Hepatic HIF2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency.

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess. The goal of this study was to determine the basis of erythropoietin excess in SLC30A10 deficiency. Here, we demonstrate that transcription factors hypoxia-inducible factor 1a (Hif1a) and 2a (Hif2a), key mediators of the cellular response to hypoxia, are both upregulated in livers of Slc30a10-deficient mice. Hepatic Hif2a deficiency corrected erythropoietin expression and polycythemia and attenuated aberrant hepatic gene expression in Slc30a10-deficient mice, while hepatic Hif1a deficiency had no discernible impact. Hepatic Hif2a deficiency also attenuated manganese excess, though the underlying cause of this is not clear at this time. Overall, our results indicate that hepatic HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency and expand our understanding of the contribution of HIFs to human disease.

Limb Length Discrepancy After Intraosseous Line Malpositioning: A Case Report.

CASE: We will present the case of a 6-year-old girl who presented with a 3-cm limb length discrepancy after intraosseous line placement at age 14 months without other known history of trauma or infection to account for the growth arrest. Imaging revealed a left proximal tibial physeal bar amenable to surgical resection with autologous lipotransfer. At 10 months postoperatively, physical examination and imaging demonstrated a stable 3-cm leg length discrepancy with an interval increase in the length of the left tibia in proportion to the growth of the right side with an increase in valgus alignment that will continue to be monitored and addressed as indicated. CONCLUSION: Pediatric intraosseous line placement presents unique challenges and can ultimately lead to physeal injury and growth arrest in the case of malpositioning.

A Dedicated Simulator Training Curriculum Improves Resident Performance in Surgical Management of Pediatric Supracondylar Humerus Fractures.

Background: The primary goal of including simulation in residency training is to improve technical skills while working outside of the operating room. Such simulation-related skill improvements have seldom been measured in the operating room. This is largely because uncontrolled variables, such as injury severity, patient comorbidity, and anatomical variation, can bias evaluation of an operating surgeon's skill. In this study, performance during the wire navigation phase of pediatric supracondylar humerus fracture fixation was quantitatively compared between 2 groups of orthopaedic residents: a standard training group consisting of residents who participated in a single simulator session of wire navigation training and an expanded training group consisting of residents who participated in a dedicated multifaceted wire navigation simulation training curriculum. Methods: To evaluate performance in the operating room, the full sequence of fluoroscopic images collected during wire navigation was quantitatively analyzed. Objective performance metrics included number of fluoroscopic images acquired, duration from placement of the first wire to that of the final wire, and wire spread at the level of the fracture. These metrics were measured from 97 pediatric supracondylar humerus fracture pinning surgeries performed by 28 different orthopaedic residents. Results: No differences were observed between the groups for wire spread in the final fluoroscopic images (t(94) = 0.75, p = 0.45), an important clinical objective of the surgery. Residents who received the expanded simulator training used significantly fewer fluoroscopic images (mean of 46 vs. 61 images, t(85) = 2.25, p < 0.03) and required less time from first to final wire placement (mean of 11.2 vs. 14.9 minutes, t(83) = 2.53, p = 0.013) than the standard training group. A post hoc review of Accreditation Council for Graduate Medical Education case logs for 24 cases from the standard training group and for 21 cases from the expanded training group indicated that, at the time of surgeries, residents who received expanded training had completed fewer comparable cases than residents in the standard training group (mean of 13 vs. 21, t(42) = 2.40 p = 0.02). Further regression analysis indicated that the expanded simulator training produced an effect comparable with that associated with completing 10.5 similar surgical case experiences. Conclusions: This study demonstrates that training on a wire navigation simulator can lead to improved performance in the operating room on a critical skill for all orthopaedic residents. By taking fewer images and less time while maintaining sufficient pin spread, simulator-trained residents were objectively measured to have improved performance in comparison with residents who had not participated in the pediatric elbow simulator curriculum. Clinical Relevance: As programs aim to provide safe and effective training for critical orthopaedic skills such as pinning a pediatric elbow, this study demonstrates a simulator curriculum that has demonstrated the transfer of skill from a learning environment to the operating room.

Orthopedic Manifestations of Hereditary Sensory and Autonomic Neuropathy IV in a 10-Year-Old Patient.

Hereditary sensory and autonomic neuropathy type IV (HSAN) is a rare and debilitating disorder highlighted by congenital absence of pain and anhidrosis. Orthopedic sequelae include physeal fractures, Charcot joint development, excessive joint laxity, soft tissue infections and recurrent painless dislocations, all of which often present in a delayed fashion. While there is no accepted guideline on management of these patients, several case studies have highlighted the importance of early diagnosis and cautioned against surgical intervention in these patients due to their inability to perceive pain and comply with post-operative restriction. The purpose of this case report is to present the clinical course of a patient with HSAN IV and the unique orthopedic challenges it presented. While some of her orthopedic injuries healed appropriately following treatment, others have gone on to have devastating complications and progressive joint destruction. Level of Evidence: IV.

Assessing the Carcinogenicity of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, in Rodents.

Vadadustat is an investigational oral hypoxia-inducible factor (HIF) prolyl-4-hydroxylase inhibitor to treat anemia due to chronic kidney disease (CKD). Some studies suggest that HIF activation promotes tumorigenesis by activating angiogenesis downstream of vascular endothelial growth factor, while other studies suggest that elevated HIF activity may produce an antitumor phenotype. To evaluate the potential carcinogenicity of vadadustat in mice and rats, we dosed CByB6F1/Tg.rasH2 hemizygous (transgenic) mice orally by gavage with 5 to 50 mg/kg/d of vadadustat for 6 months and dosed Sprague-Dawley rats orally by gavage with 2 to 20 mg/kg/d for approximately 85 weeks. Doses were selected based on the maximally tolerated dose established for each species in previous studies. The tumors that were identified in the studies were not considered to be treatment-related for statistical reasons or within the historical control range. There was no carcinogenic effect attributed to vadadustat in mice or rats.

Hypoxia-inducible factor 2 is a key determinant of manganese excess and polycythemia in SLC30A10 deficiency.

Manganese is an essential yet potentially toxic metal. Initially reported in 2012, mutations in SLC30A10 are the first known inherited cause of manganese excess. SLC30A10 is an apical membrane transport protein that exports manganese from hepatocytes into bile and from enterocytes into the lumen of the gastrointestinal tract. SLC30A10 deficiency results in impaired gastrointestinal manganese excretion, leading to severe manganese excess, neurologic deficits, liver cirrhosis, polycythemia, and erythropoietin excess. Neurologic and liver disease are attributed to manganese toxicity. Polycythemia is attributed to erythropoietin excess, but the basis of erythropoietin excess in SLC30A10 deficiency has yet to be established. Here we demonstrate that erythropoietin expression is increased in liver but decreased in kidneys in Slc30a10-deficient mice. Using pharmacologic and genetic approaches, we show that liver expression of hypoxia-inducible factor 2 (Hif2), a transcription factor that mediates the cellular response to hypoxia, is essential for erythropoietin excess and polycythemia in Slc30a10-deficient mice, while hypoxia-inducible factor 1 (HIF1) plays no discernible role. RNA-seq analysis determined that Slc30a10-deficient livers exhibit aberrant expression of a large number of genes, most of which align with cell cycle and metabolic processes, while hepatic Hif2 deficiency attenuates differential expression of half of these genes in mutant mice. One such gene downregulated in Slc30a10-deficient mice in a Hif2-dependent manner is hepcidin, a hormonal inhibitor of dietary iron absorption. Our analyses indicate that hepcidin downregulation serves to increase iron absorption to meet the demands of erythropoiesis driven by erythropoietin excess. Finally, we also observed that hepatic Hif2 deficiency attenuates tissue manganese excess, although the underlying cause of this observation is not clear at this time. Overall, our results indicate that HIF2 is a key determinant of pathophysiology in SLC30A10 deficiency.

Identifying Barriers: Current Breastfeeding Policy in Orthopedic Surgery Residency.

BACKGROUND: Family planning is a challenge for physicians at all stages of their careers but can be particularly difficult during residency. As the field of orthopedic surgery strives to increase diversity and recruit exceptional female candidates, barriers to entry should be identified. For many women, successful family planning including pregnancy, breast-feeding, and childcare, presents a daunting endeavor during residency training and a difficult topic to broach with superiors when planning future careers. Prospective residents often look to websites to obtain information regarding potential residency programs. We sought to identify current breast-feeding policies available at orthopedic residency programs via a thorough review of individual programs websites. METHODS: Residency program websites from 178 ACGME-accredited orthopedic surgery residencies were reviewed to determine currently available departmental lactation policies and facilities. Region and number of female staff and residents were recorded and organized into a central database. Descriptive analyses to determine programs with available resources was performed. Logistic regression to determine association between region and number of programs written policy available was also performed. RESULTS: 178 ACGME-accredited orthopedic surgery programs were reviewed. Five (2.8%) programs were found to have written breastfeeding policies available on the orthopedic surgery residency website. Thirty-six (20%) programs provided links to institutional GME websites which gave written lactation policies. Dedicated lactation facilities were mentioned for 3 (1.7%) programs. The average number of female attendings per program was two (range 0-19), and the average number of female residents per program was three (range 0-14). The odds of a program having a written breastfeeding policy increased along with an increasing number of female attendings, OR 1.1 (CI 1.03-1.24, p=0.01). Programs in the Southwest region of the U.S. were found to have a higher association with presence of a written breastfeeding policy, OR 3.7 (CI 1.01-13.4, p=0.04). CONCLUSION: Scarce information is available to prospective orthopedic surgery residents regarding breast-feeding policies and available lactation facilities. Only 2.8% of current programs have website information discussing breastfeeding support. Ensuring available breastfeeding support for female orthopedic surgeon trainees and the transparency of these policies by orthopedic departments could contribute to an improved perception of childbearing during residency.Level of Evidence: IV.

A Vision for Using Simulation & Virtual Coaching to Improve the Community Practice of Orthopedic Trauma Surgery.

Background: Many orthopedic surgeries involve the challenging integration of fluoroscopic image interpretation with skillful tool manipulation to enable procedures to be performed through less invasive approaches. Simulation has proved beneficial for teaching and improving these skills for residents, but similar benefits have not yet been realized for practicing orthopedic surgeons. A vision is presented to elevate community orthopedic practice and improve patient safety by advancing the use of simulators for training and assessing surgical skills. Methods: Key elements of this vision that are established include 1) methods for the objective and rigorous assessment of the performance of practicing surgeons now exist, 2) simulators are sufficiently mature and sophisticated that practicing surgeons will use them, and 3) practicing surgeons can improve their performance with appropriate feedback and coaching. Results: Data presented indicate that surgical performance can be adequately and comparably measured using structured observations made by experts or non-expert crowds, with the crowdsourcing approach being more expedient and less expensive. Rigorous measures of the surgical result and intermediate objectives obtained semi-automatically from intra-operative fluoroscopic image sequences can distinguish performances of experts from novices. Experience suggests that practicing orthopedic surgeons are open to and can be constructively engaged by a family of mature simulators as a means to evaluate and improve their surgical skills. Conclusions: The results presented support our contention that new objective assessment measures are sufficient for evaluating the performance of working surgeons. The novel class of orthopedic surgical simulators available were tested and approved by practicing physicians. There exists a clear opportunity to combine purpose-designed simulator exercises with virtual coaching to help practicing physicians retain, retrain, and improve their technical skills. This will ultimately reduce cost, increase the quality of care, and decrease complication rates. Clinical Relevance: This vision articulates a means to boost the confidence of practitioners and ease their anxiety so that they perform impactful procedures more often in community hospitals, which promises to improve treatment and reduce the cost of care while keeping patients closer to their homes and families.

Ruptured Appendicitis and Retrocecal Abscess Masquerading as Knee Pain in a Pediatric Patient: A Case Report.

BACKGROUND: Knee pain has a variety of etiologies in the pediatric population, including septic arthritis, osteomyelitis, fracture, ligamentous injury, and neoplasms. Extrinsic sources of knee pain may also be intra-abdominal, although abdominal pathology is much more likely to manifest as hip or proximal thigh musculature pain. CASE REPORT: A 5-year-old healthy male presented with atraumatic right knee pain, discomfort with weightbearing, fever, and elevated inflammatory laboratory markers. Physical examination and magnetic resonance imaging findings of the knee were benign, leading to low clinical suspicion for knee septic arthritis. Blood cultures were positive for a gastrointestinal organism, Granulicatella adiacens, suggesting abdominal pathology leading to referred pain. Ultrasound evaluation and computed tomography (CT) of the abdomen revealed a large abscess secondary to perforated appendicitis, which was treated with CT-guided drainage and i.v. antibiotics. The patient's musculoskeletal pain subsided with treatment of the appendicitis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Acute appendicitis may present as knee pain, with other signs and symptoms mimicking septic arthritis, such as fever, inability to bear weight, and elevated inflammatory markers. Considering an array of differential diagnoses in pediatric patients with apparent knee septic arthritis is crucial to prevent delay in diagnosis of alternative infectious sources.

Mycobacterium Tuberculosis Monoarthritis of the Knee in Children: A Case Report.

Mycobacterium tuberculosis monoarthritis is a rare form of TB, occurring in 1-2% of cases in the United States. Delays in definitive diagnosis and subsequent treatment are common. While case reports of tuberculous arthritis have been presented in international literature, there is a relative paucity of literature from within the United States. Given the difficulty in diagnosis and adverse outcomes of delayed diagnosis, we present the case of an 11-year-old otherwise healthy male with isolated monoarticular TB septic arthritis of the right knee. A discussion, including review of current literature, regarding presentation, diagnosis, and treatment of tuberculous monoarthritis follows. The emerging role of arthroscopy as a diagnostic and treatment modality for tuberculous monoarthritis of the knee is discussed. LEVEL OF EVIDENCE: VI.