An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission.

Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression. AAV-associated dendritic loss is accompanied by a decrease in the frequency and amplitude of miniature excitatory postsynaptic currents and an increase in the proportion of GluA2-lacking, calcium-permeable AMPA receptors. The AAV genome is rich in unmethylated CpG DNA, which is recognized by the innate immunoreceptor Toll-like receptor 9 (TLR9), and acutely blocking TLR9 preserves dendritic complexity and AMPA receptor subunit composition in AAV-injected mice. These results reveal unexpected impacts of an immune response to the AAV genome on neuronal structure and function and identify approaches to improve the safety and efficacy of AAV-mediated gene delivery in the nervous system.

Disparities in postoperative complications and perioperative events based on insurance status following elective spine surgery: A systematic review and meta-analysis.

Background: Increasing evidence demonstrates disparities among patients with differing insurance statuses in the field of spine surgery. However, no pooled analyses have performed a robust review characterizing differences in postoperative outcomes among patients with varying insurance types. Methods: A comprehensive literature search of the PUBMED, MEDLINE(R), ERIC, and EMBASE was performed for studies comparing postoperative outcomes in patients with private insurance versus government insurance. Pooled incidence rates and odds ratios were calculated for each outcome and meta-analyses were conducted for 3 perioperative events and 2 types of complications. In addition to pooled analysis, sub-analyses were performed for each outcome in specific government payer statuses. Results: Thirty-eight studies (5,018,165 total patients) were included. Compared with patients with private insurance, patients with government insurance experienced greater risk of 90-day re-admission (OR 1.84, p<.0001), non-routine discharge (OR 4.40, p<.0001), extended LOS (OR 1.82, p<.0001), any postoperative complication (OR 1.61, p<.0001), and any medical complication (OR 1.93, p<.0001). These differences persisted across outcomes in sub-analyses comparing Medicare or Medicaid to private insurance. Similarly, across all examined outcomes, Medicare patients had a higher risk of experiencing an adverse event compared with non-Medicare patients. Compared with Medicaid patients, Medicare patients were only more likely to experience non-routine discharge (OR 2.68, p=.0007). Conclusions: Patients with government insurance experience greater likelihood of morbidity across several perioperative outcomes. Additionally, Medicare patients fare worse than non-Medicare patients across outcomes, potentially due to age-based discrimination. Based on these results, it is clear that directed measures should be taken to ensure that underinsured patients receive equal access to resources and quality care.

Comparison of the Safety of Inpatient Versus Outpatient Lumbar Fusion : A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic Review and Meta-analysis. OBJECTIVE: The objective of this study is to synthesize the early data regarding and analyze the safety profile of outpatient lumbar fusion. SUMMARY OF BACKGROUND DATA: Performing lumbar fusion in an outpatient or ambulatory setting is becoming an increasingly employed strategy to provide effective value-based care. As this is an emerging option for surgeons to employ in their practices, the data is still in its infancy. METHODS: This study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies that described outcomes of inpatient and outpatient lumbar fusion cohorts were searched from PubMed, Medline, The Cochrane Library, and Embase. Rates of individual medical and surgical complications, readmission, and reoperation were collected when applicable. Patient-reported outcomes (PROMs) were additionally collected if reported. Individual pooled comparative meta-analysis was performed for outcomes of medical complications, surgical complications, readmission, and reoperation. PROMs were reviewed and qualitatively reported. RESULTS: The search yielded 14 publications that compared outpatient and inpatient cohorts with a total of 75,627 patients. Odds of readmission demonstrated no significant difference between outpatient and inpatient cohorts [OR=0.94 (0.81-1.11)]. Revision surgery similarly was no different between the cohorts [OR=0.81 (0.57-1.15)]. Pooled medical and surgical complications demonstrated significantly decreased odds for outpatient cohorts compared with inpatient cohorts [OR=0.58 (0.34-0.50), OR=0.41 (0.50-0.68), respectively]. PROM measures were largely the same between the cohorts when reported, with few studies showing better ODI and VAS Leg outcomes among outpatient cohorts compared with inpatient cohorts. CONCLUSION: Preliminary data regarding the safety of outpatient lumbar fusion demonstrates a favorable safety profile in appropriately selected patients, with PROMs remaining comparable in this setting. There is no data in the form of prospective and randomized trials which is necessary to definitively change practice.

Racial Differences in Perioperative Complications, Readmissions, and Mortalities After Elective Spine Surgery in the United States: A Systematic Review Using AI-Assisted Bibliometric Analysis.

STUDY DESIGN: Systematic Review and Meta-analysis. OBJECTIVES: To evaluate the impact of race on post-operative outcomes and complications following elective spine surgery in the United States. METHODS: PUBMED, MEDLINE(R), ERIC, EMBASE, and SCOPUS were searched for studies documenting peri-operative events for White and African American (AA) patients following elective spine surgery. Pooled odds ratios were calculated for each 90-day outcome and meta-analyses were performed for 4 peri-operative events and 7 complication categories. Sub-analyses were performed for each outcome on single institution (SI) studies and works that included <100,000 patients. RESULTS: 53 studies (5,589,069 patients, 9.8% AA) were included. Eleven included >100,000 patients. AA patients had increased rates of 90-day readmission (OR 1.33, P = .0001), non-routine discharge (OR 1.71, P = .0001), and mortality (OR 1.66, P = .0003), but not re-operation (OR 1.16, P = .1354). AA patients were more likely to have wound-related complications (OR 1.47, P = .0001) or medical complications (OR 1.35, P = .0006), specifically cardiovascular (OR 1.33, P = .0126), deep vein thrombosis/pulmonary embolism (DVT/PE) (OR 2.22, P = .0188) and genitourinary events (OR 1.17, P = .0343). SI studies could only detect racial differences in re-admissions and non-routine discharges. Studies with <100,000 patients replicated the above findings but found no differences in cardiovascular complications. Disparities in mortality were only detected when all studies were included. CONCLUSIONS: AA patients faced a greater risk of morbidity across several distinct categories of peri-operative events. SI studies can be underpowered to detect more granular complication types (genitourinary, DVT/PE). Rare events, such as mortality, require larger sample sizes to identify significant racial disparities.

Gender disparities in postoperative outcomes following elective spine surgery: a systematic review and meta-analysis.

OBJECTIVE: Several studies have described disparities between male and female patients following spine surgery, but no pooled analyses have performed a robust review characterizing differences in postoperative outcomes based on gender. The purpose of this study was to broadly assess the effects of gender on postoperative outcomes following elective spine surgery. METHODS: Between November 2022 and March 2023, PubMed, MEDLINE, ERIC, and Embase were queried using artificial intelligence-assisted software for relevant cohort studies. Cohort studies with a minimum sample of 100 patients conducted in the United States since 2010 were eligible. Studies related to trauma, tumors, infections, and spinal cord pathology were excluded. Independent extraction by multiple reviewers was performed using Nested Knowledge software. A fixed- or random-effects model was used if heterogeneity among included studies in a meta-analysis was < 50% or ≥ 50%, respectively. Risk of bias was assessed independently by multiple reviewers using the Newcastle-Ottawa Scale. Pooled effect sizes were calculated for readmission, nonroutine discharge (NRD), length of stay (LOS), extended LOS, reoperation, mortality, all medical complications (individual analyses for cardiovascular, deep venous thrombosis/pulmonary embolism, genitourinary, neurological, respiratory, and systemic infection complications), and wound-related complications. For each outcome, two subanalyses were performed with studies that used either center-based (single- or multi-institution) or high-volume (national or state-wide) databases. RESULTS: Across 124 included studies, male patients had an increased incidence of mortality (OR 0.54, p < 0.0001) and all medical complications (OR 0.80, p = 0.0114), specifically cardiovascular (OR 0.68, p < 0.0001) and respiratory (OR 0.76, p = 0.0008) complications. Female patients were more likely to experience a wound-related surgical complication (OR 1.16, p = 0.0183). These findings persisted in the high-volume database subanalyses. Only center-based subanalyses showed that female patients were at greater odds of experiencing an NRD (OR 1.18, p = 0.0476), longer LOS (SMD 0.23, p = 0.0036), and extended LOS (OR 1.28, p < 0.0001). CONCLUSIONS: Males are more likely to experience death and medical complications, whereas females were more likely to face wound-related surgical complications. At the institution level, females more often experience NRD and longer hospital stays. These findings may better inform preoperative expectation management and provide more detailed postoperative risk assessments based on the patient's gender.