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OBJECTIVES: Studies have demonstrated that socioeconomic status, insurance, race, and distance impact clinical outcomes in patients with abdominal aortic aneurysms. The purpose of this study was to assess if these factors also impact clinical outcomes in patients with thoracoabdominal aortic aneurysms (TAAAs). METHODS: We conducted a retrospective review of patients with TAAAs confirmed by computed tomography imaging between 2009 and 2019 at a single institution. Patients' zip codes were mapped to American Community Survey Data to obtain geographic poverty rates. We used the standard U.S. Census definition of high-poverty concentration as >20% of the population living at 100% of the poverty rate. Our primary outcome was overall survival, stratified by whether the patient underwent repair. RESULTS: Of 578 patients, 575 had zip code data and were analyzed. In both the nonoperative (N = 268) and operative (N = 307) groups, there were no significant differences in age, race, comorbidities, clinical urgency, surgery utilization, or surgery modality between patients living in high-poverty areas (N = 95, 16.4%) vs not. In the nonoperative group, patients from high-poverty areas were more likely to have aneurysm due to dissection (37.5% vs 17.6%, P = .03). In multivariate analyses, patients from high-poverty zip codes had significantly worse nonoperative survival (hazard ratio [HR]: 1.9, 95% confidence interval [CI]: 1.1-3.3, P = .03). In the repair group, high poverty was also a significant predictor of reduced postoperative survival (HR: 1.65, 95% CI: 1-2.63, P = .04). Adding the Gagne Index, these differences persisted in both groups (nonoperative: HR: 1.93, 95% CI: 1.01-3.70, P = .05; operative: HR: 1.62, 95% CI: 1.03-2.56, P = .04). In Kaplan-Meier analysis, the difference in postoperative survival began approximately 1.5 years after repair. Private insurance was predictive of improved postoperative survival (HR: 0.42, 95% CI: 0.18-0.95, P = .04) but reduced nonoperative survival (HR: 2.05, 95% 1.01-4.14, P = .04). Data were insufficient to determine if race impacted survival discretely from poverty status. These results were found after adjusting for age, race, sex, maximum aortic diameter, coronary artery disease, distance from the hospital, insurance, and active smoking. Interestingly, in multivariate regression, traveling greater than 100 miles was correlated with increased surgery utilization (odds ratio: 1.58, 95% CI: 1.08-2.33, P = .02) and long-term survival (HR: 0.61, 95% CI: 0.41-0.92, P = .02). CONCLUSIONS: Patients with TAAAs living in high-poverty areas had significantly more dissections and suffered a nearly doubled risk of mortality compared with patients living outside such areas. These data suggest that these disparities are attributed to the overall impacts of poverty and highlight the pressing need for research into TAAA disparities.
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Aneurisma de la Aorta Torácica , Humanos , Masculino , Estudios Retrospectivos , Femenino , Aneurisma de la Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/mortalidad , Aneurisma de la Aorta Torácica/diagnóstico por imagen , Anciano , Factores de Riesgo , Persona de Mediana Edad , Factores de Tiempo , Medición de Riesgo , Resultado del Tratamiento , Áreas de Pobreza , Disparidades en Atención de Salud , Determinantes Sociales de la Salud , Anciano de 80 o más Años , Procedimientos Endovasculares/mortalidad , Procedimientos Endovasculares/efectos adversos , Implantación de Prótesis Vascular/mortalidad , Implantación de Prótesis Vascular/efectos adversos , Aneurisma de la Aorta ToracoabdominalRESUMEN
INTRODUCTION: Degenerative spondylolisthesis causes translational and angular malalignment, resulting in a loss of segmental lordosis. This leads to compensatory adjustments in adjacent levels to maintain balance. Lateral lumbar interbody fusion (LLIF) and transforaminal lumbar interbody fusion (TLIF) are common techniques at L4-5. This study compares compensatory changes at adjacent L3-4 and L5-S1 levels six months post LLIF versus TLIF for grade 1 degenerative spondylolisthesis at L4-5. METHODS: A retrospective study included patients undergoing L4-5 LLIF or TLIF with posterior pedicle screw instrumentation (no posterior osteotomy) for grade 1 spondylolisthesis. Pre-op and 6-month post-op radiographs measured segmental lordosis (L3-L4, L4-L5, L5-S1), lumbar lordosis (LL), and pelvic incidence (PI), along with PI-LL mismatch. Multiple regressions were used for hypothesis testing. RESULTS: 113 patients (61 LLIF, 52 TLIF) were studied. TLIF showed less change in L4-5 lordosis (mean = 1.04°, SD = 4.34) compared to LLIF (mean = 4.99°, SD = 5.53) (p = 0.003). L4-5 angle changes didn't correlate with L3-4 changes, and no disparity between LLIF and TLIF was found (all p > 0.16). In LLIF, greater L4-5 lordosis change predicted reduced compensatory L5-S1 lordosis (p = 0.04), while no significant relationship was observed in TLIF patients (p = 0.12). CONCLUSION: LLIF at L4-5 increases lordosis at the operated level, with compensatory decrease at L5-S1 but not L3-4. This reciprocal loss at adjacent L5-S1 may explain inconsistent improvement in lumbar lordosis (PI-LL) post L4-5 fusion.
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Lordosis , Vértebras Lumbares , Fusión Vertebral , Espondilolistesis , Humanos , Fusión Vertebral/métodos , Vértebras Lumbares/cirugía , Vértebras Lumbares/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Lordosis/cirugía , Lordosis/diagnóstico por imagen , Femenino , Estudios Retrospectivos , Anciano , Espondilolistesis/cirugía , Espondilolistesis/diagnóstico por imagen , Resultado del Tratamiento , Sacro/cirugía , Sacro/diagnóstico por imagen , AdultoRESUMEN
SERRATE (SE) is a key factor in RNA metabolism. Here, we report that SE binds 20S core proteasome α subunit G1 (PAG1) among other components and is accumulated in their mutants. Purified PAG1-containing 20S proteasome degrades recombinant SE via an ATP- and ubiquitin-independent manner in vitro. Nevertheless, PAG1 is a positive regulator for SE in vivo, as pag1 shows comparable molecular and/or developmental defects relative to se. Furthermore, SE is poorly assembled into macromolecular complexes, exemplified by the microprocessor in pag1 compared with Col-0. SE overexpression triggered the destruction of both transgenic and endogenous protein, leading to similar phenotypes of se and SE overexpression lines. We therefore propose that PAG1 degrades the intrinsically disordered portion of SE to secure the functionality of folded SE that is assembled and protected in macromolecular complexes. This study provides insight into how the 20S proteasome regulates RNA metabolism through controlling its key factor in eukaryotes.
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Proteínas de Arabidopsis/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN de Planta/metabolismo , Proteínas de Unión al ARN/metabolismo , Arabidopsis/metabolismo , Regulación de la Expresión Génica de las Plantas , Ubiquitina/metabolismoRESUMEN
The identification of recurrent human leukocyte antigen (HLA) neoepitopes driving T cell responses against tumors poses a significant bottleneck in the development of approaches for precision cancer therapeutics. Here, we employ a bioinformatics method, Prediction of T Cell Epitopes for Cancer Therapy, to analyze sequencing data from neuroblastoma patients and identify a recurrent anaplastic lymphoma kinase mutation (ALK R1275Q) that leads to two high affinity neoepitopes when expressed in complex with common HLA alleles. Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. Subsequent determination of the X-ray structure of an HLA-A*01:01 bound neoepitope validates atomic features seen in our Rosetta models with respect to key residues relevant for MHC stability and T cell receptor recognition. Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy.