Vasanth Sathiyakumar

Targeted Nanoparticles That Deliver a Sustained, Specific Release of Paclitaxel to Irradiated Tumors

To capitalize on the response of tumor cells to XRT, we developed a controlled-release nanoparticle drug delivery system using a targeting peptide that recognizes a radiation-induced cell surface receptor. Phage display biopanning identified Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) as a peptide that selectively recognizes tumors responding to XRT. Membrane protein extracts of irradiated glioma cells identified glucose-regulated protein GRP78 as the receptor target for GIRLRG. Antibodies to GRP78 blocked the binding of GIRLRG in vitro and in vivo. Conjugation of GIRLRG to a sustained-release nanoparticle drug delivery system yielded increased paclitaxel concentration and apoptosis in irradiated breast carcinomas for up to 3 weeks. Compared with controls, a single administration of the GIRLRG-targeted nanoparticle drug delivery system to irradiated tumors delayed the in vivo tumor tripling time by 55 days (P = 0.0001) in MDA-MB-231 and 12 days in GL261 (P < 0.005). This targeting agent combines a novel recombinant peptide with a paclitaxel-encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches.

Tailored polyester nanoparticles: post-modification with dendritic transporter and targeting units via reductive amination and thiol-ene chemistry

We present synthetic strategies for the utilization of functionalized polyester nanoparticles that enable efficient chemistries to conjugate targeting units and dendritic molecular transporter entities to form potent carrier systems for targeted drug delivery and transport across biological barriers. Polyester nanoparticles that feature functionalities such as keto, amine and allyl groups to react with moieties present in bioactive compounds, could be prepared in a one-pot procedure that improves the prior-developed drop-in cross-linking method. Integrated keto functionalities were utilized with amines of the N-terminus of peptide targeting units in high yielding reductive amination reactions. Thiol-ene reaction conditions were developed to perform mild addition reactions with targeting units, such as a novel c-RGD, but also cell penetrating dendritic transporter structures. The synthesis of targeting peptide–nanoparticle conjugates (NP–P–dye), dendritic molecular transporter nanoparticle conjugates (NP–MT–dye) as well as conjugates that contained both bioactive entities (NP–P–MT–dye), could be achieved. To study these systems in vitro, imaging units such as Alexa Fluor® 594 were introduced as another additional component to label primarily the nanoparticle backbone. This work describes several efficient post-modification strategies to accommodate the demands of biomaterials for mild conjugation chemistries utilizing amine and thiol units to form polyester bioconjugates with specific functionalities as a platform for an array of therapeutic applications.

Hip fractures are risky business: an analysis of the NSQIP data.

INTRODUCTION Hip fractures are one of the most common types of orthopaedic injury with high rates of morbidity. Currently, no study has compared risk factors and adverse events following the different types of hip fracture surgeries. The purpose of this paper is to investigate the major and minor adverse events and risk factors for complication development associated with five common surgeries for the treatment of hip fractures using the NSQIP database. METHODS Using the ACS-NSQIP database, complications for five forms of hip surgeries were selected and categorized into major and minor adverse events. Demographics and clinical variables were collected and an unadjusted bivariate logistic regression analyses was performed to determine significant risk factors for adverse events. Five multivariate regressions were run for each surgery as well as a combined regression analysis. RESULTS A total of 9640 patients undergoing surgery for hip fracture were identified with an adverse events rate of 25.2% (n=2433). Open reduction and internal fixation of a femoral neck fracture had the greatest percentage of all major events (16.6%) and total adverse events (27.4%), whereas partial hip hemiarthroplasty had the greatest percentage of all minor events (11.6%). Mortality was the most common major adverse event (44.9-50.6%). For minor complications, urinary tract infections were the most common minor adverse event (52.7-62.6%). Significant risk factors for development of any adverse event included age, BMI, gender, race, active smoking status, history of COPD, history of CHF, ASA score, dyspnoea, and functional status, with various combinations of these factors significantly affecting complication development for the individual surgeries. CONCLUSIONS Hip fractures are associated with significantly high numbers of adverse events. The type of surgery affects the type of complications developed and also has an effect on what risk factors significantly predict the development of a complication. Concerted efforts from orthopaedists should be made to identify higher risk patients and prevent the most common adverse events that occur postoperatively.

Linear release nanoparticle devices for advanced targeted cancer therapies with increased efficacy

The cross-linked supramolecular structure of prepared polyester based nanoparticles enable increased and efficient small molecule drug loading after nanoparticle formation and post-modification with targeting peptides via thiol-ene ‘click’ chemistry. It could be demonstrated that the drug loading does not influence the structural integrity of the particle and its diameter was not significantly changed. A prolonged linear release profile of the drug without the typical ‘burst effect’ was observed in emulsified particles and mirrored the linear degradation profile of the investigated particles, which are critical properties for controlled and predictable pharmacokinetics in cancer therapies. Furthermore, the final peptide-targeted and drug-loaded particles were found to be readily dispersed in buffer or water, and with the confirmed biocompatibility, these novel and adjustable drug delivery systems are promising vectors for the treatment of various cancers.

Occupational Injury Among Orthopaedic Surgeons

BACKGROUND Orthopaedic surgery is a physically demanding profession that requires many hours per week in body positions known to contribute to musculoskeletal injury and pain. Injuries to surgeons can affect the delivery of care and impose costs on the health care system. The aim of this study was to determine the prevalence and types of injuries sustained at the workplace during the career of an orthopaedic surgeon as well as the impact of such injuries on practicing surgeons. METHODS A survey was developed to assess occupational injury among orthopaedic surgeons. Electronic surveys were distributed via e-mail to all orthopaedic surgeons in Tennessee. Data were analyzed to determine statistical associations of demographic and workplace factors with the rate of injury. RESULTS One hundred and forty (28%) of 495 surveys were returned, with representation from all orthopaedic subspecialties. Sixty-one (44%) of the respondents reported sustaining one or more injuries at the workplace during their career. A significant association was found between years performing surgery and prevalence of injury (p = 0.03), with surgeons working between twenty-one and thirty years reporting the most injuries. Twenty-five percent of respondents reported sustaining an injury to the hand; 19%, to the lower back; 10%, to the neck; 7%, to the shoulder; and 6%, to another area. Fourteen (10%) of all surgeons reported missing work as a result of a workplace injury, with five (4%) missing at least three weeks. Twenty-three surgeons (38% of injured respondents) reported that no institutional resources were available to support their recovery from the injury. CONCLUSIONS Our study is the first of its kind, to our knowledge, to demonstrate that many orthopaedic surgeons sustain occupational injuries during their careers. The volume of work missed suggests that occupational injury has economic implications for the health-care system and providers. Given the number of injured respondents reporting no institutional support for occupational injuries, more attention should be focused on this issue.

Gunshot-induced fractures of the extremities: a review of antibiotic and debridement practices.

The use of antibiotic prophylaxis and debridement is controversial when treating low- and high-velocity gunshot-induced fractures, and established treatment guidelines are currently unavailable. The purpose of this review was to evaluate the literature for the prophylactic antibiotic and debridement policies for (1) low-velocity gunshot fractures of the extremities, joints, and pelvis and (2) high-velocity gunshot fractures of the extremities. Low-velocity gunshot fractures of the extremities were subcategorized into operative and non-operative cases, whereas low-velocity gunshot fractures of the joints and pelvis were evaluated based on the presence or absence of concomitant bowel injury. In the absence of surgical necessity for fracture care such as concomitant absence of gross wound contamination, vascular injury, large soft-tissue defect, or associated compartment syndrome, the literature suggests that superficial debridement for low-velocity ballistic fractures with administration of antibiotics is a satisfactory alternative to extensive operative irrigation and debridement. In operative cases or those involving bowel injuries secondary to pelvic fractures, the literature provides support for and against extensive debridement but does suggest the use of intravenous antibiotics. For high-velocity ballistic injuries, the literature points towards the practice of extensive immediate debridement with prophylactic intravenous antibiotics. Our systematic review demonstrates weak evidence for superficial debridement of low-velocity ballistic fractures, extensive debridement for high-velocity ballistic injuries, and antibiotic use for both types of injury. Intra-articular fractures seem to warrant debridement, while pelvic fractures with bowel injury have conflicting evidence for debridement but stronger evidence for antibiotic use. Given a relatively low number of studies on this subject, we recommend that further high-quality research on the debridement and antibiotic use for gunshot-induced fractures of the extremities should be conducted before definitive recommendations and guidelines are developed.

The Costs of Operative Complications for Ankle Fractures: A Case Control Study

As our healthcare system moves towards bundling payments, it is vital to understand the potential financial implications associated with treatment of surgical complications. Considering that surgical treatment of ankle fractures is common, there remains minimal data relating costs to postsurgical intervention. We aimed to identify costs associated with ankle fracture complications through case-control analysis. Using retrospective analysis at a level I trauma center, 28 patients with isolated ankle fractures who developed complications (cases) were matched with 28 isolated ankle fracture patients without complications (controls) based on ASA score, age, surgery type, and fracture type. Patient charts were reviewed for demographics and complications leading to readmission/reoperation and costs were obtained from the financial department. Wilcoxon tests measured differences in the costs between the cases and controls. 28 out of 439 patients (6.4%) developed complications. Length of stay and median costs were significantly higher for cases than controls. Specifically, differences in total costs existed for infection and hardware-related pain. This is the first study to highlight the considerable costs associated with the treatment of complications due to isolated ankle fractures. Physicians must therefore emphasize methods to control surgical and nonsurgical factors that may impact postoperative complications, especially under a global payment system.

The evolution of advocacy and orthopaedic surgery.

BackgroundThe future direction of American health care has become increasingly controversial during the last decade. As healthcare costs, quality, and delivery have come under intense scrutiny, physicians play evolving roles as “advocates” for both their profession and patients via healthcare policy. Hospital-physician alignment is critical to the future success of advocacy among orthopaedic surgeons, as both hospitals and physicians are key stakeholders in health care and can work together to influence major health policy decisions.Questions/purposesWe (1) define the role of advocacy in medicine, specifically within orthopaedic surgery; (2) explore the history of physician advocacy and its evolution; (3) examine the various avenues of involvement for orthopaedic surgeons interested in advocacy; and (4) reflect on the impact of such activities on the future of orthopaedic surgery as it relates to hospital-physician alignment.MethodsWe performed a comprehensive review of the literature through a bibliographic search of MEDLINE® and Google Scholar databases from January 2000 to December 2010 to identify articles related to advocacy and orthopaedic surgery.ResultsAdvocacy among orthopaedic surgeons is critical in guiding the future of the American healthcare system. In today’s world, advocacy necessitates a wider effort to improve healthcare access, quality, and delivery for patients on a larger scale. The nature of physician advocacy among orthopaedic surgeons is grounded in the desire to serve patients and alleviate their suffering. Participation in medical societies and political campaigns are two avenues of involvement.ConclusionsThe increasing role of government in American health care will require a renewed commitment to advocacy efforts from orthopaedic surgeons. The role of advocacy is rapidly redefining the continuum of care to a trinity of clinical excellence, innovative research, and effective advocacy. Failure to recognize this growing role of advocacy limits the impact we can have for our patients.

Ankle fractures and employment: a life-changing event for patients

Abstract Purpose: Ankle fractures, one of the most common types of orthopaedic injury, have been associated with reduced functional outcome and significant changes in long-term employment. Although information on unemployment following ankle fractures can be important in cases of financial compensation, no studies have investigated rates of short-term disability and employment status among patients who have suffered isolated ankle fractures in the US. Method: We retrospectively reviewed 573 medical charts for patients who were treated for ankle fractures in the last 3 years at a level I trauma center. A total of 83 non-elderly patients that had isolated ankle fractures were contacted and surveyed over the phone. Patients were asked about employment history and current status, disability, type of fracture, and demographic information. Results: Fifty-three (62%) patients contacted were employed at the time of injury. In all, 34% (n = 18) of patients lost their job because of their injury, of which only 8 (44%) received new employment. A total of 15% (n = 8) of patients that were previously employed decided to no longer return to work. Ten patients (56%) received disability status. Conclusions: Ankle fracture patients are likely to suffer high rates of unemployment or disability shortly after their injury. Further investigations with a larger-scale, randomized patient population can provide important information on employment status following ankle fractures. Implications for Rehabilitation A total of 47.0% of ankle fracture patients are unable to return to work within 5 years following injury. Patients in labour-intensive jobs are especially vulnerable to job loss and disability. Rehabilitation should have a greater focus on occupational therapy and work-related functioning. Improving patient compliance with attendance for rehabilitation may improve employment outcomes.

Ankle Fractures and Modality of Hospital Transport at a Single Level 1 Trauma Center: Does Transport by Helicopter or Ground Ambulance Influence the Incidence of Complications?

In an era of concern over the rising cost of health care, cost-effectiveness of auxiliary services merits careful evaluation. We compared costs and benefits of Helicopter Emergency Medical Service (HEMS) with Ground Emergency Medical Service (GEMS) in patients with an isolated ankle fracture. A medical record review was conducted for patients with an isolated ankle fracture who had been transported to a level 1 trauma center by either HEMS or GEMS from January 1, 2000 to December 31, 2010. We abstracted demographic data, fracture grade, complications, and transportation mode. Transportation costs were obtained by examining medical center financial records. A total of 303 patients was included in the analysis. Of 87 (28.71%) HEMS patients, 53 (60.92%) had sustained closed injuries and 34 (39.08%) had open injuries. Of the 216 (71.29%) GEMS patients, 156 (72.22%) had closed injuries and 60 (27.78%) had open injuries. No significant difference was seen between the groups regarding the percentage of patients with open fractures or the grade of the open fracture (p = .07). No significant difference in the rate of complications was found between the 2 groups (p = 18). The mean baseline cost to transport a patient via HEMS was