Nicotinamide Riboside Promotes the Proliferation of Endogenous Neural Stem Cells to Repair Spinal Cord Injury.

Activation of endogenous neural stem cells (NSC) is one of the most potential measures for neural repair after spinal cord injury. However, methods for regulating neural stem cell behavior are still limited. Here, we investigated the effects of nicotinamide riboside promoting the proliferation of endogenous neural stem cells to repair spinal cord injury. Nicotinamide riboside promotes the proliferation of endogenous neural stem cells and regulates their differentiation into neurons. In addition, nicotinamide riboside significantly restored lower limb motor dysfunction caused by spinal cord injury. Nicotinamide riboside plays its role in promoting the proliferation of neural stem cells by activating the Wnt signaling pathway through the LGR5 gene. Knockdown of the LGR5 gene by lentivirus eliminates the effect of nicotinamide riboside on the proliferation of endogenous neural stem cells. In addition, administration of Wnt pathway inhibitors also eliminated the proliferative effect of nicotinamide riboside. Collectively, these findings demonstrate that nicotinamide promotes the proliferation of neural stem cells by targeting the LGR5 gene to activate the Wnt pathway, which provides a new way to repair spinal cord injury.

Osteogenic Induction and Anti-inflammatory Effects of Calcium-Chlorogenic Acid Nanoparticles Remodel the Osteoimmunology Microenvironment for Accelerating Bone Repair.

Successful bone regeneration requires the close cooperation between bone marrow mesenchymal stem cells (BMSCs) and macrophages, but the low osteogenic differentiation efficiency of stem cells and the excessive inflammatory response of immune cells hinder the development of the bone repair. It is necessary to develop a strategy that simultaneously regulates the osteogenic differentiation of BMSCs and the anti-inflammatory polarization of macrophages for accelerating the bone regeneration. Herein, calcium-chlorogenic acid nanoparticles (Ca-CGA NPs) were synthesized by combining the small molecular of chlorogenic acid (CGA) with Ca2+. Ca-CGA NPs internalized by cells could be dissolved to release free CGA and Ca2+ under low pH conditions in lysosomes. In vitro results demonstrated that Ca-CGA NPs could not only enhance the osteogenic differentiation of BMSCs, but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirmed that Ca-CGA NPs treatment facilitated the recovery of rat skull defect model through both the osteoinduction and immunomodulation. This study develops a new Ca-CGA NPs-based strategy to induce the differentiation of BMSCs into osteoblasts and the polarization of macrophages into M2 phenotype, which is promising for accelerating bone repair. This article is protected by copyright. All rights reserved.

Protocol for the Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study: a prospective, observational, multicentre cohort study of acute spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is a catastrophic event with devastating physical, social and occupational consequences for patients and their families. The number of patients with acute SCI in China continues to grow rapidly, but there have been no large prospective cohort studies of patients with acute SCI. This proposed study aims to establish a multicentre, extensive sample cohort of clinical data and biological samples of patients in China, which would aid the systematisation and standardisation of clinical research and treatment of acute SCI, thus reducing the heavy burden of acute SCI on patients and society. METHODS AND ANALYSIS: The Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study is an observational, multicentre cohort study of patients with acute SCI admitted to the Qilu Hospital of Shandong University and other participating centres with prospective collection of their clinical data and biological samples. We aim to recruit 2097 patients in this study. Demographics, disease history, emergency intervention information, motor and sensory examinations, surgical information, medication information and rehabilitation evaluation will be recorded. This will facilitate the development of a prediction model for complications and prognosis of patients with acute SCI and an evaluation of the current management of acute SCI. Among these variables, detailed information on surgical treatment will also be used to assess procedures for acute SCI treatment. Outcome measurements, including the International Standard for Neurological Classification of Spinal Cord Injury examinations, the occurrence of complications and death, will be performed repeatedly during follow-up. We will analyse imaging data and blood samples to develop SCI imaging markers and biomarkers. ETHICS AND DISSEMINATION: This study protocol has been approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres. The findings will be disseminated in peer-reviewed journals and academic conferences.

Variability in the prevalence of depression among adults with chronic pain: UK Biobank analysis through clinical prediction models.

BACKGROUND: The prevalence of depression among people with chronic pain remains unclear due to the heterogeneity of study samples and definitions of depression. We aimed to identify sources of variation in the prevalence of depression among people with chronic pain and generate clinical prediction models to estimate the probability of depression among individuals with chronic pain. METHODS: Participants were from the UK Biobank. The primary outcome was a "lifetime" history of depression. The model's performance was evaluated using discrimination (optimism-corrected C statistic) and calibration (calibration plot). RESULTS: Analyses included 24,405 patients with chronic pain (mean age 64.1 years). Among participants with chronic widespread pain, the prevalence of having a "lifetime" history of depression was 45.7% and varied (25.0-66.7%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.66; good calibration on the calibration plot) included age, BMI, smoking status, physical activity, socioeconomic status, gender, history of asthma, history of heart failure, and history of peripheral artery disease. Among participants with chronic regional pain, the prevalence of having a "lifetime" history of depression was 30.2% and varied (21.4-70.6%) depending on patient characteristics. The final clinical prediction model (optimism-corrected C statistic: 0.65; good calibration on the calibration plot) included age, gender, nature of pain, smoking status, regular opioid use, history of asthma, pain location that bothers you most, and BMI. CONCLUSIONS: There was substantial variability in the prevalence of depression among patients with chronic pain. Clinically relevant factors were selected to develop prediction models. Clinicians can use these models to assess patients' treatment needs. These predictors are convenient to collect during daily practice, making it easy for busy clinicians to use them.

Epidemiological age-based differences in traumatic spinal cord injury patients: A multicenter study based on 13,334 inpatients.

CONTEXT: Compared with younger traumatic spinal cord injury (TSCI) patients, the elderly had longer delays in admission to surgery, higher proportion of incomplete injury, and longer hospital stays. However, in China, the country with the largest number of TSCI patients, there have been no large-scale reports on their age differences. OBJECTIVES: To explore the age-based differences among TSCI inpatients, focusing on the demographic and clinical characteristics, treatment status, and economic burden. METHODS: We collected the medical records of 13,334 inpatients with TSCI in the 30 hospitals of China, from January 1, 2013 to December 31, 2018. Trends are expressed as annual percentage changes (APCs) and 95% confidence intervals (CIs). RESULTS: A total of 13,334 inpatients were included. Both the number and proportion of the elderly showed an increasing trend. The APC of the number and proportion in patients ≥85 years were 39.5% (95% CI, 14.3 to 70.3; P < 0.01) and 30.5% (95% CI, 8.6 to 56.9; P < 0.01), respectively. Younger patients were more likely to undergo decompression surgery, and older patients were more likely to receive high-dose methylprednisolone sodium succinate/methylprednisolone (MPSS/MP). Of the patients ≥85 years, none underwent decompression surgery within 8 h, and only 1.4% received a high dose of MPSS/MP within 8 h after injury. Elderly patients had lower hospitalization costs than younger. The total and daily medical costs during hospitalization of patients ≥85 years were 8.06 ± 18.80 (IQR: 5.79) and 0.61 ± 0.73 (IQR: 0.55) thousands dollars, respectively. CONCLUSIONS: As the first study to focus on age differences of TSCI patients in China, this study found many differences, in demographic and clinical characteristics, treatment status, and economic costs, between older and younger TSCI patients. The number and proportion of elderly patients increased, and the rate of early surgery for elderly patients is low.

Targeted Repair of Spinal Cord Injury Based on miRNA-124-3p-Loaded Mesoporous Silica Camouflaged by Stem Cell Membrane Modified with Rabies Virus Glycoprotein.

Spinal cord injury (SCI) has no effective treatment modalities. It faces a significant global therapeutical challenge, given its features of poor axon regeneration, progressive local inflammation, and inefficient systemic drug delivery due to the blood-spinal cord barrier (BSCB). To address these challenges, a new nano complex that achieves targeted drug delivery to the damaged spinal cord is proposed, which contains a mesoporous silica nanoparticle core loaded with microRNA and a cloaking layer of human umbilical cord mesenchymal stem cell membrane modified with rabies virus glycoprotein (RVG). The nano complex more readily crosses the damaged BSCB with its exosome-resembling properties, including appropriate size and a low-immunogenic cell membrane disguise and accumulates in the injury center because of RVG, where it releases abundant microRNAs to elicit axon sprouting and rehabilitate the inflammatory microenvironment. Culturing with nano complexes promotes axonal growth in neurons and M2 polarization in microglia. Furthermore, it showed that SCI mice treated with this nano complex by tail vein injection display significant improvement in axon regrowth, microenvironment regulation, and functional restoration. The efficacy and biocompatibility of the targeted delivery of microRNA by nano complexes demonstrate their immense potential as a noninvasive treatment for SCI.

Low back pain-driven inpatient stays in the United States: a nationwide repeated cross-sectional analysis.

BACKGROUND: Low back pain (LBP)-driven inpatient stays are resource-intensive and costly, yet data on contemporary national trends are limited. MATERIALS AND METHODS: This study used repeated cross-sectional analyses through a nationally representative sample (US National Inpatient Sample, 2016-2019). Outcomes included the rate of LBP-driven inpatient stays; the resource utilization (the proportion of receiving surgical treatments and hospital costs) and prognosis (hospital length of stay and the proportion of nonroutine discharge) among LBP-driven inpatient stays. LBP was classified as overall, nonspecific, and specific (i.e. cancer, cauda equina syndrome, vertebral infection, vertebral compression fracture, axial spondyloarthritis, radicular pain, and spinal canal stenosis). Analyses were further stratified by age, sex, and race/ethnicity. RESULTS: 292 987 LBP-driven inpatient stays (weighted number: 1 464 690) were included, with 269 080 (91.8%) of these for specific LBP and 23 907 (8.2%) for nonspecific LBP. The rate of LBP-driven inpatient stays varied a lot across demographic groups and LBP subtypes (e.g. for overall LBP, highest for non-Hispanic White 180.4 vs. lowest for non-Hispanic Asian/Pacific Islander 42.0 per 100 000 population). Between 2016 and 2019, the rate of nonspecific LBP-driven inpatient stays significantly decreased (relative change: 46.9%); however, substantial variations were found within subcategories of specific LBP-significant increases were found for vertebral infection (relative change: 17.2%), vertebral compression fracture (relative change: 13.4%), and spinal canal stenosis (relative change: 19.9%), while a significant decrease was found for radicular pain (relative change: 12.6%). The proportion of receiving surgical treatments also varied a lot (e.g. for overall LBP, highest for non-Hispanic White 74.4% vs. lowest for non-Hispanic Asian/Pacific Islander 62.8%), and significantly decreased between 2016 and 2019 (e.g. for nonspecific LBP, relative change: 28.6%). Variations were also observed for other outcomes. CONCLUSIONS: In the US, the burden of LBP-driven inpatient stays (i.e. rates of LBP-driven inpatient stays, resource utilization, and prognosis among LBP-driven inpatient stays) is enormous. More research is needed to understand why the burden varies considerably according to the LBP subtype (i.e. nonspecific and specific LBP as well as subcategories of specific LBP) and the subpopulation concerned (i.e. stratified by age, sex, and race/ethnicity).

Tolerant and Rapid Endochondral Bone Regeneration Using Framework-Enhanced 3D Biomineralized Matrix Hydrogels.

Tissue-engineered bone has emerged as a promising alternative for bone defect repair due to the advantages of regenerative bone healing and physiological functional reconstruction. However, there is very limited breakthrough in achieving favorable bone regeneration due to the harsh osteogenic microenvironment after bone injury, especially the avascular and hypoxic conditions. Inspired by the bone developmental mode of endochondral ossification, a novel strategy is proposed for tolerant and rapid endochondral bone regeneration using framework-enhanced 3D biomineralized matrix hydrogels. First, it is meticulously designed 3D biomimetic hydrogels with both hypoxic and osteoinductive microenvironment, and then integrated 3D-printed polycaprolactone framework to improve their mechanical strength and structural fidelity. The inherent hypoxic 3D matrix microenvironment effectively activates bone marrow mesenchymal stem cells self-regulation for early-stage chondrogenesis via TGFß/Smad signaling pathway due to the obstacle of aerobic respiration. Meanwhile, the strong biomineralized microenvironment, created by a hybrid formulation of native-constitute osteogenic inorganic salts, can synergistically regulate both bone mineralization and osteoclastic differentiation, and thus accelerate the late-stage bone maturation. Furthermore, both in vivo ectopic osteogenesis and in situ skull defect repair successfully verified the high efficiency and mechanical maintenance of endochondral bone regeneration mode, which offers a promising treatment for craniofacial bone defect repair.

Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Global, regional and national burden of traumatic brain injury and spinal cord injury, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.

OBJECTIVES: To evaluate the most up-to-date burden of traumatic brain injury (TBI) and spinal cord injury (SCI) and analyse their leading causes in different countries/territories. DESIGN: An analysis of Global Burden of Disease (GBD) data. SETTING: The epidemiological data were gathered from GBD Results Tool (1 January, 1990─31 December 2019) covering 21 GBD regions and 204 countries/ territories. PARTICIPANTS: Patients with TBI/SCI. MAIN OUTCOMES AND MEASURES: Absolute numbers and age-standardised rates/estimates of incidence, prevalence and years lived with disability (YLDs) of TBI/SCI by location in 2019, with their percentage changes from 1990 to 2019. The leading causes (eg, falls) of TBI/SCI in 204 countries/territories. RESULTS: Globally, in 2019, TBI had 27.16 million new cases, 48.99 million prevalent cases and 7.08 million YLDs. SCI had 0.91 million new cases, 20.64 million prevalent cases and 6.20 million YLDs. Global age-standardised incidence rates of TBI decreased significantly by -5.5% (95% uncertainty interval -8.9% to -3.0%) from 1990 to 2019, whereas SCI had no significant change (-6.1% (-17.3% to 1.5%)). Regionally, in 2019, Eastern Europe and High-income North America had the highest burden of TBI and SCI, respectively. Nationally, in 2019, Slovenia and Afghanistan had the highest age-standardised incidence rates of TBI and SCI, respectively. For TBI, falls were the leading cause in 74% (150/204) of countries/territories, followed by pedestrian road injuries (14%, 29/204), motor vehicle road injuries (5%, 11/204), and conflict and terrorism (2%, 4/204). For SCI, falls were the leading cause in 97% (198/204) of countries/territories, followed by conflict and terrorism (3%, 6/204). CONCLUSIONS: Global age-standardised incidence rates of TBI have decreased significantly since 1990, whereas SCI had no significant change. The leading causes of TBI/SCI globally were falls, but variations did exist between countries/territories. Policy-makers should continue to prioritise interventions to reduce falls, but priorities may vary between countries/territories.

Mendelian Randomization Study of Lipid Metabolites Reveals Causal Associations with Heel Bone Mineral Density.

BACKGROUND: Osteoporosis, which is a bone disease, is characterized by low bone mineral density and an increased risk of fractures. The heel bone mineral density is often used as a representative measure of overall bone mineral density. Lipid metabolism, which includes processes such as fatty acid metabolism, glycerol metabolism, inositol metabolism, bile acid metabolism, carnitine metabolism, ketone body metabolism, sterol and steroid metabolism, etc., may have an impact on changes in bone mineral density. While some studies have reported correlations between lipid metabolism and heel bone mineral density, the overall causal relationship between metabolites and heel bone mineral density remains unclear. OBJECTIVE: to investigate the causal relationship between lipid metabolites and heel bone mineral density using two-sample Mendelian randomization analysis. METHODS: Summary-level data from large-scale genome-wide association studies were extracted to identify genetic variants linked to lipid metabolite levels. These genetic variants were subsequently employed as instrumental variables in Mendelian randomization analysis to estimate the causal effects of each lipid metabolite on heel bone mineral density. Furthermore, metabolites that could potentially be influenced by causal relationships with bone mineral density were extracted from the KEGG and WikiPathways databases. The causal associations between these downstream metabolites and heel bone mineral density were then examined. Lastly, a sensitivity analysis was conducted to evaluate the robustness of the results and address potential sources of bias. RESULTS: A total of 130 lipid metabolites were analyzed, and it was found that acetylcarnitine, propionylcarnitine, hexadecanedioate, tetradecanedioate, myo-inositol, 1-arachidonoylglycerophosphorine, 1-linoleoylglycerophoethanolamine, and epiandrosterone sulfate had a causal relationship with heel bone mineral density (p < 0.05). Furthermore, our findings also indicate an absence of causal association between the downstream metabolites associated with the aforementioned metabolites identified in the KEGG and WikiPathways databases and heel bone mineral density. CONCLUSION: This work supports the hypothesis that lipid metabolites have an impact on bone health through demonstrating a causal relationship between specific lipid metabolites and heel bone mineral density. This study has significant implications for the development of new strategies to osteoporosis prevention and treatment.

Traumatic spinal injury-related hospitalizations in the United States, 2016-2019: a retrospective study.

BACKGROUND: Traumatic spinal injury (TSI) is associated with significant fatality and social burden; however, the epidemiology and treatment of patients with TSI in the US remain unclear. MATERIALS AND METHODS: An adult population was selected from the National Inpatient Sample database from 2016 to 2019. TSI incidence was calculated and TSI-related hospitalizations were divided into operative and nonoperative groups according to the treatments received. TSIs were classified as fracture, dislocation, internal organ injury, nerve root injury, or sprain injuries based on their nature. The annual percentage change (APC) was calculated to identify trends. In-hospital deaths were utilized to evaluate the prognosis of different TSIs. RESULTS: Overall, 95 047 adult patients were hospitalized with TSI in the US from 2016 to 2019, with an incidence rate of 48.4 per 100 000 persons in 2019 (95% CI: 46.2-50.6). The total incidence increased with an APC of 1.5% (95% CI: 0.1-3%) from 2016 to 2019. Operative TSI treatment was more common than nonoperative (32.8 vs. 3.8; 95% CI: 32.3-33.2 vs. 3.6-4%). The number of operations increased from 37 555 (95% CI: 34 674-40 436) to 40 460 (95% CI: 37 372-43 548); however, the operative rate only increased for internal organ injury (i.e. spinal cord injury [SCI])-related hospitalizations (APC, 3.6%; 95% CI: 2.8-4.4%). In-hospital mortality was highest among SCI-related hospitalizations, recorded at 3.9% (95% CI: 2.9-5%) and 28% (95% CI: 17.9-38.2%) in the operative and nonoperative groups, respectively. CONCLUSIONS: The estimated incidence of TSI in US adults increased from 2016 to 2019. The number of operations increased; however, the proportion of operations performed on TSI-related hospitalizations did not significantly change. In 2019, SCI was the highest associated mortality TSI, regardless of operative or nonoperative treatment.

3D Printed Chondrogenic Functionalized PGS Bioactive Scaffold for Cartilage Regeneration.

Tissue engineering is emerging as a promising approach for cartilage regeneration and repair. Endowing scaffolds with cartilaginous bioactivity to obtain bionic microenvironment and regulating the matching of scaffold degradation and regeneration play a crucial role in cartilage regeneration. Poly(glycerol sebacate) (PGS) is a representative thermosetting bioelastomer known for its elasticity, biodegradability, and biocompatibility and is widely used in tissue engineering. However, the modification and drug loading of the PGS scaffold is still a key challenge due to its high temperature curing conditions and limited reactive groups, which seriously hinders its further functional application. Here, a simple versatile new strategy of super swelling-absorption and cross-linked networks locking is presented to successfully create the 3D printed PGS-CS/Gel scaffold for the first time based on FDA-approved PGS, gelatin (Gel) and chondroitin sulfate (CS). The PGS-CS/Gel scaffold exhibits the desirable synergistic properties of well-organized hierarchical structures, excellent elasticity, improved hydrophilicity, and cartilaginous bioactivity, which can promote the adhesion, proliferation, and migration of chondrocytes. Importantly, the rate of cartilage regeneration can be well-matched with degradation of PGS-CS/Gel scaffold, and achieve uniform and mature cartilage tissue without scaffold residual. The bioactive scaffold can successfully repair cartilage in a rabbit trochlear groove defect model indicating a promising prospect of clinical transformation.

A critical appraisal of clinical practice guidelines on surgical treatments for spinal cord injury.

BACKGROUND CONTEXT: Spinal cord injury (SCI) is a global health problem with a heavy economic burden. Surgery is considered as the cornerstone of SCI treatment. Although various organizations have formulated different guidelines on surgical treatment for SCI, the methodological quality of these guidelines has still not been critically appraised. PURPOSE: We aim to systematically review and appraise the current guidelines on surgical treatments of SCI and summarize the related recommendations with the quality evaluation of supporting evidence. STUDY DESIGN: Systematic review. METHODS: Medline, Cochrane library, Web of Science, Embase, Google Scholar, and online guideline databases were searched from January 2000 to January 2022. The most updated and recent guidelines containing evidence-based or consensus-based recommendations and established by authoritative associations were included. The Appraisal of Guidelines for Research and Evaluation, 2nd edition instrument containing 6 domains (eg, applicability) was used to appraise the included guidelines. An evidence-grading scale (ie, level of evidence, LOE) was utilized to evaluate the quality of supporting evidence. The supporting evidence was categorized as A (the best quality), B, C, and D (the worst quality). RESULTS: Ten guidelines from 2008 to 2020 were included, however, all of them acquired the lowest scores in the domain of applicability among all the six domains. Fourteen recommendations (eight evidence-based recommendations and six consensus-based recommendations) were totally involved. The SCI types of the population and timing of surgery were studied. Regarding the SCI types of the population, eight guidelines (8/10, 80%), two guidelines (2/10, 20%), and three guidelines (3/10, 30%) recommended surgical treatment for patients with SCI without further clarification of characteristics, incomplete SCI, and traumatic central cord syndrome (TCCS), respectively. Besides, one guideline (1/10, 10%) recommended against surgery for patients with SCI without radiographic abnormality. Regarding the timing of surgery, there were eight guidelines (8/10, 80%), two guidelines (2/10, 20%), and two guidelines (2/10, 20%) with recommendations for patients with SCI without further clarification of characteristics, incomplete SCI, and TCCS, respectively. For patients with SCI without further clarification of characteristics, all eight guidelines (8/8, 100%) recommended for early surgery and five guidelines (5/8, 62.5%) recommended for the specific timing, which ranged from within 8 hours to within 48 hours. For patients with incomplete SCI, two guidelines (2/2, 100%) recommended for early surgery, without specific time thresholds. For patients with TCCS, one guideline (1/2, 50%) recommended for surgery within 24 hours, and another guideline (1/2, 50%) simply recommended for early surgery. The LOE was B in eight recommendations, C in three recommendations, and D in three recommendations. CONCLUSIONS: We remind the reader that even the highest quality guidelines often have significant flaws (eg, poor applicability), and some of the conclusions are based on consensus recommendations which is certainly less than ideal. With these caveats, we found most included guidelines (8/10, 80%) recommended early surgical treatment for patients after SCI, which was consistent between evidence-based recommendations and consensus-based recommendations. Regarding the specific timing of surgery, the recommended time threshold did vary, but it was usually within 8 to 48 hours, where the LOE was B to D.

N1-Methyladenosine modification of mRNA regulates neuronal gene expression and oxygen glucose deprivation/reoxygenation induction.

N1-Methyladenosine (m1A) is an abundant modification of transcripts, plays important roles in regulating mRNA structure and translation efficiency, and is dynamically regulated under stress. However, the characteristics and functions of mRNA m1A modification in primary neurons and oxygen glucose deprivation/reoxygenation (OGD/R) induced remain unclear. We first constructed a mouse cortical neuron OGD/R model and then used methylated RNA immunoprecipitation (MeRIP) and sequencing technology to demonstrate that m1A modification is abundant in neuron mRNAs and dynamically regulated during OGD/R induction. Our study suggests that Trmt10c, Alkbh3, and Ythdf3 may be m1A-regulating enzymes in neurons during OGD/R induction. The level and pattern of m1A modification change significantly during OGD/R induction, and differential methylation is closely associated with the nervous system. Our findings show that m1A peaks in cortical neurons aggregate at both the 5' and 3' untranslated regions. m1A modification can regulate gene expression, and peaks in different regions have different effects on gene expression. By analysing m1A-seq and RNA-seq data, we show a positive correlation between differentially methylated m1A peaks and gene expression. The correlation was verified by using qRT-PCR and MeRIP-RT-PCR. Moreover, we selected human tissue samples from Parkinson's disease (PD) and Alzheimer's disease (AD) patients from the Gene Expression Comprehensive (GEO) database to analyse the selected differentially expressed genes (DEGs) and differential methylation modification regulatory enzymes, respectively, and found similar differential expression results. We highlight the potential relationship between m1A modification and neuronal apoptosis following OGD/R induction. Furthermore, by mapping mouse cortical neurons and OGD/R-induced modification characteristics, we reveal the important role of m1A modification in OGD/R and gene expression regulation, providing new ideas for research on neurological damage.

Sex-related Differences in Epidemiology, Treatment, and Economic Burden of Traumatic Spinal Cord Injury in China (2013-2018).

STUDY DESIGN: Retrospective epidemiological study. OBJECTIVE: To describe differences based on biological sex in the epidemiology and treatment of the economic burden of traumatic spinal cord injury (TSCI) in China (2013-2018). SUMMARY OF BACKGROUND DATA: Although there have been many regional single-center studies on TSCI in China, there are few reports involving multicenter data, especially those that report on discrepancies related to biological sex. MATERIALS AND METHODS: This study is a nationally representative hospital-based retrospective study. The treatment data of TSCI patients in 30 hospitals in 11 provinces/cities from January 2013 to December 2018 were analyzed. Sociodemographic characteristics, accident and related injury characteristics, treatment methods, and hospital costs were obtained. Regression models were used to evaluate differences in the outcomes of interest based on biological sex and other factors. RESULTS: There were 13,465 individuals with TSCI, with a mean age of 50.0 years, and females (52.2) older than males (49.3). Overall, the average ratio of males to females was 3.1:1, ranging from 3.0:1 in 2013 to 2.8:1 in 2018. The overall proportion of patients with TSCI increased from 2013 to 2018 [annual percentage change (APC)=6.8%, 95% CI, 3.3-10.4] ( P < 0.05). The percent increase in females (APC=8.2%, 95% CI, 5.6-10.8) was greater than that of males (APC=6.3%, 95% CI, 2.1-10.6). Overall, high-level falls mainly affected males (30.8%), and low-level falls mainly occurred in females (36.6%). Females demonstrated a higher frequency of thoracolumbar trauma and less severe neurological impairment. CONCLUSIONS: This study suggests that although the main population of TSCI is male, the average ratio of males to females is decreasing. The frequency of TSCI may be increasing faster in females than in males. Therefore, it is necessary to develop sex-specific public prevention measures. In addition, more medical resources should be devoted to improving the ability of hospitals to perform early surgery.

Autologous exosome facilitates load and target delivery of bioactive peptides to repair spinal cord injury.

Spinal cord injury (SCI) causes motor, sensory and automatic impairment due to rarely axon regeneration. Developing effective treatment for SCI in the clinic is extremely challenging because of the restrictive axonal regenerative ability and disconnection of neural elements after injury, as well as the limited systemic drug delivery efficiency caused by blood spinal cord barrier. To develop an effective non-invasive treatment strategy for SCI in clinic, we generated an autologous plasma exosome (AP-EXO) based biological scaffold where AP-EXO was loaded with neuron targeting peptide (RVG) and growth-facilitating peptides (ILP and ISP). This scaffold can be targeted delivered to neurons in the injured area and elicit robust axon regrowth across the lesion core to the levels over 30-fold greater than naïve treatment, thus reestablish the intraspinal circuits and promote motor functional recovery after spinal cord injury in mice. More importantly, in ex vivo, human plasma exosomes (HP-EXO) loaded with combinatory peptides of RVG, ILP and ISP showed safety and no liver and kidney toxicity in the application to nude SCI mice. Combining the efficacy and safety, the AP-EXO-based personalized treatment confers functional recovery after SCI and showed immense promising in biomedical applications in treating SCI. It is helpful to expand the application of combinatory peptides and human plasma derived autologous exosomes in promoting regeneration and recovery upon SCI treatment.

A critical appraisal of clinical practice guidelines for diagnostic imaging in the spinal cord injury.

BACKGROUND CONTEXT: Spinal cord injury (SCI) is a serious health problem which carries a heavy economic burden. Imaging technologies play an important role in the diagnosis of SCI. Although several organizations have developed guidelines for diagnostic imaging of SCI, their quality has not yet been systematically assessed. PURPOSE: We aim to conduct a systematic review to appraise SCI guidelines and summarize their recommendations for diagnostic imaging of SCI. STUDY DESIGN: Systematic review. METHODS: We searched Embase, Medline, Web of Science, Cochrane, some guideline-specific databases (eg, Scottish Intercollegiate Guidelines Network) and Google Scholar from January 2000 to January 2022. We included guidelines developed by nationally recognized organizations. If multiple versions could be obtained, we included the latest one. We appraised included guidelines using the Appraisal of Guidelines for Research and Evaluation, 2nd edition instrument which contains six domains (eg, scope and purpose). We also extracted recommendations and assessed their supporting evidence using levels of evidence (LOE). The evidence was categorized as A (the best quality), B, C, and D (the worst quality). RESULTS: Seven guidelines (2008-2020) were included. They all received the lowest scores in the domain of applicability. All guidelines (7/7, 100%) recommended magnetic resonance imaging (MRI) in patients with SCI or SCI without radiographic abnormality (SCIWORA). A total of 12 recommendations involving patient age (eg, adult and child patients), timing of MRI (eg, as soon as possible and in the acute period), symptoms indicated for MRI (eg, a stiff spine and midline tenderness, suspected disc and posterior ligamentous complex injury, and neurological deficit), and types of MRI (eg, T2-weighted imaging and diffusion tensor imaging) were extracted. Among them, the LOE was C in nine (75%) recommendations and D in three (25%) recommendations. CONCLUSIONS: Seven guidelines were included in the present systematic review, and all of them showed the worst applicability scores in the Appraisal of Guidelines for Research and Evaluation, 2nd edition instrument. They all weakly recommended MRI for patients with suspected SCI or SCIWORA based on a low LOE.

Crosstalk between m6A mRNAs and m6A circRNAs and the time-specific biogenesis of m6A circRNAs after OGD/R in primary neurons.

Cerebral ischaemiareperfusion injury is an important pathological process in nervous system diseases during which neurons undergo oxygenglucose deprivation and reoxygenation (OGD/R) injury. No study has used epitranscriptomics to explore the characteristics and mechanism of injury. N6methyladenosine (m6A) is the most abundant epitranscriptomic RNA modification. However, little is known about m6A modifications in neurons, especially during OGD/R. m6A RNA immunoprecipitation sequencing (MeRIPseq) and RNA-sequencing data for normal and OGD/R-treated neurons were analysed by bioinformatics. MeRIP quantitative real-time polymerase chain reaction was used to determine the m6A modification levels on specific RNAs. We report the m6A modification profiles of the mRNA and circRNA transcriptomes of normal and OGD/R-treated neurons. Expression analysis revealed that the m6A levels did not affect m6A mRNA or m6A circRNA expression. We found crosstalk between m6A mRNAs and m6A circRNAs and identified three patterns of m6A circRNA production in neurons; thus, distinct OGD/R treatments induced the same genes to generate different m6A circRNAs. Additionally, m6A circRNA biogenesis during distinct OGD/R processes was found to be time specific. These results expand our understanding of m6A modifications in normal and OGD/R-treated neurons, providing a reference to explore epigenetic mechanisms and potential treatments for OGD/R-related diseases.