Dissecting the roles of EIF4G homologs reveals DAP5 as a modifier of CGG repeat-associated toxicity in a Drosophila model of FXTAS.

Neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG trinucleotide repeat expansion in the 5' UTR of FMR1. Expanded CGG repeat RNAs form stable secondary structures, which in turn support repeat-associated non-AUG (RAN) translation to produce toxic peptides. The parameters that impact RAN translation initiation efficiency are not well understood. Here we used a Drosophila melanogaster model of FXTAS to evaluate the role of the eIF4G family of eukaryotic translation initiation factors (EIF4G1, EIF4GII and EIF4G2/DAP5) in modulating RAN translation and CGG repeat-associated toxicity. DAP5 knockdown robustly suppressed CGG repeat-associated toxicity and inhibited RAN translation. Furthermore, knockdown of initiation factors that preferentially associate with DAP5 (such as EIF2ß, EIF3F and EIF3G) also selectively suppressed CGG repeat-induced eye degeneration. In mammalian cellular reporter assays, DAP5 knockdown exhibited modest and cell-type specific effects on RAN translation. Taken together, these data support a role for DAP5 in CGG repeat associated toxicity possibly through modulation of RAN translation.

Readmission rates in HIV-associated burkitt lymphoma patients in the USA: a nationwide readmission database (NRD) analysis.

BACKGROUND: People with human immunodeficiency virus have an increased risk of developing AIDS-defining malignancies including Burkitt lymphoma. Survival outcomes in HIV-associated Burkitt lymphoma remain worse than non-HIV-associated Burkitt lymphoma, despite widespread implementation of antiretroviral therapy. We aimed to determine the association between HIV status and risk for 30-day and 90-day readmission in the US after index hospitalization for Burkitt lymphoma. METHODS: Data were abstracted from the 2010-2020 Nationwide Readmissions Database; hospitalizations included patients with a primary BL diagnosis and were stratified by comorbid HIV. The primary outcome was all-cause readmission (30-day and 90-day). Secondary outcomes were in-hospital mortality, length of stay (LOS), and hospital cost. Between-HIV differences were evaluated via logistic and log-normal regression; multivariable models adjusted for comorbid kidney disease, hypertension, fluid and electrolyte disorders, and sepsis. RESULTS: Overall, there were 8,453 hospitalizations for BL and 6.0% carried an HIV diagnosis. Of BL hospitalizations, 68.4% were readmitted within 30-days post index BL hospitalization and 6.8% carried a HIV diagnosis. HIV-associated BL was associated with 43% higher adjusted odds of 30-day readmission (aOR 95% CI: 4% higher to 97% higher, p = 0.026). For 90-day readmission, 76.0% of BL patients were readmitted and 7.0% carried a HIV diagnosis. HIV-associated BL was not statistically associated with all-cause 90-day readmission (aOR 1.46, aOR 95% CI: 0% higher to 115% higher, p = 0.053). CONCLUSIONS: HIV-positive status is associated with an increased risk for 30-day readmission after index hospitalization for Burkitt lymphoma.

Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype.

INTRODUCTION: It is unknown how often patients with electrodiagnostic evidence of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a potentially treatable condition, present with a distal symmetric polyneuropathy (DSP) phenotype. METHODS: We reviewed the records of patients who presented to our electrodiagnostic laboratory between January 1, 2011, to December 31, 2019, and fulfilled electrodiagnostic criteria for CIDP to identify those who presented with a sensory predominant DSP phenotype. RESULTS: One hundred sixty-two patients had a chronic acquired demyelinating neuropathy, of whom 138 met criteria for typical or atypical CIDP. Nine of these patients presented with a sensory predominant DSP phenotype, among whom six were eventually diagnosed with distal acquired demyelinating symmetric (DADS) neuropathy; one with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (POEMS) syndrome; and two with idiopathic DSP. The prevalence of acquired chronic demyelinating neuropathies among all patients presenting with a DSP phenotype was estimated to be 0.34%. DISCUSSION: Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype, and electrodiagnostic testing rarely identifies treatable demyelinating neuropathies in patients who present with a DSP phenotype.

Long-Term Survival Rates and Treatment Trends of Burkitt Lymphoma in Patients with HIV-A National Cancer Database (NCDB) Study.

BACKGROUND: Burkitt lymphoma (BL) accounts for 10-35% of AIDS-defining lymphoma in people with HIV (PWH). Previous research consisting of smaller cohorts has shown decreased survival for HIV-associated BL. This study aims to compare overall mortality in BL patients with and without HIV, while investigating impact of treatment modalities in HIV-associated BL. METHODS: Using the 2004-2019 NCDB, we identified 4312 patients with stage 3 or 4 BL who had a known HIV status and received either chemotherapy alone or chemotherapy and immunotherapy. Time to death was evaluated using Kaplan-Meier survival estimates. Risk of death was evaluated using an extended multivariable Cox model adjusted for multiple factors and with a Heaviside function for HIV status by time period (0-3 month vs. 3-60 month). RESULTS: Of the 4312 patients included, 1514 (35%) had HIV. For months 0-3 from time of diagnosis, HIV status was not associated with a statistically significant increase in risk of death (HR = 1.04, 95% CI: 0.86, 1.26, p = 0.6648). From month 3to 60, positive HIV status was associated with a 55% increase in risk of death compared to those without HIV (95% CI: 1.38, 1.75, p < 0.0001). Further, this difference in hazard rates (0-3 vs. 3-60) was statistically significant (HR = 1.49, 95% CI: 1.22-1.82, p < 0.001). CONCLUSIONS: There is an increased mortality rate from months 3 to 60 in BL patients with HIV compared to patients without HIV. Additionally, risk of death in the first 3 months is significantly decreased by 45% in patients with HIV treated with combination chemotherapy and immunotherapy compared to patients without HIV receiving combination chemotherapy and immunotherapy, providing valuable clinical insight into treatment decision making in the care of HIV-associated BL.

Sports Participation and Neurological Injuries in Pediatric Patients With Chiari I Malformation.

BACKGROUND: Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with Chiari I malformation (CM-I). OBJECTIVE: To prospectively survey the treated and untreated patients with CM-I to define the risk of sports-associated neurological injury. METHODS: A prospective survey was administered to 744 pediatric patients at one neurosurgery clinic between 2010 and 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurological injury. Patients with incomplete data were called. Two hundred seven patients completed at least 1 subsequent survey and were prospectively followed (mean 1.6 years). RESULTS: Of 744 patients with completed surveys, 462 participated in sports. Sports participants were more likely to be older at presentation ( P < .001) and have rounded cerebellar tonsil morphology ( P < .001). Seasons of sports played before and after CM-I decompression (CMD) totaled 5918.7 and 936, respectively. There were 84 sports-related concussions among 55 patients; 79 in untreated patients and 5 after CMD. For all sports participants, the concussion rate was 12.3/1000 seasons of all sports, 9.2/1000 seasons of limited-contact sports, and 13.8/1000 of contact sports. The concussion rate after CMD was 5.3/1000 seasons of all sports, 9.2/1000 seasons of limited-contact sports, and 7.1/1000 seasons of contact sports. There were no reports of long-lasting neurological issues postconcussion or of permanent spinal cord injury. CONCLUSION: No permanent or catastrophic sports-associated neurological injuries were reported. The concussion rates in treated and untreated patients with CM-I were low. Therefore, sports participation in this population should be permitted in most cases.

The impact of misplaced percutaneous iliac dynamic reference frame pins used during navigated spine surgery: incidence and outcomes.

OBJECTIVE: Image guidance requires placement of a dynamic reference frame (DRF), often either onto local spinous process or by freehand intraosseous DRF placement into the ilium via the posterior superior iliac spine (PSIS). There is a paucity of studies in the literature that describe the complications of intraosseous DRF placement. The aim of this study was to describe the radiographic location, prevalence and nature of complications, and long-term clinical outcomes of attempted DRF placement into the PSIS. METHODS: All lumbosacral spine surgical procedures performed between August 2019 and February 2021 at a single institution were queried, and operations in which a DRF was targeted to the PSIS were included. Patient demographic characteristics, indications for surgery, surgical outcomes, and complications were extracted. Intraoperative CT scans were reviewed by 2 independent researchers to determine the accuracy of DRF placement into the PSIS and to assess for DRF malposition. RESULTS: Of 497 lumbar spine operations performed between August 2019 and February 2021 by 4 surgeons, 85 utilized intraoperative navigation with a PSIS pin. Thirteen operations were excluded due to an inability to visualize the entirety of the pin on intraoperative CT. Of 72 DRFs evaluated, 77.8% had been correctly placed in the PSIS. Of the 22.2% of DRFs not placed into the PSIS, 11 entered the sacrum, 6 crossed the sacroiliac joint, and 2 were deep enough to enter the pelvis. Pain at the pin site was present in 4 patients, of whom 3 had resolution of pain at the last follow-up evaluation. There were no significant complications due to DRF placement: no sacral fractures, significant navigation errors, retroperitoneal hematomas, or neurological deficits. Over a mean ± SD follow-up period of 9 ± 5.2 months, there were no incidences of pin site infection. Interrater reliability between the reviewers was 95.8%. CONCLUSIONS: This was the first study to examine radiological and clinical outcomes after DRF placement in the PSIS. In this study, a majority of pins were correctly placed within the PSIS, although 22.2% of pins were malpositioned. There were no serious complications, and a majority of those patients with persistent pin site pain had resolution at last follow-up.

Subdural hematoma prevalence and long-term developmental outcomes in patients with benign expansion of the subarachnoid spaces.

OBJECTIVE: Benign expansion of the subarachnoid spaces (BESS) is a condition seen in macrocephalic infants. BESS is associated with mild developmental delays which tend to resolve within a few years. It is accepted that patients with BESS are at increased risk of spontaneous subdural hematomas (SDHs), although the exact pathophysiology is not well understood. The prevalence of spontaneous SDH in BESS patients is poorly defined, with only a few large single-center series published. In this study the authors aimed to better define BESS prevalence and developmental outcomes through the longitudinal review of a large cohort of BESS patients. METHODS: A large retrospective review was performed at a single institution from 1995 to 2020 for patients 2 years of age or younger with a diagnosis of BESS by neurology or neurosurgery and head circumference > 85th percentile. Demographic data, head circumference, presence of developmental delay, occurrence of SDH, and need for surgery were extracted from patient charts. The subarachnoid space (SAS) size was measured from the available MR images, and the sizes of those who did and did not develop SDH were compared. RESULTS: Free text search revealed BESS mentioned within the medical records of 1410 of 2.6 million patients. After exclusion criteria, 480 patients remained eligible for the study. Thirty-two percent (n = 154) of patients were diagnosed with developmental delay, most commonly gross motor delay (53%). Gross motor delay resolved in 86% of patients at a mean age of 22.2 months. The prevalence of spontaneous SDH in this BESS population over a period of 25 years was 8.1%. There was no significant association between SAS size and SDH formation. CONCLUSIONS: This study represents results for one of the largest cohorts of patients with BESS at a single institution. Gross motor delay was the most common developmental delay diagnosed, and a majority of patients had resolution of their delay. These data support that children with BESS have a higher prevalence of SDH than the general pediatric population, although SAS size was not significantly associated with SDH development.