Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Design of adaptive exponential functional link network based non-linear filters

by Vinal Patel, Vaibhav Gandhi, Shashank Heda and Nithin V. Georg

Anatomical positional changes in the lateral lumbar interbody fusion

INTRODUCTION: ALIFs and LLIFs are now becoming more utilized for adult spinal disease. As technologies advance, so do surgical techniques, with surgeons now modifying traditional supine-ALIF and lateral-LLIF to lateral-ALIF and prone-LLIF approaches to allow for more efficient surgeries. The objective of this study is to characterize the anatomical changes in the surgical corridor that occur with changes in patient positioning. METHODS: MRIs of ten healthy volunteers were evaluated in five positions: supine, prone with hips flexed, prone with hips extended, lateral with hips flexed, and lateral with hips extended. All lateral scans were in the left lateral decubitus position. The anatomical changes of the psoas muscles, inferior vena cava, aorta, iliac vessels were assessed with relation to fixed landmarks on the disc spaces from L1 to S1. RESULTS: The most anteriorly elongated ipsilateral to approach psoas when compared to supine was seen in lateral-flexed position (- 5.82 mm, p \u3c 0.001), followed by lateral-extended (- 2.23 mm, p \u3c 0.001), then prone-flexed (- 1.40 mm, p = 0.014), and finally supine and prone-extended (- 0.21 mm, p = 0.643). The most laterally extending or thickest psoas was seen in prone-flexed (- 1.40 mm, p = 0.004) and prone-extended (- 1.17 mm, p = 0.002). The psoas was thinnest in lateral-extended (2.03 mm, p \u3c 0.001) followed by lateral-flexed (1.11 mm, p = 0.239). The contralateral psoas did not move as anteriorly as the ipsilateral. 3D volumetric analysis showed that the greatest changes in the psoas occur at its proximal and distal poles near T12-L1 and L4-S1. In lateral-flexed compared to prone-extended, the IVC moves medially to the left (p \u3c 0.001). The aorta moves laterally to the left (p = 0.005). The venous structures appeared more full and open in the lateral positions and flattened in the supine and prone positions. The arteries remain in full calibre. CONCLUSION: The MRI anatomical evaluation shows that the psoas, and therefore lumbar plexus, and vasculature move significantly with changes in positioning. This is important for preoperative planning for proper intraoperative execution from preoperative supine MRI. Understanding that the psoas and vessels move the most anteriorly in the lateral-flexed position and to a least degree in the prone-extended is essential for safe and efficient utilization of techniques such as the traditional LLIF, traditional ALIF, prone-LLIF

Influence of Spinal Deformity Construct Design on Adjacent-Segment Biomechanics

BACKGROUND: Adjacent level degeneration is a precursor to construct failure in adult spinal deformity surgery, but whether construct design affects adjacent level degeneration risk remains unclear. Here we present a biomechanical profile of common deformity correction constructs and assess adjacent level biomechanics. METHODS: Standard nondestructive flexibility tests (7.5 Nm) were performed on 21 cadaveric specimens: 14 pedicle subtraction osteotomies (PSOs) and 7 anterior column realignment (ACR) constructs. The ranges of motion (ROM) at the adjacent free level in flexion, extension, axial rotation, and lateral bending were measured and analyzed. RESULTS: ACR constructs had a lower ROM change on flexion at the proximal adjacent free level than constructs with PSO (1.02 vs. 1.32, normalized to the intact specimen, P \u3c 0.01). Lateral lumbar interbody fusion adjacent to PSO and 4 rods limits ROM at the free level more effectively than transforaminal interbody fusion and 2 rods in correction constructs with PSO. Use of 2 screws to anchor the ACR interbody further decreased ROM at the proximal adjacent free level on flexion, but adding 4 rods in this setting added no further limitation to adjacent segment motion. CONCLUSIONS: ACR constructs have less ROM change at the adjacent level compared to PSO constructs. Among constructs with ACR, anchoring the ACR interbody with 2 screws reduces motion at the proximal adjacent free level. When PSOs are used, lateral lumbar interbody fusion adjacent to the PSO level has a greater reduction in adjacent-segment motion than transforaminal interbody fusion, suggesting that deformity construct configuration influences proximal adjacent-segment biomechanics

Outcomes in the radiosurgical management of metastatic spine disease

Purpose: Stereotactic body radiation therapy (SBRT) is a common treatment option for patients with metastatic tumors of the spine. The optimal treatment-, tumor-, and patient-specific characteristics necessary to achieve durable outcomes remain less well understood given the heterogeneous nature of the patient population this modality typically serves. The objective of this analysis was to better understand the determinants underlying SBRT spine treatment outcomes. Methods and Materials: A total of 127 patients with 287 spine tumors were treated between March 2010 and May 2015. The median total doses for single-fraction and hypofractionated courses of treatment were 16 Gy (range, 16-20 Gy) and 24 Gy (range, 16-40 Gy), respectively. Radiologic local control and numeric pain score data were measured, and univariate and multivariate analyses were done to determine factors predictive of treatment response. Results: Median follow-up was 5.9 months (range, 1-61 months). Radiologic local control was achieved in 84.7% of patients at 6 months and in 74.7% of patients at 1 year. Local control was found to be affected by the Spinal Instability Neoplastic Score, and was worse in patients with scores ≥7 (hazard ratio [HR]: 4.25; 95% confidence interval [CI], 1.57-11.51). Patients who required upfront surgical intervention to alleviate spinal cord compression, address mechanical spinal instability, or both had worse local control than those who did not require surgery (HR: 2.32; 95% CI, 1.04-5.17). Patients treated with a hypofractionated course compared with a single fraction had worse radiologic local control (HR: 2.63; 95% CI, 1.27-5.45). No patients developed radiation-induced myelitis after treatment, and the vertebral compression fracture rate was 9.1% after SBRT. Conclusions: Patients with potentially unstable spines or needing upfront spinal surgery before SBRT are less likely to achieve durable radiologic local control. Additionally, patients treated with single-fraction regimens have improved local control compared with those treated with hypofractionated radiation

Reliability of a Novel Classification System for Thoracic Disc Herniations

Cross-sectional survey. To assess the reliability of a proposed novel classification system for thoracic disc herniations (TDHs). TDHs are complex entities varying substantially in many factors, including size, location, and calcification. To date, no comprehensive system exists to categorize these lesions. Our proposed system classifies 5 types of TDHs using anatomical and clinical characteristics, with subtypes for calcification. Type 0 herniations are small (≤40% of spinal canal) TDHs without significant spinal cord or nerve root effacement; type 1 are small and paracentral; type 2 are small and central; type 3 are giant (>40% of spinal canal) and paracentral; and type 4 are giant and central. Patients with types 1-4 TDHs have correlative clinical and radiographic evidence of spinal cord compression. Twenty-one US spine surgeons with substantial TDH experience rated 10 illustrative cases to determine the system's reliability. Interobserver and intraobserver reliability were determined using the Fleiss kappa coefficient. Surgeons were also surveyed to obtain consensus on surgical approaches for the various TDH types. High agreement was found for the classification system, with 80% (range 62-95%) overall agreement and high interrater and intrarater reliability (kappa 0.604 [moderate to substantial agreement] and kappa 0.630 [substantial agreement], respectively). All surgeons reported nonoperative management of type 0 TDHs. For type 1 TDHs, most respondents (71%) preferred posterior approaches. For type 2 TDHs, responses were roughly equivalent for anterolateral and posterior options. For types 3 and 4 TDHs, most respondents (72% and 68%, respectively) preferred anterolateral approaches. This novel classification system can be used to reliably categorize TDHs, standardize description, and potentially guide the selection of surgical approach. Validation of this system with regard to treatment and clinical outcomes represent lines of future study

Essential Step-by-Step Techniques for Minimally Invasive Spinal Surgery

The ultimate resource for learning and mastering minimally invasive spine surgery techniques An estimated 1.5 million instrumented spinal procedures are performed every year in the US. The majority of decompressions and about 50% of fusion procedures can be performed completely or partially using minimally invasive spine surgery (MISS) techniques. The full potential of MISS techniques has yet to be realized. Essential Step-by-Step Techniques for Minimally Invasive Spinal Surgery by internationally renowned MISS neurosurgeon Roger Härtl, spine-neurosurgeon Rodrigo Navarro-Ramirez, and an impressive group of global multidisciplinary contributors is the most comprehensive and detailed textbook written to date on this topic. The foundation of the book is built on six interacting principles critical to surgical success, and MISS in particular: Target, Technology, Technique, Teaching and Training, Testing, and Talent. The text starts with an opening chapter on the definition of MISS and introduction of these principles. Fifty-six subsequent chapters provide a comprehensive discussion on how to utilize an MISS approach for a full spectrum of spinal pathologies using nuanced variations specific to the operating surgeon. To ensure readers are well versed in all aspects of MISS, these chapters include painstaking details on indications, contraindications, pathoanatomy, operating room set-up, step-by-step techniques, and postoperative management. Key Highlights Contributions from master spine surgeons across the world provide a balanced global perspective on mastering and incorporating diverse techniques into practice Invaluable clinical pearls including tips/tricks and complication avoidance High-quality images, figures, anatomic drawings, and imaging studies illustrate relevant anatomic approaches and corridors and delineate why anatomic masteryis critical to MISS Twenty-five videos enhance the ability to learn and implement MISS approaches This is a must-have resource for practicing spine surgeons interested in MISS who wish to learn the latest techniques from master surgeons and achieve optimal patient outcomes. The text and videos also provide a robust training tool for senior-level orthopaedic and neurosurgery residents and spine fellows

Global treadmilling coordinates actin turnover and controls the size of actin networks

International audienceVarious cellular processes (including cell motility) are driven by the regulated, polarized assembly of actin filaments into distinct force-producing arrays of defined size and architecture. Branched, linear, contractile and cytosolic arrays coexist in vivo, and cells intricately control the number, length and assembly rate of filaments in these arrays. Recent in vitro and in vivo studies have revealed novel molecular mechanisms that regulate the number of filament barbed and pointed ends and their respective assembly and disassembly rates, thus defining classes of dynamically different filaments, which coexist in the same cell. We propose that a global treadmilling process, in which a steady-state amount of polymerizable actin monomers is established by the dynamics of each network, is responsible for defining the size and turnover of coexisting actin networks. Furthermore, signal-induced changes in the partitioning of actin to distinct arrays (mediated by RHO GTPases) result in the establishment of various steady-state concentrations of polymerizable monomers, thereby globally influencing the growth rate of actin filaments