Patients From Distressed Communities Who Undergo Surgery for Hip Fragility Fractures Are Less Likely to Have Advanced Care Planning Documents in Their Electronic Medical Record.

BACKGROUND: Advanced care planning documents provide a patient's healthcare team and loved ones with guidance on patients' treatment preferences when they are unable to advocate for themselves. A substantial proportion of patients will die within a few months of experiencing a hip fracture, but despite the importance of such documents, patients undergoing surgery for hip fracture seldom have discussions documented in the medical records regarding end-of-life care during their surgical admission. To the best of our knowledge, the proportion of patients older than 65 years treated with surgery for hip fractures who have advanced care planning documents in their electronic medical record (EMR) has not been explored, neither has the association between socioeconomic status and the presence of those documents in the EMR. Determining this information can help to identify opportunities to promote advanced care planning. QUESTIONS/PURPOSES: (1) What percentage of patients older than 65 years who undergo hip fracture surgery have completed advanced care planning documents uploaded in the EMR before or during their surgical hospitalization, or at any timepoint (before admission, during admission, and after admission)? (2) Are patients from distressed communities less likely to have advanced care planning documents in the EMR than patients from wealthier communities, after controlling for economic well-being as measured by the Distressed Communities Index? (3) What percentage of patients older than 65 years with hip fractures who died during their hospitalization for hip fracture surgery had advanced care planning documents uploaded in the EMR? METHODS: This was a retrospective, comparative study conducted at two geographically distinct hospitals: one urban Level I trauma center and one suburban Level II trauma center. Between 2017 and 2021, these two centers treated 850 patients for hip fractures. Among those patients, we included patients older than 65 years who were treated with open reduction and internal fixation, intramedullary nailing, hemiarthroplasty, or THA for a fragility fracture of the proximal femur. Based on that, 83% (709 of 850) of patients were eligible; a further 6% (52 of 850) were excluded because they had codes other than ICD-9 820 or ICD-10 S72.0, and another 2% (17 of 850) had incomplete datasets, leaving 75% (640 of 850) for analysis here. Most patients with incomplete datasets were in the prosperous Distressed Communities Index category. Among patients included in this study, the average age was 82 years, 70% (448 of 640) were women, and regarding the Distressed Communities Index, 32% (203 of 640) were in the prosperous category, 25% (159 of 640) were in the comfortable category, 15% (99 of 640) were in the mid-tier category, 5% (31 of 640) were in the at-risk category, and 23% (145 of 640) were in the distressed category. The primary outcome included the presence of advanced care planning documents (advanced directives, healthcare power of attorney, or physician orders for life-sustaining treatment) in the EMR before surgery, during the surgical admission, or at any time. The Distressed Communities Index was used to indicate economic well-being, and patients were identified as being in one of five Distressed Communities Index categories (prosperous, comfortable, mid-tier, at-risk, and distressed) based on ZIP Code. An exploratory analysis was conducted to determine variables associated with the presence of advanced care planning documents in the EMR. A multivariate regression was then performed for patients who did or did not have advanced care planning documents in their medical record at any time. The results are presented as ORs with the associated 95% confidence interval (CI). RESULTS: Nine percent (55 of 640) of patients had advanced care planning documents in the EMR preoperatively or during their surgical admission, and 22% (142 of 640) of patients had them in the EMR at any time. After controlling for potential confounding variables such as age, laterality (left or right hip), hospital type, and American Society of Anesthesiologists (ASA) classification, we found that patients in Distressed Communities Index categories other than prosperous had ORs lower than 0.7, with patients in the distressed category (OR 0.4 [95% CI 0.2 to 0.7]; p < 0.01) and comfortable category (OR 0.5 [95% CI 0.3 to 0.9]; p = 0.01) having a substantially lower odds of having advanced care planning documents in their EMR. Patients aged 86 to 95 years (OR 1.9 [95% CI 1.1 to 3.4]), those 96 years and older (OR 4.0 [95% CI 1.7 to 9.5]), and those with a higher ASA classification (OR 1.6 [95% CI 1.1 to 2.3]) had a higher odds of having advanced care planning documents in the EMR at any time. Among 14 patients who experienced in-hospital mortality, two had advanced care planning documents uploaded into their EMR, whereas 12 of 14 who died in the hospital did not have advanced care planning documents uploaded into their EMR. CONCLUSION: Orthopaedic surgeons should counsel patients regarding the risk for postoperative complications after fragility hip fracture surgery and engage in shared decision-making regarding advanced care planning documents with patients or, if the patients are unable, with their families. Additionally, implementing virtual education about advanced care planning documents and using easy-to-read forms may facilitate the completion of advanced care planning documents by patients older than 65 years, especially patients with low economic well-being. Limitations of this study include having a restricted number of patients in the at-risk and mid-tier Distressed Communities Index categories and a restricted number of patients identifying as non-White races/ethnicities. Future research should evaluate the effect of advanced care document presence in the EMR on end-of-life care intensity in patients treated for fragility hip fractures. LEVEL OF EVIDENCE: Level III, therapeutic study.

Minimizing Surgical Instrument Burden Increases Operating Room Efficiency and Reduces Perioperative Costs in Total Joint Arthroplasty.

BACKGROUND: Optimizing surgical trays to improve operating room efficiency and reduce costs in instrument processing is an under-appreciated strategy for cost containment. This study aimed to assess the economic impact of instrument tray optimization in total joint arthroplasty. METHODS: Thirty-five randomly selected elective primary total knee arthroplasty and total hip arthroplasty performed by 4 fellowship-trained surgeons were analyzed. Type and number of instruments used as well as timing of different steps in the sterilization process were recorded by an independent observer. Using Lean methodology, surgeons identified redundant or underutilized instruments and agreed upon the fewest number needed for each tray. Instrument utilization rates and processing time were analyzed before and after tray modifications. Annual cost savings were calculated based on a processing factor of $0.59-$11.52 per instrument. RESULTS: Only 45.5% of instruments opened for total knee arthroplasty were utilized. After optimization, 28 of 87 (32.2%) instruments were removed and the remainder could be stored in one tray. Mean set-up time decreased from 20.7 to 14.2 minutes, while 40-75 minutes were saved during the sterilization process. For total hip arthroplasty, only 36.0% of instruments were utilized. Using Lean methods, 46 of 112 (41.1%) instruments were removed and tray count was reduced to 2 trays. Mean set-up time decreased from 27.9 to 18.6 minutes, while 45-150 minutes were saved during processing. Average annual savings amounted to $281,298.05. CONCLUSION: Lean methodology can be used to eliminate redundant or underutilized instruments in total joint arthroplasty, improving surgical efficiency and generating substantial cost savings.

Accuracy and Validity of Computer Adaptive Testing for Outcome Assessment in Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: Probability-based computer algorithms that reduce patient burden are currently in high demand. These computer adaptive testing (CAT) methods improve workflow and reduce patient frustration, while achieving high measurement precision. In this study, we evaluated the accuracy and validity of the CAT Hip Disability and Osteoarthritis Outcome Score (HOOS) and the Hip Disability and Osteoarthritis Outcome Score Joint Replacement (HOOS-JR) by comparing them to the full version of these scoring systems in a subset of patients who had undergone total hip arthroplasties. METHODS: A previously developed CAT HOOS and HOOS-JR was applied to 354 and 1547 HOOS and HOOS-JR patient responses, respectively. Mean, standard deviations, Pearson's correlation coefficients, interclass correlation coefficients, frequency distribution plots, and Bland-Altman plots were used to compare the precision, validity, and accuracy between CAT scores and full-form scores. RESULTS: By modifying the questions to past responses, the CAT HOOS demonstrated a mean reduction of 30% of questions (28 vs 40 questions). There were no significant differences between the full HOOS and CAT HOOS with respect to pain (P = .73), symptoms (P = .94), quality of life (P = .99), activities of daily living (P = .82), and sports (P = .99). There were strong linear relationships between the CAT versions and the standard questionnaires (r > 0.99). The Bland-Altman plot showed that differences between CAT HOOS and full HOOS were independent of the overall scores. CONCLUSION: The CAT HOOS and HOOS-JR have high correlation and require fewer questions to finish compared to the standard full-form questionnaires. This may represent a reliable and practical alternative that may be less burdensome to patients and may help improve compliance for reporting outcome metrics.

Substantial Preoperative Work Is Unaccounted for in Total Hip and Knee Arthroplasty.

BACKGROUND: The Centers for Medicare and Medicaid Services has recently designated the codes for total hip and knee arthroplasty as misvalued and has asked the Relative Value Scale Update Committee (RUC) to review the work required to perform these procedures. Although other studies have reported time spent on perioperative and postoperative care, time spent on coordinating and performing preoperative care is not included in current RUC methodology and has yet to be addressed in literature. METHODS: We prospectively tracked a consecutive series of 438 primary total hip arthroplasty and total knee arthroplasty patients by one of the 5 surgeons over a 3-month period. Each clinical staff member tracked the amount of time to perform each preoperative care task from the last clinic visit until day of surgery. Data were analyzed separately between providers and ancillary medical staff. RESULTS: Although the current RUC review includes 40 minutes of preservice time on the day of surgery, surgeons spent an average of an additional 43.2 minutes while physician assistants and nurse practitioners spent an additional 97.9 minutes per patient on preoperative care prior to that time. Ancillary medical staff spent a mean of 110.2 minutes per patient. The most common tasks include preoperative phone calls, templating and surgical planning, and preoperative patient education classes. CONCLUSION: Surgeons and advanced practice providers spend nearly 2 hours per arthroplasty patient on preoperative care not accounted for in current RUC methodology. As readmissions, hospital stay, and complication rates continue to decline, Centers for Medicare and Medicaid Services should consider the substantial work required during the preoperative phase to allow for these improved outcomes.

General vs Spinal Anesthesia for Total Joint Arthroplasty: A Single-Institution Observational Review.

BACKGROUND: Total joint arthroplasty (TJA) can be successfully carried out under general (GA) or spinal anesthesia (SA). The existing literature does not adequately illustrate which technique is optimal. The purpose of this study is to prospectively compare the effects of anesthesia technique on TJA outcomes. METHODS: This 2-year, prospective, observational study was conducted at a single institution where patients receiving primary TJA were consecutively enrolled. Patients were contacted postoperatively to assess for any 90-day complications. The primary outcome of the study was the overall complication rate. RESULTS: A total of 2242 patients underwent total hip arthroplasty (n = 656; 29.26%) or total knee arthroplasty (n = 1586; 70.74%) between 2015 and 2017. Of these procedures, 1325 (59.10%) were carried out under SA and 917 (40.90%) were carried out under GA. Patients in the GA cohort had higher mean Charlson Comorbidity Index scores (0.05 SA vs 0.09 GA; P < .05) and higher average body mass index (29.35 SA vs 30.24 GA; P < .05). On multivariate analysis, patients in the SA cohort had a significantly lower overall complication rate relative to their GA counterparts (7.02% vs 10.14%; odds ratio, 0.66; 95% confidence interval, 0.49-0.90; P < .05). In addition, length of stay in the GA cohort was significantly longer (2.43 [SD, 1.62] vs 2.18 [SD, 0.88] days; P < .01) and a larger percentage of GA patients were discharged to a nursing facility (32.28% vs 25.06%; odds ratio, 0.55; 95% confidence interval, 0.44-0.70; P < .05). CONCLUSION: Our study demonstrates that SA for TJA is associated with a decrease in overall complications and healthcare resource utilization.

Intraoperative Surgeon Administered Adductor Canal Blockade Is Not Inferior to Anesthesiologist Administered Adductor Canal Blockade: A Prospective Randomized Trial.

BACKGROUND: Controlling postoperative pain and reducing opioid requirements after total knee arthroplasty remain a challenge, particularly in an era stressing rapid recovery protocols and early discharge. A single-shot adductor canal blockade (ACB) has been shown to be effective in decreasing postoperative pain. The purpose of the present study is to compare the efficacy of an anesthesiologist administered ACB and a surgeon administered intraoperative ACB. METHODS: Patients undergoing primary total knee arthroplasty were prospectively randomized to receive either an anesthesiologist administered (group 1) or surgeon administered (group 2) ACB using 15 mL of ropivacaine 0.5%. Primary outcomes were pain visual analog scale, range of motion, and opioid consumption. RESULTS: Thirty-four patients were randomized to group 1 and 29 to group 2. Opioid equivalents consumed were equal on postoperative day (POD) 0, 1, and 2. Patients in group 1 had statistically less pain on POD 0, but this did not reach clinical significance and there was no difference in pain on POD 1 or 2. Patients in group 1 had significantly increased active flexion POD 1, but there was no difference in active flexion on POD 0 or 6 weeks postop. There was no difference in patient satisfaction with pain control or short-term functional outcomes. CONCLUSION: Surgeon administered ACB is not inferior to anesthesiologist administered ACB with respect to pain, opioid consumption, range of motion, patient satisfaction, or short-term functional outcomes. Surgeon administered ACB is an effective alternative to anesthesiologist administered ACB.

Intraoperative Ketamine in Total Knee Arthroplasty Does Not Decrease Pain and Narcotic Consumption: A Prospective Randomized Controlled Trial.

BACKGROUND: Multiple studies have demonstrated that ketamine, a glutamate receptor blocker, may decrease postoperative pain in abdominal and orthopedic surgeries. However, its role with spinal anesthesia and total knee arthroplasty (TKA) remains unknown. The purpose of this study is to determine the efficacy of subanesthetic dosing of ketamine during TKA on postoperative pain and narcotic consumption. METHODS: In this prospective, randomized, double-blinded clinical trial, we enrolled 91 patients undergoing primary TKA with spinal anesthesia in a single institution from 2017 to 2018. Patients were randomized to receive intraoperative ketamine infusion at a rate of 6 mcg/kg/min for 75 minutes or a saline placebo. All patients received spinal anesthesia and otherwise identical surgical approaches, pain management, and rehabilitation protocols. Patient-reported visual analog pain scores were calculated preoperatively, postoperative days (POD) 0-7, and 2 weeks. Narcotic consumption was evaluated on POD 0 and 1. RESULTS: There was no difference in average pain between ketamine and placebo at all time points except for at PODs 1 (45 vs 56, P = .041) and 4 (39 vs 49, P = .040). For least pain experienced, patients administered with ketamine experienced a reduction in pain only at POD 4 (22 vs 35, P = .011). There was no difference in maximum pain cohorts at all time points of the study or in-hospital morphine equivalents between the 2 cohorts. CONCLUSION: As part of multimodal pain management protocol, intraoperative ketamine does not result in a clinically significant improvement in pain and narcotic consumption following TKA.

When Can I Drive After Orthopaedic Surgery? A Systematic Review.

BACKGROUND: Patients often ask their doctors when they can safely return to driving after orthopaedic injuries and procedures, but the data regarding this topic are diverse and sometimes conflicting. Some studies provide observer-reported outcome measures, such as brake response time or simulators, to estimate when patients can safely resume driving after surgery, and patient survey data describing when patients report a return to driving, but they do not all agree. We performed a systematic review and quality appraisal for available data regarding when patients are safe to resume driving after common orthopaedic surgeries and injuries affecting the ability to drive. QUESTIONS/PURPOSES: Based on the available evidence, we sought to determine when patients can safely return to driving after (1) lower extremity orthopaedic surgery and injuries; (2) upper extremity orthopaedic surgery and injuries; and (3) spine surgery. METHODS: A search was performed using PubMed and EMBASE®, with a list of 20 common orthopaedic procedures and the words "driving" and "brake". Selection criteria included any article that evaluated driver safety or time to driving after major orthopaedic surgery or immobilization using observer-reported outcome measures or survey data. A total of 446 articles were identified from the initial search, 48 of which met inclusion criteria; abstract-only publications and non-English-language articles were not included. The evidence base includes data for driving safety on foot, ankle, spine, and leg injuries, knee and shoulder arthroscopy, hip and knee arthroplasty, carpal tunnel surgery, and extremity immobilization. Thirty-four of the articles used observer-reported outcome measures such as total brake time, brake response time, driving simulator, and standardized driving track results, whereas the remaining 14 used survey data. RESULTS: Observer-reported outcome measures of total brake time, brake response time, and brake force postoperatively suggested patients reached presurgical norms 4 weeks after right-sided procedures such as TKA, THA, and ACL reconstruction and approximately 1 week after left-sided TKA and THA. The collected survey data suggest patients resumed driving 1 month after right-sided and left-sided TKAs. Patients who had THA reported returning to driving between 6 days and 3 months postoperatively. Observer-reported outcome measures showed that patients' driving abilities often are impaired when wearing an immobilizing cast above or below the elbow or a shoulder sling on their dominant arm. Patients reported a return to driving on average 2 months after rotator cuff repair procedures and approximately 1-3 months postoperatively for total shoulder arthroplasties. Most patients with spine surgery had normal brake response times at the time of hospital discharge. Patients reported driving 6 weeks after total disc arthroplasty and anterior cervical discectomy and fusion procedures. CONCLUSIONS: The available evidence provides a best-case scenario for when patients can return to driving. It is important for observer-reported outcome measures to have normalized before a patient can consider driving, but other factors such as strength, ROM, and use of opioid analgesics need to be considered. This review can provide a guideline for when physicians can begin to consider evaluating these other factors and discussing a return to driving with patients. Survey data suggest that patients are returning to driving before observer-reported outcome measures have normalized, indicating that physicians should tell patients to wait longer before driving. Further research is needed to correlate observer-reported outcome measures with adverse events, such as motor vehicle accidents, and clinical tests that can be performed in the office. LEVEL OF EVIDENCE: Level III, therapeutic study.

Vascular Complications After Total Knee Arthroplasty-A Single Institutional Experience.

BACKGROUND: Vascular complications during total knee arthroplasty (TKA) are uncommon but potentially devastating. We evaluated cases of vascular complication during TKA in our high-volume, community hospital system. METHODS: Patients were identified by cross-referencing billing codes for TKA with diagnosis codes for vascular complication during the same hospital stay between January 1, 2010 and December 31, 2014. Clinical and radiographic data, time to diagnosis, intervention, and outcomes were collected. RESULTS: We identified 13 vascular complications in 9951 TKAs (0.13%). Average age was 66.2 years (95% CI: 5.55; range: 54.1-87.9), 12 (92.3%) were female, average body mass index was 32.3 (5.17; 20-50), and average Charlson Comorbidity Index was 4.08 (1.03; 2-7). Black females (relative risk = 18.33, 95% CI: 6.20-54.22) were at particularly high risk. Preoperatively, 6 knees exhibited varus coronal malalignment and 2 valgus malalignment (only 1 >15°). None had flexion contracture >10°. Four knees exhibited vascular calcifications on preoperative radiographs. Twelve were diagnosed and treated the same day as index TKA and 1 on postoperative day 2. All underwent interventions: 9 stents, 2 endarterectomies, 1 thrombectomy, and 1 bypass. One patient sustained a peroneal nerve injury; 3 had persistent stiffness postoperatively that improved after manipulation. There were no revision surgeries, further vascular intervention, compartment syndrome, periprosthetic joint infection, amputation, or mortality. CONCLUSION: Incidence of vascular complications at our community-based hospital system is in line with previous reports. Black race and female gender were significant risk factors. Although outcomes were remarkable for a high rate of stiffness and one peroneal neuropathy, the devastating complications of amputation, compartment syndrome, periprosthetic joint infection, or early mortality were not observed.

Do Standard Surgical Guides Produce Accurate and Precise Femoral Bone Resections During Total Knee Arthroplasty?

PURPOSE: Accurate alignment and balanced flexion and extension gaps are critical elements in achieving a successful outcome following total knee arthroplasty (TKA). The ability to make accurate and precise bone cuts is essential in the creation of balanced gaps. We sought to determine if one type of modern-day standard surgical instrument using an intramedullary rod and posterior referencing produces accurate and precise distal and posterior femoral bone resections. MATERIALS AND METHODS: Seventy-five consecutive patients undergoing TKA were divided into three groups, with 25 patients in each group receiving one of three implant designs: 25 Stryker Triathlon® CR (Stryker, Mahwah, NJ), 25 Zimmer NexGen® Flex CR (Zimmer, Warsaw, IN), and 25 StelKast Proven Gen-FlexTM CR (StelKast, Pittsburgh, PA). Flexion-extension gap matching was determined using only the medial flexion and extension gaps. Accuracy was determined by comparing actual resection thickness to desired resection thickness. "Optimal" accuracy was considered to be within 1.0mm of desired, and "near-optimal" accuracy was considered to be within 2.0mm of the desired resection thickness. Precision was determined by the variability of resection thicknesses within each system. RESULTS: Data demonstrated a lack of accuracy and precision across all three tested systems, with each system resulting in certain unique tendencies. Only one out of 75 cases resulted in optimal resection accuracy with all three cuts (Zimmer). When lowering the threshold to include both optimal and near-optimal (within 2 mm of error) with all three cuts, only one third of Stryker and Zimmer cases and two thirds of StelKast cases achieved this threshold, representing 44% of cases (33/75). CONCLUSIONS: Improvements in instrumentation to increase accuracy and precision may be warranted. Errors in fixation may be due to the instrumentation itself, and altering instrumentation to include less modularity, provide more stable fixation, and more reliably seal the implant on the femur may be of benefit.

The fetal anterior cruciate ligament: an anatomic and histologic study.

PURPOSE: The purposes of this study were to better understand the fetal development of the anterior cruciate ligament (ACL); to identify the gross anatomy of the ACL; to perform a complete histologic evaluation of the ligament, particularly with respect to the distinction between bundles; and to evaluate ACL length, diameter, cellularity, vascularity, and insertion sites. METHODS: By use of 40 intact knee joints of human fetuses, the gross anatomy of the ACL was inspected under a stereomicroscope (n = 40). The histologic evaluation was performed on the sagittal (n = 20) and transverse (n = 10) sections. RESULTS: The gross observations revealed the presence of 2 distinct bundles: anteromedial (AM) and posterolateral (PL). The femoral origin of each ACL bundle was located in the posterior aspect of the medial surface of the lateral femoral condyle. The footprint of the tibial insertion was ovoid, with the AM bundle located anterior and medial to the PL bundle. The mean length of the ACL was 3.7 mm, the mean width was 1.1 mm, and the mean thickness was 0.9 mm. There was high cellularity, with approximately 5,600 cells/mm2, and intense vascularity. The AM and PL bundles were divided by a well-defined septum. The femoral origin had less dense connective tissue compared with the tibial insertion. CONCLUSIONS: From the time of fetal development, the ACL is composed of 2 bundles, AM and PL. The gross morphology of the ACL in fetuses is similar to that reported in adults; the histology is diverse in cellularity and vascularity. CLINICAL RELEVANCE: This study provides useful information about the anatomy and histology of the fetal ACL.

Biologic modification of animal models of intervertebral disc degeneration.

Intervertebral disc degeneration is a chronic process that can become manifest in clinical disorders such as idiopathic low back pain, sciatica, disc herniation, spinal stenosis, and myelopathy. The limited available treatment options (including discectomy and spinal fusion) for these and other disabling conditions that arise from intervertebral disc degeneration are highly invasive, achieve limited success, and only address acute symptoms while doing nothing to halt the process of degeneration. Although the precise pathophysiology of intervertebral disc degeneration has yet to be clearly delineated, the progressive decline in aggrecan, the primary proteoglycan of the nucleus pulposus, appears to be a final common pathway. Animal models as well as in vitro studies of the process of disc degeneration have yielded many potentially useful targets for the reversal of disc degeneration. One current research trend is the use of established animal models of disc degeneration to study the role of therapeutic modalities in reversing the process of degeneration, often with use of the delivery of genes or gene products that influence the anabolic and catabolic pathways of the disc. This article reviews the ability of gene-product delivery systems and gene therapy to alter biologic processes in animal models of disc degeneration and examines future trends in this field.

Gene therapy for disc repair.

BACKGROUND CONTEXT: Recent advances in our understanding of the biologic makeup and environment of the intervertebral disc (IVD) have led to increased interest in the development of novel treatments for disc degeneration. Certain genes found to alter rates of matrix synthesis and catabolism within the disc have provided targets for scientists seeking to alter the balance between the two. To this end, gene therapy has emerged as a potential therapeutic option, and recent research efforts have yielded very promising results. PURPOSE: To update and consolidate information regarding the recent advances in gene therapy and its application to IVD degeneration. STUDY DESIGN/SETTING: Review of recent and ongoing research in the field of gene therapy, particularly regarding its application to the treatment of IVD degeneration. METHODS: Literature review. RESULTS: With its unique ability to provide sustained delivery of potentially therapeutic agents, gene therapy has shown much promise with regard to the treatment of IVD degeneration. There have been many exciting developments such as safer and more reliable vector constructs, favorable results using therapeutic transgenes in disc cells both in vitro and in vivo, and improvement in transgene regulation, and investigators continue to explore ways in which gene therapy can become a powerful tool in the future treatment of disc degeneration. CONCLUSIONS: With continued perseverance and dedication, many advances have been made in the application of gene therapy to the IVD, and it continues to demonstrate great potential to become a powerful tool in the future treatment of disc degeneration.

Increased incidence of patella baja after total knee arthroplasty revision for infection.

The incidence of patella baja in total knee arthroplasty (TKA) revisions for aseptic and septic causes is not well defined. We retrospectively reviewed 101 mobile-bearing TKA revisions performed between 2003 and 2009. Aseptic (n=67) and septic (n=34) revisions were compared for patella baja. A nonarticulating spacer was used as the initial treatment for infected cases. The Insall-Salvati ratio was radiographically measured before surgery (preexplant for septic revisions) and at latest follow-up (postreplant for septic revisions). Mean (SD) Insall-Salvati ratio did not differ between groups before surgery, 1.00 (0.25) for aseptic and 0.96 (0.22) for septic, but differed significantly after surgery, 0.99 (0.23) for aseptic and 0.77 (0.24) for septic. After correcting for preoperative patellar height, there was a statistically significant postoperative difference between aseptic cases, 1.09 (0.19), and septic cases, 0.82 (0.21). There was also a significant difference in mean (SD) postoperative range of motion (ROM) between aseptic cases, 108.0° (20.7°), and septic cases, 92.2° (34.6°), and decreased ROM between cases with patella baja, 95.1° (31.6°) and cases without patella baja, 106.8° (23.6°). TKA revisions done for septic causes using a nonarticulating spacer resulted in a higher incidence of patella baja and decreased ROM.

Safety assessment of intradiscal gene therapy II: effect of dosing and vector choice.

STUDY DESIGN: Clinical, biochemical, and histologic analysis was performed after in vivo delivery of cDNA encoding various anabolic cytokines and marker genes to the lumbar epidural space of New Zealand white rabbits, using both adenoviral and adeno-associated viral vectors. OBJECTIVE: To mimic errant or misplaced doses of gene therapy to better ascertain the potential risks associated with alternative vectors and transgene products with regard to their application to problems of the intervertebral disc. SUMMARY OF BACKGROUND DATA: Work done with several anabolic cytokines including bone morphogenic proteins and transforming growth factors, has demonstrated the potential of gene therapy. Recently, data has been published demonstrating that improperly dosed or delivered adenoviral-mediated gene therapy within the subarachnoid space can result in significant morbidity in rabbits. There are currently no studies examining the effect of these errors within the epidural space or using an adeno-associated viral (AAV) vector. METHODS: Using either adenoviral or AAV vectors, complementary DNA (cDNA) encoding anabolic cytokines bone morphogenic protein-2 (BMP-2) and transforming growth factor-beta 1 and marker proteins LacZ and green fluorescent protein were injected into the epidural space of 37 New Zealand white rabbits at the L5/6 level. Rabbits were then observed clinically for up to 6 weeks, after which the rabbits were sacrificed in order to perform a comprehensive biochemical and histologic analysis. RESULTS: Following adenoviral-mediated delivery of anabolic cytokine cDNA, up to eighty percent of rabbits demonstrated significant clinical, biochemical, and histologic morbidity. Conversely, AAV-mediated delivery of any cDNA and adenoviral-mediated delivery of marker protein cDNA resulted in no clinical, histologic, or biochemical morbidity. CONCLUSION: Properly dosed and directed gene therapy seems to be both safe and potentially efficacious. This study suggests that side effects of gene therapy may be due to a combination of dosing, transgene product, and vector choice, and that newer AAV vectors may reduce these side-effects and decrease the risk of this technology.

Regulation of transgene expression using an inducible system for improved safety of intervertebral disc gene therapy.

STUDY DESIGN: Human nucleus pulposus cells (NPCs) were transduced with an adenoviral vector that expresses Fas Ligand (FasL) and green fluorescent protein (GFP) under the control of a tetracycline-regulated gene expression system to test the transgene control. OBJECTIVES: To describe the application of a Tet-off gene regulation system for intervertebral disc (IVD) gene therapy. SUMMARY OF BACKGROUND DATA: Gene therapy has proven its ability to beneficially modulate the biologic processes of the IVD cells in vitro and in vivo. However, we have observed that expression of transgenic growth factors outside the IVD in the event of a misdirected injection has potentially detrimental consequences (e.g., toxicity). To date, a safety system that allows the control transgene expression has not been produced for intradiscal gene therapy. METHODS: Human NPCs were transduced with Ad/FasL-GFPTET, at 0, 50, 100, and 200 MOI. After 1 day (time 0) cells were cultured in the presence of tetracycline (1, 10, 100 mg/L) for 3 days, and then tetracycline was withdrawn. The transgene expression was evaluated either daily by flow cytometry (from time 0 to day 6) or by imaging the GFP signal (time 0, day 3 and day 9). RESULTS: NPC expression of GFP 1 day after transduction was proportional to the MOI used. GFP expression was decreased after 3 days of tetracycline administration at all concentrations used. The expression of GFP recovered after removal of tetracycline. CONCLUSIONS: The transgene expressed by the transduced NPC was efficiently regulated by inclusion of tetracycline in culture media. The presence of tetracycline turns off the protein expression and the subsequent absence allows it to recover again, demonstrating the ability to control gene expression in NPCs. Therefore, we propose a Tet-off inducible system as an efficient tool for modulating the transgene expression to avoid the toxicity that could result from a missed injection.