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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
Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016-23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients.
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Trastorno del Espectro Autista , Acueducto del Mesencéfalo/anomalías , Enfermedades Genéticas Ligadas al Cromosoma X , Hidrocefalia , Niño , Humanos , Trastorno del Espectro Autista/genética , Factores de Transcripción/genética , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/genética , Epigénesis Genética , Proteínas del Ojo/genética , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
BACKGROUND: Non-hypothalamic glioneural hamartomas are rare entities known to cause medically refractory epilepsy. Olfactory bulb hamartomas, in particular, are exceptionally rare. METHODS: We describe a case of an olfactory bulb hamartoma that was surgically resected at our institution. We also performed a literature review of all glioneural hamartomas and discuss the clinical presentation, diagnosis, and management of these lesions. RESULTS: Herein, we present the unusual case of a typically developing 17-year-old boy with a near life-long history of drug-resistant epilepsy, found to have a 0.8 × 1.0 cm right olfactory bulb hamartoma. Endoscopic endonasal trans-cribriform resection of the lesion led to seizure freedom in the 6-month follow-up period (Engel class 1 outcome). Comprehensive literature review revealed only one other sporadic case, which was also successfully treated with total surgical resection. CONCLUSIONS: Our case of an olfactory bulb hamartoma adds to the limited literature currently available, illustrating key clinical characteristics of these exceedingly rare lesions and outlining an effective, minimally invasive, and low-morbidity treatment strategy.
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INTRODUCTION: Intraventricular hemorrhage (IVH) can ensue permanent neurologic dysfunction, morbidity, and mortality. While previous reports have identified disparities based on patient gender or weight, no prior study has assessed how race may influence in neonatal or infantile IVH patients. The aim of this study was to investigate the impact of race on adverse event (AE) rates, length of stay (LOS), and total cost of admission among newborns with IVH. METHODS: Using the 2016-2019 National Inpatient Sample database, newborns diagnosed with IVH were identified using ICD-10-CM codes. Patients were stratified based on race. Patient characteristics and inpatient outcomes were assessed. Multivariate logistic regression analyses were used to identify the impact of race on extended LOS and exorbitant cost. RESULTS: Of 1435 patients, 650 were White (45.3%), 270 African American (AA) (18.8%), 300 Hispanic (20.9%), and 215 Other (15.0%). A higher percentage of AA and Other patients than Hispanic and White patients were < 28 days old (p = 0.008). Each of the cohorts had largely similar presenting comorbidities and symptoms, although AA patients did have significantly higher rates of NEC (p < 0.001). There were no observed differences in rates of AEs, rates of mortality, mean LOS, or mean total cost of admission. Similarly, on multivariate analysis, no race was identified as a significant independent predictor of extended LOS or exorbitant cost. CONCLUSIONS: Our study found that in newborns with IVH, race is not associated with proxies of poor healthcare outcomes like prolonged LOS or excessive cost. Further studies are needed to validate these findings.
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Tiempo de Internación , Humanos , Recién Nacido , Masculino , Femenino , Tiempo de Internación/estadística & datos numéricos , Disparidades en Atención de Salud/etnología , Negro o Afroamericano , Hemorragia Cerebral Intraventricular/epidemiología , Hemorragia Cerebral/etnología , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/economía , Hemorragia Cerebral/mortalidad , Población BlancaRESUMEN
PURPOSE: To provide an up-to-date review of the epidemiology, histopathology, molecular biology, and etiology of spinal meningiomas, as well as discuss the clinical presentation, clinical evaluation, and most recent treatment recommendations for these lesions. METHODS: PubMed and Google Scholar search was performed for studies related to meningiomas of the spine. The terms "meningioma," "spinal meningioma," "spine meningioma," "meningioma of the spine," "benign spinal tumors," and "benign spine tumors," were used to identify relevant studies. All studies, including primary data papers, meta-analyses, systematic reviews, general reviews, case reports, and clinical trials were considered for review. RESULTS: Eighty-four studies were identified in the review. There were 22 studies discussing adverse postoperative outcomes, 21 studies discussing tumor genetics, 19 studies discussing epidemiology and current literature, 9 studies discussing radiation modalities and impact on subsequent tumor development, 5 studies on characteristic imaging findings, 5 studies discussing hormone use/receptor status on tumor development, 2 discussing operative techniques and 1 discussing tumor identification. CONCLUSION: Investigations into spinal meningiomas generally lag behind that of intracranial meningiomas. Recent advancements in the molecular profiling of spinal meningiomas has expanded our understanding of these tumors, increasing our appreciation for their heterogeneity. Continued investigation into the defining characteristics of different spinal meningiomas will aid in treatment planning and prognostication.
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Neoplasias Meníngeas , Meningioma , Neoplasias de la Médula Espinal , Neoplasias de la Columna Vertebral , Humanos , Meningioma/diagnóstico , Meningioma/epidemiología , Meningioma/genética , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/epidemiología , Neoplasias Meníngeas/genética , Columna Vertebral/patología , Neoplasias de la Médula Espinal/diagnóstico , Neoplasias de la Médula Espinal/epidemiología , Neoplasias de la Médula Espinal/terapia , Neoplasias de la Columna Vertebral/diagnóstico , Neoplasias de la Columna Vertebral/epidemiología , Neoplasias de la Columna Vertebral/genéticaRESUMEN
PURPOSE: The Hospital Frailty Risk Score (HFRS) is a frailty-identifying metric developed using ICD-10-CM codes. While other studies have examined frailty in adult spinal deformity (ASD), the HFRS has not been assessed in this population. The aim of this study was to utilize the HFRS to investigate the impact of frailty on outcomes in ASD patients undergoing posterior spinal fusion (PSF). METHODS: A retrospective study was performed using the 2016-2019 National Inpatient Sample database. Adults with ASD undergoing elective PSF were identified using ICD-10-CM codes. Patients were categorized into HFRS-based frailty cohorts: Low (HFRS < 5) and Intermediate-High (HFRS ≥ 5). Patient demographics, comorbidities, intraoperative variables, and outcomes were assessed. Multivariate regression analyses were used to determine whether HFRS independently predicted extended length of stay (LOS), non-routine discharge, and increased cost. RESULTS: Of the 7500 patients identified, 4000 (53.3%) were in the Low HFRS cohort and 3500 (46.7%) were in the Intermediate-High HFRS cohort. On average, age increased progressively with increasing HFRS scores (p < 0.001). The frail cohort experienced more postoperative adverse events (p < 0.001), greater LOS (p < 0.001), accrued greater admission costs (p < 0.001), and had a higher rate of non-routine discharge (p < 0.001). On multivariate analysis, Intermediate-High HFRS was independently associated with extended LOS (OR: 2.58, p < 0.001) and non-routine discharge (OR: 1.63, p < 0.001), though not increased admission cost (OR: 1.01, p = 0.929). CONCLUSION: Our study identified HFRS to be significantly associated with prolonged hospitalizations and non-routine discharge. Other factors that were found to be associated with increased healthcare resource utilization include age, Hispanic race, West hospital region, large hospital size, and increasing number of AEs.
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BACKGROUND: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer's disease. METHODS: The concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. RESULTS: We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a preliminary validation study, on unique individual samples compared to the discovery cohort, using a targeted LC-MS/MS assay on a subset of discovered biomarkers. We found that targets that displayed a high degree of isoform specific changes in the 2D gels were not changed in the targeted MS assay which reports on the total level of the biomarker. CONCLUSIONS: This demonstrates that further development of mass spectrometry assays is needed to capture the isoform complexity that exists in theses biological samples. However, this study indicates that a peripheral protein signature has potential to aid in the characterization of AD.
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Since the first human release of radionuclides on Earth at the end of the Second World War, impact assessments have been implemented. Radionuclides are now ubiquitous, and the impact of local accidental release on human activities, although of low probability, is of tremendous social and economic consequences. Although radionuclide inventories (at various scales) are essential as input data for impact assessment, crucial information on physicochemical speciation is lacking. Among the metallic radionuclides of interest, cobalt-60 is one of the most important activation products generated in the nuclear industry. In this work, a marine model ecosystem has been defined because seawater and more generally marine ecosystems are final receptacles of metal pollution. A multistep approach from quantitative uptake to understanding of the accumulation mechanism has been implemented with the sea urchin Paracentrotus lividus. In a well-controlled aquarium, the day-by-day uptake of cobalt and its quantification in different compartments of the sea urchin were monitored with various conditions of exposure by combining ICP-OES analysis and γ spectrometry. Cobalt is mainly distributed following the rating intestinal tract ⫠gonads > shell spines. Cobalt speciation in seawater and inside the gonads and the intestinal tract was determined using extended X-ray absorption fine structure (EXAFS). The cobalt inside the gonads and the intestinal tract is mainly complexed by the toposome, the main protein in the sea urchin P. lividus. Complexation with purified toposome was characterized and a complexation site combining EXAFS and AIMD (ab initio molecular dynamics) was proposed implying monodentate carboxylates.
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Paracentrotus , Animales , Cobalto , Ecosistema , Gónadas , Humanos , Paracentrotus/química , Agua de MarRESUMEN
Reparative inflammation is an important protective response that eliminates foreign organisms, damaged cells, and physical irritants. However, inappropriately triggered or sustained inflammation can respectively initiate, propagate, or prolong disease. Post-hemorrhagic (PHH) and post-infectious hydrocephalus (PIH) are the most common forms of hydrocephalus worldwide. They are treated using neurosurgical cerebrospinal fluid (CSF) diversion techniques with high complication and failure rates. Despite their distinct etiologies, clinical studies in human patients have shown PHH and PIH share similar CSF cytokine and immune cell profiles. Here, in light of recent work in model systems, we discuss the concept of "inflammatory hydrocephalus" to emphasize potential shared mechanisms and potential therapeutic vulnerabilities of these disorders. We propose that this change of emphasis could shift our thinking of PHH and PIH from a framework of life-long neurosurgical disorders to that of preventable conditions amenable to immunomodulation.
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Hidrocefalia , Citocinas , Hemorragia , Humanos , Hidrocefalia/cirugía , InflamaciónRESUMEN
AIM: Secondary prophylaxis with 3-4 weekly benzathine penicillin G injections is necessary to prevent disease morbidity and cardiac mortality in patients with acute rheumatic fever (ARF) and rheumatic heart disease (RHD). This study aimed to determine secondary prophylaxis adherence rates in the Far North Queensland paediatric population and to identify factors contributing to suboptimal adherence. METHODS: A retrospective analysis of data recorded in the online RHD register for Queensland, Australia, was performed for a 10-year study period. The proportion of benzathine penicillin G injections delivered within intervals of ≤28 days and ≤35 days was measured. A multi-level mixed model logistic regression assessed the influence of age, gender, ethnicity, suburb, Accessibility and Remoteness Index of Australia class, number of people per dwelling, Index of Relative Socio-economic Advantage and Disadvantage, Index of Education and Occupation, year of inclusion on an ARF/RHD register and individual effect. RESULTS: The study included 277 children and analysis of 7374 injections. No children received ≥80% of recommended injections within a 28-day interval. Four percent received ≥50% of injections within ≤28 days and 46% received ≥50% of injections at an extended interval of ≤35 days. Increasing age was associated with reduced delivery of injections within 35 days. Increasing year of inclusion was associated with improved delivery within 28 days. The random effect of individual patients was significantly associated with adherence. CONCLUSIONS: Improved timely delivery of secondary prophylaxis for ARF and RHD is needed as current adherence is very low. Interventions should focus on factors specific to each individual child or family unit.
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Fiebre Reumática , Cardiopatía Reumática , Adolescente , Antibacterianos/uso terapéutico , Niño , Femenino , Humanos , Masculino , Penicilina G Benzatina , Queensland , Reproducibilidad de los Resultados , Estudios Retrospectivos , Fiebre Reumática/tratamiento farmacológico , Fiebre Reumática/prevención & control , Factores de RiesgoRESUMEN
Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.
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ADN Mitocondrial/sangre , Sarcoidosis Pulmonar/sangre , Adulto , Anciano , Biomarcadores/sangre , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar , Estudios de Casos y Controles , Femenino , Células HEK293 , Proteína HMGB1/metabolismo , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , ATPasas de Translocación de Protón Mitocondriales/sangre , Fenotipo , Sarcoidosis Pulmonar/fisiopatología , Receptor Toll-Like 9/metabolismoRESUMEN
Uranium speciation and bioaccumulation were investigated in the sea urchin Paracentrotus lividus. Through accumulation experiments in a well-controlled aquarium followed by ICP-OES analysis, the quantification of uranium in the different compartments of the sea urchin was performed. Uranium is mainly distributed in the test (skeletal components), as it is the major constituent of the sea urchin, but in terms of quantity of uranium per gram of compartment, the following rating: intestinal tract > gonads â« test, was obtained. Combining both extended X-ray Absorption Spectroscopy and time-resolved laser-induced fluorescence spectroscopic analysis, it was possible to identify two different forms of uranium in the sea urchin, one in the test, as a carbonato-calcium complex, and the second one in the gonads and intestinal tract, as a protein complex. Toposome is a major calcium-binding transferrin-like protein contained within the sea urchin. EXAFS data fitting of both contaminated organs in vivo and the uranium-toposome complex from protein purified out of the gonads revealed that it is suspected to complex uranium in gonads and intestinal tract. This hypothesis is also supported by the results from two imaging techniques, i.e., Transmission Electron Microscopy and Scanning Transmission X-ray Microscopy. This thorough investigation of uranium uptake in sea urchin is one of the few attempts to assess the speciation in a living marine organism in vivo.
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Paracentrotus , Uranio , Animales , GónadasRESUMEN
A transition-metal-free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4-quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro-type reduction followed by an Evans-Tishchenko reaction. When isoquinolines featuring a proton at the 4-position are used, a tandem methylation-hydroxymethylation occurs, leading to the formation of 2 new C-C bonds in one pot.
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OBJECTIVES: To determine the prevalence of rheumatic heart disease (RHD) in school-aged children and young people in Timor-Leste. DESIGN: Prospective cross-sectional survey. Echocardiography was performed by Australian cardiologists to determine the presence of RHD. Demographic data were also collected. Patients in whom RHD was detected were entered into a register to allow monitoring of adherence to secondary prophylaxis; the first dose of benzathine penicillin G (BPG) was administered on the day of screening. SETTING: Schools in urban (Dili) and rural (Ermera) Timor-Leste. PARTICIPANTS: School students aged 5-20 years. OUTCOME MEASURES: Definite and borderline RHD, as defined by World Heart Federation echocardiographic criteria. RESULTS: 1365 participants were screened; their median age was 11 years (IQR, 9-14 years), and 53% were girls. The estimated prevalence of definite RHD was 18.3 cases per 1000 population (95% CI, 12.3-27.0 per 1000), and of definite or borderline RHD 35.2 per 1000 (95% CI, 26.5-46.4 per 1000). Definite (adjusted odds ratio [aOR], 3.5; 95% CI, 1.3-9.4) and definite or borderline RHD (aOR, 2.7; 95% CI, 1.4-5.2) were more prevalent among girls than boys. Eleven children (0.8%) had congenital heart disease. Of the 25 children in whom definite RHD was identified, 21 (84%) received education and a first dose of BPG on the day of screening; all 25 have since received education about primary care for RHD and have commenced penicillin prophylaxis. CONCLUSIONS: The rates of RHD in Timor-Leste are among the highest in the world, and prevalence is higher among girls than boys. Community engagement is essential for ensuring follow-up and the effective delivery of secondary prophylaxis.
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Ecocardiografía , Cardiopatía Reumática/diagnóstico por imagen , Cardiopatía Reumática/epidemiología , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Masculino , Prevalencia , Estudios Prospectivos , Timor Oriental/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Population-based registries report 95% 5-year survival for children undergoing surgery for CHD. This study investigated paediatric cardiac surgical outcomes in the Australian indigenous population. METHODS: All children who underwent cardiac surgery between May, 2008 and August, 2014 were studied. Demographic information including socio-economic status, diagnoses and co-morbidities, and treatment and outcome data were collected at time of surgery and at last follow-up. RESULTS: A total of 1528 children with a mean age 3.4±4.6 years were studied. Among them, 123 (8.1%) children were identified as indigenous, and 52.7% (62) of indigenous patients were in the lowest third of the socio-economic index compared with 28.2% (456) of non-indigenous patients (p⩽0.001). The indigenous sample had a significantly higher Comprehensive Aristotle Complexity score (indigenous 9.4±4.2 versus non-indigenous 8.7±3.9, p=0.04). The probability of having long-term follow-up did not differ between groups (indigenous 93.8% versus non-indigenous 95.6%, p=0.17). No difference was noted in 30-day mortality (indigenous 3.2% versus non-indigenous 1.4%, p=0.13). The 6-year survival for the entire cohort was 95.9%. The Cox survival analysis demonstrated higher 6-year mortality in the indigenous group - indigenous 8.1% versus non-indigenous 5.0%; hazard ratio (HR)=2.1; 95% confidence intervals (CI): 1.1, 4.2; p=0.03. Freedom from surgical re-intervention was 79%, and was not significantly associated with the indigenous status (HR=1.4; 95% CI: 0.9, 1.9; p=0.11). When long-term survival was adjusted for the Comprehensive Aristotle Complexity score, no difference in outcomes between the populations was demonstrated (HR=1.6; 95% CI: 0.8, 3.2; p=0.19). CONCLUSION: The indigenous population experienced higher late mortality. This apparent relationship is explained by increased patient complexity, which may reflect negative social and environmental factors.
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Procedimientos Quirúrgicos Cardíacos/estadística & datos numéricos , Cardiopatías Congénitas/etnología , Cardiopatías Congénitas/mortalidad , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Adolescente , Australia/epidemiología , Niño , Preescolar , Comorbilidad , Femenino , Cardiopatías Congénitas/cirugía , Cardiopatías/cirugía , Humanos , Masculino , Modelos de Riesgos Proporcionales , Queensland/epidemiología , Sistema de Registros , Distribución por Sexo , Factores Socioeconómicos , SobrevidaRESUMEN
BACKGROUND: The current paradigm of intracellular redox chemistry maintains that cells establish a reducing environment maintained by a pool of small molecule and protein thiol to protect against oxidative damage. This strategy is conserved in mesophilic organisms from all domains of life, but has been confounded in thermophilic organisms where evidence suggests that intracellular proteins have abundant disulfides. METHODS: Chemical labeling and 2-dimensional gel electrophoresis were used to capture disulfide bonding in the proteome of the model thermophile Sulfolobus solfataricus. The redox poise of the metabolome was characterized using both chemical labeling and untargeted liquid chromatography mass spectrometry. Gene annotation was undertaken using support vector machine based pattern recognition. RESULTS: Proteomic analysis indicated the intracellular protein thiol of S. solfataricus was primarily in the disulfide form. Metabolic characterization revealed a lack of reduced small molecule thiol. Glutathione was found primarily in the oxidized state (GSSG), at relatively low concentration. Combined with genetic analysis, this evidence shows that pathways for synthesis of glutathione do exist in the archaeal domain. CONCLUSIONS: In observed thermophilic organisms, thiol abundance and redox poise suggest that this system is not directly utilized for protection against oxidative damage. Instead, a more oxidized intracellular environment promotes disulfide bonding, a critical adaptation for protein thermostability. GENERAL SIGNIFICANCE: Based on the placement of thermophilic archaea close to the last universal common ancestor in rRNA phylogenies, we hypothesize that thiol-based redox systems are derived from metabolic pathways originally tasked with promoting protein stability.
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Disulfuros/química , Glutatión/química , Metaboloma , Proteínas/química , Proteoma/análisis , Sulfolobus solfataricus/metabolismo , Adaptación Fisiológica , Cromatografía Liquida , Cisteína/química , Cisteína/metabolismo , Disulfuros/metabolismo , Electroforesis en Gel Bidimensional , Glutatión/metabolismo , Calor , NADP/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Proteínas/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónAsunto(s)
Proteínas de Unión al ADN/genética , Neoplasias Neuroepiteliales/genética , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Factores de Transcripción/genética , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Neoplasias Neuroepiteliales/patología , Proteínas de Fusión Oncogénica/aislamiento & purificación , PediatríaRESUMEN
OBJECTIVE: The rise of spinal surgery for ankylosing spondylitis (AS) necessitates balancing health care costs with quality patient care. Frailty has been independently associated with adverse outcomes and increased costs. This study investigates whether frailty is an independent predictor of poor outcomes after elective surgery for AS. METHODS: Using the National Inpatient Sample (NIS) database, a retrospective study was conducted on adult patients with AS who underwent posterior spinal fusion for fracture between 2016 and 2019. Each patient was assigned a modified frailty index (mFI) score and categorized as prefrail (mFI = 0 or 1), moderately frail (mFI = 2), and highly frail (mFI≥3). Multivariate logistic regression analyses were used to identify independent predictors of extended length of stay, non-routine discharge (NRD), and exorbitant admission costs. RESULTS: Of the 1910 patients, 35.3% were prefrail, 31.2% moderately frail, and 33.5% highly frail. Age was significantly different across groups (P < 0.001), and frailty was associated with increased comorbidities (P < 0.001). Mean length of stay (P = 0.007), NRD rate (P < 0.001), and mean cost of admission (P = 0.002) all significantly increased with increasing frailty. However, frailty was not an independent predictor of extended hospital stay, NRD, or higher costs on multivariate analysis. Instead, predictors included multiple adverse events, number of comorbidities, and race. CONCLUSIONS: While frailty in patients with AS is associated with older age, greater comorbidities, and increased adverse events, it was not an independent predictor of extended hospital stay, NRD, or higher hospital costs. Further research is required to understand the full impact of frailty on surgical outcomes and develop effective interventions.
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Fragilidad , Fracturas de la Columna Vertebral , Espondilitis Anquilosante , Adulto , Humanos , Fragilidad/complicaciones , Fracturas de la Columna Vertebral/cirugía , Estudios Retrospectivos , Espondilitis Anquilosante/complicaciones , Espondilitis Anquilosante/cirugía , Factores de Riesgo , Aceptación de la Atención de Salud , Complicaciones Posoperatorias/epidemiologíaRESUMEN
INTRODUCTION: Affective disorders (AD) have been shown to influence patient outcomes and healthcare resource utilization across several pathologies, though this relationship has not been described in patients with Chiari I malformations (CM-I). The aim of this study was to determine the impact of comorbid AD on postoperative events and healthcare resource utilization in adults following suboccipital decompression for CM-I. METHODS: A retrospective study was performed using the 2016-2019 National Inpatient Sample database. Adults who underwent suboccipital decompression for CM-I were identified using ICD-10-CM codes. Patients were stratified into two cohorts, those with AD and those without (No AD). Patient demographics, comorbidities, operative characteristics, perioperative adverse events (AEs), and healthcare resource utilization were assessed. Multivariate logistic regression analyses were used to identify independent predictors of prolonged length of stay (LOS), exorbitant admission costs, and non-routine discharge (NRD). RESULTS: A total of 3985 patients were identified, of which 2780 (69.8%) were in the No AD cohort and 1205 (30.2%) were in the AD cohort. Patient demographics were similar, except for a greater proportion of Female patients than the No AD cohort (p = 0.004). Prevalence of some comorbidities varied between cohorts, including obesity (p = 0.030), ADHD (p < 0.001), GERD (p < 0.001), smoking (p < 0.001), and chronic pulmonary disease (p < 0.001). The AD cohort had a greater proportion of patients with 1-2 (p < 0.001) or ≥ 3 comorbidities (p < 0.001) compared to the No AD cohort. A greater proportion of patients in the AD cohort presented with headache compared to the No AD cohort (p = 0.003). Incidence of syringomyelia was greater in the No AD cohort (p = 0.002). A greater proportion of patients in the No AD cohort underwent duraplasty only (without cervical laminectomy) compared to the AD cohort (p = 0.021). Healthcare resource utilization was similar between cohorts, with no significant differences in mean LOS (No AD: 3.78 ± 3.51 days vs. 3.68 ± 2.71 days, p = 0.659), NRD (No AD: 3.8% vs. AD: 5.4%, p = 0.260), or mean admission costs (No AD: $20,254 ± 14,023 vs. AD: $29,897 ± 22,586, p = 0.284). On multivariate analysis, AD was not independently associated with extended LOS [OR (95%CI): 1.09 (0.72-1.65), p = 0.669], increased hospital costs [OR (95%CI): 0.98 (0.63-1.52), p = 0.930], or NRD [OR (95%CI): 1.39 (0.65-2.96), p = 0.302]. CONCLUSION: Our study suggests that the presence of an AD may not have as much of an impact on postoperative events and healthcare resource utilization in adult patients undergoing Chiari decompression. Additional studies may be warranted to identify other potential implications that AD may have in other aspects of healthcare in this patient population.
Asunto(s)
Malformación de Arnold-Chiari , Descompresión Quirúrgica , Adulto , Humanos , Femenino , Descompresión Quirúrgica/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Costos de Hospital , Malformación de Arnold-Chiari/epidemiología , Malformación de Arnold-Chiari/cirugía , Malformación de Arnold-Chiari/complicaciones , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND: Skull lesions are a common finding in children, with dermoid cysts and eosinophilic granulomas observed most frequently. However, primary intraosseous xanthomas of the calvaria, which are lytic, expansile lesions that develop without underlying hyperlipidemic disease, are rare in children, with only one prior case reported. OBSERVATIONS: The authors describe the case of a healthy 6-year-old male who presented with a 2-month history of an enlarging midline skull mass that developed after a recent minor trauma. Imaging showed a full-thickness, lytic frontal bone lesion with an aggressive appearance and heterogeneous contrast enhancement. The patient underwent gross-total resection of the lesion with placement of a mesh cranioplasty. Histopathology revealed a primary intraosseous xanthoma. The patient was discharged on postoperative day 2 and required no further treatment at the 1-month follow-up. LESSONS: This is the first reported case of a primary intraosseous xanthoma in the frontal bone of a pediatric patient. It emphasizes the need to include primary xanthomas in the differential diagnosis for pediatric skull lesions, particularly when the lesion has an aggressive radiographic appearance or the patient has a history of focal trauma. Furthermore, our findings indicate that resection, together with subsequent monitoring for lesion reccurrence, is an adequate first-line treatment.