IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease.

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.

Subregional analysis of striatum iron in Parkinson's disease and rapid eye movement sleep behaviour disorder.

The loss of dopamine in the striatum underlies motor symptoms of Parkinson's disease (PD). Rapid eye movement sleep behaviour disorder (RBD) is considered prodromal PD and has shown similar neural changes in the striatum. Alterations in brain iron suggest neurodegeneration; however, the literature on striatal iron has been inconsistent in PD and scant in RBD. Toward clarifying pathophysiological changes in PD and RBD, and uncovering possible biomarkers, we imaged 26 early-stage PD patients, 16 RBD patients, and 39 age-matched healthy controls with 3 T MRI. We compared mean susceptibility using quantitative susceptibility mapping (QSM) in the standard striatum (caudate, putamen, and nucleus accumbens) and tractography-parcellated striatum. Diffusion MRI permitted parcellation of the striatum into seven subregions based on the cortical areas of maximal connectivity from the Tziortzi atlas. No significant differences in mean susceptibility were found in the standard striatum anatomy. For the parcellated striatum, the caudal motor subregion, the most affected region in PD, showed lower iron levels compared to healthy controls. Receiver operating characteristic curves using mean susceptibility in the caudal motor striatum showed a good diagnostic accuracy of 0.80 when classifying early-stage PD from healthy controls. This study highlights that tractography-based parcellation of the striatum could enhance sensitivity to changes in iron levels, which have not been consistent in the PD literature. The decreased caudal motor striatum iron was sufficiently sensitive to PD, but not RBD. QSM in the striatum could contribute to development of a multivariate or multimodal biomarker of early-stage PD, but further work in larger datasets is needed to confirm its utility in prodromal groups.

Emerging Minimally Invasive Percutaneous Procedures for Periacetabular Osteolytic Metastases.

➤: Periacetabular osteolytic skeletal metastases are frequently associated with pain and impaired ambulatory function. Minimally invasive techniques allow for the restoration of ambulation without interrupting critical systemic cancer therapy. ➤: The open surgical management of massive periacetabular osteolytic lesions, such as by curettage, internal fixation, or complex total hip reconstruction, is associated with blood loss, hospitalization, rehabilitation, and complications such as infection or delayed wound-healing. ➤: Minimally invasive percutaneous procedures have become increasingly popular for the management of periacetabular osteolytic metastases by interventional oncologists and orthopaedic surgeons before complex open surgical procedures are considered. ➤: Minimally invasive procedures may include various methods of cancer ablation and reinforcement techniques. Minimally invasive procedures may entail cancer ablation, polymethylmethacrylate (PMMA) cement reinforcement, balloon osteoplasty, percutaneous screw fixation, or combinations of the aforementioned techniques (e.g., ablation-osteoplasty-reinforcement-internal fixation [AORIF]).

Knee Reconstruction following Sarcoma Resection Utilizing Pedicled Anterolateral Thigh Propeller Flap: A Case Series.

Coverage of knee wounds with exposure or violation of the joint capsule has long been a challenge to plastic surgeons. Wide resection and radiation treatment for soft-tissue sarcomas further this difficulty due to resultant diminished vascularity and soft tissue fibrosis. Traditional muscle flaps such as the gastrocnemius may be within the radiated field, limiting their arc of rotation to the knee. We present a series of exposed knee joint reconstructions using pedicled propeller flaps after sarcoma resection. Three patients diagnosed with soft tissue sarcomas underwent neoadjuvant radiation followed by wide local resection by orthopedic oncology. All patients had underlying knee joint exposure and underwent successful soft tissue reconstruction utilizing pedicled anterolateral thigh (ALT) propeller flaps. The ALT flap is widely used in plastic surgery for reconstruction of soft tissue defects due to its reliable vascularity, long pedicle, versatility, low donor-site morbidity, and large size. As a propeller flap, we demonstrate this is a viable alternative for reconstruction when the vascular plexus around the knee is unreliable after neoadjuvant radiation. Extending the ALT propeller flap with a large proximal skin paddle provides a nonmicrosurgical alternative to traditional muscle flaps at this location. The ALT propeller flap is an excellent option for reconstruction of large defects of the knee, especially in the setting of a radiated wound bed with unpredictable vascularity. In our case series, all three patients underwent successful reconstruction of exposed knee joints after resection of soft tissue sarcoma utilizing ALT propeller flaps.

Incidence and Recovery of Vocal Fold Immobility Following Pediatric Cardiac Operations.

BACKGROUND: Loss of laryngeal function after congenital cardiac surgery causes morbidity and prolongs hospitalization. Early diagnosis of vocal fold immobility (VFI) and referral to pediatric otolaryngology (pOTO) aids in laryngeal rehabilitation. Understanding the incidence and recovery rates of VFI enables counseling for families of infants undergoing high-risk surgery. METHODS: A retrospective chart review from November 2014 to July 2019 of infants postcardiac surgery where the aortic arch or surrounding structures were manipulated and were screened via flexible fiberoptic laryngoscopy (FFL) at a single institution was performed. Patients were divided into five surgical categories: Norwood procedure, aortic arch augmentation via median sternotomy, arterial switch operation, coarctation repair via lateral thoracotomy, and cardiac surgeries including ligation of a patent ductus arteriosus (PDA). Patients undergoing isolated PDA ligation were excluded. RESULTS: One hundred ninety-nine qualifying operations occurred during this period; 28 patients did not undergo FFL before discharge and were excluded from the analysis. Immediately following cardiac surgery, 34% (58 of 171 patients) had VFI. Follow-up was completed by 38 of 58 patients with VFI. Complete recovery was demonstrated in 63% (24 of 38) of patients by 6 months and in 86% (33 of 38) within 18 months. The highest risk occurred with the Norwood procedure and arch augmentation via median sternotomy. CONCLUSIONS: Infants undergoing surgery involving the aortic arch and surrounding structures have high rates of VFI. Follow-up by pOTO is recommended to optimize laryngeal rehabilitation. Most patients have spontaneous recovery within 18 months of cardiac surgery.

Multifocal Xanthoma of Bone.

We report a case of a 40-year-old woman with hyperlipidemia and associated multifocal xanthoma of bone requiring prophylactic fixation of her bilateral femurs. Although xanthomas of bone are themselves a benign process, their presence may indicate that the patient has poorly controlled lipids and is at an increased risk of cardiovascular disease. Lytic lesions may require prophylactic fixation to prevent pathologic fracture.

ChAdOx1 nCoV-19 (AZD1222) vaccine candidate significantly reduces SARS-CoV-2 shedding in ferrets.

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.

Single-Institution Experience of Synovial Sarcoma.

OBJECTIVES: The purpose of this study was to investigate the patient population and outcomes of synovial sarcoma at a single institution. METHODS: A retrospective review of the medical records of 28 patients with synovial sarcoma diagnosed from 1992 to 2017 was performed. Demographics, staging, disease location, treatment, and response to treatment were reviewed. RESULTS: Individuals with larger tumors at the time of presentation had an increased risk of death. An additional factor associated with poor prognosis in synovial sarcoma was increasing patient age. The patient population had a higher rate of nonextremity disease and lower overall survival when compared with national averages. CONCLUSIONS: Nonextremity disease and large size of tumor at presentation may have contributed to the disparity in institutional outcomes from the national averages. The advanced presentation of synovial sarcoma remains a significant challenge in improving patient survival.

Percutaneous Microwave Ablation and Cementoplasty: Clinical Utility in the Treatment of Painful Extraspinal Osseous Metastatic Disease and Myeloma.

OBJECTIVE. The purpose of this study was to review the efficacy and durability of pain control and local tumor control using microwave ablation and cementoplasty in treating extraspinal osseous tumors. Painful osseous metastases are a common cause of cancer-related morbidity. Percutaneous thermal ablation presents an attractive minimally invasive option in this vulnerable patient group. MATERIALS AND METHODS. A retrospective review included 65 patients (35 men, 30 women) with 77 tumors who underwent image-guided microwave ablation and cementoplasty at a tertiary referral academic center over 18 months. Procedural efficacy was determined with a visual analog scale before the procedure and 24 hours, 2-4 weeks, and 20-24 weeks after the procedure. Locoregional control was assessed at follow-up cross-sectional imaging. RESULTS. The 77 tumors were in the following locations: ilium, 38; acetabulum on supraacetabular region, 23; femur, five; humerus, four; shoulder, four; sternum, three. The tumors were 15 multiple myelomas and metastases from cancers of the following organs: colon, nine; lung, 15; breast, 12; thyroid, seven; prostate, three; and kidney, four. Complete, successful ablation of all 77 tumors was achieved. Mean ablation time was 6 minutes 15 seconds (SD, 12 seconds), and mean energy used was 5.49 (SD, 2.97) kJ. The mean visual analog scale scores were 6.32 (SD, 1.94) before the procedure, 1.01 (SD, 1.24) at 24 hours, 1.71 (SD, 1.31) at 2-4 weeks, and 2.01 (SD, 1.42) at 20-24 weeks. Follow-up imaging at 20-24 weeks showed no local progression in 42 of 65 patients (64.6%). Six patients died 24-52 weeks after the procedure. No procedure-related complications were reported. CONCLUSION. Microwave ablation is efficacious in alleviating pain due to osseous metastases. The modality has promise for locoregional control of metastases, particularly in the context of oligometastatic (limited disseminated) disease.

Impact of Marriage on Birth Outcomes: Pregnancy Risk Assessment Monitoring System, 2012-2014.

Marriage has been associated with improved pregnancy outcomes. However, as Americans become increasingly accepting of pregnancy and childbearing outside of marriage, many believe the father can support the mother without the parents being married. Some question whether the present normalization of childbearing outside of marriage will negate the protective effect of marriage on pregnancy outcomes. Data from the Centers for Disease Control and Prevention Pregnancy Risk Assessment Monitoring System were used to obtain data from a sample of 138,118 live singleton deliveries from 2012 to 2014. Odds ratios were compared between married and unmarried mothers for outcomes of preterm delivery, a small for gestational age infant, neonatal intensive care unit admission, vaginal delivery, and breastfeeding initiation. Logistic regression analyses were used to adjust for maternal age, maternal and paternal race, maternal medical comorbidities, maternal smoking status, and receipt of Medicaid. Adjusted odds ratios (AOR) showed married women had a lower risk of preterm delivery (AOR = .877, 95% confidence interval [CI; .811-.948]), a small for gestational age baby (AOR = .838, 95% CI [.726-.967]), and a neonatal intensive care admission (AOR = .808, 95% CI [.754-.866]). Women who were married were more likely to have a vaginal delivery (AOR = 1.144, 95% CI [1.085-1.211]) and to initiate breastfeeding (AOR = 1.601, 95% CI [1.490-1.719]). These data demonstrate that despite a normalization in society of childbearing outside of marriage, there continues to be an association of marriage with improved birth outcomes. Summary: Marriage is associated with a lower risk of preterm delivery, small for gestational age infants, and neonatal intensive care unit admission. These differences persist even after correcting for potentially confounding socioeconomic factors.

Animal infection studies of two recently discovered African bat paramyxoviruses, Achimota 1 and Achimota 2.

Bats are implicated as the natural reservoirs for several highly pathogenic viruses that can infect other animal species, including man. Here, we investigate the potential for two recently discovered bat rubulaviruses, Achimota virus 1 (AchPV1) and Achimota virus 2 (AchPV2), isolated from urine collected under urban bat (Eidolon helvum) roosts in Ghana, West Africa, to infect small laboratory animals. AchPV1 and AchPV2 are classified in the family Paramyxoviridae and cluster with other bat derived zoonotic rubulaviruses (i.e. Sosuga, Menangle and Tioman viruses). To assess the susceptibility of AchPV1 and AchPV2 in animals, infection studies were conducted in ferrets, guinea pigs and mice. Seroconversion, immunohistological evidence of infection, and viral shedding were identified in ferrets and guinea pigs, but not in mice. Infection was associated with respiratory disease in ferrets. Viral genome was detected in a range of tissues from ferrets and guinea pigs, however virus isolation was only achieved from ferret tissues. The results from this study indicate Achimota viruses (AchPVs) are able to cross the species barrier. Consequently, vigilance for infection with and disease caused by these viruses in people and domesticated animals is warranted in sub-Saharan Africa and the Arabian Peninsula where the reservoir hosts are present.

CD8 T cells contribute to lacrimal gland pathology in the nonobese diabetic mouse model of Sjögren syndrome.

Sjögren syndrome is an autoimmune disease characterized by targeted destruction of the lacrimal and salivary glands resulting in symptoms of severe ocular and oral dryness. Despite its prevalence, the mechanisms driving autoimmune manifestations are unclear. In patients and in the nonobese diabetic (NOD) mouse model of Sjögren syndrome, lymphocytic infiltrates consist of CD4 and CD8 T cells, although the role of CD8 T cells in disease pathogenesis has been largely unexplored. Here, we evaluated the contribution of CD8 T cells to lacrimal and salivary gland autoimmunity. Within the lacrimal and salivary glands of NOD mice, CD8 T cells were proliferating, expressed an activated phenotype, and produced inflammatory cytokines. Transfer of purified CD8 T cells isolated from the cervical lymph nodes (LNs) of NOD mice into NOD-severe combined immunodeficiency recipients resulted in inflammation of the lacrimal glands, but was not sufficient to cause inflammation of the salivary glands. Lacrimal gland-infiltrating CD8 T cells displayed a cytotoxic phenotype, and epithelial cell damage in the lacrimal glands was observed in recipients of CD8 T cells regardless of the presence of CD4 T cells. Collectively, our results demonstrate that CD8 T cells have a pathogenic role in lacrimal gland autoimmunity. The gland-specific pathogenicity of CD8 T cells makes them a valuable resource to further understand the mechanisms that discriminate lacrimal versus salivary gland autoimmunity and for the development of new therapeutics that target the early stages of disease.

Multimodality Imaging in Pediatric Osteosarcoma in the Era of Image Gently and Image Wisely Campaign With a Close Look at the CT Scan Radiation Dose.

The increasing use of serial multimodality imaging in the management of pediatric osteosarcoma raises concern of over exposure to ionizing radiation in children, especially from repeated computed tomographic (CT) scans. This study reviews the utilization of multimodality imaging in patients with osteosarcoma at our institution and analyzes any potential radiation-related complications. Twenty-eight patients were identified. Three patients developed late complications-acute myeloid leukemia, myelodysplastic syndrome, and early menopause. Using the patient's age and body part imaged, CT dose length product and effective dose was estimated with the use of a conversion factor for 19 patients. The effective doses were higher in the 3 patients with late complications than the other patients in the cohort (P=0.018). These results suggest an increased risk for adverse effects with higher CT exposures and effective doses. On the basis of our data and published data, methods to decrease the doses of radiation from medical imaging need to be explored. The number of CT scans may be limited. Implementing the Image Gently concept to decrease radiation exposure can be beneficial in modification of CT acquisition parameters.

Pediatric osteosarcoma: a single institution's experience.

OBJECTIVES: The aim of the study was to evaluate outcomes with an examination of individual predictors influencing survival at a single institution. METHODS: This was a retrospective review of the 28 pediatric osteosarcoma patients diagnosed and studied from 2000 through 2012. Twenty-eight patient charts and imaging studies were reviewed for age, race, sex, location, extent of disease at presentation, imaging results, histology, treatment options, and overall survival. RESULTS: Of the 28 patients who were identified, the median age at diagnosis was 14 years. The majority of the patients were male African Americans with the tumor located in the lower long bones and most had conventional osteosarcoma histology. Four patients had metastasis at diagnosis. Of the 28 patients, 16 patients underwent limb salvage surgery, 6 underwent amputation, 4 had biopsy only, 1 had hip disarticulation, and 1 moved out of state and had no information available. All 28 patients received chemotherapy. Four patients received additional radiation therapy. On follow-up, 15 patients were still alive at last clinical contact and 13 died. Of the deceased, the median survival time was 2.3 years. The patient who lived the longest survived 8.3 years. Metastasis at diagnosis was associated with poorer outcome (P = 0.002). The 5-year overall survival rate was 40% (95% confidence interval 18-62) for our entire population of patients. CONCLUSIONS: Survival in our patient cohort tended to be at the lower end of the spectrum reported by other contemporary treatment centers of excellence or Surveillance, Epidemiology, and End Results databases probably because of the large number of African American patients with associated poor socioeconomic status. Future studies should be conducted to explore biological and nonbiological factors that may affect the prognosis in this disease.

Identification of hematopoietic-specific regulatory elements from the CD45 gene and use for lentiviral tracking of transplanted cells.

The development of a hematopoietic reporter is crucial for determining the fate of lineages derived from cell-based therapies. A marking system will enable safer embryonic stem and induced pluripotent stem cell-based derivation of blood lineages and facilitate the development of efficient cellular reprogramming strategies based on direct fibroblast conversion. Here we report that the protein tyrosine phosphatase CD45 is an ideal candidate gene on which to base a hematopoietic reporter. CD45 regulatory elements were discovered by analyzing transcription factor chromatin occupancy (ChIP-seq) and promoter nuclease sensitivity (DNase-seq) to identify minimally sufficient sequences required for expression. After cloning the CD45 regulatory elements into an attenuated lentiviral backbone, we found that two transcriptional initiation regions were essential for high-level expression. Expressing CD45 promoters containing these regions and tethered to green fluorescent protein (GFP) in a primary B-cell differentiation assay and a transplantation model resulted in high levels of GFP in lymphoid, myeloid, and nucleated erythroid cells in mouse and human blood cell lineages. Moreover, GFP levels remained high 5 months after secondary transplantation, indicating persistence of the reporter. No CD45-driven GFP expression is observed after fibroblast or embryonic stem cell transduction. The GFP reporter is seen only after embryonic stem cells differentiate into hematopoietic cell progenitors and lineages, suggesting that this hematopoietic reporter system could be useful in validating potential autologous blood cell therapies.

High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures.

Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49f(hi) /CD90(lo) cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49f(hi) /CD90(lo) cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs.

Biochemical, conformational, and immunogenic analysis of soluble trimeric forms of henipavirus fusion glycoproteins.

The henipaviruses, Hendra virus (HeV) and Nipah virus (NiV), are paramyxoviruses discovered in the mid- to late 1990s that possess a broad host tropism and are known to cause severe and often fatal disease in both humans and animals. HeV and NiV infect cells by a pH-independent membrane fusion mechanism facilitated by their attachment (G) and fusion (F) glycoproteins. Here, several soluble forms of henipavirus F (sF) were engineered and characterized. Recombinant sF was produced by deleting the transmembrane (TM) and cytoplasmic tail (CT) domains and appending a glycosylphosphatidylinositol (GPI) anchor signal sequence followed by GPI-phospholipase D digestion, appending a trimeric coiled-coil (GCNt) domain (sF(GCNt)), or deleting the TM, CT, and fusion peptide domain. These sF glycoproteins were produced as F(0) precursors, and all were apparent stable trimers recognized by NiV-specific antisera. Surprisingly, however, only the GCNt-appended constructs (sF(GCNt)) could elicit cross-reactive henipavirus-neutralizing antibody in mice. In addition, sF(GCNt) constructs could be triggered in vitro by protease cleavage and heat to transition from an apparent prefusion to postfusion conformation, transitioning through an intermediate that could be captured by a peptide corresponding to the C-terminal heptad repeat domain of F. The pre- and postfusion structures of sF(GCNt) and non-GCNt-appended sF could be revealed by electron microscopy and were distinguishable by F-specific monoclonal antibodies. These data suggest that only certain sF constructs could serve as potential subunit vaccine immunogens against henipaviruses and also establish important tools for further structural, functional, and diagnostic studies on these important emerging viruses.

Antigen capture ELISA system for henipaviruses using polyclonal antibodies obtained by DNA immunization.

A novel antigen-capture sandwich ELISA system targeting the glycoproteins of the henipaviruses Nipah virus (NiV) and Hendra virus (HeV) was developed. Utilizing purified polyclonal antibodies derived from NiV glycoprotein-encoding DNA-immunized rabbits, we established a system that can detect the native antigenic structures of the henipavirus surface glycoproteins using simplified and inexpensive methods. The lowest detection limit against live viruses was achieved for NiV Bangladesh strain, 2.5 × 10(4) TCID(50). Considering the recent emergence of genetic variants of henipaviruses and the resultant problems that arise for PCR-based detection, this system could serve as an alternative rapid diagnostic and detection assay.

Pelvic fractures in women of childbearing age.

BACKGROUND: Pelvic fractures represent major injury. Women of childbearing age who have sustained pelvic fractures question whether they can have children and what type of delivery will be possible. QUESTIONS/PURPOSES: (1) Genitourinary and sexual dysfunction can be expected in women of child bearing age with pelvic fractures; (2) functional outcomes of women with pelvic fractures are related to fracture pattern and whether they were treated with surgery; (3) women treated nonoperatively and those treated operatively with fixation sparing the pubic symphysis can deliver children vaginally. METHODS: We retrospectively reviewed 71 women with pelvic fractures. Forty-one had stable fractures and 25 had unstable fractures; five radiographs could not be located to classify fractures. Forty women had surgery for their pelvic fractures. RESULTS: Thirty-five women (49%) had one or more genitourinary complaints; 26 women (38%) had pain with sexual intercourse. The overall SF-12 score and physical and mental health component were lower in women who had surgical fixation of their pelvic fracture. Overall SF-12 scores were similar in women who did and did not have children after their pelvic fracture. Twenty-six women had children after their pelvic fracture: 10 (38%) delivered vaginally; 16 (62%) had a cesarean section. Four (40%) of the women who delivered vaginally had surgical fixation of their fracture, including rami screws and/or sacroiliac screws. CONCLUSIONS: Our data suggest the cesarean section rate is still more than double standard norms, but vaginal delivery after pelvic fracture, even in those treated with surgical fixation sparing the pubic symphysis, is possible. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.