TMEM16F inhibition limits pain-associated behavior and improves motor function by promoting microglia M2 polarization in mice.

Spinal cord injury (SCI) leads to sensorimotor deficits and autonomic changes. Macrophages and microglia could be polarized into the classically activated pro-inflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype. Transmembrane protein with unknown function 16F (TMEM16F) exhibits functional diversity and may contribute to microglial function. However, the effects of TMEM16F on the modulation of macrophage/microglial polarization are still not fully understood. In the study, TMEM16F up-regulation was detected after SCI in mice, and TMEM16F protein was found in macrophages/microglia in injured spinal cord sections. Depletion of TMEM16F improved motor function in male mice with SCI. M1-type macrophages/microglia accumulated in lower numbers in the injured spinal cord of TMEM16F-knockout (KO) mice. M2 polarization inhibited by SCI was improved in mice with TMEM16F deficiency. TMEM16F deletion also attenuated microglial/macrophage pro-inflammatory response. Furthermore, significant down-regulation of A disintegrin and metalloprotease 17 (ADAM17) was observed in TMEM16F-KO mice. Importantly, TMEM16F-promoted M1 polarization and -inhibited M1 polarization were largely associated with the suppression of ADAM17. Overall, our findings provided new insights into the regulatory mechanisms of macrophage/microglial polarization, thereby possibly facilitating the development of new therapeutic strategies for SCI through the regulation of TMEM16F/ADAM17 signaling.

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.

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.

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.

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.

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.

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).

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).

Eight Surgical Interventions for Lumbar Disc Herniation: A Network Meta-Analysis on Complications.

Objective: Therapeutic options for lumbar disc surgery (LDH) have been rapidly evolved worldwide. Conventional pair meta-analysis has shown inconsistent results of the safety of different surgical interventions for LDH. A network pooling evaluation of randomized controlled trials (RCT) was conducted to compare eight surgical interventions on complications for patients with LDH. Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for RCT from inception to June 2020, with registration in PROSPERO (CRD42020176821). This study is conducted in accordance with Cochrane guidelines. Primary outcomes include intraoperative, post-operative, and overall complications, reoperation, operation time, and blood loss. Results: A total of 27 RCT with 2,948 participants and eight interventions, including automated percutaneous lumbar discectomy (APLD), chemonucleolysis (CN), microdiscectomy (MD), micro-endoscopic discectomy (MED), open discectomy (OD), percutaneous endoscopic lumbar discectomy (PELD), percutaneous laser disc decompression (PLDD), and tubular discectomy (TD) were enrolled. The pooling results suggested that PELD and PLDD are with lower intraoperative and post-operative complication rates, respectively. TD, PELD, PLDD, and MED were the safest procedures for LDH according to complications, reoperation, operation time, and blood loss. Conclusion: The results of this study provided evidence that PELD and PLDD were with lower intraoperative and post-operative complication rates, respectively. TD, PELD, PLDD, and MED were the safest procedures for LDH according to complications, reoperation, operation time, and blood loss. Systematic Review Registration: PROSPERO, identifier CRD42020176821.

Management for lumbar spinal stenosis: Protocol for a network meta-analysis and systematic review.

INTRODUCTION: Lumbar spinal stenosis (LSS) is caused by structural changes of the spine, which lead to several severe symptoms, including back pain, leg pain, numbness and tingling in the legs, as well as reduced physical function. However, there is little evidence suggesting whether a patient with LSS should be treated with surgery. If surgery is recommended, which type of surgery benefits the patient most? To answer these questions, we will conduct a network meta-analysis and a systematic review to compare surgical and nonsurgical interventions in terms of efficacy as well as safety in adult patients with LSS. METHODS AND ANALYSIS: We will search the PubMed, Cochrane library, and EMBASE databases for articles published prior to October 10, 2019. We will search for randomized controlled trials assessing surgical and nonsurgical interventions for adult patients with degenerative LSS without any language restrictions. The primary outcome measures will be pain and disability. The secondary outcomes will include adverse events (number of events or number of people with each type of adverse event), reoperations, complications, blood loss and operation time. We will obtain the full texts of the potentially relevant studies and independently assess them. The quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation framework. A random-effects network meta-analysis will be performed to analyze all the evidence under the frequentist framework, and the ranking results will be presented. We will generate plots depicting the network geometry using Stata. The network meta-analysis will be performed according to the Bayesian framework. Ethics and dissemination Ethics approval is not required. The research will be published in a peer-reviewed journal.