The Relationship Between Height and Income With Potential Application to Treatment of Limb Length Discrepancy.

Purpose When treating limb length discrepancy (LLD), decisions regarding lengthening versus contralateral shortening require careful consideration of deformity and patient factors. Using the National Longitudinal Survey of Youth 1979 (NLSY79) database, and income as a quantitative representation of overall socioeconomic benefit, we sought to determine the height at which incremental gains in height have the greatest value. Methods Using the NLSY79 database, we collected demographic data, height, yearly income from wages, college education (full- or part-time), and receipt of government financial aid. Multiple-linear regression and graphical analysis were performed. Results The study population included 9,652 individuals, 4,775 (49.5%) males and 4,877 (50.5%) females. Mean heights were 70.0±3.0 inches and 64.3±2.6 inches for males and females, respectively. Multiple-linear regression analysis (adjusted-r²=0.33) demonstrated height had a standardized-ß=0.097 (p<0.001), even when accounting for confounding factors. Using graphical analysis, we estimated cut-offs of 74 inches for males and 69 inches for females, beyond which income decreased with incremental height. Conclusions Using income as a quantitative representation of socioeconomic value, our analysis found income increased with incremental height in individuals with predicted heights up to 74 inches for males and 69 inches for females. Shortening procedures might receive more consideration at predicted heights greater than these cut-offs, while lengthening might be more strongly considered at the lower ranges of height. Additionally, our multiple-linear regression analysis confirms the correlation between height and income, when factoring in other predictors of income.

Characterization of Induction and Targeting of Senescent Mesenchymal Stromal Cells.

Mesenchymal stromal cells (MSCs) from older donors have limited potential for bone tissue formation compared with cells from younger donors, and cellular senescence has been postulated as an underlying cause. There is a critical need for methods to induce premature senescence to study this phenomenon efficiently and reproducibly. However, the field lacks consensus on the appropriate method to induce and characterize senescence. Moreover, we have a limited understanding of the effects of commonly used induction methods on senescent phenotype. To address this significant challenge, we assessed the effect of replicative, hydrogen peroxide, etoposide, and irradiation-induced senescence on human MSCs using a battery of senescent cell characteristics. All methods arrested proliferation and resulted in increased cell spreading compared with low passage controls. Etoposide and irradiation increased expression of senescence-related genes in MSCs at early time points, proinflammatory cytokine secretion, DNA damage, and production of senescence-associated ß-galactosidase. We then evaluated the effect of fisetin, a flavonoid and candidate senolytic agent, to clear senescent cells and promote osteogenic differentiation of MSCs entrapped in gelatin methacryloyl (GelMA) hydrogels in vitro. When studying a mixture of nonsenescent and senescent MSCs, we did not observe decreases in senescent markers or increases in osteogenesis with fisetin treatment. However, the application of the same treatment toward a heterogeneous population of human bone marrow-derived cells entrapped in GelMA decreased senescent markers and increased osteogenesis after 14 days in culture. These results identify best practices for inducing prematurely senescent MSCs and motivate the need for further study of fisetin as a senolytic agent. Impact Statement The accumulation of senescent cells within the body has detrimental effects on tissue homeostasis. To study the role of senescent cells on tissue repair and regeneration, there is a need for effective means to induce premature cell senescence. Herein, we characterized the influence of common stressors to induce premature senescence in human mesenchymal stromal cells (MSCs). Irradiation of MSCs resulted in a phenotype most similar to quiescent, high-passage cells. These studies establish key biomarkers for evaluation when studying senescent cells in vitro.

Do All Fractures Need Surgery?

Common fractures managed by orthopaedic surgeons include ankle fractures, proximal humerus fractures in patients older than 60 years, humeral shaft fractures, and distal radius fractures. Recent trends indicate that surgical management is the best option for most fractures. However, there is limited evidence regarding whether most of these fractures need surgery, or whether there is a subset that could be managed without surgery, with no change in outcomes, or even possibly having improved results with lower complication rates with nonsurgical care.

Future modalities to assess fracture healing.

Objectives: Fracture healing remains a complex process routinely evaluated in clinical practice with sequential radiographs. Assessing the presence of union is a critical issue in patient care, with widespread implications in terms of overall decision-making and postoperative rehabilitation. Nonunion assessment, whether it be with radiographs or more advanced imaging, has far-reaching consequences for the patient in addition to the health care system. The purpose of this review was to explore new, emerging modalities for the assessment of fracture healing. Methods: A review of the current, relevant literature regarding the use of serologic markers and radiostereometric analysis was conducted, and the results were summarized. Results: Emerging techniques to assess fracture healing have been evaluated, including the use of serologic markers as well as radiostereometric analysis. Their potential applications extend beyond the simple assessment of a united fracture, with the capacity to predict nonunion at earlier phases of care. Conclusions: While early results appear promising, the current application of serologic markers and radiostereometric analysis as a means to assess fracture healing remains limited, and future larger-scale studies are needed to establish concrete and tailored guidelines for use.

Dual Magnetically Expandable Intramedullary Nails for Treatment of a Large Bony Defect in a Patient with Sarcoma: A Case Report.

Aim: To describe the surgical technique of performing an all-internal lengthening to address a large diaphyseal femur defect in the sarcoma patient. Background: Various strategies exist to address large intercalary bone defects with various biomechanical and biological implications. Case description: A 23-year-old female with high-grade osteosarcoma of her left femur underwent wide resection and an internal reconstruction of a 12.5-cm femoral defect using dual magnetic lengthening intramedullary nails resulting in restoration of leg lengths, and pre-resection function with minimal residual disability. Conclusion: Preoperative chemotherapy, wide resection and post-operative chemotherapy for osteosarcoma are the current standard of care. Resection often leads to large bone defects requiring complex reconstruction. Following intercalary bone resection, biological reconstruction is a consideration. An all-inside technique was developed in an effort to minimise complications of long-term external fixation for distraction osteogenesis, or extensile secondary grafting procedures for induced membrane strategy. Clinical significance: This previously unreported surgical technique allows for an all-internal lengthening of large diaphyseal bone defects. While specifically used in an oncologic post-resection setting, this technique is applicable to the broader limb reconstruction and lengthening practice and overcomes some inherent limitations to previously described techniques. How to cite this article: Copp J, Magister S, Napora J, et al. Dual Magnetically Expandable Intramedullary Nails for Treatment of a Large Bony Defect in a Patient with Sarcoma: A Case Report. Strategies Trauma Limb Reconstr 2022;17(3):189-194.

Weight-bearing status may influence rates of radiographic healing following reamed, intramedullary fixation of diaphyseal femur fractures.

OBJECTIVE: To investigate the effect of weight-bearing status on radiographic healing of diaphyseal femur fractures. DESIGN: Retrospective 1:1 matched cohort study. SETTING: Single-level 1 trauma center. PARTICIPANTS: One-hundred forty-four (N = 154) patients matched 1:1 in non-weight bearing (NWB) and weight-bearing as tolerated (WBAT) groups. INTERVENTION: Non-weight bearing following reamed, statically locked intramedullary fixation of diaphyseal femur fracture, generally due to concurrent lower extremity fracture. MAIN OUTCOME MEASUREMENT: Postoperative radiographic healing using modified Radiographic Union Scale for Tibia fractures (mRUST) scores. RESULTS: Groups were well matched on age, sex, race, prevalence of tobacco and alcohol use, diabetes mellitus status, Injury Severity Score, fracture pattern and shaft location, vascular injury, open fracture prevalence, and operative characteristics. Radiographic follow-up was similar between groups (231 vs 228 days, P = .914). At 6 to 8 weeks status post intramedullary fixation, the median mRUST score in the NWB group (9) was lower than that of the WBAT group (10) (mean: 8.4 vs 9.7, P = .004). At 12 to 16 weeks, the median mRUST in the NWB group (10) was again lower than the WBAT group (12) (mean: 9.9 vs 11.7, P = .003). The median number of days to 3 cortices of bridging callous was 85 in the WBAT group, compared with 122 in the NWB group (P = .029). Median time to mRUST scores of 12 (111 vs 162 days, P = .008), 13 (218 vs 278 days, P = .023), and 14 (255 vs 320 days, P = .028) were all longer in the NWB group compared with the WBAT group. CONCLUSIONS: Non-weight bearing after intramedullary fixation of diaphyseal femur fractures delays radiographic healing, with median time to 3 cortices of bridging callous increased from 85 days in WBAT groups to 122 days in NWB groups. These results provide clinicians with an understanding of the expected postoperative course, as well as further support the need to expeditiously advance weight-bearing status.Level of Evidence: IV.

Novel resuscitation strategies in patients with a pelvic fracture.

Patients with a pelvic ring injury and hemodynamic instability can be challenging to manage with high rates of morbidity and mortality rates. Protocol-based resuscitation strategies are critical to successfully manage these potentially severely injured patients in a well-coordinated manner. While some aspects of treatment may vary slightly from institution to institution, it is critical to identify pelvic injuries and their associated injuries expediently. The first step at the scene of injury or in the trauma resuscitation bay should be the immediate application of a circumferential pelvic sheet or binder, initiation of physiologically optimal fluid resuscitation in the form 1:1:1 (pRBC:FFP:platelets) or whole blood, and to consider TXA as a safe adjunct to treat coagulopathy. Providers should have a very low threshold for emergent operative intervention in the form of pelvic external fixation and/or pelvic packing. This occurs in addition to simultaneous interventions addressing the other possible sources of bleeding in patients demonstrating signs of hemorrhagic shock and failure to respond to early resuscitation and external pelvic tamponade. Finally, while arterial injury is only present in a small percentage of patients with a pelvic ring injury, percutaneous vascular intervention with selective angiography and REBOA have been shown to be efficacious for patients with clinical indicators of arterial injury or who remain hemodynamically unstable despite external pelvic tamponade and packing to address venous bleeding. They should be performed when as early as possible for patients in true extremis limit further hemorrhage and allow resuscitation efforts to continue.

Is Timing to Surgery an Independent Risk Factor for Complications Following Operative Treatment of Periprosthetic Lower Extremity Fractures?

OBJECTIVE: To identify whether timing to surgery was related to major 30-day morbidity and mortality rates in periprosthetic hip and knee fractures [OTA/AO 3 (IV.3, V.3), OTA/AO 4 (V4)]. DESIGN: Retrospective database review. SETTING: Hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. PATIENTS: Patients in the NSQIP database with periprosthetic hip or knee fractures between 2007 and 2015. INTERVENTION: Surgical management of periprosthetic hip and knee fractures including revision or open reduction internal fixation. MAIN OUTCOME MEASUREMENTS: Major 30-day morbidity and mortality after operative treatment of periprosthetic hip or knee fractures. RESULTS: A total of 1265 patients, mean age 72, including 883 periprosthetic hip and 382 periprosthetic fractures about the knee were reviewed. Delay in surgery greater than 72 hours is a risk factor for increased 30-day morbidity in periprosthetic hip and knee fractures [relative risk = 2.90 (95% confidence interval: 1.74-4.71); P-value ≤ 0.001] and risk factor for increased 30-day mortality [relative risk = 8.98 (95% confidence interval: 2.14-37.74); P-value = 0.003]. CONCLUSIONS: Using NSQIP database to analyze periprosthetic hip and knee fractures, delay to surgery is an independent risk factor for increased 30-day major morbidity and mortality when controlling for patient functional status and comorbidities. Although patient optimization and surgical planning are paramount, minimizing extended delays to surgery is a potentially modifiable risk factor in the geriatric periprosthetic lower extremity fracture patient. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Combined Surgical Approach to Young Adults with Hip Dysplasia and Concomitant Intra-Articular Pathology Using Intra-Abdominal Monitoring.

Background: Combined hip arthroscopy and periacetabular osteotomy (PAO) allows for treatment of intra-articular hip pathology with simultaneous correction of acetabular version and femoral head coverage in patients with symptomatic hip dysplasia. Currently, scant data is available to surgeons regarding optimal technique, sequence of repair, perioperative management, and the use of intra-abdominal monitoring in patients undergoing these combined procedures. The purpose of this study is to describe a two-surgeon, muscle-sparing, approach for sequential hip arthroscopy and PAO for the treatment of adults with acetabular dysplasia and concomitant intra-articular hip pathology. Methods: In this article, we present the indications for combined hip arthroscopy and PAO, in addition to patient set-up and positioning. A detailed discussion of hip arthroscopy and a muscle sparing PAO techniques are then presented, with overview of a novel intra-abdominal pressure monitoring technique and post-operative rehabilitation protocol. Results: Through technical refinement and experience, our indications and protocol for the treatment of patients with symptomatic acetabular dysplasia with concomitant intra-articular hip pathology involves a refined and reproducible, two surgeon procedure utilizing hip arthroscopy followed by PAO. The use of intra-abdominal monitoring allows for assessment of intra-peritoneal pressures to monitor for the development of abdominal compartment syndrome secondary to fluid extravasation. Conclusion: The performance of concomitant hip arthroscopy and PAO for concurrent hip dysplasia and intra-articular hip pathology represents an increasingly common approach in hip preservation surgery. The hip arthroscopy and muscle-sparing PAO protocol using intra-abdominal monitoring described here serves to further refine and advance the indications and technical aspects of this challenging procedure.Level of Evidence: V.

Are Readmissions After Total Knee Arthroplasty Preventable?

Readmission within 90 days following total joint arthroplasty has become a central quality measure of reimbursement initiatives; however, the validity of readmission rates as a measure of hospital care quality and the proportion of readmissions that are preventable are unknown. The purpose of this study is to determine if readmissions within 30 and 90 days after total knee arthroplasty (TKA) were related to orthopaedic or medical etiology and identify if these readmissions were preventable. We retrospectively reviewed 1,625 elective TKAs performed between 2011 and 2014 at our institution. Readmissions within 30 and 90 days were categorized into orthopaedic and medical etiologies and an expert research panel determined if readmissions were potentially preventable based on objective criteria from national or peer-reviewed consensus guidelines. Out of the 1,625 TKAs performed during the study period, there were a total of 79 (4.8%) readmissions within 90 days of surgery, of which 17 (22%) were of orthopaedic etiology and 62 (78%) were of medical etiology. Fifty-two (66%) of the 79 readmissions occurred within 30 days, with 11 (21%) of orthopaedic and 41 (80%) of medical etiology. Only 2 of 79 (3%) readmissions within 90 days were deemed potentially preventable, and neither of them were orthopaedic in nature. Hospital readmissions after total joint arthroplasty are inevitable; however, only a small percentage (3%) of readmissions to our health care system was potentially preventable. Orthopaedic readmissions constituted a minority of the proportion of readmissions at 30 or 90 days, and none were deemed preventable.

Honey-Based Salve and Burdock Leaf Dressings as an Alternative to Surgical Debridement of a Traumatic Wound Eschar.

Objective: Nonviable necrotic eschar is an impedance to wound healing and can ultimately lead to failure of soft tissue coverage in traumatic or high-risk wounds. Topical therapeutic agents can provide a less invasive management alternative to surgical debridement of eschar. Approach: The case of a 40-year-old male with a traumatic right lower extremity amputation complicated by surgical incision ischemic eschar formation is reported. Honey-based salve with burdock leaf dressings was used to noninvasively manage eschar extending over the incision site. Images were obtained for 5 months of follow-up. Results: Five-month follow-up demonstrated complete resolution of eschar and re-epithelialization of skin in the affected region. Innovation: Honey-based salve with burdock leaf dressings shows promise for enhancing healing outcomes in traumatic wounds that develop nonviable eschar. Conclusion: Surgical debridement of an amputation stump with large ischemic eschar was avoided with the use of honey-based salve with burdock leaf dressings.

Biomimetic Targeting of Nanoparticles to Immune Cell Subsets via Cognate Antigen Interactions.

Within the body, cellular recognition is mediated in large part by receptor-ligand interactions that result from the surface marker expression of the participant cells. In the case of immune cells, these interactions can be highly specific, enabling them to carry out their protective functions in fighting off infection and malignancy. In this work, we demonstrate the biomimetic targeting of antigen-specific immune cell populations by using nanoparticles functionalized with natural membrane derived from cells expressing the cognate antigen. Using red blood cell (RBC)-specific B cells as a model target, it is shown that RBC membrane-coated nanoparticles exhibit enhanced affinity compared with control nanoparticles. The concept is further demonstrated using murine models of alloimmunity and autoimmunity, where B cells elicited against RBCs can be positively labeled using the biomimetic nanoparticles. This strategy for antigen-specific immune cell targeting may have utility for the detection and treatment of various autoimmune conditions, and it may additionally have implications for the prevention of immune cell malignancies.

Organ-specific metastases obtained by culturing colorectal cancer cells on tissue-specific decellularized scaffolds.

Metastatic disease remains the primary cause of mortality in cancer patients. Yet the number of available in vitro models to study metastasis is limited by challenges in the recapitulation of the metastatic microenvironment in vitro, and by difficulties in maintaining colonized-tissue specificity in the expansion and maintenance of metastatic cells. Here, we show that decellularized scaffolds that retain tissue-specific extracellular-matrix components and bound signalling molecules enable, when seeded with colorectal cancer cells, the spontaneous formation of three-dimensional cell colonies that histologically, molecularly and phenotypically resemble in vivo metastases. Lung and liver metastases obtained by culturing colorectal cancer cells on, respectively, lung and liver decellularized scaffolds retained their tissue-specific tropism when injected in mice. We also found that the engineered metastases contained signet ring cells, which has not previously been observed ex vivo. A culture system with tissue-specific decellularized scaffolds represents a simple and powerful approach for the study of organ-specific cancer metastases.

Safe and Immunocompatible Nanocarriers Cloaked in RBC Membranes for Drug Delivery to Treat Solid Tumors.

The therapeutic potential of nanoparticle-based drug carriers depends largely on their ability to evade the host immune system while delivering their cargo safely to the site of action. Of particular interest are simple strategies for the functionalization of nanoparticle surfaces that are both inherently safe and can also bestow immunoevasive properties, allowing for extended blood circulation times. Here, we evaluated a recently reported cell membrane-coated nanoparticle platform as a drug delivery vehicle for the treatment of a murine model of lymphoma. These biomimetic nanoparticles, consisting of a biodegradable polymeric material cloaked with natural red blood cell membrane, were shown to efficiently deliver a model chemotherapeutic, doxorubicin, to solid tumor sites for significantly increased tumor growth inhibition compared with conventional free drug treatment. Importantly, the nanoparticles also showed excellent immunocompatibility as well as an advantageous safety profile compared with the free drug, making them attractive for potential translation. This study demonstrates the promise of using a biomembrane-coating approach as the basis for the design of functional, safe, and immunocompatible nanocarriers for cancer drug delivery.

Clearance of pathological antibodies using biomimetic nanoparticles.

Pathological antibodies have been demonstrated to play a key role in type II immune hypersensitivity reactions, resulting in the destruction of healthy tissues and leading to considerable morbidity for the patient. Unfortunately, current treatments present significant iatrogenic risk while still falling short for many patients in achieving clinical remission. In the present work, we explored the capability of target cell membrane-coated nanoparticles to abrogate the effect of pathological antibodies in an effort to minimize disease burden, without the need for drug-based immune suppression. Inspired by antibody-driven pathology, we used intact RBC membranes stabilized by biodegradable polymeric nanoparticle cores to serve as an alternative target for pathological antibodies in an antibody-induced anemia disease model. Through both in vitro and in vivo studies, we demonstrated efficacy of RBC membrane-cloaked nanoparticles to bind and neutralize anti-RBC polyclonal IgG effectively, and thus preserve circulating RBCs.

Cancer cell membrane-coated nanoparticles for anticancer vaccination and drug delivery.

Cell-derived nanoparticles have been garnering increased attention due to their ability to mimic many of the natural properties displayed by their source cells. This top-down engineering approach can be applied toward the development of novel therapeutic strategies owing to the unique interactions enabled through the retention of complex antigenic information. Herein, we report on the biological functionalization of polymeric nanoparticles with a layer of membrane coating derived from cancer cells. The resulting core-shell nanostructures, which carry the full array of cancer cell membrane antigens, offer a robust platform with applicability toward multiple modes of anticancer therapy. We demonstrate that by coupling the particles with an immunological adjuvant, the resulting formulation can be used to promote a tumor-specific immune response for use in vaccine applications. Moreover, we show that by taking advantage of the inherent homotypic binding phenomenon frequently observed among tumor cells the membrane functionalization allows for a unique cancer targeting strategy that can be utilized for drug delivery applications.

A biomimetic nanosponge that absorbs pore-forming toxins.

Detoxification treatments such as toxin-targeted anti-virulence therapy offer ways to cleanse the body of virulence factors that are caused by bacterial infections, venomous injuries and biological weaponry. Because existing detoxification platforms such as antisera, monoclonal antibodies, small-molecule inhibitors and molecularly imprinted polymers act by targeting the molecular structures of toxins, customized treatments are required for different diseases. Here, we show a biomimetic toxin nanosponge that functions as a toxin decoy in vivo. The nanosponge, which consists of a polymeric nanoparticle core surrounded by red blood cell membranes, absorbs membrane-damaging toxins and diverts them away from their cellular targets. In a mouse model, the nanosponges markedly reduce the toxicity of staphylococcal alpha-haemolysin (α-toxin) and thus improve the survival rate of toxin-challenged mice. This biologically inspired toxin nanosponge presents a detoxification treatment that can potentially treat a variety of injuries and diseases caused by pore-forming toxins.

Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery.

One of the promises of nanoparticle (NP) carriers is the reformulation of promising therapeutics that have failed clinical development due to pharmacologic challenges. However, current nanomedicine research has been focused on the delivery of established and novel therapeutics. Here we demonstrate proof of the principle of using NPs to revive the clinical potential of abandoned compounds using wortmannin (Wtmn) as a model drug. Wtmn is a potent inhibitor of phosphatidylinositol 3' kinase-related kinases but failed clinical translation due to drug-delivery challenges. We engineered a NP formulation of Wtmn and demonstrated that NP Wtmn has higher solubility and lower toxicity compared with Wtmn. To establish the clinical translation potential of NP Wtmn, we evaluated the therapeutic as a radiosensitizer in vitro and in vivo. NP Wtmn was found to be a potent radiosensitizer and was significantly more effective than the commonly used radiosensitizer cisplatin in vitro in three cancer cell lines. The mechanism of action of NP Wtmn radiosensitization was found to be through the inhibition of DNA-dependent protein kinase phosphorylation. Finally, NP Wtmn was shown to be an effective radiosensitizer in vivo using two murine xenograft models of cancer. Our results demonstrate that NP drug-delivery systems can promote the readoption of abandoned drugs such as Wtmn by overcoming drug-delivery challenges.