A critical role for microglia in regulating metabolic homeostasis and neural repair after spinal cord injury.

Traumatic spinal cord injury (SCI) often results in severe immune and metabolic disorders, aggravating neurological damage and inhibiting locomotor functional recovery. Microglia, as resident immune cells of the spinal cord, play crucial roles in maintaining neural homeostasis under physiological conditions. However, the precise role of microglia in regulating immune and metabolic functions in SCI is still unclear and is easily confused with that of macrophages. In this study, we pharmacologically depleted microglia to explore the role of microglia after SCI. We found that microglia are beneficial for the recovery of locomotor function. Depleting microglia disrupted glial scar formation, reducing neurogenesis and angiogenesis. Using liquid chromatography tandem mass spectrometry (LC‒MS/MS), we discovered that depleting microglia significantly inhibits lipid metabolism processes such as fatty acid degradation, unsaturated fatty acid biosynthesis, glycophospholipid metabolism, and sphingolipid metabolism, accompanied by the accumulation of multiple organic acids. Subsequent studies demonstrated that microglial depletion increased the inhibition of FASN after SCI. FASN inhibition exacerbated malonyl-CoA accumulation and significantly impeded the activity of mTORC1. Moreover, microglial depletion exacerbated the oxidative stress of neurons. In summary, our results indicate that microglia alleviate neural damage and metabolic disorders after SCI, which is beneficial for achieving optimal neuroprotection and neural repair.

Surgical interventions for degenerative lumbar spinal stenosis: a systematic review with network meta-analysis.

BACKGROUND: Several surgical options for degenerative lumbar spinal stenosis (LSS) are available, but current guidelines do not recommend which one should be prioritized. Although previous network meta-analyses (NMAs) have been performed on this topic, they have major methodological problems and could not provide the convincing evidence and clinical practical information required. METHODS: Randomized controlled trials (RCTs) comparing at least two surgical interventions were included by searching AMED, CINAHL, EMBASE, the Cochrane Library, and MEDLINE (inception to August 2023). A frequentist random-effects NMA was performed for physical function and adverse events due to any reason. For physical function, three follow-up time points were included: short-term (< 6 months post-intervention), mid-term (≥ 6 months but < 12 months), and long-term (≥ 12 months). Laminectomy was the reference comparison intervention. RESULTS: A total of 43 RCTs involving 5017 participants were included in the systematic review and 28 RCTs encompassing 14 types of surgical interventions were included in the NMA. For improving physical function (scale 0-100), endoscopic-assisted laminotomy (mean difference: - 8.61, 95% confidence interval: - 10.52 to - 6.69; moderate-quality evidence), laminectomy combined with Coflex (- 8.41, - 13.21 to - 3.61; moderate quality evidence), and X-stop (- 6.65, - 8.60 to - 4.71; low-quality evidence) had small effects at short-term follow-up; no statistical difference was observed at mid-term follow-up (very low- to low-quality evidence); at long-term follow-up, endoscopic-assisted laminotomy (- 7.02, - 12.95 to - 1.08; very low-quality evidence) and X-stop (- 10.04, - 18.16 to - 1.93; very low-quality evidence) had a small and moderate effect, respectively. Compared with laminectomy, endoscopic-assisted laminotomy was associated with fewer adverse events due to any reason (odds ratio: 0.27, 0.09 to 0.86; low-quality evidence). CONCLUSIONS: For adults with degenerative LSS, endoscopic-assisted laminotomy may be the safest and most effective intervention in improving physical function. However, the available data were insufficient to indicate whether the effect was sustainable after 6 months. TRIAL REGISTRATION: PROSPERO (CRD42018094180).

miR-NPs-RVG promote spinal cord injury repair: implications from spinal cord-derived microvascular endothelial cells.

BACKGROUND: Spinal cord injury (SCI) often leads to a loss of motor and sensory function. Axon regeneration and outgrowth are key events for functional recovery after spinal cord injury. Endogenous growth of axons is associated with a variety of factors. Inspired by the relationship between developing nerves and blood vessels, we believe spinal cord-derived microvascular endothelial cells (SCMECs) play an important role in axon growth. RESULTS: We found SCMECs could promote axon growth when co-cultured with neurons in direct and indirect co-culture systems via downregulating the miR-323-5p expression of neurons. In rats with spinal cord injury, neuron-targeting nanoparticles were employed to regulate miR-323-5p expression in residual neurons and promote function recovery. CONCLUSIONS: Our study suggests that SCMEC can promote axon outgrowth by downregulating miR-323-5p expression within neurons, and miR-323-5p could be selected as a potential target for spinal cord injury repair.

Dynamic changes in pyroptosis following spinal cord injury and the identification of crucial molecular signatures through machine learning and single-cell sequencing.

The pathological cascade of spinal cord injury (SCI) is highly intricate. The onset of neuroinflammation can exacerbate the extent of damage. Pyroptosis is a form of inflammation-linked programmed cell death (PCD), the inhibition of pyroptosis can partially mitigate neuroinflammation. It is imperative to delineate the principal cell types susceptible to pyroptosis and concomitantly identify key genes associated with this process. We initially defined the pyroptosis-related genes (PRGs) and analyzed their expression at different time points post SCI. The results demonstrate a substantial upregulation of differentially expressed genes (DEGs) related to pyroptosis on the 7 days post-injury (dpi), these DEGs in the 7 dpi are closely related to the inflammatory response. Subsequently, immune infiltration analysis revealed a predominant presence of inflammatory microglia. Through correlation analysis, we postulated that pyroptosis primarily manifested within the inflammatory microglia. Employing machine learning algorithms, we identified four pyroptosis-related molecular signatures, which were experimentally validated using BV2 cells and spinal cord tissue samples. The robustness of the identified molecular signatures was further confirmed through single-cell sequencing data analysis. Overall, our study elucidates the temporal dynamics of pyroptosis and identifies key molecular signatures following SCI. These findings can provide novel evidence for therapeutic interventions in SCI.

Machine learning identifies key cells and therapeutic targets during ferroptosis after spinal cord injury.

Ferroptosis, a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation, is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury. Thus, in this study, bulk RNA sequencing data (GSE47681 and GSE5296) and single-cell RNA sequencing data (GSE162610) were acquired from gene expression databases. We then conducted differential analysis and immune infiltration analysis. Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms. Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes. Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells, confirming the high expression of Atf3 and Piezo1 in these cells. Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide. In a mouse model of T8 spinal cord injury, low-dose cycloheximide treatment was found to improve neurological function, decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase, and increase levels of the anti-inflammatory cytokine arginase 1. Correspondingly, the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia, while the expression of Acsl4 decreased. Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury, identify the key cell types and genes involved in ferroptosis after spinal cord injury, and validate the efficacy of potential drug therapies, pointing to new directions in the treatment of spinal cord injury.

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 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 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) are synthesized by combining the small molecules of chlorogenic acid (CGA) with Ca2+. Ca-CGA NPs internalized by cells can be dissolved to release free CGA and Ca2+ under low pH conditions in lysosomes. In vitro results demonstrate that Ca-CGA NPs can not only enhance the osteogenic differentiation of BMSCs but also promote the phenotype transformation of macrophages from M1 to M2. Furthermore, in vivo experiments confirm that Ca-CGA NPs treatment facilitates the recovery of rat skull defect model through both 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.

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.

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.

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.

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.