Expansion of Human Regulatory T-Cells From Patients With Type 1 Diabetes

OBJECTIVE—Regulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells—a need forming the basis for these studies

Big Data in the Clinical Neurosciences

The clinical neurosciences have historically been at the forefront of innovation, often incorporating the newest research methods into practice. This chapter will explore the adoption, implementation, and refinement of big data and predictive modeling using machine learning within neurosurgery. Initial development of national databases arose from surgeons aiming to improve outcome predictions for patients with traumatic brain injury in the 1960s. In the following decades, other surgical specialties began building databases that left a lasting impact on the current national neurosurgical databases, particularly in spine surgery. Significant contributions to the literature have been made as a result of the numerous registries today, leading to broad quality improvements for neurosurgical patients. Important limitations of large databases do exist, including lack of standardized reporting and challenges in data extraction from medical records. New vistas will include the use of metadata to track human function, performance, and pain in a real-time manner to augment the reliance on traditional patient-reported outcome measures (PROMs). Overall, big data has demonstrated significant utility within neurosurgical research and machine learning-powered analyses have highlighted several promising areas of interest for future exploration

The Value of a Synthetic Model-based Training Lab to Increase Proficiency with Endoscopic Approaches to the Spine

Introduction: The learning curve associated with endoscopic approaches to the spine is well established. In this study, we present our endoscopic training methodology and discuss the concepts and rationale of laboratory training as it relates to improving comfort and skill with endoscopic techniques. Materials and Methods: A three-part endoscopic training laboratory for neurosurgical trainees and attendings was organized at the University of Miami, which included a lecture, instrumentation demonstration, and both synthetic model and cadaveric practice sessions. Participants completed pre- and post-lab surveys gauging their comfort and competency in the transforaminal approach to the lumbar spine. Results: There were a total of 22 participants, with eight completing the pre-lab survey and 10 completing the post-lab survey. Sixteen participants engaged in the lab practical, with six of these participants performing the transforaminal approach on both the model and the cadaver. An increase in comfort level was demonstrated on the post-lab survey (5.9/10) for the transforaminal approach as compared to the pre-lab survey (2.6/10). Additionally, participants found the training model to be an effective teaching aid for the transforaminal technique (8.8/10). Conclusions: We believe that our study demonstrates the utility of simulated model-based training for gaining comfort and proficiency with endoscopic approaches to the spine and introduces a safe, cost-effective method of educating practitioners on novel endoscopic approaches

Expansion of human regulatory T-cells from patients with type 1 diabetes.

ObjectiveRegulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells-a need forming the basis for these studies.Research design and methodsTregs from recent-onset type 1 diabetic patients and healthy control subjects were isolated by fluorescence-activated cell sorting and compared for their capacity to expand in vitro in response to anti-CD3-anti-CD28-coated microbeads and IL-2. Expanded cells were examined for suppressive function, lineage markers and FOXP3, and cytokine production.ResultsBoth CD4+CD127(lo/-) and CD4+CD127(lo/-)CD25+ T-cells could be expanded and used as Tregs. However, expansion of CD4+CD127(lo/-) cells required the addition of rapamycin to maintain lineage purity. In contrast, expansion of CD4+CD127(lo/-)CD25+ T-cells, especially the CD45RA+ subset, resulted in high yield, functional Tregs that maintained higher FOXP3 expression in the absence of rapamycin. Tregs from type 1 diabetic patients and control subjects expanded similarly and were equally capable of suppressing T-cell proliferation. Regulatory cytokines were produced by Tregs after culture; however, a portion of FOXP3+ cells were capable of producing interferon (IFN)-gamma after reactivation. IFN-gamma production was observed from both CD45RO+ and CD45RA+ Treg populations.ConclusionsThe results support the feasibility of isolating Tregs for in vitro expansion. Based on expansion capacity, FOXP3 stability, and functional properties, the CD4+CD127(lo/-)CD25+ T-cells represent a viable cell population for cellular therapy in this autoimmune disease

Surgical Management of Thoracolumbar Adjacent Segment Disease: Techniques and Outcomes in 107 Patients Undergoing Surgical Intervention

Adjacent segment disease (ASD) is a known sequela of thoracolumbar instrumented fusions. Various surgical options are available to address ASD in patients with intractable symptoms who have failed conservative measures. However, the optimal treatment strategy for symptomatic ASD has not been established. We examined several clinical outcomes utilizing different surgical interventions for symptomatic ASD. A retrospective review was performed for a consecutive series of patients undergoing revision surgery for thoracolumbar ASD between October 2011 and February 2022. Patients were treated with endoscopic decompression ( = 17), microdiscectomy ( = 9), lateral lumbar interbody fusion (LLIF; = 26), or open laminectomy and fusion (LF; = 55). The primary outcomes compared between groups were re-operation rates and numeric pain scores for leg and back at 2 weeks, 10 weeks, 6 months, and 12 months postoperation. Secondary outcomes included time to re-operation, estimated blood loss, and length of stay. Of the 257 patients who underwent revision surgery for symptomatic ASD, 107 patients met inclusion criteria with a minimum of 1-year follow-up. The mean age of all patients was 67.90 ± 10.51 years. There was no statistically significant difference between groups in age, gender, preoperative American Society of Anesthesiologists scoring, number of previously fused levels, or preoperative numeric leg and back pain scores. The re-operation rates were significantly lower in LF (12.7%) and LLIF cohorts (19.2%) compared with microdiscectomy (33%) and endoscopic decompression (52.9%; = 0.005). Only LF and LLIF cohorts experienced significantly decreased pain scores at all 4 follow-up visits (2 weeks, 10 weeks, 6 months, and 12 months; < 0.001 and < 0.05, respectively) relative to preoperative scores. Symptomatic ASD often requires treatment with revision surgery. Fusion surgeries (either stand-alone lateral interbody or posterolateral with instrumentation) were most effective and durable with respect to alleviating pain and avoiding additional revisions within the first 12 months following revision surgery. This study emphasizes the importance of risk-stratifying patients to identify the least invasive approach that treats their symptoms and reduces the risk of future surgeries

Dual-Sized Microparticle System for Generating Suppressive Dendritic Cells Prevents and Reverses Type 1 Diabetes in the Nonobese Diabetic Mouse Model

Antigen specificity is a primary goal in developing curative therapies for autoimmune disease. Dendritic cells (DCs), as the most effective antigen presenting cells in the body, represent a key target to mediate restoration of antigen-specific immune regulation. Here, we describe an injectable, dual-sized microparticle (MP) approach that employs phagocytosable ∼1 μm and nonphagocytosable ∼30 μm MPs to deliver tolerance-promoting factors both intracellularly and extracellularly, as well as the type 1 diabetes autoantigen, insulin, to DCs for reprogramming of immune responses and remediation of autoimmunity. This poly(lactic-co-glycolic acid) (PLGA) MP system prevented diabetes onset in 60% of nonobese diabetic (NOD) mice when administered subcutaneously in 8 week old mice. Prevention of disease was dependent upon antigen inclusion and required encapsulation of factors in MPs. Moreover, administration of this "suppressive-vaccine" boosted pancreatic lymph node and splenic regulatory T cells (Tregs), upregulated PD-1 on CD4+ and CD8+ T cells, and reversed hyperglycemia for up to 100 days in recent-onset NOD mice. Our results demonstrate that a MP-based platform can reeducate the immune system in an antigen-specific manner, augment immunomodulation compared to soluble administration of drugs, and provide a promising alternative to systemic immunosuppression for autoimmunity

Minimally Invasive Spinal Deformity Surgery: Analysis of Patients Who Fail to Reach Minimal Clinically Important Difference.

BACKGROUND: It is well known that clinical improvements following surgical intervention are variable. While all surgeons strive to maximize reliability and degree of improvement, certain patients will fail to achieve meaningful gains. We aim to analyze patients who failed to reach minimal clinically important difference (MCID) in an effort to improve outcomes for minimally invasive deformity surgery. METHODS: Data were collected on a multicenter registry of minimally invasive surgery adult spinal deformity surgeries. Patient inclusion criteria were age ≥18 years, coronal Cobb ≥20 degrees, pelvic incidence-lumbar lordosis ≥10 degrees, or a sagittal vertical axis \u3e5 cm. All patients had minimum 2 years\u27 follow-up (N = 222). MCID was defined as 12.8 or more points of improvement in the Oswestry Disability Index. Up to 2 different etiologies for failure were allowed per patient. RESULTS: We identified 78 cases (35%) where the patient failed to achieve MCID at long-term follow-up. A total of 82 identifiable causes were seen in these patients with 14 patients having multiple causes. In 6 patients, the etiology was unclear. The causes were subclassified as neurologic, medical, structural, under treatment, degenerative progression, traumatic, idiopathic, and floor effects. In 71% of cases, an identifiable cause was related to the spine, whereas in 35% the cause was not related to the spine. CONCLUSIONS: Definable causes of failed MIS ASD surgery are often identifiable and similar to open surgery. In some cases the cause is treatable and structural. However, it is also common to see failure due to pathologies unrelated to the index surgery