The impact of phosphodiesterase inhibition on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review.

Study design: Systematic review. Objective: The objective of this study was to evaluate the impact of phosphodiesterase (PDE) inhibitors on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury (SCI). Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered with PROSPERO (CRD42019150639). Searches were performed in MEDLINE and Embase. Studies were included if they evaluated the impact of PDE inhibitors on neurobehavioral outcomes in preclinical models of traumatic or non-traumatic SCI. Data were extracted from relevant studies, including sample characteristics, injury model, and neurobehavioral assessment and outcomes. Risk of bias was assessed using the SYRCLE checklist. Results: The search yielded a total of 1,679 studies, of which 22 met inclusion criteria. Sample sizes ranged from 11 to 144 animals. PDE inhibitors used include rolipram (n = 16), cilostazol (n = 4), roflumilast (n = 1), and PDE4-I (n = 1). The injury models used were traumatic SCI (n = 18), spinal cord ischemia (n = 3), and degenerative cervical myelopathy (n = 1). The most commonly assessed outcome measures were Basso, Beattie, Bresnahan (BBB) locomotor score (n = 13), and grid walking (n = 7). Of the 22 papers that met the final inclusion criteria, 12 showed a significant improvement in neurobehavioral outcomes following the use of PDE inhibitors, four papers had mixed findings and six found PDE inhibitors to be ineffective in improving neurobehavioral recovery following an SCI. Notably, these findings were broadly consistent across different PDE inhibitors and spinal cord injury models. Conclusion: In preclinical models of traumatic and non-traumatic SCI, the administration of PDE inhibitors appeared to be associated with statistically significant improvements in neurobehavioral outcomes in a majority of included studies. However, the evidence was inconsistent with a high risk of bias. This review provides a foundation to aid the interpretation of subsequent clinical trials of PDE inhibitors in spinal cord injury. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150639, identifier: CRD42019150639.

Meeting the Shared Goals of a Student-Selected Component: Pilot Evaluation of a Collaborative Systematic Review.

BACKGROUND: Research methodology is insufficiently featured in undergraduate medical curricula. Student-selected components are designed to offer some research opportunities but frequently fail to meet student or supervisor expectations, such as completion or publication. We hypothesized that a collaborative, educational approach to a systematic review (SR), whereby medical students worked together, may improve student experience and increase success. OBJECTIVE: This study aimed to establish whether offering a small team of students the opportunity to take part in the screening phase of SRs led by an experienced postgraduate team could enhance the learning experience of students, overcome the barriers to successful research engagement, and deliver published output. METHODS: Postgraduate researchers from the University of Cambridge led a team of 14 medical students to work on 2 neurosurgical SRs. One student was appointed as the lead for each SR. All students were provided with training on SR methodology and participated in title and abstract screening using Rayyan software. Students completed prepilot, midscreening, and postscreening questionnaires on their research background, perceptions, knowledge, confidence, and experience. Questions were scored on a Likert scale of 1 (strongly disagree) to 10 (strongly agree). RESULTS: Of the 14 students involved, 29% (n=4) reported that they had received sufficient training in research methodology at medical school. Positive trends in student knowledge, confidence, and experience of SR methodology were noted across the 3 questionnaire time points. Mean responses to "I am satisfied with the level of guidance I am receiving," "I am enjoying being involved in the SR process," and "I could not gain this understanding of research from passive learning e.g., textbook or lecture" were greater than 8.0 at all time points. Students reported "being involved in this research has made me more likely to do research in the future" (mean 8.57, SD 1.50) and that "this collaborative SR improved my research experience" (mean 8.50, SD 1.56). CONCLUSIONS: This collaborative approach appears to be a potentially useful method of providing students with research experience; however, it requires further evaluation.

Provision and Perception of Physiotherapy in the Nonoperative Management of Degenerative Cervical Myelopathy (DCM): A Cross-Sectional Questionnaire of People Living With DCM.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: Degenerative cervical myelopathy (DCM) is a common syndrome of acquired spinal cord impairment caused by canal stenosis secondary to arthritic changes of the spine. International guidelines consider physiotherapy an option for mild, stable DCM; however, few studies have been conducted on nonoperative management. The objective was to determine current usage and perceptions of nonoperative physiotherapy for DCM. METHODS: Persons with DCM were recruited to a web-based survey. Participants with complete responses that had not received surgery were included (n = 167). Variables included symptom duration, treatment history, current disability, and demographic characteristics. RESULTS: Disease and demographic characteristics were equivalent between those who did and did not receive physiotherapy. In all, 19.5% of physiotherapy recipients reported subjective benefit from physiotherapy. Those perceiving benefit had significantly higher mJOA (modified Japanese Orthopaedic Association) scores, lower neck pain scores, and shorter symptom duration. In multivariate logistic regression analysis, those with mild DCM were more likely to perceive benefit than those with severe DCM, as were those with moderate DCM (to a lesser extent). Individuals whose diagnosis was delayed 1 to 2 years were less likely to perceive benefit than those that waited 0 to 6 months. CONCLUSIONS: The provision of nonoperative physiotherapy in the management of DCM is inconsistent and appears to differ from international guidelines. Few patients perceived benefit from physiotherapy; however, this was more likely in those with mild DCM and in those with shorter symptom durations. Further work is needed to establish the appropriate role of physiotherapy for this population.

Gathering Global Perspectives to Establish the Research Priorities and Minimum Data Sets for Degenerative Cervical Myelopathy: Sampling Strategy of the First Round Consensus Surveys of AO Spine RECODE-DCM.

STUDY DESIGN: Survey. INTRODUCTION: AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (AO Spine RECODE-DCM) is an international initiative that aims to accelerate knowledge discovery and improve outcomes by developing a consensus framework for research. This includes defining the top research priorities, an index term and a minimum data set (core outcome set and core data elements set - core outcome set (COS)/core data elements (CDE)). OBJECTIVE: To describe how perspectives were gathered and report the detailed sampling characteristics. METHODS: A two-stage, electronic survey was used to gather and seek initial consensus. Perspectives were sought from spinal surgeons, other healthcare professionals and people with degenerative cervical myelopathy (DCM). Participants were allocated to one of two parallel streams: (1) priority setting or (2) minimum dataset. An email campaign was developed to advertise the survey to relevant global stakeholder individuals and organisations. People with DCM were recruited using the international DCM charity Myelopathy.org and its social media channels. A network of global partners was recruited to act as project ambassadors. Data from Google Analytics, MailChimp and Calibrum helped optimise survey dissemination. RESULTS: Survey engagement was high amongst the three stakeholder groups: 208 people with DCM, 389 spinal surgeons and 157 other healthcare professionals. Individuals from 76 different countries participated; the United States, United Kingdom and Canada were the most common countries of participants. CONCLUSION: AO Spine RECODE-DCM recruited a diverse and sufficient number of participants for an international PSP and COS/CDE process. Whilst PSP and COS/CDE have been undertaken in other fields, to our knowledge, this is the first time they have been combined in one process.

Systematic review of the impact of cannabinoids on neurobehavioral outcomes in preclinical models of traumatic and nontraumatic spinal cord injury.

STUDY DESIGN: Systematic review. OBJECTIVES: To evaluate the impact of cannabinoids on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI), with the aim of determining suitability for clinical trials involving SCI patients. METHODS: A systematic search was performed in MEDLINE and Embase databases, following registration with PROPSERO (CRD42019149671). Studies evaluating the impact of cannabinoids (agonists or antagonists) on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI were included. Data extracted from relevant studies, included sample characteristics, injury model, neurobehavioural outcomes assessed and study results. PRISMA guidelines were followed and the SYRCLE checklist was used to assess risk of bias. RESULTS: The search returned 8714 studies, 19 of which met our inclusion criteria. Sample sizes ranged from 23 to 390 animals. WIN 55,212-2 (n = 6) and AM 630 (n = 8) were the most used cannabinoid receptor agonist and antagonist respectively. Acute SCI models included traumatic injury (n = 16), ischaemia/reperfusion injury (n = 2), spinal cord cryoinjury (n = 1) and spinal cord ischaemia (n = 1). Assessment tools used assessed locomotor function, pain and anxiety. Cannabinoid receptor agonists resulted in statistically significant improvement in locomotor function in 9 out of 10 studies and pain outcomes in 6 out of 6 studies. CONCLUSION: Modulation of the endo-cannabinoid system has demonstrated significant improvement in both pain and locomotor function in pre-clinical SCI models; however, the risk of bias is unclear in all studies. These results may help to contextualise future translational clinical trials investigating whether cannabinoids can improve pain and locomotor function in SCI patients.

Current surgical practice for multi-level degenerative cervical myelopathy: Findings from an international survey of spinal surgeons.

Degenerative cervical myelopathy (DCM) results from compression of the cervical spine cord as a result of age related changes in the cervical spine, and affects up to 2% of adults, leading to progressive disability. Surgical decompression is the mainstay of treatment, but there remains significant variation in surgical approaches used. This survey was conducted in order to define current practice amongst spine surgeons worldwide, as a possible prelude to further studies comparing surgical approaches. METHODS: An electronic survey was developed and piloted by the investigators using SurveyMonkey. Collected data was categorical and is presented using summary statistics. Where applicable, statistical comparisons were made using a Chi-Squared test. The level of significance for all statistical analyses was defined as p < 0.05. All analysis, including graphs was performed using R (R Studio). RESULTS: 127 surgeons, from 30 countries completed the survey; principally UK (66, 52%) and North America (15, 12%). Respondents were predominantly Neurosurgeons by training (108, 85%) of whom 84 (75%) reported Spinal Surgery as the principal part of their practice. The majority indicated they selected their surgical procedure for multi-level DCM on a case by case basis (62, 49%). Overall, a posterior approach was more popular for multi-level DCM (74, 58%). Region, speciality or annual multi-level case load did not influence this significantly. However, there was a trend for North American surgeons to be more likely to favour a posterior approach. CONCLUSIONS: A posterior approach was favoured and more commonly used to treat multi-level DCM, in an international cohort of surgeons. Posterior techniques including laminectomy, laminectomy and fusion or laminoplasty appeared to be equally popular.

Rho kinase-dependent apical constriction counteracts M-phase apical expansion to enable mouse neural tube closure.

Cellular generation of mechanical forces required to close the presumptive spinal neural tube, the 'posterior neuropore' (PNP), involves interkinetic nuclear migration (INM) and apical constriction. Both processes change the apical surface area of neuroepithelial cells, but how they are biomechanically integrated is unknown. Rho kinase (Rock; herein referring to both ROCK1 and ROCK2) inhibition in mouse whole embryo culture progressively widens the PNP. PNP widening is not caused by increased mechanical tension opposing closure, as evidenced by diminished recoil following laser ablation. Rather, Rock inhibition diminishes neuroepithelial apical constriction, producing increased apical areas in neuroepithelial cells despite diminished tension. Neuroepithelial apices are also dynamically related to INM progression, with the smallest dimensions achieved in cells positive for the pan-M phase marker Rb phosphorylated at S780 (pRB-S780). A brief (2 h) Rock inhibition selectively increases the apical area of pRB-S780-positive cells, but not pre-anaphase cells positive for phosphorylated histone 3 (pHH3+). Longer inhibition (8 h, more than one cell cycle) increases apical areas in pHH3+ cells, suggesting cell cycle-dependent accumulation of cells with larger apical surfaces during PNP widening. Consequently, arresting cell cycle progression with hydroxyurea prevents PNP widening following Rock inhibition. Thus, Rock-dependent apical constriction compensates for the PNP-widening effects of INM to enable progression of closure.This article has an associated First Person interview with the first authors of the paper.