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Intervertebral disc (IVD) degeneration contributes largely to pathoanatomical and degenerative changes of spinal structure that increase the risk of low back pain. Apoptosis in nucleus pulposus (NP) can aggravate IVD degeneration, and increasing studies have shown that interventions targeting NP cell apoptosis can ameliorate IVD degeneration, exhibiting their potential for use as therapeutic strategies. Recent data have shown that advanced glycation end products (AGEs) accumulate in NP tissues in parallel with the progression of IVD degeneration and form a microenvironment of oxidative stress. This study examined whether AGEs accumulation aggravates NP cell apoptosis and IVD degeneration, and explored the mechanisms underlying these effects. We observed that the viability and proliferation of human NP cells were significantly suppressed by AGEs treatment, mainly due to apoptosis. Furthermore, activation of the mitochondrial apoptosis pathway was detected after AGEs treatment. In addition, the molecular data showed that AGEs could significantly aggravate the generation of mitochondrial reactive oxygen species and prolonged activation of the mitochondrial permeability transition pore, as well as the increased level of Bax protein and decreased level of Bcl-2 protein in mitochondria. These effects could be reduced by antioxidant (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (MitoTEMPO) and Visomitin (SKQ1). Importantly, we identified that impairment of Sirtuin3 (SIRT3) function and the mitochondrial antioxidant network were vital mechanisms in AGEs-induced oxidative stress and secondary human NP cell apoptosis. Finally, based on findings that nicotinamide mononucleotide (NMN) could restore SIRT3 function and rescue human NP cell apoptosis through adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-γ coactivator 1α (AMPK-PGC-1α) pathway in vitro, we confirmed its protective effect on AGEs-induced IVD degeneration in vivo. In conclusion, our data demonstrate that SIRT3 protects against AGEs-induced human NP cell apoptosis and IVD degeneration. Targeting SIRT3 to improve mitochondrial redox homeostasis may represent a potential therapeutic strategy for attenuating AGEs-associated IVD degeneration.

Study Design. A systematic review and meta-analysis. Objective. The objective of this study was to investigate the incidence of surgical site infection (SSI) in patients following spine surgery and the rate of microorganisms in these cases. Summary of Background Data. Many studies have investigated the incidence and risk factors of SSI following spinal surgery, whereas no meta-analysis studies have been conducted regarding the comprehensive epidemiological incidence of SSI after spine surgery. Methods. We searched the PubMed, Embase, and Cochrane Library databases for relevant studies that reported the incidence of SSI after spine surgery, and manually screened reference lists for additional studies. Relevant incidence estimates were calculated. Subgroup analysis, sensitivity analysis, and publication bias assessment were also performed. Results. Our meta-analysis included 27 studies, with 603 SSI cases in 22,475 patients. The pooled SSI incidence was 3.1%. Subgroup analysis revealed that the incidence of superficial SSI was 1.4% and the incidence of deep SSI was 1.7%. Highest incidence (13.0%) was found in patients with neuromuscular scoliosis among the different indications. The incidences of SSI in cervical, thoracic, and lumbar spine were 3.4%, 3.7%, and 2.7%, respectively. Compared with posterior approach surgery (5.0%), anterior approach showed a lower incidence (2.3%) of SSI. Instrumented surgery had a higher incidence of SSI than noninstrumented surgery (4.4% vs. 1.4%). Patients with minimally invasive surgery (1.5%) had a lower SSI incidence than open surgery (3.8%). Lower incidence of SSI was found when vancomycin powder was applied locally during the surgery (1.9%) compared with those not used (4.8%). In addition, the rates of Staphylococcus aureus, Staphylococcus epidermidis, and methicillin-resistant Staphylococci in microbiological culture results were 37.9%, 22.7%, and 23.1%, respectively. Conclusion. The pooled incidence of SSI following spine surgery was 3.1%. These figures may be useful in the estimation of the probability of SSI following spine surgery. Level of Evidence: 3

, a novel coronavirus that is related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in phylogenetic distance was identified. 1 This virus, which was later designated as SARS-CoV-2, also causes acute respiratory disease syndrome (ARDS) termed coronavirus disease 2019 (COVID-19), which was declared as a pandemic by the World Health Organization in March 2020. Although the majority of patients of COVID-19 show moderate symptoms such as dry cough and fatigue, up to 20% cases develop severe symptoms characterized as ARDS, a clinical pulmonary phenomenon marked by the development of bilateral infiltrates and hypoxemia. 2 The median incubation period of SARS-CoV-2 infection is~4-5 days before symptom onset, and the majority of symptomatic patients develop symptoms within 11.5 days. Within 5-6 days of symptom onset, SARS-CoV-2 viral load reaches its peak, which is much earlier than SARS-CoV. 3 Severe COVID-19 cases progress to ARDS with hypoxemia around 8-12 days after symptom onset. 2 Although various independent factors such as older age and existing diseases contribute to mortality, the majority of fatal patients die of complications such as ARDS, myocardial injury, acute kidney injury, and sepsis. 2,3 The pathogenesis of COVID-19 has been heavily investigated in the past months. Pathophysiology in COVID-19 is characterized by diffuse alveolar damage, focal reactive hyperplasia of pneumocytes, inflammatory cellular infiltration, vasculitis, hypercoagulability, neutrophilia, and lymphopenia. 4 Studies have suggested that hyper-inflammation is linked to more severe disease of COVID-19, which is characterized by a cytokine releasing syndrome (CRS). 3,5 It has been reported that some inflammatory cytokines (such as IL-6, IL-10, and TNF-α) and chemokines (such as CXCL10/ IP-10, CCL2/MCP-1, and CCL3/MIP-1α) are upregulated in COVID-19 patients. 2 However, these studies are limited by the small sample size, narrowed cytokine and chemokine spectrum, and absence of temporal kinetic analysis of these factors with disease progression. Currently, limited information is available on host factors and biomarkers affecting individual outcomes in COVID-19. Identification of host plasma factors that are correlated to COVID-19 progression may provide potential biomarkers and targets for developing therapeutics. To systematically investigate the kinetic changes of plasma levels of cytokines, chemokines and growth factors (CCGFs) over the disease courses in COVID-19 patients as well as the correlations between the CCGF profiles and disease severity, we measured levels of 48 CCGFs in plasma of mild, severe and fatal COVID-19 patients collected at different stages of disease courses. We collected sera from 6 fatal, 7 severe, and 10 mild patients at day 1, 5, 10, and 14 after diagnosis. One sample was collected from each of the 4 healthy donors. We measured the levels of

Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.

Objective Mitochondrial dysfunction, oxidative stress and nucleus pulposus (NP) cell apoptosis are important contributors to the development and pathogenesis of intervertebral disc degeneration (IDD). Here, we comprehensively evaluated the effects of mitochondrial dynamics, mitophagic flux and Nrf2 signalling on the mitochondrial quality control, ROS production and NP cell survival in in vitro and ex vivo compression models of IDD and explored the effects of the mitochondria‐targeted anti‐oxidant MitoQ and its mechanism. Material and methods Human NP cells were exposed to mechanical compression to mimic pathological conditions. Results Compression promoted oxidative stress, mitochondrial dysfunction and NP cell apoptosis. Mechanistically, compression disrupted the mitochondrial fission/fusion balance, inducing fatal fission. Concomitantly, PINK1/Parkin‐mediated mitophagy was activated, whereas mitophagic flux was blocked. Nrf2 anti‐oxidant pathway was insufficiently activated. These caused the damaged mitochondria accumulation and persistent oxidative damage. Moreover, MitoQ restored the mitochondrial dynamics balance, alleviated the impairment of mitophagosome‐lysosome fusion and lysosomal function and enhanced the Nrf2 activity. Consequently, damaged mitochondria were eliminated, redox balance was improved, and cell survival increased. Additionally, MitoQ alleviated IDD in an ex vivo rat compression model. Conclusions These findings suggest that comodulation of mitochondrial dynamics, mitophagic flux and Nrf2 signalling alleviates sustained mitochondrial dysfunction and oxidative stress and represents a promising therapeutic strategy for IDD; furthermore, our results provide evidence that MitoQ might serve as an effective therapeutic agent for this disorder.

Background: Intervertebral disc degeneration (IDD) is a major contributor to lower back pain, however, the molecular and pathogenetic mechanisms underlying IDD are poorly understood. As a high-risk factor for IDD, compression stress was reported to induce apoptosis of nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation during IDD progression. Circular RNA (circRNA) is a class of endogenous non-coding RNA (ncRNA) and has been reported to function in several diseases. However, whether and how circRNA regulates compression-induced damage of NP cells remains vague. Here, we aimed to investigate the key role of circRNA in compression loading-induced IDD. Methods: We analysed the circRNA expression of three samples from compression-treated NP cells and three control samples using circRNA microarray assays and further investigated the circRNA involved in compression-induced damage of NP cells (circRNA-CIDN). We investigated the effects of circRNA-CIDN on compression-induced cell apoptosis and NP ECM degradation in vitro and ex vivo. We observed that circRNA-CIDN bound to miRNAs as a miRNA sponge based on luciferase and RNA immunoprecipitation (RIP) assays. Findings:: CircRNA-CIDN was significantly downregulated in compression-treated human NP cells, as validated by circRNA microarray and qRT-PCR analysis, and overexpressing circRNA-CIDN inhibited compression-induced apoptosis and NP ECM degradation. Further studies demonstrated that circRNA-CIDN served as a sponge for miR-34a-5p, an important miRNA that enhanced compression-induced damage of NP cells via repressing the silent mating type information regulation 2 homolog 1 (SIRT1). CircRNA-CIDN was also verified to contain IDD development in an ex vivo IDD model. Interpretation: Our results revealed that circRNA-CIDN binding to miR-34a-5p played an important role in mitigating compression loading-induced nucleus pulposus cell damage via targeting SIRT1, providing a potential therapeutic strategy for IDD treatment.

Seasonal human coronaviruses (HCoVs) including HCoV-229E,-OC43,-NL63 and-HKU1 widely spread in global human populations. However, the relevance of humoral response against seasonal HCoVs to COVID-19 pathogenesis is elusive. In this study, we profiled the temporal changes of IgG antibody against spike proteins (S-IgG) of SARS-CoV-2 and seasonal HCoVs in 838 plasma samples collected from 344 COVID-19 patients. We tested the antigenic cross-reactivities of S protein between SARS-CoV-2 and seasonal HCoVs and evaluated the correlations between the levels of HCoV-OC43 S-IgG and the disease severity in COVID-19 patients. We found that SARS-CoV-2 S-IgG titers mounted until days 22-28, whereas HCoV-OC43 antibody titers increased until days 15-21 and then plateaued until day 46. However, IgG titers against HCoV-NL63,-229E, and-HKU1 showed no significant increase. A two-way crossreactivity was identified between SARS-CoV-2 and HCoV-OC43. Neutralizing antibodies against SARS-CoV-2 were not detectable in healthy controls who were positive for HCoV-OC43 S-IgG. HCoV-OC43 S-IgG titers were significantly higher in patients with severe disease than those in mild patients at days 1-21 post symptom onset (PSO). Higher levels of HCoV-OC43 S-IgG were also observed in patients requiring mechanical ventilation. At days 1-10 PSO, HCoV-OC43 S-IgG titers correlated to disease severity in the age group over 60. Our data indicate that there is a correlation between cross-reactive antibody against HCoV-OC43 spike protein and disease severity in COVID-19 patients.