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BACKGROUND: Isolated unilateral alar ligament injury (IUALI) is a rare and likely underreported occurrence after upper cervical trauma, with only 16 cases documented in the literature to date. Patients generally present with neck pain, and definitive diagnosis is typically made by magnetic resonance imaging (MRI). Unfortunately, likely due in part to its rarity, there are no formal guidelines for the treatment of an IUALI. Furthermore, there is a limited understanding of the long-term consequences associated with its inadequate treatment. OBSERVATIONS: Here, the authors report on three pediatric patients, each found to have an IUALI after significant trauma. All patients presented with neck tenderness, and two of the three had associated pain-limited range of neck motion. Imaging revealed either a laterally deviated odontoid process on cervical radiographs and/or MRI evidence of ligamentous strain or discontinuity. Each patient was placed in a hard cervical collar for 1 to 2 months with excellent resolution of symptoms. A comprehensive review of the literature showed that all patients with IUALI who had undergone external immobilization with either rigid cervical collar or halo fixation had favorable outcomes at follow-up. LESSONS: For patients with IUALI, a moderate course of nonsurgical management with rigid external immobilization appears to be an adequate first-line treatment.
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OBJECTIVE: Nonsyndromic craniosynostosis (nsCS), characterized by premature cranial suture fusion, is considered a primary skull disorder in which impact on neurodevelopment, if present, results from the mechanical hindrance of brain growth. Despite surgical repair of the cranial defect, neurocognitive deficits persist in nearly half of affected children. Therefore, the authors performed a functional genomics analysis of nsCS to determine when, where, and in what cell types nsCS-associated genes converge during development. METHODS: The authors integrated whole-exome sequencing data from 291 nsCS proband-parent trios with 29,803 single-cell transcriptomes of the prenatal and postnatal neurocranial complex to inform when, where, and in what cell types nsCS-mutated genes might exert their pathophysiological effects. RESULTS: The authors found that nsCS-mutated genes converged in cranial osteoprogenitors and pial fibroblasts and their transcriptional networks that regulate both skull ossification and cerebral neurogenesis. Nonsyndromic CS-mutated genes also converged in inhibitory neurons and gene coexpression modules that overlapped with autism and other developmental disorders. Ligand-receptor cell-cell communication analysis uncovered crosstalk between suture osteoblasts and neurons via the nsCS-associated BMP, FGF, and noncanonical WNT signaling pathways. CONCLUSIONS: These data implicate a concurrent impact of nsCS-associated de novo mutations on cranial morphogenesis and cortical development via cell- and non-cell-autonomous mechanisms in a developmental nexus of fetal osteoblasts, pial fibroblasts, and neurons. These results suggest that neurodevelopmental outcomes in nsCS patients may be driven more by mutational status than surgical technique.
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Suturas Craneales , Craneosinostosis , Niño , Embarazo , Femenino , Humanos , Suturas Craneales/metabolismo , Cráneo , Craneosinostosis/cirugía , Neurogénesis , Mutación/genéticaRESUMEN
OBJECTIVE: Insurance disparities have been suggested to influence the medical and surgical outcomes of adult patients with spinal cord injury (SCI), with a paucity of studies demonstrating their impact on the outcomes of pediatric and adolescent SCI patients. The aim of this study was to assess the impact of insurance status on healthcare utilization and outcomes in adolescent patients presenting with SCI. METHODS: An administrative database study was performed using the 2017 admission year from 753 facilities using the National Trauma Data Bank. Adolescent patients (11-17 years old) with cervical/thoracic SCIs were identified using International Classification of Diseases, Tenth Revision, Clinical Modification coding. Patients were categorized by governmental insurance versus private insurance/self-pay. Patient demographics, comorbidities, imaging, procedures, hospital adverse events (AEs), and length of stay (LOS) data were collected. Multivariate regression analyses were used to determine the effect of insurance status on LOS, any imaging or procedure, or any AE. RESULTS: Of the 488 patients identified, 220 (45.1%) held governmental insurance while 268 (54.9%) were privately insured. Age was similar between the cohorts (p = 0.616), with the governmental insurance cohort (GI cohort) having a significantly lower proportion of non-Hispanic White patients than the private insurance cohort (PI cohort) (GI: 43.2% vs PI: 72.4%, p < 0.001). While transportation accident was the most common mechanism of injury for both cohorts, assault was significantly greater in the GI cohort (GI: 21.8% vs PI: 3.0%, p < 0.001). A significantly greater proportion of patients in the PI cohort received any imaging (GI: 65.9% vs PI: 75.0%, p = 0.028), while there were no significant differences in procedures performed (p = 0.069) or hospital AEs (p = 0.386) between the cohorts. The median (IQR) LOS (p = 0.186) and discharge disposition (p = 0.302) were similar between the cohorts. On multivariate analysis, with respect to governmental insurance, private insurance was not independently associated with obtaining any imaging (OR 1.38, p = 0.139), undergoing any procedure (OR 1.09, p = 0.721), hospital AEs (OR 1.11, p = 0.709), or LOS (adjusted risk ratio -2.56, p = 0.203). CONCLUSIONS: This study suggests that insurance status may not independently influence healthcare resource utilization and outcomes in adolescent patients presenting with SCIs. Further studies are needed to corroborate these findings.
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Traumatismos de la Médula Espinal , Adulto , Humanos , Adolescente , Niño , Traumatismos de la Médula Espinal/diagnóstico por imagen , Traumatismos de la Médula Espinal/epidemiología , Traumatismos de la Médula Espinal/terapia , Hospitalización , Tiempo de Internación , Cobertura del Seguro , Aceptación de la Atención de Salud , Estudios RetrospectivosRESUMEN
BACKGROUND: Hirayama disease, a cervical myelopathy characterized most commonly by a self-limiting atrophic weakness of the upper extremities, is a rare entity, scarcely reported in the literature. Diagnosis is made by spinal magnetic resonance imaging (MRI), which typically shows loss of normal cervical lordosis, anterior displacement of the cord during flexion, and a large epidural cervical fat pad. Treatment options include observation or cervical immobilization by collar or surgical decompression and fusion. OBSERVATIONS: Here, the authors report an unusual case of a Hirayama-like disease in a young White male athlete who presented with rapidly progressive paresthesia in all 4 extremities and no weakness. Imaging showed characteristic findings of Hirayama disease as well as worsened cervical kyphosis and spinal cord compression in cervical neck extension, which has not previously been reported. Two-level anterior cervical discectomy and fusion and posterior spinal fusion improved both cervical kyphosis on extension and symptoms. LESSONS: Given the disease's self-limiting nature, and a lack of current reporting, there remains no consensus on how to manage these patients. Such findings presented here demonstrate the potentially heterogeneous MRI findings that can be observed in Hirayama disease and emphasize the utility of aggressive surgical management in young, active patients whereby a cervical collar may not be tolerated.
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Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.
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Quistes Aracnoideos , Multiómica , Humanos , Animales , Ratones , Quistes Aracnoideos/diagnóstico por imagen , Quistes Aracnoideos/genética , Encéfalo/diagnóstico por imagen , Exoma/genética , Pruebas GenéticasRESUMEN
The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.
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Plexo Coroideo , Hidrocefalia , Humanos , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Plexo Coroideo/metabolismo , Hidrocefalia/líquido cefalorraquídeo , Hidrocefalia/inmunología , Inmunidad Innata , Síndrome de Liberación de Citoquinas/patologíaRESUMEN
Hypotension secondary to autonomic dysfunction is a common complication of acute spinal cord injury (SCI) that may worsen neurologic outcomes. Midodrine, an enteral α-1 agonist, is often used to facilitate weaning intravenous (IV) vasopressors, but its use can be limited by reflex bradycardia. Alternative enteral agents to facilitate this wean in the acute post-SCI setting have not been described. We aim to describe novel application of droxidopa, an enteral precursor of norepinephrine that is approved to treat neurogenic orthostatic hypotension, in the acute post-SCI setting. Droxidopa may be an alternative enteral therapy for those intolerant of midodrine due to reflex bradycardia. We describe two patients suffering traumatic cervical SCI who were successfully weaned off IV vasopressors with droxidopa after failing with midodrine. The first patient was a 64-year-old male who underwent C3-6 laminectomies and fusion after a ten-foot fall resulting in quadriparesis. Post-operatively, the addition of midodrine in an attempt to wean off IV vasopressors resulted in significant reflexive bradycardia. Treatment with droxidopa facilitated rapidly weaning IV vasopressors and transfer to a lower level of care within 72 hours of treatment initiation. The second patient was a 73-year-old male who underwent C3-5 laminectomies and fusion for a traumatic hyperflexion injury causing paraplegia. The addition of midodrine resulted in severe bradycardia, prompting consideration of pacemaker placement. However, with the addition of droxidopa, this was avoided, and the patient was weaned off IV vasopressors on dual oral therapy with midodrine and droxidopa. Droxidopa may be a viable enteral therapy to treat hypotension in patients after acute SCI who are otherwise not tolerating midodrine in order to wean off IV vasopressors. This strategy may avoid pacemaker placement and facilitate shorter stays in the intensive care unit, particularly for patients who are stable but require continued intensive care unit admission for IV vasopressors, which can be cost ineffective and human resource depleting.
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Importance: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, Setting, and Participants: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main Outcomes and Measures: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and Relevance: These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
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Forminas/genética , Enfermedad de Moyamoya/genética , Adulto , Edad de Inicio , Moléculas de Adhesión Celular/genética , Niño , Preescolar , Estudios de Cohortes , Simulación por Computador , Exoma/genética , Femenino , Variación Genética , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/diagnóstico por imagen , Fenotipo , Análisis de Secuencia de ARN , Población Blanca , Secuenciación del ExomaRESUMEN
Gliosarcoma is a variant of glioblastoma with equally poor prognosis and characterized by mixed glial and mesenchymal pathology. Metastasis is not uncommon but the involvement of the spinal cord is rare, and comprehensive genetic characterization of spinal gliosarcoma is lacking. We describe a patient initially diagnosed with a low-grade brain glioma via biopsy, followed by adjuvant radiation and temozolomide treatment. Nearly 2 years after diagnosis, she developed neurological deficits from an intradural, extramedullary tumor anterior to the spinal cord at T4, which was resected and diagnosed as gliosarcoma. Whole-exome sequencing (WES) of this tumor revealed a hypermutated phenotype, characterized by somatic mutations in key DNA mismatch repair (MMR) pathway genes, an abundance of C>T transitions within the identified somatic single nucleotide variations, and microsatellite stability, together consistent with temozolomide-mediated hypermutagenesis. This is the first report of a hypermutator phenotype in gliosarcoma, which may represent a novel genomic mechanism of progression from lower grade glioma.
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Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole-exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious STAG2 mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an EGFR mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently STAG2 mutated clone, with rare mutations in PTPN11 and BRAF, the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying STAG2 deficiency. As such, this case represents a novel report following the clinical and genetic progression of a STAG2 mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although STAG2 deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role for STAG2 mutations in gliomagenesis and resistance to standard therapies.
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Pediatric midline tumors are devastating high-grade lesions with a dismal prognosis and no curative surgical options. Here, the authors report the clinical presentation, surgical management, whole-exome sequencing (WES), and clonality analysis of a patient with a radically resected H3K27M-mutant pineal parenchymal tumor (PPT) and spine metastases consistent with PPT of intermediate differentiation (PPTID). They identified somatic mutations in H3F3A (H3K27M), FGFR1, and NF1 both in the original PPT and in the PPTID metastases. They also found 12q amplification containing CDK4/MDM2 and chromosome 17 loss of heterozygosity overlapping with NF1 that resulted in biallelic NF1 loss. They noted a hypermutated phenotype with increased C>T transitions within the PPTID metastases and 2p amplification overlapping with the MYCN locus. Clonality analysis detected three founder clones maintained during progression and metastasis. Tumor clones present within the PPTID metastases but not the pineal midline tumor harbored mutations in APC and TIMP2.While the majority of H3K27M mutations are found in pediatric midline gliomas, it is increasingly recognized that this mutation is present in a wider range of lesions with a varied morphological appearance. The present case appears to be the first description of H3K27M mutation in PPTID. Somatic mutations in H3F3A, FGFR1, and NF1 have been suggested to be driver mutations in pediatric midline gliomas. Their clonality and presence in over 80% of tumor cells in our patient's PPTID are consistent with similarly crucial roles in early tumorigenesis, with progression mediated by copy number variations and chromosomal aberrations involving known oncogenes and tumor suppressors. The roles of APC and TIMP2 mutations in progression and metastasis remain to be investigated.
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OBJECTIVE: In the past decade, a gradual transition of health policy to value-based healthcare has brought increased attention to measuring the quality of care delivered. In spine surgery, adolescents with scoliosis are a population particularly at risk for depression, anxious feelings, and impaired quality of life related to back pain and cosmetic appearance of the deformity. With the rising prevalence of mental health ailments, it is necessary to evaluate the impact of concurrent affective disorders on patient care after spinal surgery in adolescents. The aim of this study was to investigate the impact that affective disorders have on perioperative complication rates, length of stay (LOS), and total costs in adolescents undergoing elective posterior spinal fusion (PSF) (≥ 4 levels) for idiopathic scoliosis. METHODS: A retrospective study of the Kids' Inpatient Database for the year 2012 was performed. Adolescent patients (age range 10-17 years old) with AIS undergoing elective PSF (≥ 4 levels) were selected using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Patients were categorized into 2 groups at discharge: affective disorder or no affective disorder. Patient demographics, comorbidities, complications, LOS, discharge disposition, and total cost were assessed. The primary outcomes were perioperative complication rates, LOS, total cost, and discharge dispositions. RESULTS: There were 3759 adolescents included in this study, of whom 164 (4.4%) were identified with an affective disorder (no affective disorder: n = 3595). Adolescents with affective disorders were significantly older than adolescents with no affective disorders (affective disorder: 14.4 ± 1.9 years vs no affective disorder: 13.9 ± 1.8 years, p = 0.001), and had significantly different proportions of race (p = 0.005). Aside from hospital region (p = 0.016), no other patient- or hospital-level factors differed between the cohorts. Patient comorbidities did not differ significantly between cohorts. The number of vertebral levels involved was similar between the cohorts, with the majority of patients having 9 or more levels involved (affective disorder: 76.8% vs no affective disorder: 79.5%, p = 0.403). Postoperative complications were similar between the cohorts, with no significant difference in the proportion of patients experiencing a postoperative complication (p = 0.079) or number of complications (p = 0.124). The mean length of stay and mean total cost were similar between the cohorts. Moreover, the routine and nonroutine discharge dispositions were also similar between the cohorts, with the majority of patients having routine discharges (affective disorder: 93.9% vs no affective disorder: 94.9%, p = 0.591). CONCLUSIONS: This study suggests that affective disorders may not have a significant impact on surgical outcomes in adolescent patients undergoing surgery for scoliosis in comparison with adults. Further studies are necessary to elucidate how affective disorders affect adolescent patients with idiopathic scoliosis, which may improve provider approach in managing these patients perioperatively and at follow-up in hopes to better the overall patient satisfaction and quality of care delivered.
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Hiperhidrosis/diagnóstico por imagen , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico por imagen , Niño , Femenino , Humanos , EnseñanzaRESUMEN
OBJECTIVE: Health policy changes have led to increased emphasis on value-based care to improve resource utilization and reduce inpatient hospital length of stay (LOS). Recently, LOS has become a major determinant of quality of care and resource utilization. For adolescent idiopathic scoliosis (AIS), the determinants of extended LOS after elective posterior spinal fusion (PSF) remain relatively unknown. In the present study, the authors investigated the impact of patient and hospital-level risk factors on extended LOS following elective PSF surgery (≥ 4 levels) for AIS. METHODS: The Kids' Inpatient Database (KID) was queried for the year 2012. Adolescent patients (age range 10-17 years) with AIS undergoing elective PSF (≥ 4 levels) were selected using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Extended hospital LOS was defined as greater than the 75th percentile for the entire cohort (> 6 days), and patients were dichotomized as having normal LOS or extended LOS. Patient demographics, comorbidities, complications, LOS, discharge disposition, and total cost were recorded. A multivariate logistic regression model was used to determine the odds ratio for risk-adjusted LOS. The primary outcome was the degree to which patient comorbidities or postoperative complications correlated with extended LOS. RESULTS: Comorbidities were overall significantly higher in the extended-LOS cohort than the normal-LOS cohort. Patients with extended LOS had a significantly greater proportion of blood transfusion (p < 0.001) and ≥ 9 vertebral levels fused (p < 0.001). The overall complication rates were greater in the extended-LOS cohort (20.3% [normal-LOS group] vs 43.5% [extended-LOS group]; p < 0.001). On average, the extended-LOS cohort incurred $18,916 more in total cost than the normal-LOS group ($54,697 ± $24,217 vs $73,613 ± $38,689, respectively; p < 0.001) and had more patients discharged to locations other than home (p < 0.001) than did patients in the normal-LOS cohort. On multivariate logistic regression, several risk factors were associated with extended LOS, including female sex, obesity, hypertension, fluid electrolyte disorder, paralysis, blood transfusion, ≥ 9 vertebrae fused, dural injury, and nerve cord injury. The odds ratio for extended LOS was 1.95 (95% CI 1.50-2.52) for patients with 1 complication and 5.43 (95% CI 3.35-8.71) for patients with > 1 complication. CONCLUSIONS: The authors' study using the KID demonstrates that patient comorbidities and intra- and postoperative complications all contribute to extended LOS after spinal fusion for AIS. Identifying multimodality interventions focused on reducing LOS, bettering patient outcomes, and lowering healthcare costs are necessary to improve the overall value of care for patients undergoing spinal fusion for AIS.
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There are several approaches to correct sagittal synostosis. Regardless of technique, the goals are to (1) release the fused suture and (2) impart a normocephalic head shape with resultant functional and aesthetic benefits. This article and video detail the authors' preferred technique for the treatment of sagittal synostosis. This novel method involves three-dimensional planning and an open approach to focus on immediate correction of the anteroposterior, mediolateral, and vertex dimensions, using vault remodeling, pedicled osseous ("Maltese") crosses, and corset pericranial flaps.
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Trasplante Óseo/métodos , Craneosinostosis/cirugía , Procedimientos de Cirugía Plástica/métodos , Cirugía Asistida por Computador/métodos , Humanos , Imagenología Tridimensional , Lactante , Masculino , Resultado del TratamientoAsunto(s)
Hematoma Intracraneal Subdural/diagnóstico por imagen , Hematoma Subdural Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/diagnóstico por imagen , Pérdida de Líquido Cefalorraquídeo/cirugía , Craneotomía , Duramadre/cirugía , Hematoma Intracraneal Subdural/cirugía , Hematoma Subdural Espinal/complicaciones , Hematoma Subdural Espinal/cirugía , Humanos , Lactante , Laminectomía , Vértebras Lumbares , Imagen por Resonancia Magnética , Masculino , Complicaciones Posoperatorias/cirugía , Compresión de la Médula Espinal/etiología , Compresión de la Médula Espinal/cirugía , Vértebras TorácicasRESUMEN
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for â¼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.
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Ensamble y Desensamble de Cromatina/genética , Mutación , Malformaciones de la Vena de Galeno/genética , Efrinas/metabolismo , Femenino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Metaloendopeptidasas/genética , Linaje , Penetrancia , Receptor EphB4/genética , Transducción de Señal , Malformaciones de la Vena de Galeno/patologíaRESUMEN
Objective. The use of cerebrospinal shunts is the standard of care for hydrocephalus. However, shunts are extremely vulnerable to failure and lack noninvasive methods to monitor their viability. We review current shunt technologies and attempts to improve their function. Methods. A PubMed search was performed to find literature on shunts and shunt function. Company brochures and websites were also used. Results. Fixed and variable pressure valves from four major companies are discussed. Also reviewed are siphon resistive devices, intracranial pressure sensors, and recent attempts on the development of cerebrospinal fluid sensors, including a micromechanical flow sensor we have recently developed. Conclusions. While variable pressure valves and siphon resistive devices have both had considerable success in dealing with variable intracranial pressure, a more sophisticated, continuous monitoring system is needed to ensure shunt viability and patient safety. An integrated flow sensor may provide the ability to track fluid flow and determine shunt functionality.
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Hidrocefalia/fisiopatología , Presión Intracraneal/fisiología , Derivaciones del Líquido Cefalorraquídeo , HumanosRESUMEN
Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10-7), SMARCC1 (p = 8.15 × 10-10), and PTCH1 (p = 1.06 × 10-6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10-4). Together, these probands account for â¼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
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Hidrocefalia/diagnóstico , Hidrocefalia/genética , Mutación/genética , Células-Madre Neurales/fisiología , Estudios de Cohortes , Exoma/genética , Femenino , Humanos , Masculino , Células-Madre Neurales/patología , Receptor Patched-1/genética , Linaje , Factores de Transcripción/genética , Secuenciación del Exoma/métodosRESUMEN
Congenital hemangiomas are tumor-like vascular malformations with poorly understood pathogenesis. We report the case of a neonate with a massive congenital scalp hemangioma that required urgent neurosurgical removal on the second day of life because of concern for high-flow arteriovenous shunting. Exome sequencing identified a rare damaging de novo germline mutation in MYH9 (c.5308C>T, p.[Arg1770Cys]), encoding the MYH9 nonmuscle myosin IIA. MYH9 has a probability of loss-of-function intolerance (pLI) score of >0.99 and is highly intolerant to missense variation (z score = 5.59). The p.(Arg1770Cys) mutation substitutes an evolutionarily conserved amino acid in the protein's critical myosin tail domain and is predicted to be highly deleterious by SIFT, PolyPhen-2, MetaSVM, and CADD. MYH9 is a known regulator of cytokinesis, VEGF-regulated angiogenesis, and p53-dependent tumorigenesis. These findings reveal a novel association of germline de novo MYH9 mutation with congenital hemangioma.