Impact of Bleeding Risk and Inflammation on Cardiovascular Outcomes After Percutaneous Coronary Intervention.

BACKGROUND: Markers of systemic inflammation, such as high-sensitivity C-reactive protein (hsCRP), have been associated with the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). Whether this risk varies according to the presence of high bleeding risk (HBR) conditions is unclear. OBJECTIVES: The aim of this study was to evaluate the impact of systemic inflammation, as measured by hsCRP levels and cardiovascular outcomes in patients stratified by HBR status following PCI. METHODS: Consecutive patients undergoing PCI between 2012 and 2019 with baseline hsCRP levels were included. High hsCRP was defined as >3 mg/L, and HBR was defined per the Academic Research Consortium HBR criteria. The primary outcome was MACCE, including all-cause death, myocardial infarction, or stroke at 1 year. All bleeding was assessed as a secondary outcome. RESULTS: A total of 15,150 patients were included, and 40.4% (n = 6,125) qualified as HBR. The adjusted risk for MACCE was consistently higher in patients with high hsCRP in both HBR (adjusted HR [aHR]: 1.49; 95% CI: 1.18-1.87) and non-HBR (aHR: 1.87; 95% CI: 1.31-2.66) subgroups, with no interaction between HBR status and hsCRP level (Pinteraction = 0.26). Conversely, although bleeding risk was higher in the HBR cohort, hsCRP did not predict the occurrence of bleeding in either the HBR (aHR: 1.04; 95% CI: 0.82-1.31) or the non-HBR (aHR: 0.99; 95% CI: 0.71-1.39) subgroup (Pinteraction = 0.539). CONCLUSIONS: Elevated hsCRP at the time of PCI is associated with a higher risk for ischemic but not bleeding events, irrespective of HBR status.

Discontinuation and nonpublication of clinical trials in orthopaedic oncology.

BACKGROUND: Despite the pivotal role of clinical trials in advancing orthopaedic oncology knowledge and treatment strategies, the persistent issues of trial discontinuation and nonpublication are significant problems. This study conducted an analysis examining clinical trial discontinuation rates, associations between intervention types and discontinuation/nonpublication, and the role of funding, enrollment size, and their implications for trial success and completion. METHODS: This study, conducted on May 1, 2023, utilized a cross-sectional design to comprehensively analyze phase 3 and 4 randomized controlled trials within the realm of orthopaedic oncology. We specifically incorporated Phase 3 and 4 trials as they are designed to evaluate prolonged outcomes in human subjects and are more likely to reach publication. Study characteristics of interest included the intervention utilized in the clinical trial, presence of funding, whether the trial was published, completed, and trial enrollment size. The investigation involved an examination of ClinicalTrials.gov, a prominent online repository of clinical trial data managed by the National Library of Medicine of the USA. Descriptive statistics and multivariate logistic regressions were used to determine statistical significance. RESULTS: Among the cohort of 130 trials, 19.2% were prematurely discontinued. Completion rates varied based on intervention type; 111 pharmaceutical trials demonstrated a completion rate of 83.8%, whereas 19 non-pharmaceutical trials exhibited a completion rate of 8.0% (P < .001). Surgical trials, totaling 10, showed a completion rate of 90%. The overall trial publication rate was 86.15%, with pharmaceutical interventions achieving a publication rate of 91.96%. Larger-scale trials (≥ 261 participants) emerged as a protective factor against both discontinuation (Adjusted Odds Ratio [AOR]: 0.85, 95% Confidence Interval [CI] 0.42-0.95) and nonpublication (AOR: 0.19, 95% CI 0.13-.47), compared to smaller-scale trials. CONCLUSION: This study accentuates the heightened vulnerability of non-pharmaceutical interventions and trials exhibiting lower rates of enrollment to the issues of discontinuation and nonpublication. Moving forward, the advancement of clinical trials necessitates a concerted effort to enhance trial methodologies, especially concerning nonpharmaceutical interventions, along with a meticulous refinement of participant enrollment criteria.

Incomplete Intestinal Metaplasia of the Stomach Is more Related to Bile Reflux than Chronic Gastritis.

OBJECTIVE: Incomplete intestinal metaplasia (IIM) of the stomach is associated with higher risk of progression to dysplasia and gastric cancer than complete intestinal metaplasia (CIM). Whether the causative factors underlying IIM are different from those underlying CIM is currently unknown. In a recent study, bile acids were found to induce gastric intestinal metaplasia (IM) in mice by activating STAT3 signaling and accelerated the development of dysplasia. The aim of this study was to determine whether there are differences in associations between IIM and CIM and clinicopathologic features known to be associated with intestinal metaplasia, bile reflux, and activated STAT3. METHODS: Fifty-two consecutive gastric biopsies with IM were examined for the type of metaplasia, presence of inflammation, and Helicobacter pylori (H. pylori) status. Immunohistochemical staining was performed for phospho-STAT3 (p-STAT3) and evaluated by image analysis. The type of IM was then correlated with relevant clinicopathologic variables and p-STAT3 expression. RESULTS: Seven cases had IIM only, 31 had CIM only, and 14 had both CIM and IIM (CIIM). Significantly fewer cases with IIM had chronic gastritis than either CIM or CIIM (43%, 93%, 79%, respectively, p=0.005). H. pylori was not detected in any of the IIM cases but was positive in 29% of CIM and 29% of CIIM. Fifty-seven percent of patients with IIM had a history of cholecystectomy compared to 25% of those with CIM and 23% of those with CIIM. The mean BMI was 32.3 kg/m2 for patients with IIM compared to 28 kg/m2 for those with CIM and 31.2 kg/m2 for those with CIIM. Median p-STAT3 for biopsies with was IIM was 6.36 compared to 3.54 for CIM and 6.27 for CIIM. Reactive gastropathy was present in 57% of biopsies with IIM, 39% of CIM and 50% of CIIM. CONCLUSION: In contrast to CIM, IIM is significantly less likely to be associated with chronic gastritis. CIIM also tended to be less associated with H. pylori infection and more associated with reactive gastropathy, history of cholecystectomy, higher BMI, and higher median p-STAT3. These results tend to suggest that IIM is probably more likely to be associated with bile reflux than H. pylori-associated gastritis. Larger studies are needed to confirm these findings.Presented in part at Digestive Disease Week 2023, Chicago, IL, May 6, 2023.

Proximal Junctional Kyphosis and Failure: Strategies for Prevention.

Proximal junctional kyphosis (PJK) and proximal junctional failure/fractures (PJF) are common complications following long-segment posterior instrumented fusions for adult spinal deformity. As progression to PJF involves clinical consequences for patients and requires costly revisions that may undermine the utility of surgery and are ultimately unsustainable for health care systems, preventative strategies to minimize the occurrence of PJF are of tremendous importance. In this article, the authors present a detailed outline of PJK and PJF with a focus on surgical strategies aimed at preventing their occurrence..

Degenerative lumbar spondylolisthesis: review of current classifications and proposal of a novel classification system.

PURPOSE: To review existing classification systems for degenerative spondylolisthesis (DS), propose a novel classification designed to better address clinically relevant radiographic and clinical features of disease, and determine the inter- and intraobserver reliability of this new system for classifying DS. METHODS: The proposed classification system includes four components: 1) segmental dynamic instability, 2) location of spinal stenosis, 3) sagittal alignment, and 4) primary clinical presentation. To establish the reliability of this system, 12 observers graded 10 premarked test cases twice each. Kappa values were calculated to assess the inter- and intraobserver reliability for each of the four components separately. RESULTS: Interobserver reliability for dynamic instability, location of stenosis, sagittal alignment, and clinical presentation was 0.94, 0.80, 0.87, and 1.00, respectively. Intraobserver reliability for dynamic instability, location of stenosis, sagittal alignment, and clinical presentation were 0.91, 0.88, 0.87, and 0.97, respectively. CONCLUSION: The UCSF DS classification system provides a novel framework for assessing DS based on radiographic and clinical parameters with established implications for surgical treatment. The almost perfect interobserver and intraobserver reliability observed for all components of this system demonstrates that it is simple and easy to use. In clinical practice, this classification may allow subclassification of similar patients into groups that may benefit from distinct treatment strategies, leading to the development of algorithms to help guide selection of an optimal surgical approach. Future work will focus on the clinical validation of this system, with the goal of providing for more evidence-based, standardized approaches to treatment and improved outcomes for patients with DS.

Impact of Clinical Presentation on Outcomes After Rotational Atherectomy in Patients Who Underwent Percutaneous Coronary Intervention.

Rotational atherectomy (RA) is widely used in the percutaneous treatment of heavily calcified coronary artery lesions in patients with chronic coronary syndromes (CCS). However, the safety and efficacy of RA in acute coronary syndrome (ACS) is not well established and is considered a relative contraindication. Therefore, we sought to evaluate the efficacy and safety of RA in patients presenting with non-ST-elevation myocardial infarction (NSTEMI), unstable angina (UA), and CCS. Consecutive patients who underwent percutaneous coronary intervention with RA between 2012 and 2019 at a tertiary single center were included. Patients presenting with ST-elevation myocardial infarction (MI) were excluded. The primary end points of interest were procedural success and procedural complications. The secondary end point was the risk of death or MI at 1 year. A total of 2,122 patients who underwent RA were included, of whom 1,271 presented with a CCS (59.9%), 632 presented with UA (29.8%), and 219 presented with NSTEMI (10.3%). Although an increased rate of slow-flow/no-reflow was noted in the UA population (p = 0.03), no significant difference in procedural success or procedural complications, including coronary dissection, perforation, or side-branch closure, was noted (p = NS). At 1 year, there were no significant differences in death or MI between CCS and non-ST-elevation ACS (NSTE-ACS: UA + NSTEMI; adjusted hazard ratio 1.39, 95% confidence interval 0.91 to 2.12); however, patients who presented with NSTEMI had a higher risk of death or MI than CCS (adjusted hazard ratio 1.79, 95% confidence interval 1.01 to 3.17). Use of RA in NSTE-ACS was associated with similar procedural success without an increased risk of procedural complications compared with patients with CCS. Although patients presenting with NSTEMI remained at higher risk of long-term adverse events, RA appears to be safe and feasible in patients with heavily calcified coronary lesions presenting with NSTE-ACS.

Navigated Hybrid Open/Muscle-sparing Approach to 2-level Cement Augmentation of the UIV and UIV+1 for Prevention of Proximal Junctional Failure: Supplemental Manuscript to Operative Video.

STUDY DESIGN: Operative video and supplemental manuscript. OBJECTIVE: To present a cement augmentation technique of the upper instrumented vertebra (UIV) and UIV+1 for prevention of proximal junctional fractures (PJFs) in multi-level thoracolumbar posterior instrumented fusions. SUMMARY OF BACKGROUND DATA: PJFs are unfortunately a common occurrence after multi-level thoracolumbar instrumented fusions to the pelvis for adult spinal deformity that can result in significant functional disability and often require costly revision operations. As such, their prevention is key. METHODS: A surgical video illustrates the nuances of a 2-level cement augmentation technique, consisting of an open vertebroplasty of the UIV through fenestrated screws and a muscle-sparing kyphoplasty of the UIV+1. RESULTS: Utility of performing an open vertebroplasty of the UIV through fenestrated screws and muscle-sparing kyphoplasty of the UIV+1 lies in its ability to minimize soft-tissue disruption at the adjacent segment while providing additional structural support to the anterior column at this high-risk zone. CONCLUSIONS: Cement augmentation of the UIV and UIV+1 consisting of a hybrid open vertebroplasty and muscle-sparing kyphoplasty can be an effective strategy to decrease the incidence of PJF after multi-level posterior thoracolumbar instrumented fusions to the pelvis for adult spinal deformity.

Predictive models to assess risk of extended length of stay in adults with spinal deformity and lumbar degenerative pathology: development and internal validation.

BACKGROUND CONTEXT: Postoperative recovery after adult spinal deformity (ASD) operations is arduous, fraught with complications, and often requires extended hospital stays. A need exists for a method to rapidly predict patients at risk for extended length of stay (eLOS) in the preoperative setting. PURPOSE: To develop a machine learning model to preoperatively estimate the likelihood of eLOS following elective multi-level lumbar/thoracolumbar spinal instrumented fusions (≥3 segments) for ASD. STUDY DESIGN/SETTING: Retrospectively from a state-level inpatient database hosted by the Health care cost and Utilization Project. PATIENT SAMPLE: Of 8,866 patients of age ≥50 with ASD undergoing elective lumbar or thoracolumbar multilevel instrumented fusions. OUTCOME MEASURES: The primary outcome was eLOS (>7 days). METHODS: Predictive variables consisted of demographics, comorbidities, and operative information. Significant variables from univariate and multivariate analyses were used to develop a logistic regression-based predictive model that use six predictors. Model accuracy was assessed through area under the curve (AUC), sensitivity, and specificity. RESULTS: Of 8,866 patients met inclusion criteria. A saturated logistic model with all significant variables from multivariate analysis was developed (AUC=0.77), followed by generation of a simplified logistic model through stepwise logistic regression (AUC=0.76). Peak AUC was reached with inclusion of six selected predictors (combined anterior and posterior approach, surgery to both lumbar and thoracic regions, ≥8 level fusion, malnutrition, congestive heart failure, and academic institution). A cutoff of 0.18 for eLOS yielded a sensitivity of 77% and specificity of 68%. CONCLUSIONS: This predictive model can facilitate identification of adults at risk for eLOS following elective multilevel lumbar/thoracolumbar spinal instrumented fusions for ASD. With a fair diagnostic accuracy, the predictive calculator will ideally enable clinicians to improve preoperative planning, guide patient expectations, enable optimization of modifiable risk factors, facilitate appropriate discharge planning, stratify financial risk, and accurately identify patients who may represent high-cost outliers. Future prospective studies that validate this risk assessment tool on external datasets would be valuable.

Preoperative medical assessment for adult spinal deformity surgery: a state-of-the-art review.

INTRODUCTION: The purpose of this study is to provide a state-of-the-art review regarding risk factors for perioperative complications in adult spinal deformity (ASD) surgery. The review includes levels of evidence for risk factors associated with complications in ASD surgery. METHODS: Using the PubMed database, we searched for complications, risk factors, and adult spinal deformity. The included publications were assessed for level of evidence as described in clinical practice guidelines published by the North American Spine Society, with summary statements generated for each risk factor (Bono et al. in Spine J 9:1046-1051, 2009). RESULTS: Frailty had good evidence (Grade A) as a risk for complications in ASD patients. Fair evidence (Grade B) was assigned for bone quality, smoking, hyperglycemia and diabetes, nutritional status, immunosuppression/steroid use, cardiovascular disease, pulmonary disease, and renal disease. Indeterminate evidence (Grade I) was assigned for pre-operative cognitive function, mental health, social support, and opioid utilization. CONCLUSIONS: Identification of risk factors for perioperative complications in ASD surgery is a priority for empowering informed choices for patients and surgeons and managing patient expectations. Risk factors with grade A and B evidence should be identified prior to elective surgery and modified to reduce the risk of perioperative complications.

Development and internal validation of predictive models to assess risk of post-acute care facility discharge in adults undergoing multi-level instrumented fusions for lumbar degenerative pathology and spinal deformity.

PURPOSE: To develop a model for factors predictive of Post-Acute Care Facility (PACF) discharge in adult patients undergoing elective multi-level (≥ 3 segments) lumbar/thoracolumbar spinal instrumented fusions. METHODS: The State Inpatient Databases acquired from the Healthcare Cost and Utilization Project from 2005 to 2013 were queried for adult patients who underwent elective multi-level thoracolumbar fusions for spinal deformity. Outcome variables were classified as discharge to home or PACF. Predictive variables included demographic, pre-operative, and operative factors. Univariate and multivariate logistic regression analyses informed development of a logistic regression-based predictive model using seven selected variables. Performance metrics included area under the curve (AUC), sensitivity, and specificity. RESULTS: Included for analysis were 8866 patients. The logistic model including significant variables from multivariate analysis yielded an AUC of 0.75. Stepwise logistic regression was used to simplify the model and assess number of variables needed to reach peak AUC, which included seven selected predictors (insurance, interspaces fused, gender, age, surgical region, CCI, and revision surgery) and had an AUC of 0.74. Model cut-off for predictive PACF discharge was 0.41, yielding a sensitivity of 75% and specificity of 59%. CONCLUSIONS: The seven variables associated significantly with PACF discharge (age > 60, female gender, non-private insurance, primary operations, instrumented fusion involving 8+ interspaces, thoracolumbar region, and higher CCI scores) may aid in identification of adults at risk for discharge to a PACF following elective multi-level lumbar/thoracolumbar spinal fusions for spinal deformity. This may in turn inform discharge planning and expectation management.

Risk factors for extended length of stay and non-home discharge in adults treated with multi-level fusion for lumbar degenerative pathology and deformity.

PURPOSE: To identify independent risk factors, including the Risk Assessment and Prediction Tool (RAPT) score, associated with extended length of stay (eLOS) and non-home discharge following elective multi-level instrumented spine fusion operations for diagnosis of adult spinal deformity (ASD) and lumbar degenerative pathology. METHODS: Adults who underwent multi-level ([Formula: see text] segments) instrumented spine fusions for ASD and lumbar degenerative pathology at a single institution (2016-2021) were reviewed. Presence of a pre-operative RAPT score was used as an inclusion criterion. Excluded were patients who underwent non-elective operations, revisions, operations for trauma, malignancy, and/or infections. Outcomes were eLOS (> 7 days) and discharge location (home vs. non-home). Predictor variables included demographics, comorbidities, operative information, Surgical Invasiveness Index (SII), and RAPT score. Fisher's exact test was used for univariate analysis, and significant variables were implemented in multivariate binary logistic regression, with generation of 95% percent confidence intervals (CI), odds ratios (OR), and p-values. RESULTS: Included for analysis were 355 patients. Post-operatively, 36.6% (n = 130) had eLOS and 53.2% (n = 189) had a non-home discharge. Risk factors significant for a non-home discharge were older age (> 70 years), SII > 36, pre-op RAPT < 10, DMII, diagnosis of depression or anxiety, and eLOS. Risk factors significant for an eLOS were SII > 20, RAPT < 6, and an ASA score of 3. CONCLUSION: The RAPT score and SII were most important significant predictors of eLOS and non-home discharges following multi-level instrumented fusions for lumbar spinal pathology and deformity. Preoperative optimization of the RAPT's individual components may provide a useful strategy for decreasing LOS and modifying discharge disposition.

Predictive Models for Length of Stay and Discharge Disposition in Elective Spine Surgery: Development, Validation, and Comparison to the ACS NSQIP Risk Calculator.

STUDY DESIGN: A retrospective study at a single academic institution. OBJECTIVE: The purpose of this study is to utilize machine learning to predict hospital length of stay (LOS) and discharge disposition following adult elective spine surgery, and to compare performance metrics of machine learning models to the American College of Surgeon's National Surgical Quality Improvement Program's (ACS NSQIP) prediction calculator. SUMMARY OF BACKGROUND DATA: A total of 3678 adult patients undergoing elective spine surgery between 2014 and 2019, acquired from the electronic health record. METHODS: Patients were divided into three stratified cohorts: cervical degenerative, lumbar degenerative, and adult spinal deformity groups. Predictive variables included demographics, body mass index, surgical region, surgical invasiveness, surgical approach, and comorbidities. Regression, classification trees, and least absolute shrinkage and selection operator (LASSO) were used to build predictive models. Validation of the models was conducted on 16% of patients (N=587), using area under the receiver operator curve (AUROC), sensitivity, specificity, and correlation. Patient data were manually entered into the ACS NSQIP online risk calculator to compare performance. Outcome variables were discharge disposition (home vs. rehabilitation) and LOS (days). RESULTS: Of 3678 patients analyzed, 51.4% were male (n=1890) and 48.6% were female (n=1788). The average LOS was 3.66 days. In all, 78% were discharged home and 22% discharged to rehabilitation. Compared with NSQIP (Pearson R2 =0.16), the predictions of poisson regression ( R2 =0.29) and LASSO ( R2 =0.29) models were significantly more correlated with observed LOS ( P =0.025 and 0.004, respectively). Of the models generated to predict discharge location, logistic regression yielded an AUROC of 0.79, which was statistically equivalent to the AUROC of 0.75 for NSQIP ( P =0.135). CONCLUSION: The predictive models developed in this study can enable accurate preoperative estimation of LOS and risk of rehabilitation discharge for adult patients undergoing elective spine surgery. The demonstrated models exhibited better performance than NSQIP for prediction of LOS and equivalent performance to NSQIP for prediction of discharge location.

Challenges and Complications in Freehand S2-Alar-Iliac Spinopelvic Fixation and the Potential for Robotics to Enhance Patient Safety.

STUDY DESIGN: Narrative Summary Review for Navigation & Robotics Focus Issue. OBJECTIVE: To discuss the challenges and complications of S2-Alar-Iliac (S2AI) spinopelvic fixation using freehand techniques, and to introduce the utility of navigation & robotics to enhance patient safety. METHODS: This study involved search of literature using the PubMed database, including retrospective clinical studies, anatomic reports, and surgical reports. The intention was to find literature that discussed complications regarding screw malfunction from manual S2AI placement, anatomical complexity of the sacroiliac joint, and outcomes of S2AI procedures conducted with robotic guidance systems. RESULTS: The sacroiliac joint presents numerous complexities that can lead to challenges in free-hand placement of the S2-alar-iliac screw. Anatomic considerations of the S2AI screw involve close proximity to vital neurovascular structures, including: superior gluteal vessels, external iliac vessels, pudendal vessels, superior gluteal nerves, sciatic nerve, sympathetic chain ganglia, and pudendal nerves. The complications associated with manual S2AI screw installation include screw misplacement, breach of cortical bone, and injury to neurovascular structures. Robotic techniques for establishing S2AI screws involve greater accuracy of screw placement and reduced complications. CONCLUSIONS: Accurate placement of S2AI screws is compromised by variation in pelvic anatomy and by a pathway that traverses dense cortical bone of the sacroiliac joint. Accurate placement of S2AI screws is important for patient safety regarding neurovascular structures, and for effective, stable fixation across the SI joint. Robotic navigation of S2AI fixation offers significant utility in improving the accuracy of screw placement and patient safety.

Transcatheter Mitral Valve Repair for Severe,Symptomatic Mitral Regurgitation in Patients with Left Ventricular Assist Devices.

Patients with symptomatic stage D heart failure who require left ventricular assist device (LVAD) support and suffer concomitant severe mitral regurgitation are often difficult to manage. One reason is due to cardiac anatomic constraints that limit optimization of the mechanical assist device. Typically, these patients are not candidates for repeat sternotomy with surgical mitral valve repair, and heart transplantation may not be feasible or timely. This case describes two patients with LVAD support who received transcatheter edge-to-edge mitral valve repair for severe, symptomatic mitral regurgitation. We believe this procedure may be a therapeutic option in stable patients with severe mitral regurgitation who require mechanical support.

Downregulation of Estrogen Receptor Beta1 Expression in Sessile Serrated Adenomas.

OBJECTIVE: CpG island methylator phenotype (CIMP)-positive colorectal cancers (CRC) and CRC with microsatellite instability (MSI) were reported to have a decreased expression of estrogen receptor, beta1 (ER-ß1), and methylation accompanied by decreased expression for the caudal-related homeobox, transcription factor 2 (CDX2). While precursor lesions of these cancers, known as sessile serrated adenomas (SSA), were found to have decreased CDX2 expression, the status of ER-ß1 expression in SSA is unknown. The aim of this study is to determine ER-ß1 expression in SSA and its relation to CDX2 expression. METHODS: Sections of formalin fixed and paraffin embedded tissue from 62 consecutive cases of SSA were stained by immunohistochemistry for ER-ß1 and CDX2. SSA with ER-ß1 or CDX2 expression similar to that of a normal colon were scored as 0, while those with a loss of expression in <10% of SSA crypts as 1, 11-25% as 2, 26-50% as 3, 51-75% as 4, and CDX2 loss in >75% of the SSA crypts scored as 5. RESULTS: There is a significant correlation between a loss of CDX2 and the loss of ER-ß1 scores in SSA (p<0.001). The downregulation of CDX2 was greater in SSA arising from the right colon compared to the left colon and rectum (p=0.012). Similarly, downregulation of ER-ß1 was greater in SSA arising in the right colon compared to the left colon and rectum (p=0.014). CONCLUSIONS: Our findings show significant downregulation of both ER-ß1 and CDX2 expression in SSA, especially in the right colon. These findings suggest that ER-ß1 downregulation plays a significant role in the malignant progression of SSA.

TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1). SINE compounds modestly extend cellular survival in neuronal ALS/FTD models and mitigate motor symptoms in an in vivo rat ALS model. At high doses, SINE compounds block nuclear egress of an XPO1 cargo reporter, but not at lower concentrations that were associated with neuroprotection. Neither SINE compounds nor leptomycin B, a separate XPO1 inhibitor, enhanced nuclear TDP43 levels, while depletion of XPO1 or other exportins had little effect on TDP43 localization, suggesting that no single exporter is necessary for TDP43 export. Supporting this hypothesis, we find overexpression of XPO1, XPO7 and NXF1 are each sufficient to promote nuclear TDP43 egress. Taken together, our results indicate that redundant pathways regulate TDP43 nuclear export, and that therapeutic prevention of cytoplasmic TDP43 accumulation in ALS/FTD may be enhanced by targeting several overlapping mechanisms.