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.

Mechanical properties of the spinal cord and brain: Comparison with clinical-grade biomaterials for tissue engineering and regenerative medicine.

Disorders affecting the central nervous system are a leading cause of disability in the world. Regenerative medicine using biomaterial-based therapies is a growing field that has potential application in the areas of spinal cord injury, neurodegenerative disorders and stroke. The mechanical properties of biomaterials implanted into the central nervous system are critical for effective integration with host tissue, but the biomechanical properties of the host tissue remain poorly characterised and assessing the stiffness of both soft biomaterials and central nervous system tissue remains challenging. Here, we describe a bespoke mechanical characterisation method that facilitates robust measurement of fresh spinal cord and brain tissue and allows direct like-for-like mechanical benchmarking for matching clinical-grade hydrogels suitable for regenerative medicine. We report differences in the mechanical properties of spinal cord tissue dependent on anatomical origin, regional variations in brain tissue stiffness, and quantify the extent of mechanical anisotropy within the cervical spinal cord. We then demonstrate that the mechanical properties of clinical-grade collagen, fibrin and alginate hydrogels can be tuned to closely mimic the mechanical properties of different regions within the central nervous system.

Cell Therapies for Spinal Cord Injury: Trends and Challenges of Current Clinical Trials.

Cell therapies have the potential to revolutionize the treatment of spinal cord injury. Basic research has progressed significantly in recent years, with a plethora of cell types now reaching early-phase human clinical trials, offering new strategies to repair the spinal cord. However, despite initial enthusiasm for preclinical and early-phase clinical trials, there has been a notable hiatus in the translation of cell therapies to routine clinical practice. Here, we review cell therapies that have reached clinical trials for spinal cord injury, providing a snapshot of all registered human trials and a summary of all published studies. Of registered trials, the majority have used autologous cells and approximately a third have been government funded, a third industry sponsored, and a third funded by university or healthcare systems. A total of 37 cell therapy trials have been published, primarily using stem cells, although a smaller number have used Schwann cells or olfactory ensheathing cells. Significant challenges remain for cell therapy trials in this area, including achieving stringent regulatory standards, ensuring appropriately powered efficacy trials, and establishing sustainable long-term funding. However, cell therapies hold great promise for human spinal cord repair and future trials must continue to capitalize on the exciting developments emerging from preclinical studies.

Development of a "Surgical Shadowing Scheme" to improve undergraduate experiences of surgery.

PURPOSE: To establish a sustainable model for a "Surgical Shadowing Scheme" (SSS) and assess how this affects undergraduate attitudes to surgical careers. PATIENTS AND METHODS: Surgeons at university teaching hospitals associated with UCL Medical School and UCL Partners, United Kingdom, were approached for their willingness to participate in the scheme. Medical students were then invited to apply for the scheme, where students were individually matched to operating theater sessions with surgeons in their specialty of choice. Feedback was subsequently obtained, evaluating experiences of the placement and the effect this had on future career aspirations. RESULTS: After running for four consecutive years, approximately 220 students have participated in the scheme across a range of surgical units and specialties. A total of 91.5% of the students were pre-clinical (years 1-3), whilst the remainder were clinical (years 4-6). Fifty-four percent were female and 46% male. Eighty-three percent of the students did not have any previous experience of the specialty that they shadowed, and 67% agreed that participating in the scheme had either "increased" or "strongly increased" their desire to pursue a surgical career. Ninety-four percent said they would "recommend" or "strongly recommend" the SSS to a peer. Over a third of students reported scrubbing-up during their placements and 35% of these directly assisted the lead surgeon. Traditionally male-dominated surgical sub-specialties recruited a high proportion of female students. CONCLUSION: This is the first published example of an established "Surgical Shadowing Scheme" for medical undergraduates. Our SSS has been highly valued by students and indicates that even a single high-quality surgical exposure is sufficient to increase the desire of undergraduates to pursue a surgical career. We hope that this SSS will act as a blueprint for other centers to develop their own shadowing schemes, in turn helping to ensure that surgery continues to inspire and attract the very best candidates for the future.

A pilot study to assess the utility of a freely downloadable mobile application simulator for undergraduate clinical skills training: a single-blinded, randomised controlled trial.

BACKGROUND: Medical simulators offer an invaluable educational resource for medical trainees. However, owing to cost and portability restrictions, they have traditionally been limited to simulation centres. With the advent of sophisticated mobile technology, simulators have become cheaper and more accessible. Touch Surgery is one such freely downloadable mobile application simulator (MAS) used by over one million healthcare professionals worldwide. Nevertheless, to date, it has never been formally validated as an adjunct in undergraduate medical education. METHODS: Medical students in the final 3 years of their programme were recruited and randomised to one of three revision interventions: 1) no formal revision resources, 2) traditional revision resources, or 3) MAS. Students completed pre-test questionnaires and were then assessed on their ability to complete an undisclosed male urinary catheterisation scenario. Following a one-hour quarantined revision period, all students repeated the scenario. Both attempts were scored by allocation-blinded examiners against an objective 46-point mark scheme. RESULTS: A total of 27 medical students were randomised (n = 9 per group). Mean scores improved between baseline and post-revision attempts by 8.7% (p = 0.003), 19.8% (p = 0.0001), and 15.9% (p = 0.001) for no resources, traditional resources, and MAS, respectively. However, when comparing mean score improvements between groups there were no significant differences. CONCLUSIONS: Mobile simulators offer an unconventional, yet potentially useful adjunct to enhance undergraduate clinical skills education. Our results indicate that MAS's perform comparably to current gold-standard revision resources; however, they may confer significant advantages in terms of cost-effectiveness and practice flexibility. TRIAL REGISTRATION: Not applicable.

Biomechanical properties of the spinal cord: implications for tissue engineering and clinical translation.

Spinal cord injury is a severely debilitating condition which can leave individuals paralyzed and suffering from autonomic dysfunction. Regenerative medicine may offer a promising solution to this problem. Previous research has focused primarily on exploring the cellular and biological aspects of the spinal cord, yet relatively little remains known about the biomechanical properties of spinal cord tissue. Given that a number of regenerative strategies aim to deliver cells and materials in the form of tissue-engineered therapies, understanding the biomechanical properties of host spinal cord tissue is important. We review the relevant biomechanical properties of spinal cord tissue and provide the baseline knowledge required to apply these important physical concepts to spinal cord tissue engineering.

Synthesis and in vitro pharmacology of substituted quinoline-2,4-dicarboxylic acids as inhibitors of vesicular glutamate transport.

The vesicular glutamate transport (VGLUT) system selectively mediates the uptake of L-glutamate into synaptic vesicles. Uptake is linked to an H+-ATPase that provides coupling among ATP hydrolysis, an electrochemical proton gradient, and glutamate transport. Substituted quinoline-2,4-dicarboxylic acids (QDCs), prepared by condensation of dimethyl ketoglutaconate (DKG) with substituted anilines and subsequent hydrolysis, were investigated as potential VGLUT inhibitors in synaptic vesicles. A brief panel of substituted QDCs was previously reported (Carrigan et al. Bioorg. Med. Chem. Lett. 1999, 9, 2607-2612)(1) and showed that certain substituents led to more potent competitive inhibitors of VGLUT. Using these compounds as leads, an expanded series of QDC analogues were prepared either by condensation of DKG with novel anilines or via aryl-coupling (Suzuki or Heck) to dimethyl 6-bromoquinolinedicarboxylate. From the panel of almost 50 substituted QDCs tested as inhibitors of the VGLUT system, the 6-PhCH=CH-QDC (K(i) = 167 microM), 6-PhCH2CH2-QDC (K(i) = 143 microM), 6-(4'-phenylstyryl)-QDC (K(i) = 64 microM), and 6-biphenyl-4-yl-QDC (K(i) = 41 microM) were found to be the most potent blockers. A preliminary assessment of the key elements needed for binding to the VGLUT protein based on the structure-activity relationships for the panel of substituted QDCs is discussed herein. The substituted QDCs represent the first synthetically derived VGLUT inhibitors and are promising templates for the development of selective transporter inhibitors.