A Rapid MRI Protocol for the Evaluation of Acute Pediatric Musculoskeletal Infections: Eliminating Contrast and Decreasing Anesthesia, Scan Time, and Hospital Length of Stay and Charges.

BACKGROUND: Acute musculoskeletal infection affects >1 in 6,000 children in the United States annually. Magnetic resonance imaging (MRI) is the gold standard for the diagnosis of musculoskeletal infection, but it traditionally requires contrast and anesthesia for children, delaying management. A rapid MRI protocol involves MRI without anesthesia and with limited non-contrast sequences optimized for fluid detection and diffusion-weighted images to identify abscesses. We hypothesized that a rapid MRI protocol would improve imaging and treatment efficiency for pediatric patients undergoing musculoskeletal infection evaluation without substantially affecting accuracy. METHODS: This was a single-center, retrospective study of patients undergoing evaluation for musculoskeletal infection before (60 patients in the traditional cohort [TC]) and after (68 patients in the rapid cohort [RC]) implementation of the rapid MRI protocol. Sociodemographic and clinical variables were extracted from electronic health records, and statistical comparisons were performed. RESULTS: The anesthesia rates were 53% for the TC and 4% for the RC, and the contrast administration rates were 88% for the TC and 0% for the RC. The median time to MRI after ordering was 6.5 hours (95% confidence interval [CI], 5.0 to 8.6 hours) for the TC and 2.2 hours (95% CI, 1.4 to 3.6 hours) for the RC (p < 0.01). The median duration of MRI was 63.2 minutes (95% CI, 56.8 to 69.6 minutes) for the TC and 24.0 minutes (95% CI, 21.1 to 29.5 minutes) for the RC (p < 0.01). The median hospital length of stay was 5.3 days (95% CI, 3.7 to 6.9 days) for the TC and 3.7 days (95% CI, 1.9 to 4.1 days) for the RC (p < 0.01). The median hospital charges were $47,309 (95% CI, $39,137 to $58,769) for the TC and $32,824 (95% CI, $22,865 to $45,339) for the RC (p < 0.01). Only 2 positive cases of musculoskeletal infection in the RC were missed on the initial imaging, but these instances were not attributable to the rapid protocol itself. Although 10 of 68 rapid MRI scans resulted in nondiagnostic outcomes due to patient motion, only 6 of 68 required repeat MRI with anesthesia. CONCLUSIONS: In patients evaluated for musculoskeletal infection, the rapid MRI protocol eliminated contrast and minimized anesthesia while improving MRI access and decreased scan and interpretation times, hospital length of stay, and hospital charges. The rapid MRI protocol had high sensitivity for diagnosing musculoskeletal infection and a low rate of imaging failure. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Epidemiology of Physeal Fractures and Clinically Significant Growth Disturbances Affecting the Distal Tibia, Proximal Tibia, and Distal Femur: A Retrospective Cohort Study.

INTRODUCTION: Childhood fractures involving the physis potentially result in premature physeal closure that can lead to growth disturbances. Growth disturbances are challenging to treat with associated complications. Current literature focusing on physeal injuries to lower extremity long bones and risk factors for growth disturbance development is limited. The purpose of this study was to provide a review of growth disturbances among proximal tibial, distal tibial, and distal femoral physeal fractures. METHODS: Data were retrospectively collected from patients undergoing fracture treatment at a level I pediatric trauma center between 2008 and 2018. The study was limited to patients 0.5 to 18.9 years with a tibial or distal femoral physeal fracture, injury radiograph, and appropriate follow-up for determination of fracture healing. The cumulative incidence of clinically significant growth disturbance (CSGD) (a growth disturbance requiring subsequent physeal bar resection, osteotomy, and/or epiphysiodesis) was estimated, and descriptive statistics were used to summarize demographics and clinical characteristics among patients with and without CSGD. RESULTS: A total of 1,585 patients met the inclusion criteria. The incidence of CSGD was 5.0% (95% confidence interval, 3.8% to 6.6%). All cases of growth disturbance occurred within 2 years of initial injury. The risk of CSGD peaked at 10.2 years for males and 9.1 years for females. Complex fractures that required surgical treatment, distal femoral and proximal tibial fractures, age, and initial treatment at an outside hospital were significantly associated with an increased risk of a CSGD. DISCUSSION: All CSGDs occurred within 2 years of injury, indicating that these injuries should be followed for a period of at least 2 years. Patients with distal femoral or proximal tibial physeal fractures that undergo surgical treatment are at highest risk for developing a CSGD. LEVEL OF EVIDENCE: Level III Retrospective Cohort Study.

Analysis of Physeal Fractures from the United States National Trauma Data Bank.

BACKGROUND: Pediatric long-bone physeal fractures can lead to growth deformities. Previous studies have reported that physeal fractures make up 18-30% of total fractures. This study aimed to characterize physeal fractures with respect to sex, age, anatomic location, and Salter-Harris (SH) classification from a current multicenter national database. METHODS: A retrospective cohort study was performed using the 2016 United States National Trauma Data Bank (NTDB). Patients ≤ 18 years of age with a fracture of the humerus, radius, ulna, femur, tibia, or fibula were included. RESULTS: The NTDB captured 132,018 patients and 58,015 total fractures. Physeal fractures made up 5.7% (3291) of all long-bone fractures, with males accounting for 71.0% (2338). Lower extremity physeal injuries comprised 58.6% (1929) of all physeal fractures. The most common site of physeal injury was the tibia comprising 31.8% (1047), 73.9% (774) of which were distal tibia fractures. Physeal fractures were greatest at 11 years of age for females and 14 years of age for males. Most fractures were SH Type II fractures. DISCUSSION AND CONCLUSIONS: Our analysis indicates that 5.7% of pediatric long-bone fractures involved the physis, with the distal tibia being the most common. These findings suggest a lower incidence of physeal fractures than previous studies and warrant further investigation.

Lower extremity physeal fractures and post-traumatic surgical deformities; National Trauma Data Bank and institutional cohorts.

Background: Pediatric lower extremity physeal fractures carry a risk of developing deformities. Most epidemiological evidence is over 25 years old, single institution, and lacks follow-up, while recent studies report variable results. Understanding their epidemiology and deformity risk is important for patient counseling and follow-up. Methods: The National Trauma Data Bank (NTDB) from 2016 was queried to describe the modern epidemiology of physeal fractures. This was contrasted with our 10-year experience of surgically treated deformities. Basic descriptive statistics, Chi-square analysis, prevalence ratios and multivariable linear regression were used to interpret results. Results: The NTDB contained 22,048 non-physeal and 1,929 physeal fractures of the femur, tibia, and fibula. Physeal fracture prevalence rose after 8 years of age but decreased for girls 2 years sooner than boys. Salter Harris (SH) type 2 fractures predominated. Physeal fractures were more commonly associated with lower energy mechanisms of injury. Distal tibia fractures were more prevalent in the NTDB cohort, while distal femur and SH-1 fractures were more prevalent in the operative cohort. Over 10 years, only 52 (5.3%) of the deformity-correcting surgeries at our institution were for physeal fracture sequelae. Age at injury and intraarticular fractures were associated with shorter times from injury to deformity correction. Conclusion: Lower extremity physeal fractures are uncommon. Fracture pattern prevalence differs from an operative cohort. Proximal tibia physeal fractures appear to be an underappreciated source of deformity. The risk of developing deformity requiring operative intervention appears to be low and is generally treated within 2 years of initial injury.

IS (Idiopathic Scoliosis) etiology: Multifactorial genetic research continues. A systematic review 1950 to 2017.

OBJECTIVE: IS (idiopathic scoliosis) is a common spinal condition occurring in otherwise completely healthy adolescents. The root cause of IS remains unclear. This systematic review will focus on an update of genetic factors and IS etiology. Though it is generally accepted that the condition is not due to a single gene effect, etiology studies continue looking for a root cause including genetic variants. Though susceptibility from multiple genetic components is plausible based on known family history data, the literature remains unclear regarding multifactorial genetic influences. The objective of this study was to critically evaluate the evidence behind genetic causes (not single gene) of IS through a systematic review and strength-of-study analysis of existing genetic and genome-wide association studies (GWAS). We used the protocol of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). METHODS: PubMed was searched for the terms IS, scoliotic, spinal curve, genetic, gene, etiology, polymorphisms. Articles were assessed for risk-of-bias. Level-of-evidence grading was completed via Oxford Centre for Evidence-Based Medicine criteria. The assessment scores factor strength of a study in determining a positive or negative association to a gene etiology. RESULTS: After screening of 36 eligible papers, 8 relevant studies met inclusion criteria at this time, 3 were in favor of a genetic factor for IS, whereas 5 studies were against it. CONCLUSION: Based on the literature analyzed, there is moderate evidence with a low risk-of-bias that does not clarify a genetic cause of IS. The 2 studies in favor of a genetic etiology were completed in homogeneous populations, limiting their generalizability. Relying on a genetic etiology alone for IS may over simplify its multifactorial nature and limit appreciation of other influences.

Can EOS Imaging Substitute for Conventional Radiography in Measurement of Acetabular Morphology in the Young Dysplastic Hip?

BACKGROUND: EOS imaging offers a low-radiation alternative to conventional radiography (CR) and has little to no magnification effects. However, it is unclear how radiographic measures may be affected using EOS. The present study aims to determine the reproducibility of measures of acetabular morphology on EOS images as compared with CR, and to directly compare the 2 imaging modalities. METHODS: A total of 21 consecutive patients (66.7% female; 14.4±4.7 y) indicated for an open hip preservation procedure with both an anterior-posterior pelvis radiograph and EOS image performed preoperatively were included. Three orthopaedic surgeons measured Tönnis angle, lateral center edge angle (LCEA), acetabular depth-width ratio (ADR), and extrusion index (EI). Measurements were performed twice, 2 weeks apart. Reliability between observers and time points was measured using intraclass correlation coefficients, and agreement between time points and modalities was measured using Bland-Altman analysis. RESULTS: On EOS images, inter-rater reliability was 0.86 for Tönnis angle, 0.86 for LCEA, 0.74 for ADR, and 0.93 for EI. On CR, inter-rater reliability was 0.86 for Tönnis anlge, 0.90 for LCEA, 0.82 for ADR, and 0.84 for EI. In the agreement analysis, biases between imaging modalities were observed. On average, raters measured Tönnis angle and EI higher on EOS images than CR (2.22 degrees, 1.09%, respectively); and LCEA and ADR lower on EOS images than CR (1.54 degrees, 1.14% respectively). Limits of agreement (LOA) between modalities were similar to that of LOA observed in intra-rater analysis. CONCLUSIONS: Measures of acetabular morphology performed on EOS images have similarly high intra-rater and inter-rater reliability compared with CR. Measures performed on EOS also have similar intra-rater agreement as compared with CR. Intermodality agreement had similar LOA as intra-rater agreement on either individual imaging modality. Small biases between imaging modalities were detected. LEVELS OF EVIDENCE: Level I-diagnostic study: investigating a diagnostic test.

The Community Orthopaedic Surgeon Taking Trauma Call: Radial Neck Fracture Pearls and Pitfalls.

Pediatric radial neck fractures will inevitably be encountered by the general orthopaedist, and they carry great potential for poor outcomes. Acceptable displacement varies by age, and unlike adults, most of these injuries can be managed by closed means. If they are taken to the operating room, the mainstays of treatment are percutaneous techniques. Increasing patient age, inadequate reduction, unnecessary open reductions, and prolonged immobilization are all associated with worse outcomes, most commonly manifesting as significant elbow stiffness. Knowledge of the age-specific acceptable displacement criteria, a stepwise approach to closed and percutaneous techniques, and safe strategies for open reduction when needed as a last resort will greatly improve treatment success.

Porous scaffolds support extrahepatic human islet transplantation, engraftment, and function in mice.

Islet transplantation as a therapy or cure for type 1 diabetes has significant promise but has been limited by islet mass requirements and long-term graft failure. The intrahepatic and intravascular site may be responsible for significant loss of transplanted islets. Nonencapsulating biomaterial scaffolds provide a strategy for architecturally defining and modulating extrahepatic sites beyond the endogenous milieu to enhance islet survival and function. We utilized scaffolds to transplant human islets into the intraperitoneal fat of immunodeficient mice. A smaller human islet mass than previously reported reversed murine diabetes and restored glycemic control at human blood glucose levels. Graft function was highly dependent on the islet number transplanted and directly correlated to islet viability, as determined by the ATP-to-DNA ratio. Islets engrafted and revascularized in host tissue, and glucose tolerance testing indicated performance equivalent to healthy mice. Addition of extracellular matrix, specifically collagen IV, to scaffold surfaces improved graft function compared to serum-supplemented media. Porous scaffolds can facilitate efficient human islet transplantation and provide a platform for modulating the islet microenvironment, in ways not possible with current clinical strategies, to enhance islet engraftment and function.

Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models.

Intraportal transplantation of islets has successfully treated select patients with type 1 diabetes. However, intravascular infusion and the intrahepatic site contribute to significant early and late islet loss, yet a clinical alternative has remained elusive. We investigated non-encapsulating, porous, biodegradable polymer scaffolds as a vehicle for islet transplantation into extrahepatic sites, using syngeneic mouse and allogeneic porcine models. Scaffold architecture was modified to enhance cell infiltration leading to revascularization of the islets with minimal inflammatory response. In the diabetic mouse model, 125 islets seeded on scaffolds implanted into the epididymal fat pad restored normoglycemia within an average of 1.95 days and transplantation of only 75 islets required 12.1 days. Increasing the pore size to increase islet-islet interactions did not significantly impact islet function. The porcine model was used to investigate early islet engraftment. Increasing the islet seeding density led to a greater mass of engrafted islets, though the efficiency of islet survival decreased. Transplantation into the porcine omentum provided greater islet engraftment than the gastric submucosa. These results demonstrate scaffolds support murine islet transplantation with high efficiency, and feasibility studies in large animals support continued pre-clinical studies with scaffolds as a platform to control the transplant microenvironment.

Permanent protection of PLG scaffold transplanted allogeneic islet grafts in diabetic mice treated with ECDI-fixed donor splenocyte infusions.

Allogeneic islet cell transplantation is a promising treatment for human type 1 diabetes. Currently, human islets are transplanted via intra-portal infusions. While successful, it leads to significant early islet attrition from instant blood-mediated inflammatory reaction. An extra-hepatic site was established by transplanting islet-loaded microporous poly(lactide-co-glycolide) (PLG) scaffolds into the epididymal fat pad in syngeneic islet transplant models. This study examined this technology in allogeneic islet transplantation and determined whether transplant tolerance could be effectively induced to protect PLG scaffold transplanted allogeneic islets. The efficacy of an established tolerance induction strategy using donor splenocytes treated with ethylcarbodiimide(ECDI) was tested. ECDI-fixed donor splenocytes were infused 7 days before and 1 day after islet transplantation. Immediate normoglycemia was restored, and treated mice maintained indefinite normoglycemia whereas untreated mice rejected islet grafts within 20 days of transplantation. Interestingly, efficacy of tolerance induction was superior in PLG scaffold compared with intra-portal transplanted islets. Protection of PLG scaffold islet allografts was associated with several mechanisms of immune regulation. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that does not impair tolerance induction. This approach of combining tolerance induction with scaffold islet transplantation has potential therapeutic implications for human islet transplantation.

Engineering surfaces for substrate-mediated gene delivery using recombinant proteins.

Immobilized fibronectin and other natural proteins have been utilized to enhance substrate-mediated gene delivery, with apparent contributions from the intrinsic bioactivity and also physical properties of the immobilized proteins. In this report, we investigated the use of recombinant proteins, compared to the full-length fibronectin protein, as surface coatings for gene delivery to investigate the mechanisms by which fibronectin enhances gene transfer. The recombinant fibronectin fragment FNIII(7-10) (FNIII) contains the alpha(5)beta(1) binding domain of fibronectin and supports cell adhesion, whereas the recombinant protein polymer PP-12 is also negatively charged and has a molecular weight similar to FNIII, but lacks cell binding domains. Transfection was compared on surfaces modified with FNIII, full-length fibronectin, or PP-12. The full-length fibronectin provided the greatest extent of transgene expression relative to FNIII or PP-12, which was consistent with the amount of DNA that associated with cells. FNIII had 4.2-fold or 4.7-fold lower expression levels relative to fibronectin for polyplexes and lipoplexes, respectively. PP-12 produced expression levels that were 317-fold and 12.0-fold less than fibronectin for polyplexes and lipoplexes, respectively. Although expression was greater on FNIII relative to PP-12, the levels of DNA associated per cell with FNIII were similar to or less than those with PP-12, suggesting that the bioactive sequences may contribute to an enhanced intracellular trafficking. For lipoplexes delivered on FNIII, the efficiency of intracellular trafficking and levels of caveolar DNA were greater than that observed with either the full-length fibronectin or PP-12. For polyplexes, fibronectin fragment resulted in greater intracellular trafficking efficiency compared to PP-12 protein polymer. Recombinant proteins can be employed in place of full-length extracellular matrix proteins for substrate-mediated gene delivery, and bioactive sequences can influence one or more steps in the gene delivery process to maximize transfection.

Efficacy of immobilized polyplexes and lipoplexes for substrate-mediated gene delivery.

Non-viral gene delivery by immobilization of complexes to cell-adhesive biomaterials, a process termed substrate-mediated delivery, has many in vitro research applications such as transfected cell arrays or models of tissue growth. In this report, we quantitatively investigate the efficiency of gene delivery by surface immobilization, and compare this efficiency to the more typical bolus delivery. The ability to immobilize vectors while allowing cellular internalization is impacted by the biomaterial and vector properties. Thus, to compare this efficiency between vector types and delivery methods, transfection conditions were initially identified that maximized transgene expression. For surface delivery from tissue culture polystyrene, DNA complexes were immobilized to pre-adsorbed serum proteins prior to cell seeding, while for bolus delivery, complexes were added to the media above adherent cells. Mathematical modeling of vector binding, release, and cell association using a two-site model indicated that the kinetics of polyplex binding to cells was faster than for lipoplexes, yet both vectors have a half-life on the surface of approximately 17 min. For bolus and surface delivery, the majority of the DNA in the system remained in solution or on the surface, respectively. For polyplexes, the efficiency of trafficking of cell-associated polyplexes to the nucleus for surface delivery is similar or less than bolus delivery, suggesting that surface immobilization may decrease the activity of the complex. The efficiency of nuclear association for cell-associated lipoplexes is similar or greater for surface delivery relative to bolus. These studies suggest that strategies to enhance surface delivery for polyplexes should target the vector design to enhance its potency, whereas enhancing lipoplex delivery should target the material design to increase internalization.

Self-assembling peptide-lipoplexes for substrate-mediated gene delivery.

The efficiency of biomaterial-based gene delivery is determined by the interaction of the material and the vector. For lipoplexes, surface immobilization has been used to transfect cells for applications such as cell arrays and model tissue formation through patterned transfection. Further increases in the delivery efficiency are limited by cellular internalization, which may be overcome by altering the material/vector interactions. In this report, we investigated the modification of the lipoplex physical properties through self-assembly with cationic peptides, and subsequently quantified cellular association, internalization and nuclear accumulation of DNA and transfection. Relative to lipid alone, peptide-lipoplexes enhanced transfection by up to 4.6-fold. The presence of the peptide in the lipoplex increased internalization efficiency by up to 4.5-fold, decreased the percentage of lysosomal DNA by 2.1-fold and increased the efficiency of nuclear accumulation by 3.0-fold. In addition, an analysis of internalization pathways for peptide-lipoplexes indicated a greater role of clathrin and caveolae-mediated endocytosis relative to macropinocytosis, which was not observed for peptide-free lipoplexes. These results demonstrate peptide-induced enhancement of gene transfer by surface immobilization due to increased cellular internalization and nuclear accumulation, which has numerous applications ranging from cell-based assays to regenerative medicine.