles UK Ltd, Farnham, United Kingdom) were evaluated in vitro for x-ray attenuation, composition, size, drug loading and elution, and correlation between attenuation and doxorubicin concentration. In vivo conspicuity was evaluated in a VX2 tumor model. RESULTS: Lipiodol was loaded into lyophilized beads using two glass syringes and a three-way stopcock. Maximum bead attenuation was achieved within 30 minutes. X-ray attenuation of radiopaque beads increased linearly (21-867 HU) with the amount of beads (0.4-12.5 vol%; R(2) = 0.9989). Doxorubicin loading efficiency and total amount eluted were similar to DC Bead (Biocompatibles UK Ltd); however, the elution rate was slower for radiopaque DEBs (P < .05). Doxorubicin concentration linearly correlated with x-ray attenuation of radiopaque DEBs (R(2) = 0. 99). Radiopaque DEBs were seen in tumor feeding arteries after administration by fluoroscopy, computed tomography, and micro-computed tomography, and their location was confirmed by histology. CONCLUSIONS: A simple, rapid method to produce radiopaque DEBs was developed. These radiopaque DEBs provided sufficient conspicuity to be visualized with x-ray imaging techniques.

Development of an on-animal separation-based sensor for monitoring drug metabolism in freely roaming sheep.

The development of an on-animal separation-based sensor that can be employed for monitoring drug metabolism in a freely roaming sheep is described. The system consists of microdialysis sampling coupled to microchip electrophoresis with electrochemical detection (MD-ME-EC). Separations were accomplished using an all-glass chip with integrated platinum working and reference electrodes. Discrete samples from the microdialysis flow were introduced into the electrophoresis chip using a flow-gated injection approach. Electrochemical detection was accomplished in-channel using a two-electrode isolated potentiostat. Nitrite was separated by microchip electrophoresis using reverse polarity and a run buffer consisting of 50 mM phosphate at pH 7.4. The entire system was under telemetry control. The system was first tested with rats to monitor the production of nitrite following perfusion of nitroglycerin into the subdermal tissue using a linear probe. The data acquired using the on-line MD-ME-EC system were compared to those obtained by off-line analysis using liquid chromatography with electrochemical detection (LC-EC), using a second microdialysis probe implanted parallel to the first probe in the same animal. The MD-ME-EC device was then used on-animal to monitor the subdermal metabolism of nitroglycerin in sheep. The ultimate goal is to use this device to simultaneously monitor drug metabolism and behavior in a freely roaming animal.

Efficacy of exercise intervention as determined by the McKenzie System of Mechanical Diagnosis and Therapy for knee osteoarthritis: a randomized controlled trial.

STUDY DESIGN: Randomized controlled trial. Objectives To examine the efficacy of exercise intervention in patients with knee osteoarthritis (OA), as directed by Mechanical Diagnosis and Therapy (MDT) assessment, and, secondarily, to explore outcomes between MDT assessment-defined subgroups within the exercise group. BACKGROUND: Due to the high physical and economic burden of knee OA, the effectiveness of conservative interventions and determining those patients who will respond to them should be investigated. METHODS: Patients with knee OA (n = 180) were randomized to an exercise intervention group or a control group. The intervention group, in which patients classified as having knee derangements (MDT derangement) received MDT directional exercises and patients classified as nonresponders (MDT nonresponders) received evidence-based exercises, was compared to a control group that received no exercise intervention. Pain and function were assessed at baseline, 2 weeks, and 3 months, using the P4 pain scale and Knee injury and Osteoarthritis Outcome Score (KOOS) pain and function subscales. Two-way analysis of covariance was used to examine treatment and time effects. Multiple comparisons were examined, and mean differences with 95% confidence intervals (CIs) were reported. RESULTS: The exercise intervention group had significantly improved P4 scores (mean difference, -6; 95% CI: -8, -3), KOOS pain scores (mean difference, 9; 95% CI: 5, 13), and KOOS function scores (mean difference, 11; 95% CI: 7, 15) compared to those of the control group at 2 weeks. At 3 months, the exercise intervention group had significantly improved KOOS pain scores (mean difference, 7; 95% CI: 3, 11) and KOOS function scores (mean difference, 5; 95% CI: 1, 9) compared to controls. CONCLUSION: Patients with knee OA who were prescribed exercises based on an MDT assessment had superior outcomes compared to those of wait-list controls. The MDT subgroup of knee derangement may warrant further investigation in patients with knee OA. Protocol registered at ClinicalTrials.gov (NCT01641874). LEVEL OF EVIDENCE: Therapy, level 1b-.