Relationship Between Age and Pathology With Treatment of Pediatric and Adolescent Discoid Lateral Meniscus: A Report From the SCORE Multicenter Database.

BACKGROUND: Surgical treatment options of discoid lateral meniscus in pediatric patients consist of saucerization with or without meniscal repair, meniscocapular stabilization, and, less often, subtotal meniscectomy. PURPOSE: To describe a large, prospectively collected multicenter cohort of discoid menisci undergoing surgical intervention, and further investigate corresponding treatment of discoid menisci. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A multicenter quality improvement registry (16 institutions, 26 surgeons), Sports Cohort Outcomes Registry, was queried. Patient characteristics, discoid type, presence and type of intrasubstance meniscal tear, peripheral rim instability, repair technique, and partial meniscectomy/debridement beyond saucerization were reviewed. Discoid meniscus characteristics were compared between age groups (<14 and >14 years old), based on receiver operating characteristic curve, and discoid morphology (complete and incomplete). RESULTS: In total, 274 patients were identified (mean age, 12.4 years; range, 3-18 years), of whom 55.6% had complete discoid. Meniscal repairs were performed in 55.1% of patients. Overall, 48.5% of patients had rim instability and 36.8% had >1 location of peripheral rim instability. Of the patients, 21.5% underwent meniscal debridement beyond saucerization, with 8.4% undergoing a subtotal meniscectomy. Patients <14 years of age were more likely to have a complete discoid meniscus (P < .001), peripheral rim instability (P = .005), and longitudinal tears (P = .015) and require a meniscal repair (P < .001). Patients ≥14 years of age were more likely to have a radial/oblique tear (P = .015) and require additional debridement beyond the physiologic rim (P = .003). Overall, 70% of patients <14 years of age were found to have a complete discoid meniscus necessitating saucerization, and >50% in this young age group required peripheral stabilization/repair. CONCLUSION: To preserve physiological "normal" meniscus, a repair may be indicated in >50% of patients <14 years of age but occurred in <50% of those >14 years. Additional resection beyond the physiological rim may be needed in 15% of younger patients and 30% of those aged >14 years.

Bethlem Myopathy (Collagen VI-Related Dystrophies): A Retrospective Cohort Study on Musculoskeletal Pathologies and Clinical Course.

BACKGROUND: Collagen VI-related myopathies with pathologic COL6A1, COL6A2, and COL6A3 variants manifest as a phenotypic continuum of rare disorders, including Bethlem myopathy (BM), characterized by early onset muscle weakness, proximal joint contractures, and distal joint laxity. Herein we discuss the concomitant orthopedic manifestations of BM, potential management strategies, and patient outcomes. METHODS: An IRB-approved retrospective cohort study (n=23) from 2 pediatric institutions with a confirmed diagnosis of BM. Charts were reviewed for demographic data, age of disease presentation and diagnosis, COL6 genotype, diagnosis method, ambulation status, need for assistance, musculoskeletal abnormalities, other systemic comorbidities, advanced imaging and screening diagnostics, previous surgical interventions, and progression of the disease. RESULTS: The mean age was 11.65 years (range 3 to 19 y). Mean age at initial presentation with symptoms was 4.18 years old, whereas diagnosis was delayed until 8.22 years old on average. Muscle weakness was the most common presenting symptom (65.2%), and 73.9% of patients required some use of assistive or mobility devices. Overall, 30.4% of patients were diagnosed with scoliosis; 57.1% required operative intervention for their scoliosis; 43.5% of patients had acetabular dysplasia; 10% required open reduction of a dislocated hip; 10% required closed reduction with hip spica application; 10% required bilateral periacetabular osteotomies for instability; 91.3% of patients developed foot and ankle deformities; 33.3% of patients underwent posteromedial-lateral equinovarus releases; 28.6% required an Achilles tendon lengthening, and 86.9% of patients had muscle tendon contractures, the most common locations being the ankle (55%) and elbow (40%). CONCLUSION: Although often less severe than other more common neuropathies and myopathies like Charcot-Marie-Tooth disease and Duchenne muscular dystrophy, BM does lead to progressive musculoskeletal deformity and disability. Its relative rarity makes it less familiar to providers and likely contributes to delays in diagnosis. Scoliosis, hip dysplasia, and equinus and varus ankle deformities are the most common musculoskeletal deformities. Physicians and surgeons should appropriately counsel patients and families about the clinical course of this disorder and the potential need for mobility assistance or surgical procedures. LEVEL OF EVIDENCE: III, Prognostic. study.

A potent tumor-selective ERK pathway inactivator with high therapeutic index.

FDA-approved BRAF and MEK small molecule inhibitors have demonstrated some level of efficacy in patients with metastatic melanomas. However, these "targeted" therapeutics have a very low therapeutic index, since these agents affect normal cells, causing undesirable, even fatal, side effects. To address these significant drawbacks, here, we have reengineered the anthrax toxin-based protein delivery system to develop a potent, tumor-selective MEK inactivator. This toxin-based MEK inactivator exhibits potent activity against a wide range of solid tumors, with the highest activity seen when directed toward tumors containing the BRAFV600E mutation. We demonstrate that this reengineered MEK inactivator also exhibits an extremely high therapeutic index (>15), due to its in vitro and in vivo activity being strictly dependent on the expression of multiple tumor-associated factors including tumor-associated proteases matrix metalloproteinase, urokinase plasminogen activator, and anthrax toxin receptor capillary morphogenesis protein-2. Furthermore, we have improved the specificity of this MEK inactivator, restricting its enzymatic activity to only target the ERK pathway, thereby greatly diminishing off-target toxicity. Together, these data suggest that engineered bacterial toxins can be modified to have significant in vitro and in vivo therapeutic effects with high therapeutic index.

SARS-CoV-2 colonization of maternal and fetal cells of the human placenta promotes alteration of local renin-angiotensin system.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears to increase the risk of adverse pregnancy outcomes, such as pre-eclampsia in pregnant women. The mechanism(s) by which this occurs remains unclear. METHODS: We investigated the pathophysiology of SARS-CoV-2 at maternal-fetal interface in pregnant women who tested positive for the virus using RNA in situ hybridization (viral RNA), immunohistochemistry, and hematoxylin and eosin staining. To investigate whether viral infection alters the renin angiotensin system (RAS) in placenta, which controls blood pressure, we treated human trophoblasts with recombinant spike protein or a live modified virus with a vesicular stomatitis viral backbone expressing spike protein (VSV-S). FINDINGS: Viral colonization was highest in maternal decidua, fetal trophoblasts, Hofbauer cells, and in placentas delivered prematurely. We localized SARS-CoV-2 to cells expressing angiotensin-converting enzyme 2 (ACE2) and demonstrate that infected placentas had significantly reduced ACE2. In response to both spike protein and VSV-S, cellular ACE2 decreased although angiotensin II receptor type 1 (AT1R) increased with concomitant increase in soluble fms-like tyrosine kinase-1 (sFlt1). Viral infection decreased pro-angiogenic factors, AT2R, and placental growth factor, which competitively binds to sFlt1. Sera from infected pregnant women had elevated levels of sFlt1 and angiotensin II type 1-receptor autoantibodies prior to delivery, both signatory markers of pre-eclampsia. CONCLUSIONS: SARS-CoV-2 colonizes ACE2-expressing maternal and fetal cells in the placenta. Infection in pregnant women correlates with alteration of placental RAS. As RAS regulates blood pressure, SARS-CoV-2 infection may thus increase adverse hemodynamic outcomes, such as pre-eclampsia in pregnant women. FUNDING: NIH/NICHD grants R01 HD091218 and 3R01HD091218-04S1 (RADx-UP Supplement).

Group therapy on in utero colonization: seeking common truths and a way forward.

The human microbiome refers to the genetic composition of microorganisms in a particular location in the human body. Emerging evidence over the past many years suggests that the microbiome constitute drivers of human fate almost at par with our genome and epigenome. It is now well accepted after decades of disbelief that a broad understanding of human development, health, physiology, and disease requires understanding of the microbiome along with the genome and epigenome. We are learning daily of the interdependent relationships between microbiome/microbiota and immune responses, mood, cancer progression, response to therapies, aging, obesity, antibiotic usage, and overusage and much more. The next frontier in microbiome field is understanding when does this influence begin? Does the human microbiome initiate at the time of birth or are developing human fetuses already primed with microbes and their products in utero. In this commentary, we reflect on evidence gathered thus far on this question and identify the unknown common truths. We present a way forward to continue understanding our microbial colleagues and our interwoven fates.

Distal Radius Fractures in Patients Aged 50 Years or Older: Obstacles to Bone Health Analysis and Follow-Up in a Community Setting.

Purpose: To determine barriers to implementing an osteoporosis protocol in a community institution following distal radius (DR) fragility fracture to help prevent subsequent fragility fractures. Methods: This cross-sectional study included elderly patients with DR fractures that occurred between 2016 and 2018. Exclusion criteria were age under 50 years, high-energy mechanism, and inability to follow-up locally. Patients were directed to follow-up with the hospital's osteoporosis center (OC) or an endocrinologist. Patients were contacted to identify if care was established with the OC and screened for potential barriers in evaluation for bone health. Primary outcomes included the completion of a follow-up visit with an osteoporosis care provider and identification of barriers for patients who did not complete this visit. Secondary outcomes included whether or not patients obtained bone health labs, dual-energy x-ray absorptiometry (DEXA) scans, and/or underwent medical treatment for osteoporosis. Results: One hundred seventy-five patients met final inclusion criteria and were contacted after discharge. Fifty patients agreed to follow-up with the OC, voicemails were left for 66 patients, only 70 (60.3%) patients actually followed up for bone health analysis. Patients were lost to follow-up due to lack of accessibility (32 patients; death, incorrect phone number, no voicemail, or impaired cognition), and lack of interest (27 patients). Ninety-six (54.9%) patients received appropriate treatment based on bone health labs and/or DEXA scan. Ninety (51.4%) patients had chemical treatment for osteoporosis. Fifty-five patients underwent DEXA scans with equal distribution of patients with normal, osteopenic, and osteoporotic bone. Forty-three (78%) patients who had DEXA scans underwent treatment. Conclusions: Establishing a protocol for follow-up for bone health assessment following a DR fracture is challenging. Only half of the patients underwent evaluation and management of their bone health. It is imperative to understand the barriers for at-risk patients to provide them with care that will improve their quality of life. Type of study/level of evidence: Diagnostic III.

Spinal Cord Compression Secondary to Metastatic Sinonasal Undifferentiated Carcinoma.

Sinonasal undifferentiated carcinoma (SNUC) is a rare malignancy of the upper airways and anterior skull base that carries a poor prognosis. The tumor is known to be invasive into the surrounding structures of the skull base and brain. To date, there is only one existing case report documenting drop metastasis to the intradural extramedullary spinal cord. To the best of our knowledge, we present the second case of metastatic SNUC to the spine. This report describes a 59-year-old male with a history of head and neck SNUC who presented with thoracic back pain and bilateral lower extremity paresis. Neuroimaging demonstrated an extradural thoracic mass with severe spinal cord compression. The patient underwent thoracic laminectomy and fusion for decompression of the spinal cord and internal stabilization. The pathology returned as SNUC. The patient was subsequently lost to follow-up from our institution. Metastatic SNUC is rare. We discuss the relevant clinical imaging and review the literature. Such a malignancy portends a very poor prognosis.

AFAP1 Is a Novel Downstream Mediator of TGF-ß1 for CCN2 Induction in Osteoblasts.

BACKGROUND: CCN2 acts as an anabolic growth factor to regulate osteoblast differentiation and function. CCN2 is induced by TGF-ß1 and acts as a mediator of TGF-ß1 induced matrix production in osteoblasts and Src is required for CCN2 induction by TGF-ß1; however, the molecular mechanisms that control CCN2 induction in osteoblasts are poorly understood. AFAP1 binds activated forms of Src and can direct the activation of Src in certain cell types, however a role for AFAP1 downstream of TGF-ß1 or in osteoblats is undefined. In this study, we investigated the role of AFAP1 for CCN2 induction by TGF-ß1 in primary osteoblasts. RESULTS: We demonstrated that AFAP1 expression in osteoblasts occurs in a biphasic pattern with maximal expression levels occurring during osteoblast proliferation (~day 3), reduced expression during matrix production/maturation (~day 14-21), an a further increase in expression during mineralization (~day 21). AFAP1 expression is induced by TGF-ß1 treatment in osteoblasts during days 7, 14 and 21. In osteoblasts, AFAP1 binds to Src and is required for Src activation by TGF-ß1 and CCN2 promoter activity and protein induction by TGF-ß1 treatment was impaired using AFAP1 siRNA, indicating the requirement of AFAP1 for CCN2 induction by TGF-ß1. We also demonstrated that TGF-ß1 induction of extracellular matrix protein collagen XIIa occurs in an AFAP1 dependent fashion. CONCLUSIONS: This study demonstrates that AFAP1 is an essential downstream signaling component of TGF-ß1 for Src activation, CCN2 induction and collagen XIIa in osteoblasts.