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BACKGROUND: Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome. METHODS: A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively. RESULTS: Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. CONCLUSIONS: Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.
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Síndrome de Brugada , Células-Tronco Pluripotentes Induzidas , Canais de Sódio Disparados por Voltagem , Animais , Humanos , Potenciais de Ação , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Estudo de Associação Genômica Ampla , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Microtúbulos/metabolismo , Miócitos Cardíacos/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
BACKGROUND/OBJECTIVES: Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos. RESULTS: The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix-Loop-Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function. CONCLUSION: In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.
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Anormalidades Múltiplas , Nanismo , Osteocondrodisplasias , Animais , Feminino , Humanos , Gravidez , Mutação com Ganho de Função , Irã (Geográfico) , RNA Mensageiro , Proteínas com Domínio T/genética , Fatores de Transcrição , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
PURPOSE: Geographic access to physicians has been shown to be unevenly distributed in the USA, with those in closer proximity having superior outcomes. The purpose of this study was to describe how geographic access to pediatric neurosurgeons varies across socioeconomic and demographic factors. METHODS: Actively practicing neurosurgeons were identified by matching several registries and membership logs. This data was used to find their primary practice locations and the distance the average person in a county must travel to visit a surgeon. Counties were categorized into "surgeon deserts" and "surgeon clusters," which were counties where providers were significantly further or closer to its residents, respectively, compared to the national average. These groups were also compared for differences in population characteristics using data obtained from the 2020 American Community Survey. RESULTS: A total of 439 pediatric neurosurgeons were identified. The average person in a surgeon desert and cluster was found to be 189.2 ± 78.1 miles and 39.7 ± 19.6 miles away from the nearest pediatric neurosurgeon, respectively. Multivariate analyses showed that higher Rural-Urban Continuum (RUC) codes (p < 0.001), and higher percentages of American Indian (p < 0.001) and Hispanic (p < 0.001) residents were independently associated with counties where the average person traveled significantly further to surgeons. CONCLUSION: Patients residing in counties with greater RUC codes and higher percentages of American Indian and Hispanic residents on average need to travel significantly greater distances to access pediatric neurosurgeons.
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Neurocirurgiões , Cirurgiões , Humanos , Criança , Estados Unidos , Fatores Sociodemográficos , Análise Multivariada , Sistema de RegistrosRESUMO
The thoracolumbar junction is a complex and challenging anatomical region due to its heterogeneous array of planes and structures.1 Navigating this region during a lateral approach to the spine is a challenge that requires a thorough understanding of the anatomy. We present a case of a 54-year-old woman with a 7-year history of breast cancer who presented with low back pain after running a marathon. To date, the patient had deferred medical management. Imaging revealed Stage IV differentiated invasive ductal carcinoma with extensive bony metastatic disease in multiple areas of the spine. The patient underwent a right-sided minimally invasive retrodiaphragmatic approach to the thoracolumbar junction for L1 corpectomy, placement of an expandable cage, and posterior percutaneous pedicle screw segmental fixation from T11 to L3 with robotic guidance. Patient consent was obtained for the following procedure, and IRB approval was not required for publication of this single patient case report.
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STUDY DESIGN: Retrospective Matched Cohort. OBJECTIVE: Despite known consequences to the facet joints following lumbar total disc replacement (TDR), there is limited data on facet injection usage for persistent postoperative pain. This study uses real-world data to compare the usage of therapeutic lumbar facet injections as a measure of symptomatic facet arthrosis following single-level, stand-alone TDR vs anterolateral lumbar interbody fusion (ALIF/LLIF). METHODS: The PearlDiver database was queried for patients (2010-2021) with lumbar degenerative disc disease who received either a single-level, stand-alone TDR or ALIF/LLIF. All patients were followed for ≥2 years and excluded if they had a history of facet injections or spinal trauma, fracture, infection, or neoplasm. The two cohorts were matched 1:1 based on age, sex, insurance, year of operation, and medical comorbidities. The primary outcome was the use of therapeutic lumbar facet injections at 1-, 2-, and 5-year follow-up. Secondary outcomes included subsequent lumbar surgeries and surgical complications. RESULTS: After 1:1 matching, each cohort had 1203 patients. Lumbar facet injections occurred significantly more frequently in the TDR group at 1-year (6.07% vs 1.66%, P < .0001), 2-year (8.40% vs 3.74%%, P < .0001), and 5-year (11.47% vs 6.40%, P < .0001) follow-up. 5-year injection-free probability curves demonstrated an 87.1% injection-free rate for TDR vs 92.9% for ALIF/LLIF. There was no clinical difference in the incidence of subsequent lumbar surgeries or complications. CONCLUSION: Compared with ALIF/LLIF, patients who underwent TDR received significantly more facet injections, suggesting a greater progression of symptomatic facet arthrosis. TDR was not protective against reoperations compared to ALIF/LLIF.
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BACKGROUND CONTEXT: Facet joint violation by pedicle screws may lead to adjacent-segment disease and postoperative pain. Previous studies have reported the incidence of rostral facet joint violation using various pedicle screw insertion techniques. However, the incidence of facet joint violations with robotic guidance has not been determined. PURPOSE: To investigate and compare the incidence of rostral facet joint violation by pedicle screws under robotic guidance and computerized tomography (CT) navigation guidance. STUDY DESIGN/SETTING: Retrospective Matched Cohort PATIENT SAMPLE: All patients who underwent robotic-assisted lumbar fusion at a major spine center up until 2023 were retrospectively identified and matched 1:3 to patients undergoing CT navigation guidance based by on age, sex, rostral vertebral level, and length of construct. Inclusion criteria consisted of age greater than 18 years, bilateral pedicle screw fixation, and presence of a postoperative CT scan of the lumbar spine or abdomen/pelvis at any point in the post-operative period. OUTCOME MEASURES: Rostral facet joint violations METHODS: Descriptive statistics were used to compare cohorts: frequencies, chi-squared analysis for categorical variables, and t-test for continuous variables. RESULTS: A total of 408 rostral pedicle screws were implanted in 204 patients (Robot: 102; Navigation: 306). Overall, 13 (12.3%) rostral facet joint violations were observed in the robot cohort and 75 (24.5%) in the navigation cohort (p=0.01). Specifically, fewer robotic violations were observed at the L2 (3.5% vs 32.1%, p=0.003) and L3 levels (3.9% vs. 18.1%, p=0.08) compared to navigation. No difference was observed at L4 and L5. Bilateral violations are significantly reduced with robotic approaches (5.3% vs. 14.4%, p=0.03). Lastly, more facet joint violations were observed during open approaches (robot: 18.8%, navigation: 27.3%) than percutaneous approaches (robot: 11.6%, navigation: 7.1%) in both groups (p<0.001). The rate of L4 facet violations was 18.8% in the robotic cohort and 27.3% in the navigation cohort. The rate of L5 facet violations was 31.3% in the robotic cohort and 29.2% in the navigation cohort. CONCLUSIONS: Use of robotic assistance in lumbar pedicle screws significantly reduced the rate of rostral facet joint violations compared to navigation guidance at L2 and L3 levels, but not at L4 and L5, with facet violations approaching nearly one-third of the patients at L5 screws. Rostral facet violations can play a significant role in adjacent segment degeneration and disease. Technical factors and trajectory issues likely play a role and addressing these components should minimize unintended facet violation and proximal adding on.
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STUDY DESIGN: Retrospective Cohort. OBJECTIVES: Most data regarding cervical disc arthroplasty (CDA) outcomes are from highly controlled clinical trials with strict inclusion/exclusion criteria. This study aimed to identify risk factors for CDA reoperation, in "real world" clinical practice using a national insurance claims database. METHODS: The PearlDiver database was queried for patients (2010-2020) who underwent a subsequent cervical procedure following a single-level CDA. Patients with less than 2 years follow-up were excluded. Primary outcome was to evaluate risk factors for reoperation. Secondary outcome was to evaluate the types of reoperations. Risk factors were compared using descriptive statistics. Multivariate regression analyses were used to ascertain the association among risk factors and reoperation. RESULTS: Of 14,202 patients who met inclusion criteria, 916 (6.5%) underwent reoperation. Patients undergoing reoperation were slightly older with higher Elixhauser Comorbidity Index (ECI) scores, however both were not risk factors for reoperation. Patients with diagnoses such as smoking, myelopathy, inflammatory disorders, spinal deformity, trauma, or a history of prior cervical surgery were at greater risk for reoperation. No association was found between the year of index surgery and reoperation risk. The most common reoperation procedure was cervical fusion. CONCLUSIONS: As billed for in the United States since 2010, CDA was associated with a 6.5% reoperation rate over a mean follow-up time of 5.3 years. Smoking, myelopathy, inflammatory disorders, spinal deformity, and a history of prior cervical surgery or trauma are risk factors for reoperation following CDA. Though patients who underwent a reoperation were older, age was not found to be an independent risk factor for a subsequent procedure.
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Introduction: Management of spondylolysis in adolescents is generally successful with conservative management. Uncommonly, surgical fixation is necessary for refractory cases. Direct repair with intralaminar screws is one commonly utilized technique. Recently, less invasive spinal procedures are becoming viable with the enabling of technologies, including robotics. Case description: A 14-year-old baseball player and surfer presented with low back pain, diagnosed by MRI as bony edema and stress fractures of the posterior spinal elements. After 18 months, the pain was unresponsive to rest, physical therapy, and bracing. There was no radicular pain or neurologic symptoms. Computed tomography (CT) revealed bilateral, chronic nonhealing pars defects at L5. He underwent outpatient, robot-assisted percutaneous intralaminar fixation with hydroxyapatite-coated screws through a 2 cm skin incision. Outcome: On postoperative day 1, the patient reported relief of his preoperative pain and he was ambulating without difficulty. At 2 weeks follow-up, the patient was completely pain free and surfing. At 2 months follow-up, low-dose CT demonstrated partial incorporation of the hydroxyapatite-coated screws, and the patient returned to sports. At 6 months follow-up, the patient had no pain and was swinging his baseball bat with full force. Low-dose CT revealed complete healing of the defects with full incorporation of the hydroxyapatite-coated screws. Conclusions: A novel minimally invasive robotic percutaneous approach for direct spondylolysis repair using hydroxyapatite-coated screws is a potential surgical treatment option for non-healing pars defects in adolescent patients.
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CASE: A healthy 5-year-old boy presented with a gradual onset of headaches and acute global right-sided weakness over 10 days. The work-up revealed unstable os odontoideum leading to multiple posterior circulation infarcts with vertebral artery dissection. He underwent antiplatelet therapy, cervical collar immobilization, and delayed occiput to C2 posterior spinal fusion and instrumentation with iliac crest autograft. At 2-year follow-up, the patient had a solid fusion mass, appropriate cervical alignment, and was without neurologic sequelae. CONCLUSION: This case adds to a sparse body of literature in the management of vertebral artery dissection with vertebrobasilar insufficiency secondary to unstable os odontoideum.
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Articulação Atlantoaxial , Vértebra Cervical Áxis , Processo Odontoide , Fusão Vertebral , Dissecação da Artéria Vertebral , Masculino , Humanos , Pré-Escolar , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/diagnóstico por imagem , Processo Odontoide/cirurgia , Articulação Atlantoaxial/cirurgia , InfartoRESUMO
STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: This study compares reoperation rates and complications following single-level ALIF/LLIF and TLIF/PLIF. SUMMARY OF BACKGROUND DATA: Anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), transforaminal lumbar interbody fusion (TLIF), and posterior lumbar interbody fusion (PLIF) are widely used for degenerative disc disease. Lumbar interbody fusions have high rates of reoperation primarily related to adjacent segment pathology and pseudarthrosis. METHODS: The PearlDiver database was queried for patients (2010-2021) who had single-level ALIF/LLIF or TLIF/PLIF with same-day, single-level posterior instrumentation. ALIF/LLIF were combined and similarly, TLIF/PLIF were combined, given how these operations are indistinguishable with Current Procedural Terminology (CPT) coding. All patients were followed for ≥2 years and excluded if they had spinal traumas, fractures, infections, or neoplasms prior to surgery. The two cohorts, ALIF/LLIF and TLIF/PLIF, were matched 1:1 based on age, sex, Elixhauser-Comorbidity Index (ECI), smoking status, and diabetes. The primary outcome was the incidence of all-cause subsequent lumbar operations. Secondary outcomes included 90-day surgical complications. RESULTS: After 1:1 matching, each cohort contained 14,070 patients. All-cause subsequent lumbar operations were nearly identical at 5-year follow-up (9.4% ALIF/LLIF vs. 9.5% TLIF/PLIF, P=0.91) (Table 2). Survival analysis using all-cause subsequent lumbar operations as the endpoint showed an equivalent 10-year survival rate of 86.0% (95%CI: 85.2-86.8) (Figure 1). Within 90 days, TLIF/PLIF had more infections (1.3% vs. 1.7%, P=0.007) and dural injuries (0.2% vs. 0.4%, P=0.001). There was no difference in wound dehiscence, hardware complications, or medical complications (Table 3). CONCLUSION: As utilized in real-world clinical practice, single-level anterolateral versus posterior approaches for interbody fusion have no effect on long term reoperation rates.
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OBJECTIVES: To determine whether the prone or lateral position is associated with postoperative sciatic nerve palsy in posterior acetabular fracture fixation. DESIGN: Retrospective cohort study. SETTING: Three Level I trauma centers. PATIENTS: Patients with acetabular fractures treated with a posterior approach (n = 1045). INTERVENTION: Posterior acetabular fixation in the prone or lateral positions. OUTCOME MEASUREMENTS: The primary outcome was the prevalence of postoperative sciatic nerve palsy by position. Secondary outcomes were risk factors for nerve palsy, using multiple regression analysis and propensity scoring. RESULTS: The rate of postoperative sciatic nerve palsy was 9.5% (43/455) in the prone position and 1.5% (9/590) in the lateral position ( P < 0.001). Intraoperative blood loss and surgical duration were significantly higher for patients who developed a postoperative sciatic nerve palsy. Subgroup analysis showed that position did not influence palsy prevalence in posterior wall fractures. For other fracture patterns, propensity score analysis demonstrated a significantly increased odds ratio of palsy in the prone position [aOR 7.14 (2.22-23.00); P = 0.001]. CONCLUSIONS: With the exception of posterior wall fracture patterns, the results of this study suggest that factors associated with increased risk for postoperative sciatic nerve palsy after a posterior approach are fractures treated in the prone position, increased blood loss, and prolonged operative duration. These risks should be considered alongside the other goals (eg, reduction quality) of acetabular fracture surgery when choosing surgical positioning. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.