Cytoplasmic Escape of Mitochondrial DNA Mediated by Mfn2 Downregulation Promotes Microglial Activation via cGas-Sting Axis in Spinal Cord Injury.

Neuroinflammation is associated with poor outcomes in patients with spinal cord injury (SCI). Recent studies have demonstrated that stimulator of interferon genes (Sting) plays a key role in inflammatory diseases. However, the role of Sting in SCI remains unclear. In the present study, it is found that increased Sting expression is mainly derived from activated microglia after SCI. Interestingly, knockout of Sting in microglia can improve the recovery of neurological function after SCI. Microglial Sting knockout restrains the polarization of microglia toward the M1 phenotype and alleviates neuronal death. Furthermore, it is found that the downregulation of mitofusin 2 (Mfn2) expression in microglial cells leads to an imbalance in mitochondrial fusion and division, inducing the release of mitochondrial DNA (mtDNA), which mediates the activation of the cGas-Sting signaling pathway and aggravates inflammatory response damage after SCI. A biomimetic microglial nanoparticle strategy to deliver MASM7 (named MSNs-MASM7@MI) is established. In vitro, MSNs-MASM7@MI showed no biological toxicity and effectively delivered MASM7. In vivo, MSNs-MASM7@MI improves nerve function after SCI. The study provides evidence that cGas-Sting signaling senses Mfn2-dependent mtDNA release and that its activation may play a key role in SCI. These findings provide new perspectives and potential therapeutic targets for SCI treatment.

Efficacy and safety of pharmacologic therapies for prevention of osteoporotic vertebral fractures in postmenopausal women.

Background: There are many pharmaceutical interventions available to prevent osteoporotic vertebral fractures in postmenopausal women, but the efficacy and safety of these drugs are unknown. This study aimed to investigate the efficacy and safety of drugs in the prevention of osteoporotic vertebral fractures. Methods: PubMed, Embase, and the Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) published up to February 15, 2020, including postmenopausal women with osteoporosis. Network meta-analysis was conducted based on the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The relative risk (RR) and 95% confidence interval (CI) were used to report the results. This study was registered with PROSPERO, number CRD42020201167. Main Outcomes were incidences of new vertebral fracture and serious adverse events. Results: Fifty-five RCTs (n = 104 580) evaluating vertebral fractures of sixteen kinds of pharmacologic therapies were included in the network meta-analysis. Abaloparatide (RR, 0.21; [95% CI, 0.09 to 0.51]), alendronate (RR, 0.55; [95% CI, 0.38 to 0.81]), calcitonin (RR, 0.44; [95% CI, 0.25 to 0.78]), denosumab (RR, 0.33; [95% CI, 0.14 to 0.61]), parathyroid hormone (PTH) (RR, 0.32; [95% CI, 0.10 to 0.97]), risedronate (RR, 0.65; [95% CI, 0.42 to 1.00]), romosozumab (RR, 0.31; [95% CI, 0.16 to 0.61]), strontium ranelate (RR, 0.62; [95% CI, 0.42 to 0.93]), teriparatide (RR, 0.27; [95% CI, 0.17 to 0.43]), and zoledronate (RR, 0.41; [95% CI, 0.93]) were associated with lower vertebral fracture risk compared to placebo. PTH was associated with more adverse event rates. For any two drug treatments, the RR of serious adverse events was not statistically significant. Hormone replacement therapy (HRT) and calcitonin may be slower to work because they have only been shown to reduce the risk of vertebral fractures in long-term (>18 months) follow-up. Conclusions: A variety of drugs are safe and effective in preventing osteoporotic vertebral fractures. HRT and calcitonin only reduced the risk of vertebral fractures during a follow-up of 21-72 months.

Comparison of posterior decompression techniques and conventional laminectomy for lumbar spinal stenosis.

Objectives: To compare the efficacy of posterior decompression techniques with conventional laminectomy for lumbar spinal stenosis. Methods: The Embase, PubMed, and Cochrane Library databases were searched with no language limitations from inception to January 13, 2022. The main outcomes were functional disability, perceived recovery, leg and back pain, complications. A random effects model was used to pooled data. Risk ratio (RR), mean difference (MD) and 95% confidence interval (CI) were used to report results. The study protocol was published in PROSPERO (CRD42022302218). Results: 14 trials including 1,106 participants were included in the final analysis. Bilateral laminotomy was significantly more efficacious in improve functionality than laminectomy [MD: -2.94; (95% CI, -4.12 to -1.76)]. Low incidence of iatrogenic instability due to bilateral laminectomy compared with laminectomy [RR: 0.11; (95% CI, 0.02 to 0.59)]. In addition, between those who received bilateral laminotomy and those undergoing laminectomy, the result showed significant difference regarding recovery [RR: 1.31; (95% CI, 1.03 to 1.67)]. Conclusions: This study provides evidence that bilateral laminotomy has advantages in functional recovery, postoperative stability, and postoperative rehabilitation outcomes. Further research is needed to determine whether posterior techniques provide a safe and effective option for conventional laminectomy.

The Anticancer Effect of Metformin Combined with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients with or Without Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.

INTRODUCTION: Despite the growing evidence for the anticancer effect of metformin or its combination with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), the efficacies and side effects of such strategies in non-small cell lung cancer (NSCLC) patients with or without type 2 diabetes mellitus (T2DM) are not well understood. This meta-analysis was performed to determine the efficacy and side effects of metformin combined with EGFR-TKIs (MET-EGFR-TKIs) for the treatment of NSCLC with or without T2DM. METHODS: PubMed and Cochrane Library databases were used to retrieve relevant studies through August 2020 using the keywords "metformin", "EGFR-TKIs" ("gefitinib" or "erlotinib" or "afatinib" or "icotinib" or "dacomitinib") and "lung cancer". The patients in the experimental group received MET-EGFR-TKIs, while those in the control group received only EGFR-TKIs. The outcome analysis reported overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Random-effect models and fixed-effect models were used to estimate the combined hazard ratio (HR) and odds ratio (OR) depending on the data heterogeneity. Three studies (including 1996 patients) were included in the current meta-analysis. RESULTS: There were significant differences in PFS (HR 0.84; 95% confidence interval (CI) 0.75-0.95; P = 0.004) and OS (HR 0.77; 95% CI, 0.50-1.04; P < 0.001) between the MET-EGFR-TKI and EGFR-TKI groups. Although the ORR (OR 1.38; 95% CI 0.66-2.88; P = 0.105) and DCR (OR 2.61, 95% CI 0.68-9.95, P = 0.160) were improved, there was no statistical significance. OS subgroup analysis showed that the combination was more effective in NSCLC with T2DM than in NSCLC without T2DM (HR 0.84; 95% CI 0.74-0.95; P < 0.005). CONCLUSIONS: MET-EGFR-TKIs provided benefits for PFS and OS, and OS subgroup analysis showed that patients with NSCLC with T2DM received greater benefit than NSCLC patients without T2DM. However, further large-scale, well-designed randomized controlled trials (RCTs) are warranted to confirm the findings in the present investigation.

Clinical Efficacy and Safety of Surgical Treatments in Patients With Pure Cervical Radiculopathy.

Background: Traditionally paired meta-analysis revealed inconsistencies in the safety and effectiveness of surgical interventions. We conducted a network meta-analysis to assess various treatments' clinical efficacy and safety for pure cervical radiculopathy. Methods: The Embase, PubMed, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing different treatment options for patients with pure cervical radiculopathy from inception until October 23, 2021. The primary outcomes were postoperative success rates, postoperative complication rates, and postoperative reoperation rates. The pooled data were subjected to a random-effects consistency model. The protocol was published in PROSPERO (CRD42021284819). Results: This study included 23 RCTs (n = 1,844) that evaluated various treatments for patients with pure cervical radiculopathy. There were no statistical differences between treatments in the consistency model in terms of major clinical effectiveness and safety outcomes. Postoperative success rates were higher for anterior cervical foraminotomy (ACF: probability 38%), posterior cervical foraminotomy (PCF: 24%), and anterior cervical discectomy with fusion and additional plating (ACDFP: 21%). Postoperative complication rates ranked from high to low as follows: cervical disc replacement (CDR: probability 32%), physiotherapy (25%), ACF (25%). Autologous bone graft (ABG) had better relief from arm pain (probability 71%) and neck disability (71%). Among the seven surgical interventions with a statistical difference, anterior cervical discectomy with allograft bone graft plus plating (ABGP) had the shortest surgery time. Conclusions: According to current results, all surgical interventions can achieve satisfactory results, and there are no statistically significant differences. As a result, based on their strengths and patient-related factors, surgeons can exercise discretion in determining the appropriate surgical intervention for pure cervical radiculopathy.Systematic Review Registration: CRD42021284819.

Association Between Vitamin D Supplementation and Fall Prevention.

Background: Falls occur frequently among older individuals, leading to high morbidity and mortality. This study was to assess the efficacy of vitamin D in preventing older individuals from falling. Methods: We searched the PubMed, Cochrane Library, and EMBASE databases systematically using the keywords "vitamin D" and "fall" for randomized controlled trials (RCTs) comparing the effects of vitamin D with or without calcium supplements with those of a placebo or no treatment on fall incidence in adults older than 50 years. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs) and 95% CIs with random-effects models. Results: A total of 38 RCTs involving 61 350 participants fulfilled the inclusion criteria. Compared with placebo, high-dose vitamin D (≥ 700 IU) can prevent falls [RR, 0.87 (95% CI 0.79 to 0.96); ARD, -0.06 (95% CI, -0.10 to -0.02)]. Low-dose vitamin D (<700 IU) was not significantly associated with falls. Subgroup analysis showed that supplemental calcium, 25(OH) D concentration and frequency influenced the effect of vitamin D in preventing falls. Sensitivity analysis showed that vitamin D prevented falls, which was consistent with the primary analysis. In addition, the active form of vitamin D also prevented falls. Conclusion: In this meta-analysis of RCTs, doses of 700 IU to 2000 IU of supplemental vitamin D per day were associated with a lower risk of falling among ambulatory and institutionalized older adults. However, this conclusion should be cautiously interpreted, given the small differences in outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020179390.

Decompression alone or decompression and fusion in degenerative lumbar spondylolisthesis.

Background: Clinically, there are substantive practice variations in surgical management of degenerative lumbar spondylolisthesis. We aimed at evaluating whether decompression alone outcomes for patients with degenerative lumbar spondylolisthesis are comparable to those of decompression with fusion. Methods: In this meta-analysis, the Embase, PubMed, and Cochrane Library databases were searched from inception to February 16th, 2022. Randomised controlled trials (RCTs) and cohort studies comparing decompression alone with decompression and fusion for patients with degenerative lumbar spondylolisthesis were included in this study. There were no language limitations. Odds ratio (OR), mean difference (MD) and 95% confidence interval (CI) were used to report results in the random-effects model. Main outcomes included Oswestry disability index (ODI), pain, clinical satisfaction, complication and reoperation rates. The study protocol was published in PROSPERO (CRD42022310645). Findings: Thirty-three studies (6 RCTs and 27 cohort studies) involving 94 953 participants were included. Differences in post-operative ODI between decompression alone and decompression with fusion were not significant. A small difference for back (MD, 0.13; [95% CI, 0.08 to 0.18]; I 2:0.00%) and leg pain (MD, 0.30; [95% CI, 0.09 to 0.51]; I 2:48.35%) was observed on the 3rd post-operative month. The results did not reveal significant differences in leg pain and back pain between decompression alone and fusion groups on the 6th, 12th, and 24th post-operative months. Difference in clinical satisfaction between decompression alone and decompression with fusion were not significant from RCTs (OR, 0.26; [95% CI, 0.03 to 1.92]; I 2:83.27%). Complications (OR, 1.54; [95% CI, 1.16 to 2.05]; I 2:48.88%), operation time (MD, 83.39; [95% CI, 55.93 to 110.85]; I 2:98.75%), intra-operative blood loss (MD, 264.58; [95% CI, 174.99 to 354.16]; I 2:95.61%) and length of hospital stay (MD, 2.85; [95% CI, 1.60 to 4.10]; I 2:99.49%) were higher with fusion. Interpretation: Clinical effectiveness of decompression alone was comparable to that of decompression with fusion for degenerative lumbar spondylolisthesis. Decompression alone is recommended for patients with degenerative lumbar spondylolisthesis. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81871818), Tangdu Hospital Seed Talent Program (Fei-Long Wei), Natural Science Basic Research Plan in Shaanxi Province of China (No.2019JM-265) and Social Talent Fund of Tangdu Hospital (No.2021SHRC034).

Association of robot-assisted techniques with the accuracy rates of pedicle screw placement: A network pooling analysis.

Background: Traditional paired meta-analyses have yielded inconsistent results for the safety and effectiveness of robotic-assisted pedicle screw placement due to the high heterogeneity within studies. This study evaluated the clinical effectiveness and safety of robotic-assisted pedicle screw placement. Methods: The Embase, PubMed, and Cochrane Library databases were searched with no language limitations from inception to Jan 4, 2022. Odds ratio (OR), mean difference (MD), and 95% confidence interval (CI) were used to report results. The main outcomes were accuracy of pedicle screw placement, proximal facet joint violation, and complications. The study protocol was published in PROSPERO (CRD42022301417). Findings: 26 trials including 2046 participants evaluating robotic-assisted pedicle screw placement were included in this study. Our pooled results showed that Renaissance (OR 2.86; [95% CI 1.79 to 4.57]) and TiRobot (OR 3.10; [95% CI 2.19 to 4.40]) yielded higher rates of perfect pedicle screw insertion (Grades A) than the conventional freehand technique. Renaissance (OR 2.82; [95% CI 1.51 to 5.25]) and TiRobot (OR 4.58; [95% CI 2.65 to 7.89]) yielded higher rates of clinically acceptable pedicle screw insertion (Grades A+B). However, ROSA, SpineAssist, and Orthobot were not associated with higher perfect pedicle screw insertion and clinically acceptable pedicle screw insertion rates. Robot-assisted techniques were associated with low rates of proximal facet joint violation (OR 0.18; [95% CI 0.10 to 0.32]; I2:9.55%) and overall complications (OR 0.38; [95% CI 0.23 to 0.63]; I2:27.05%). Moreover, robot-assisted techniques were associated with lower radiation doses (MD -14.38; [95% CI -25.62 to -3.13]; I2:100.00%). Interpretation: Our findings suggest that only Renaissance and TiRobot systems are associated with high accuracy rates of pedicle screw placement. Robotic-assisted techniques hold great promise in spinal surgery due to their safety and effectiveness. Funding: This work was supported by grants from the National Natural Science Foundation of China (No. 81871818), Tangdu Hospital Seed Talent Program (Fei-Long Wei) and Natural Science Basic Research Plan in Shaanxi Province of China (No.2019JM-265).

Oblique Lateral Interbody Fusion vs. Minimally Invasive Transforaminal Lumbar Interbody Fusion for Lumbar Spinal Stenosis: A Retrospective Cohort Study.

Background: Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is an effective surgical option for lumbar spinal stenosis (LSS) with spondylolisthesis. However, few studies have discussed oblique lateral interbody fusion (OLIF) with MIS-TLIF. Objective: To evaluate postoperative improvements, complications, and reoperation rates between patients with LSS undergoing OLIF or MIS-TLIF. Methods: We retrospectively studied 113 LLS patients who underwent OLIF (53) or MIS-TLIF (60) with percutaneous pedicle screw fixation between January 2016 and December 2018. We measured estimated blood loss, operative time, hospital stay, reoperation, and complication incidence, visual analog scale (VAS), Oswestry Disability Index (ODI), Japanese Orthopedic Association (JOA), and Short Form-36 (SF-36) scores, discal and foraminal height and lumbar lordotic angle. Results: The mean age was 58.81 ± 0.9 years. The TLIF group had increased operation time, blood loss, and hospital stays (p = 0.007, 0.001, and 0.016, respectively). Postoperatively, VAS and ODI scores significantly decreased while JOA and SF-36 scores significantly increased. The postoperative differences in main outcomes between the groups were insignificant (all p > 0.05). The OLIF group had the lowest rates of overall (9.8% OLIF vs. 12.9% MIS-TLIF), intraoperative (3.9% OLIF vs. 4.8% MIS-TLIF), and postoperative complications (5.9% OLIF vs. 8.1% MIS-TLIF), but the differences were insignificant (p = 0.607, 0.813, and 0.653, respectively). The reoperation rate did not differ significantly (3.8% OLIF vs. 3.3% MIS-TLIF) (p = 0.842). OLIF restored disc height (74.4 vs. 32.0%), foraminal height (27.4 vs. 18.2%), and lumbar lordotic angle (3.5 vs. 1.1%) with greater success than did MIS-TLIF. Conclusion: Patients undergoing OLIF with LSS improved similarly to MIS-TLIF patients. OLIF restored disc height, foraminal height and lumbar lordotic angle more successfully than did MIS-TLIF.

Exploring the Pharmacological Potential of Metformin for Neurodegenerative Diseases.

Metformin, one of the first-line of hypoglycemic drugs, has cardioprotective, anti-inflammatory and anticancer activities, in addition to its proven hypoglycemic effects. Furthermore, the preventive and therapeutic potential of metformin for neurodegenerative diseases has become a topic of concern. Increasing research suggests that metformin can prevent the progression of neurodegenerative diseases. In recent years, many studies have investigated the neuroprotective effect of metformin in the treatment of neurodegenerative diseases. It has been revealed that metformin can play a neuroprotective role by regulating energy metabolism, oxidative stress, inflammatory response and protein deposition of cells, and avoiding neuronal dysfunction and neuronal death. On the contrary, some have hypothesized that metformin has a two-sided effect which may accelerate the progression of neurodegenerative diseases. In this review, the results of animal experiments and clinical studies are reviewed to discuss the application prospects of metformin in neurodegenerative diseases.