Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization.

JOURNAL/nrgr/04.03/01300535-202410000-00027/figure1/v/2024-02-06T055622Z/r/image-tiff Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Quantitative anatomical analysis of lumbar interspaces based on 3D CT imaging: optimized segment selection for lumbar puncture in different age groups.

BACKGROUND: Optimal lumbar puncture segment selection remains controversial. This study aims to analyze anatomical differences among L3-4, L4-5, and L5-S1 segments across age groups and provide quantitative evidence for optimized selection. METHODS: 80 cases of CT images were collected with patients aged 10-80 years old. Threedimensional models containing L3-S1 vertebrae, dural sac, and nerve roots were reconstructed. Computer simulation determined the optimal puncture angles for the L3-4, L4-5, and L5-S1 segments. The effective dural sac area (ALDS), traversing nerve root area (ATNR), and area of the lumbar inter-laminar space (ALILS) were measured. Puncture efficacy ratio (ALDS/ALILS) and nerve injury risk ratio (ATNR/ALILS) were calculated. Cases were divided into four groups: A (10-20 years), B (21-40 years), C (41-60 years), and D (61-80 years). Statistical analysis was performed using SPSS. RESULTS: 1) ALDS was similar among segments; 2) ATNR was greatest at L5-S1; 3) ALILS was greatest at L5-S1; 4) Puncture efficacy ratio was highest at L3-4 and lowest at L5-S1; 5) Nerve injury risk was highest at L5-S1. In group D, L5-S1 ALDS was larger than L3-4 and L4-5. ALDS decreased after age 40. Age variations were minimal across parameters. CONCLUSION: The comprehensive analysis demonstrated L3-4 as the optimal first-choice segment for ages 10-60 years, conferring maximal efficacy and safety. L5-S1 can serve as an alternative option for ages 61-80 years when upper interspaces narrow. This study provides quantitative imaging evidence supporting age-specific, optimized lumbar puncture segment selection.

Hypoxic-preconditioned mesenchymal stem cell-derived small extracellular vesicles promote the recovery of spinal cord injury by affecting the phenotype of astrocytes through the miR-21/JAK2/STAT3 pathway.

BACKGROUND: Secondary injury after spinal cord injury (SCI) is a major obstacle to their neurological recovery. Among them, changes in astrocyte phenotype regulate secondary injury dominated by neuroinflammation. Hypoxia-preconditioned mesenchymal stem cells (MSCs)-derived extracellular vesicle (H-EV) plays a multifaceted role in secondary injury by interacting with cellular components and signaling pathways. They possess anti-inflammatory properties, regulate oxidative stress, and modulate apoptotic pathways, promoting cell survival and reducing neuronal loss. Given the unique aspects of secondary injury, H-EV shows promise as a therapeutic approach to mitigate its devastating consequences. Our study aimed to determine whether H-EV could promote SCI repair by altering the phenotype of astrocytes. METHODS: Rat bone marrow MSCs (BMSCs) and EVs secreted by them were extracted and characterized. After the SCI model was successfully constructed, EV and H-EV were administered into the tail vein of the rats, respectively, and then their motor function was evaluated by the Basso-Beattie-Bresnahan (BBB) score, Catwalk footprint analysis, and electrophysiological monitoring. The lesion size of the spinal cord was evaluated by hematoxylin-eosin (HE) staining. The key point was to use glial fibrillary acidic protein (GFAP) as a marker of reactive astrocytes to co-localize with A1-type marker complement C3 and A2-type marker S100A10, respectively, to observe phenotypic changes in astrocytes within tissues. The western blot (WB) of the spinal cord was also used to verify the results. We also compared the efficacy differences in apoptosis and inflammatory responses using terminal deoxynucleotidyl transferase dUTP terminal labeling (TUNEL) assay, WB, and enzyme-linked immunosorbent assay (ELISA). Experiments in vitro were also performed to verify the results. Subsequently, we performed microRNA (miRNA) sequencing analysis of EV and H-EV and carried out a series of knockdown and overexpression experiments to further validate the mechanism by which miRNA in H-EV plays a role in promoting astrocyte phenotypic changes, as well as the regulated signaling pathways, using WB both in vivo and in vitro. RESULTS: Our findings suggest that H-EV is more effective than EV in the recovery of motor function, anti-apoptosis, and anti-inflammatory effects after SCI, both in vivo and in vitro. More importantly, H-EV promoted the conversion of A1 astrocytes into A2 astrocytes more than EV. Moreover, miR-21, which was found to be highly expressed in H-EV by miRNA sequencing results, was also demonstrated to influence changes in astrocyte phenotype through a series of knockdown and overexpression experiments. At the same time, we also found that H-EV might affect astrocyte phenotypic alterations by delivering miR-21 targeting the JAK2/STAT3 signaling pathway. CONCLUSION: H-EV exerts neuroprotective effects by delivering miR-21 to promote astrocyte transformation from the A1 phenotype to the A2 phenotype, providing new targets and ideas for the treatment of SCI.

Mesenchymal stem cell-derived extracellular vesicles therapy in traumatic central nervous system diseases: a systematic review and meta-analysis.

Although there are challenges in treating traumatic central nervous system diseases, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have recently proven to be a promising non-cellular therapy. We comprehensively evaluated the efficacy of mesenchymal stem cell-derived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies. Our meta-analysis was registered at PROSPERO (CRD42022327904, May 24, 2022). To fully retrieve the most relevant articles, the following databases were thoroughly searched: PubMed, Web of Science, The Cochrane Library, and Ovid-Embase (up to April 1, 2022). The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system diseases. The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)'s risk of bias tool was used to examine the risk of publication bias in animal studies. After screening 2347 studies, 60 studies were included in this study. A meta-analysis was conducted for spinal cord injury (n = 52) and traumatic brain injury (n = 8). The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal cord injury animals, including rat Basso, Beattie and Bresnahan locomotor rating scale scores (standardized mean difference [SMD]: 2.36, 95% confidence interval [CI]: 1.96-2.76, P < 0.01, I2 = 71%) and mouse Basso Mouse Scale scores (SMD = 2.31, 95% CI: 1.57-3.04, P = 0.01, I2 = 60%) compared with controls. Further, mesenchymal stem cell-derived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals, including the modified Neurological Severity Score (SMD = -4.48, 95% CI: -6.12 to -2.84, P < 0.01, I2 = 79%) and Foot Fault Test (SMD = -3.26, 95% CI: -4.09 to -2.42, P = 0.28, I2 = 21%) compared with controls. Subgroup analyses showed that characteristics may be related to the therapeutic effect of mesenchymal stem cell-derived extracellular vesicles. For Basso, Beattie and Bresnahan locomotor rating scale scores, the efficacy of allogeneic mesenchymal stem cell-derived extracellular vesicles was higher than that of xenogeneic mesenchymal stem cell-derived extracellular vesicles (allogeneic: SMD = 2.54, 95% CI: 2.05-3.02, P = 0.0116, I2 = 65.5%; xenogeneic: SMD: 1.78, 95%CI: 1.1-2.45, P = 0.0116, I2 = 74.6%). Mesenchymal stem cell-derived extracellular vesicles separated by ultrafiltration centrifugation combined with density gradient ultracentrifugation (SMD = 3.58, 95% CI: 2.62-4.53, P < 0.0001, I2 = 31%) may be more effective than other EV isolation methods. For mouse Basso Mouse Scale scores, placenta-derived mesenchymal stem cell-derived extracellular vesicles worked better than bone mesenchymal stem cell-derived extracellular vesicles (placenta: SMD = 5.25, 95% CI: 2.45-8.06, P = 0.0421, I2 = 0%; bone marrow: SMD = 1.82, 95% CI: 1.23-2.41, P = 0.0421, I2 = 0%). For modified Neurological Severity Score, bone marrow-derived MSC-EVs worked better than adipose-derived MSC-EVs (bone marrow: SMD = -4.86, 95% CI: -6.66 to -3.06, P = 0.0306, I2 = 81%; adipose: SMD = -2.37, 95% CI: -3.73 to -1.01, P = 0.0306, I2 = 0%). Intravenous administration (SMD = -5.47, 95% CI: -6.98 to -3.97, P = 0.0002, I2 = 53.3%) and dose of administration equal to 100 µg (SMD = -5.47, 95% CI: -6.98 to -3.97, P < 0.0001, I2 = 53.3%) showed better results than other administration routes and doses. The heterogeneity of studies was small, and sensitivity analysis also indicated stable results. Last, the methodological quality of all trials was mostly satisfactory. In conclusion, in the treatment of traumatic central nervous system diseases, mesenchymal stem cell-derived extracellular vesicles may play a crucial role in promoting motor function recovery.

Efficacy of extracellular vesicles of different cell origins in traumatic brain injury: A systematic review and network meta-analysis.

Background: There was still no effective treatment for traumatic brain injury (TBI). Recently, many preclinical studies had shown promising efficacy of extracellular vesicles (EVs) from various cell sources. Our aim was to compare which cell-derived EVs were most effective in treating TBI through a network meta-analysis. Methods: We searched four databases and screened various cell-derived EVs for use in preclinical studies of TBI treatment. A systematic review and network meta-analysis were conducted for two outcome indicators, modified Neurological Severity Score (mNSS) and Morris Water Maze (MWM), and they were ranked by the surface under the cumulative ranking curves (SUCRA). Bias risk assessment was performed with SYRCLE. R software (version 4.1.3, Boston, MA, USA) was used for data analysis. Results: A total of 20 studies were included in this study, involving 383 animals. Astrocyte-derived extracellular vesicles (AEVs) ranked first in response to mNSS at day 1 (SUCRA: 0.26%), day 3 (SUCRA: 16.32%), and day 7 (SUCRA: 9.64%) post-TBI. Extracellular vesicles derived from mesenchymal stem cells (MSCEVs) were most effective in mNSS assessment on day 14 (SUCRA: 21.94%) and day 28 (SUCRA: 6.26%), as well as MWM's escape latency (SUCRA: 6.16%) and time spent in the target quadrant (SUCRA: 86.52%). The result of mNSS analysis on day 21 showed that neural stem cell-derived extracellular vesicles (NSCEVs) had the best curative effect (SUCRA: 6.76%). Conclusion: AEVs may be the best choice to improve early mNSS recovery after TBI. The efficacy of MSCEVs may be the best in the late mNSS and MWM after TBI. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023377350.

Feasibility and efficacy of spinal microtubular technique for resection of lumbar dumbbell-shaped tumors.

Objective: Minimally invasive surgical resection of lumbar dumbbell-shaped tumors is rarely reported. We retrospectively collected clinical data of lumbar dumbbell-shaped tumors treated with the spinal microtubular technique to evaluate the feasibility, complications and efficacy of the surgical methods. Methods: From September 2013 to August 2021, clinical data of patients with lumbar dumbbell-shaped tumors that underwent paravertebral approach and micro-tubular tumorectomy (PAMT) were collected; neurological function was assessed using the pain visual analog scale (VAS) and the Japanese Orthopaedic Association (JOA) score. Results: A total of 46 patients that underwent PAMT were included in this study. In all patients, total resection of the tumor was performed at one stage (100%). The median follow-up period was 27.5 months (P25, P75: 16.5- 57 months). Symptoms such as pain or lower extremity weakness were significantly relieved in 46 patients. The postoperative VAS score and JOA score were significantly higher compared with preoperative scores (p <0.001), and the patients had no tumor recurrence or spinal instability. According to the Eden classification, there were 7 cases of type I, 8 cases of type II, 15 cases of type III, and 16 cases of type IV. In the comparison of the improvement of VAS score at 12 months after PAMT, there were significant differences among different types of tumors (H =15.756, p =0.001); type I was better than type III (Z =2.768, p =0.029) and type IV (Z =2.763, p =0.029), and type II was also better than type III (Z =2.679, p =0.037) and type IV (Z =2.708, p =0.034). With respect to estimated blood loss (Z =-3.041, p =0.013) and postoperative hospital stays (Z =-3.003, p =0.014), type IV was less than type III; and type IV was also less than type II about operation time (Z =-2.653, p =0.040). Conclusion: In small lumbar dumbbell-shaped tumors, PAMT is indicated for Eden types I-IV and different pathological types of tumors, and can achieve complete resection of the tumor (GTR) in one stage with a good prognosis.

Efficacy of miRNA-modified mesenchymal stem cell extracellular vesicles in spinal cord injury: A systematic review of the literature and network meta-analysis.

Background: Although some previous studies have indicated that extracellular vesicles (EVs) secreted from miRNA-modified mesenchymal stem cells (MSCs) may be more effective as compared with control EVs in the treatment of rats with spinal cord injuries (SCI), the efficacy of this treatment modality remains controversial. Objectives: The current study comprehensively evaluated the efficacy of different administered doses of EVs, including miRNA-overexpressing MSCs-derived EVs, among SCI rats. The efficacy of EVs' treatment was evaluated in different SCI models to provide evidence for preclinical trials. Methods: We extensively searched the following databases to identify relevant studies: PubMed, Embase, Scopus, The Cochrane Library, and Web of Science (from inception to July 20, 2022). Two trained investigators independently screened literature, extracted the data, and evaluated literature quality. Results: Thirteen studies were included in this network meta-analysis. The results demonstrated that miRNA-overexpressing MSCs-derived EVs (100 and 200 µg of total protein of EVs) significantly improved hind limb motor function in rats at early stages of SCI (i.e., at 3 days after injury) as compared with EVs (100 and 200 µg of total protein of EVs, respectively). However, in the middle and late stages (14 and 28 days), there were no statistically significant differences between EVs with 200 µg dosages and miRNA-loaded EVs with 100 µg dosages. In the late stages (28 days), there were no statistically significant differences between EVs with 100 µg dosages and miRNA-loaded EVs with 200 µg dosages. We found that miRNA-overexpressing MSCs-derived EVs significantly improved motor function among early-stage SCI rats in a compression and contusion model (3 days) as compared with MSCs-derived EVs and miRNA-overexpressing MSCs-derived EVs likewise significantly improved motor function among SCI rats in a contusion model at middle and late stages (14 and 28 days). Conclusion: Our results suggest that miRNA-overexpressing MSCs-derived EVs (200 µg of total protein of EVs) may be the best choice for the effective treatment of SCI, and miRNA-overexpressing MSCs-derived EVs may likewise be the best choice for treating contusions. However, there are some risks of bias in our included studies, and the mechanisms underlying the efficacy of EVs remain unclear.Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=282051, identifier: CRD42021282051.

Mesenchymal Stem Cell-Derived Exosomal MiRNAs Promote M2 Macrophages Polarization: Therapeutic Opportunities for Spinal Cord Injury.

Spinal cord injury (SCI) is an enormous public health concern affecting approximately 250,000-500,000 people worldwide each year. It is mostly irreversible considering the limitations of currently available treatments, and its prevention and management have been the prime focus of many studies. Mesenchymal stem cell (MSC) transplantation is one of the most promising treatments for SCI. The role of MSCs in SCI has been studied extensively, and MSCs have been shown to have many limitations. Moreover, the therapeutic effects of MSCs are more likely related to paracrine effects. In SCIs, macrophages from peripheral sources differentiate into M1 macrophages, promoting inflammation and aggravating neuronal damage; however, studies have shown that MSC-derived exosomes can induce the polarization of macrophages from the M1 to the M2 phenotype, thereby promoting nerve function recovery in patients with SCI. In this review, we discussed the research progress of MSC-derived exosomal miRNAs in promoting M2 macrophage differentiation in the SCI, and introduced some exosomal miRNAs that can regulate the differentiation of M2 macrophages in non-SCI; it is hoped that the regulatory role of these exosome-derived miRNAs can be confirmed in SCI.

Clinical Evaluation of Paraspinal Mini-Tubular Lumbar Decompression and Minimally Invasive Transforaminal Lumbar Interbody Fusion for Lumbar Spondylolisthesis Grade I with Lumbar Spinal Stenosis: A Cohort Study.

Objective: To investigate the clinical outcome data and difference in efficacy between paraspinal mini-tubular lumbar decompression (PMTD) and minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) in the treatment of degenerative lumbar spondylolisthesis grade I with lumbar spinal stenosis (DLS-I-LSS). Methods: Patients with DLS-I-LSS, who underwent PMTD or MIS TLIF from September 2017 to March 2020, were included retrospectively. The follow-up period was 24 months after surgery. Outcome measurements included the Oswestry disability index (ODI) score, visual analog scale (VAS) low back pain score, VAS leg pain score, surgical data, and adverse events. Results: A total of 104 patients with DLS-I-LSS were included in this study. The average improvement in ODI at 12 months (2.0%, 95% CI, -5.7% to 1.8%; p = 0.30) and 24 months (1.7%, 95% CI, -2.7% to 6.1%; p = 0.45) after surgery between the two groups were not statistically significant. The improvement in VAS low back pain score after 24 months and improvement in VAS leg pain score were not significantly different between the two groups. Compared with the PMTD group, the MIS TLIF group had more estimated blood loss and longer hospital stays. The cumulative reoperation rates were 5.66% and 1.96% in the MIS TLIF and PMTD groups, respectively (p = 0.68). The results of multivariate analysis showed that BMI, diabetes, and baseline ODI score were the main factors influencing the improvement in ODI in patients with DLS-I-LSS after minimally invasive surgery, accounting for 50.5% of the total variance. Conclusions: The clinical effectiveness of PMTD was non-inferior to that of MIS TLIF for DLS-I-LSS; however, there was a reduced duration of hospital stay, operation time, blood loss, and hospitalization costs in the PMTD group. BMI, presence or absence of diabetes and baseline ODI score were influencing factors for the improvement of ODI (Trial Registration: ChiCTR2000040025).

Clinical Evaluation of Surgery for Single-Segment Lumbar Spinal Stenosis: A Systematic Review and Bayesian Network Meta-Analysis.

To compare the efficacy and safety of different surgical procedures for patients with single-segment lumbar spinal stenosis (LSS), Bayesian network meta-analysis (NMA) was conducted in this study. Randomized controlled trials (RCTs) which reported 2 years' results after surgery were searched from PubMed, Embase, and Cochrane Register of Controlled Trials up to February 2021. Eligible RCTs that contained at least two of the following surgical procedures, bilateral decompression via the unilateral approach (BDUL), decompression with conventional laminectomy (CL), decompression with fusion (DF), endoscopic decompression (ED), interspinous process devices only (IPDs), decompression with interlaminar stabilization (DILS), decompression with lumbar spinal process-splitting laminectomy (LSPSL), and minimally invasive tubular decompression (MTD), would be included after screening based on the inclusion and exclusion criteria. The primary outcome was Oswestry Disability Index (ODI). Twenty eligible RCTs were included, with a total of 2201 patients enrolled. The NMA showed that the following surgical procedures ranked first (surface under the cumulative ranking) when compared with CL and DF: DILS for ODI (SUCRA 87.8%); LSPSL for back pain (95%); and MTD for leg pain (95.6%). MTD ranked among the top three surgical procedures for most outcomes. The quality of the synthesized evidence was low according to the Grading of Recommendations Assessment, Development, and Evaluation criteria. DILS, LSPSL, MTD, IPDs, and ED are the most effective procedures for patients with single-segment LSS. Because of combining efficacy and safety, MTD may be the most promising routine surgical option for treating single-segment LSS.

The Role of Exosomes and Exosomal Noncoding RNAs From Different Cell Sources in Spinal Cord Injury.

Spinal cord injury (SCI) not only affects the quality of life of patients but also poses a heavy burden on their families. Therefore, it is essential to prevent the occurrence of SCI; for unpreventable SCI, it is critical to develop effective treatments. In recent years, various major breakthroughs have been made in cell therapy to protect and regenerate the damaged spinal cord via various mechanisms such as immune regulation, paracrine signaling, extracellular matrix (ECM) modification, and lost cell replacement. Nevertheless, many recent studies have shown that the cell therapy has many disadvantages, such as tumorigenicity, low survival rate, and immune rejection. Because of these disadvantages, the clinical application of cell therapy is limited. In recent years, the role of exosomes in various diseases and their therapeutic potential have attracted much attention. The same is true for exosomal noncoding RNAs (ncRNAs), which do not encode proteins but affect transcriptional and translational processes by targeting specific mRNAs. This review focuses on the mechanism of action of exosomes obtained from different cell sources in the treatment of SCI and the regulatory role and therapeutic potential of exosomal ncRNAs. This review also discusses the future opportunities and challenges, proposing that exosomes and exosomal ncRNAs might be promising tools for the treatment of SCI.

Comparing the Efficacy and Safety of Cell Transplantation for Spinal Cord Injury: A Systematic Review and Bayesian Network Meta-Analysis.

Objective: To compare the safety and effectiveness of transplanted cells from different sources for spinal cord injury (SCI). Design: A systematic review and Bayesian network meta-analysis. Data Sources: Medline, Embase, and the Cochrane Central Register of Controlled Trials. Study Selection: We included randomized controlled trials, case-control studies, and case series related to cell transplantation for SCI patients, that included at least 1 of the following outcome measures: American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS grade), ASIA motor score, ASIA sensory score, the Functional Independence Measure score (FIM), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), or adverse events. Follow-up data were analyzed at 6 and 12 months. Results: Forty-four eligible trials, involving 1,266 patients, investigated 6 treatments: olfactory ensheathing cells (OECs), neural stem cells/ neural progenitor cells (NSCs), mesenchymal stem cells (MSCs), Schwann cells, macrophages, and combinations of cells (MSCs plus Schwann cells). Macrophages improved the AIS grade at 12 months (mean 0.42, 95% credible interval: 0-0.91, low certainty) and FIM score at 12 months (42.83, 36.33-49.18, very low certainty). MSCs improved the AIS grade at 6 months (0.42, 0.15-0.73, moderate certainty), the motor score at 6 months (4.43, 0.91-7.78, moderate certainty), light touch at 6 (10.01, 5.81-13.88, moderate certainty) and 12 months (11.48, 6.31-16.64, moderate certainty), pinprick score at 6 (14.54, 9.76-19.46, moderate certainty) and 12 months (12.48, 7.09-18.12, moderate certainty), and the IANR-SCIFRS at 6 (3.96, 0.62-6.97, moderate certainty) and 12 months (5.54, 2.45-8.42, moderate certainty). OECs improved the FIM score at 6 months (9.35, 1.71-17.00, moderate certainty). No intervention improved the motor score significantly at 12 months. The certainty of other interventions was low or very low. Overall, the number of adverse events associated with transplanted cells was low. Conclusions: Patients with SCI who receive transplantation of macrophages, MSCs, NSCs, or OECs may have improved disease prognosis. MSCs are the primary recommendations. Further exploration of the mechanism of cell transplantation in the treatment of SCI, transplantation time window, transplantation methods, and monitoring of the number of transplanted cells and cell survival is needed. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD 42021282043.

Clinical evaluation of paraspinal mini-tubular technique vs. laminoplasty for spinal intradural extramedullary tumors: Study protocol for a multicenter, randomized controlled trial.

The development of minimally invasive surgery has promoted the use of the paraspinal mini-tubular technique (PMTT) for spinal tumors. The similarity of the efficacy of PMTT to that of traditional surgery remains unclear; randomized controlled trials (RCTs) have not been conducted to investigate this technique for spinal tumors. The conventional surgery used for such tumors is laminoplasty (LP). To compare the differences between the two surgical techniques, an RCT is significantly required. Therefore, a prospective, multi-center, non-inferiority RCT was designed to compare the safety and effectiveness of LP and PMTT for treating spinal intradural extramedullary (IDEM) tumors. Moreover, the availability of PMTT, including its advantages and disadvantages, surgical indications, procedures, complications, and prognosis, would be explored. Overall, 280 patients will be randomly allocated to the PMTT and LP groups in a 1:1 ratio. The trial hypothesis is that PMTT has superior or equivalent efficacy and cost-effectiveness to LP. The primary outcome is the Japanese Orthopedic Association score. The non-inferiority margin for the primary outcome is five. The Ethics Committee of Fujian Medical University Union Hospital, Fuzhou, China, has approved this study (project number: FJMUUH05). Any results of the trial will be published in international peer-reviewed journals and disseminated through presentations at scientific conferences. Trial registration number: ChiCTR2100047582.

Perceived-stigma level of COVID-19 patients in China in the early stage of the epidemic: A cross-sectional research.

OBJECTIVE: To investigate the perceived-stigma level of COVID-19 patients in the early stage of the epidemic and analysed related factors and correlations that affected the stigma levels. METHODS: The COVID-19 patients were selected using the convenience sampling method. Perceived-stigma level was evaluated using the Social Impact Scale (SIS). Frequency was used to describe the general information and disease investigation status of COVID-19 patients; mean and standard deviation were used for describing stigma levels, Wilcoxon signed-ranks test (nonparametric test) was applied for pairwise comparison. Kruskal-Wallis non-parametric test for grade data, and Dwass-Steel-Critchlow-Fligner test for multiple comparative analysis. Multiple linear regression analysis was performed, and statistically significant indicators in single-factor analysis were included to investigate the independent factors of stigma. The p<0.05 was considered statistically significant. RESULTS: SIS score of the 122 COVID-19 patients averaged 57.37±9.99 points. There were statistically significant differences in perceived-stigma levels among patients of different ages (p = 0.008), occupation (p <0.001), marital status (p = 0.009), and disease severity (p = 0.020). Multivariate logistic regression analysis revealed that age was the main influencing factor of stigma (p<0.05). CONCLUSIONS: The overall perceived-stigma level of COVID-19 patients in the early stage of the epidemic was moderate. Younger, unmarried, and severely ill patients had a higher level of perceived-stigma, with age being the main factor. More attention should be given to the young COVID-19 patients.

Efficacy of One-stage Paravertebral Approach using a Micro-Tubular Technique in Treating Thoracic Dumbbell Tumors.

OBJECTIVE: The aim of the present study was to investigate the feasibility and efficacy of one-stage surgical resection of thoracic dumbbell tumors using a paravertebral approach and a micro-tubular technique. METHODS: Clinical data of thoracic dumbbell tumors resected using a paravertebral approach and a micro-tubular technique (14 mm, non-expandable type) in the Department of Neurosurgery at our hospital from July 2014 to July 2019 were retrospectively analyzed. Tumors were found between T1 and T12 vertebrae. Operation time, blood loss, hospitalization, recovery of neurological function, complications, the Japanese Orthopaedic Association (JOA) score, and the visual analogue scale (VAS) score were used to evaluate clinical efficacy. RESULTS: In all 31 cases, tumors were completely resected in one operation, with a mean blood loss of 53.23 ± 33.08 mL (20-150 mL) and a mean operation time of 95.16 ± 20.31 min (60-180 min). According to the Eden classification, there were four type II cases, 16 type III cases, and 11 type IV cases. The incidence of tumors in the lower thoracic segment (T8-T12) was 51.6% (16/31 cases), while the incidences in the upper thoracic segment (T1-T4) and middle segment (T5-T8) were 25.8% (8/31 cases) and 22.6% (7/31 cases), respectively. Pathological diagnoses were schwannoma (n = 22), gangliocytoma (n = 4), metastatic tumor (n = 2), neurofibroma (n = 1), granuloma (n = 1), and lipoma (n = 1). After surgery, symptoms were relieved in all patients. VAS and JOA scores significantly improved (P < 0.001). There was no pleural or lung injury, and there were no complications, such as cerebrospinal fluid leakage. The average follow-up duration was 29 months (13-59 months), during which time no tumor recurrence or spinal instability occurred. The group of Eden type II tumors had lower JOA scores at 12 months postoperatively, longer operation times, and more estimated blood loss compared with other groups (P < 0.05). There were no significant influences on VAS scores at 12 months postoperatively and postoperative hospital stay from the different types of tumors. CONCLUSION: The paravertebral approach with a micro-tubular technique is a safe and effective minimally invasive surgical approach for thoracic dumbbell tumors that allows one-stage tumor resection using a single incision. Using this approach significantly reduces intraoperative blood loss and postoperative complications, shortens hospital stay, and reduces the rates of postoperative spinal instability.

Comparative Clinical Effectiveness and Safety of Bone Morphogenetic Protein Versus Autologous Iliac Crest Bone Graft in Lumbar Fusion: A Meta-analysis and Systematic Review.

STUDY DESIGN: This is a systematic literature review and meta-analysis. OBJECTIVE: We aimed to evaluate the efficacy and safety of recombinant human bone morphogenetic protein (RhBMP) and autologous iliac crest bone graft (ICBG) in lumbar fusion. SUMMARY OF BACKGROUND DATA: RhBMP has been emphasized in lumbar fusion due to high fusion success rate. However, ICBG remains the criterion standard graft approach for lumbar fusion. The safety and effectiveness of rhBMP are controversial. METHODS: Prospective randomized controlled trials were searched from PubMed, EMBASE, and Cochrane Central Register of Controlled Trails by using Medical Subject Headings terms "bone morphogenetic protein,' "bone transplantation,' and "spinal fusion.' Two independent investigators screened eligible studies, assessed the bias of original articles, extracted data including fusion success, Oswestry disability index improvement, improved short form 36 questionnaire scores, adverse events and re-operation, and a subgroup analysis. The GRADE approach was used to grade quality of evidence. RESULTS: Twenty randomized controlled trials (2185 patients) met the inclusion criteria. There were higher fusion success rate (odds ratio [OR] 3.79, 95% confidence interval [CI] 1.88-7.63, P = 0.0002), better improvement of Oswestry Disability Index (mean difference 1.54, 95% CI 0.18-2.89, P = 0.03), and lower re-operation rate (OR 0.59, 95% CI 0.43-0.80, P = 0.0007) in rhBMP group. Heterogeneity was obvious in fusion success rate (I = 58%); hence, a subgroup analysis, based on protein type (rhBMP-2 or rhBMP-7), was performed, which suggested that only rhBMP-2 was better than ICBG for lumbar fusion. There was no difference in the incidence of adverse events between rhBMP and ICBG (OR 0.91, 95% CI 0.70-1.18, P = 0.47). CONCLUSION: In lumbar fusion, rhBMP-2 exhibited a higher fusion success rate and reduced the risk of re-operation. No difference in complication rate is between rhBMP (rhBMP-2 and rhBMP-7) and ICBG. We suggest rhBMP especially rhBMP-2 as an effective substitute for ICBG for lumbar fusion. LEVEL OF EVIDENCE: 1.

Comparative Clinical Effectiveness of Tubular Microdiscectomy and Conventional Microdiscectomy for Lumbar Disc Herniation: A Systematic Review and Network Meta-Analysis.

STUDY DESIGN: This study is a systematic literature review and meta-analysis. OBJECTIVE: To evaluate the efficacy of tubular microdiscectomy (TMD) compared with conventional microdiscectomy (CMD) for lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: TMD has developed rapidly due to reduced tissue trauma by minimization of the required access to spine and disc herniation; however, CMD remains the standard of care for this patient group. To date, it remains debatable whether TMD is superior to CMD for LDH. METHODS: We performed a comprehensive database search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trails for prospective randomized controlled trials (RCTs), through using Medical Subject Headings (MeSH) terms "microdiscectomy," "tubular microdiscectomy," "minimally invasive surgery," and "spinal disease." The retrieved results were last updated on March 15, 2018. Two independent investigators selected qualified studies, extracted indispensable data, assessed risk of bias of original papers. The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach was used to grade quality of evidence. If I >50, the heterogeneity is considerable. RESULTS: Four RCT studies (total n = 605), involving 610 individuals with a follow-up period of no less than 12 months, were selected for further review. We assessed these studies as low overall risk of bias. There was low-quality evidence that TMD was superior to CMD considering postoperative Oswestry Disability Index scores (SMD, -3.43, 95% CI, -4.64 to -2.21, P < 0.00001). Compared with CMD, the TMD group exhibited significantly worse Short Form-36 physical function scores (SMD, -4.83, 95% CI, -8.94 to -0.72, P = 0.02). There were no significant differences in the visual analogue scale (P = 0.30), operative time (P = 0.68), dural tear (P = 0.52), and reoperation (P = 0.98). CONCLUSION: The benefits 1 year after TMD were similar to that of CMD. There was no significant difference in the incidence of reoperation and dural tear. LEVEL OF EVIDENCE: 1.