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Spinal cord injury (SCI), for which there currently is no cure, is a heavy burden on patient physiology and psychology. The microenvironment of the injured spinal cord is complicated. According to our previous work and the advancements in SCI research, ‘microenvironment imbalance’ is the main cause of the poor regeneration and recovery of SCI. Microenvironment imbalance is defined as an increase in inhibitory factors and decrease in promoting factors for tissues, cells and molecules at different times and spaces. There are imbalance of hemorrhage and ischemia, glial scar formation, demyelination and re-myelination at the tissue’s level. The cellular level imbalance involves an imbalance in the differentiation of endogenous stem cells and the transformation phenotypes of microglia and macrophages. The molecular level includes an imbalance of neurotrophic factors and their pro-peptides, cytokines, and chemokines. The imbalanced microenvironment of the spinal cord impairs regeneration and functional recovery. This review will aid in the understanding of the pathological processes involved in and the development of comprehensive treatments for SCI.

ObjectivesTo 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.DesignAn analysis of Global Burden of Disease (GBD) data.SettingThe epidemiological data were gathered from GBD Results Tool (1 January, 1990─31 December 2019) covering 21 GBD regions and 204 countries/ territories.ParticipantsPatients with TBI/SCI.Main outcomes and measuresAbsolute 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.ResultsGlobally, 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).ConclusionsGlobal 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.

Nowadays, the efficacy of teriparatide in treating osteoporosis was widely accepted, but the discussion about using teriparatide to enhance fracture healing hasn't come to an agreement. This meta-analysis was conducted to evaluate the effectiveness of teriparatide for fracture healing. We searched PubMed, the Cochrane Library, and Embase in August 2016 for randomized controlled trials (RCTs) which concerned the treatment of teriparatide for fracture healing. Finally, a total of 380 patients were randomly assigned in the 5 trials included in this meta-analysis. There was a significant effectiveness with regards to function improvement in patients following fracture, however, there was no significant effectiveness with regards to time of radiographic fracture healing, fracture healing rate and reduction in pain. This analysis showed that administration of teriparatide following fracture lacked the effectiveness for fracture healing. Moreover, teriparatide administration had no apparent adverse effects. These results should be interpreted with caution because of some clear limitations. If we want to confirm whether teriparatide improves fracture healing, more high-quality randomized controlled trials are needed.

BackgroundAging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction.MethodsTherapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM.ResultsThree molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score.ConclusionAging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.

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 TGFβ/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. In this study, a tolerant and rapid endochondral bone regeneration strategy is proposed using 3D‐printed PCL framework‐enhanced biomineralized matrix hydrogels with both hypoxic and osteoinductive microenvironment, which can effectively regulate BMSC‐based endochondral ossification (ECO) for tissue‐engineered bone construction. The current study eventually realized satisfactory ectopic osteogenesis in nude mice and skull defect repair in rabbits by the high‐efficiency ECO mode.

Cerebral ischaemia‒reperfusion injury (IRI), during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m 1 A) is an RNA modification that can affect gene expression and RNA stability. The m 1 A landscape and potential functions of m 1 A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m 1 A modification in normal and OGD/R-treated mouse neurons and the effect of m 1 A on diverse RNAs. We investigated the m 1 A landscape in primary neurons, identified m 1 A-modified RNAs, and found that OGD/R increased the number of m 1 A RNAs. m 1 A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA–RNA binding proteins (RBPs) interactions and circRNA translation. We showed that m 1 A modification mediates the circRNA/lncRNA‒miRNA–mRNA competing endogenous RNA (ceRNA) mechanism and that 3' untranslated region (3’UTR) modification of mRNAs can hinder miRNA–mRNA binding. Three modification patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m 1 A-regulatory specificity. Systematic analysis of the m 1 A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA modification and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.

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. Graphical Abstract

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).

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.