P7C3-A20 neuroprotection is independent of Wallerian degeneration in Primary Neuronal Culture

The anti-apoptotic, neuroprotective compound P7C3-A20 reduces neurological deficits when administered to murine in vivo models of traumatic brain injury. P7C3-A20 is thought to exert its activity through small-molecule activation of the enzyme nicotinamide phosphoribosyltransferase (NAMPT). This enzyme converts nicotinamide to nicotinamide mononucleotide (NMN), the precursor to nicotinamide adenine dinucleotide (NAD) synthesis. Alterations to this bioenergetic pathway have been shown to induce Wallerian degeneration of the distal neurite following injury. This study aimed to establish whether P7C3-A20, through induction of NAMPT activity, would affect the rate of Wallerian degeneration. The model systems used were dissociated primary cortical neurons, dissociated superior cervical ganglion neurons, and superior cervical ganglion explants. P7C3-A20 failed to demonstrate any protection against Wallerian degeneration induced by neurite transection or vincristine administration. Furthermore, there was a concentration dependent neurotoxicity. These findings are important in understanding the mechanism by which P7C3-A20 mediates its effects- a key step before moving to human clinical trials.Wellcome Trus

Traumatic Axonal Injury: Mechanisms and Translational Opportunities.

Traumatic axonal injury (TAI) is an important pathoanatomical subgroup of traumatic brain injury (TBI) and a major driver of mortality and functional impairment. Experimental models have provided insights into the effects of mechanical deformation on the neuronal cytoskeleton and the subsequent processes that drive axonal injury. There is also increasing recognition that axonal or white matter loss may progress for years post-injury and represent one mechanistic framework for progressive neurodegeneration after TBI. Previous trials of novel therapies have failed to make an impact on clinical outcome, in both TBI in general and TAI in particular. Recent advances in understanding the cellular and molecular mechanisms of injury have the potential to translate into novel therapeutic targets.CSH is supported by a Wellcome Trust PhD for Clinicians. MPC is funded by the John and Lucille van Geest Foundation. DKM is supported by a Senior Investigator Award from the National Institute for Health Research, UK (NIHR), by the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, and a Framework Program 7 grant from the European Union (CENTER-TBI; Grant No: 602150)This is the final version of the article. It first appeared from Elsevier via https://doi.org/ 10.1016/j.tins.2016.03.00

Moving towards a unified classification of glioblastomas utilizing artificial intelligence and deep machine learning integration

Glioblastoma a deadly brain cancer that is nearly universally fatal. Accurate prognostication and the successful application of emerging precision medicine in glioblastoma relies upon the resolution and exactitude of classification. We discuss limitations of our current classification systems and their inability to capture the full heterogeneity of the disease. We review the various layers of data that are available to substratify glioblastoma and we discuss how artificial intelligence and machine learning tools provide the opportunity to organize and integrate this data in a nuanced way. In doing so there is the potential to generate clinically relevant disease sub-stratifications, which could help predict neuro-oncological patient outcomes with greater certainty. We discuss limitations of this approach and how these might be overcome. The development of a comprehensive unified classification of glioblastoma would be a major advance in the field. This will require the fusion of advances in understanding glioblastoma biology with technological innovation in data processing and organization

DNA Methylation: Basic Biology and Application to Traumatic Brain Injury.

This article reviews the literature pertinent to epigenetic changes, and in particular, DNA methylation following traumatic brain injury (TBI). TBI is a heterogeneous disease that is a major cause of death and long-term disability. The links between TBI and epigenetics, the process by which environmental factors alter gene expression without changing the underlying DNA sequence, is an expanding area of research that may have profound consequences for understanding the disease, and for clinical care. There are various epigenetic changes that may occur as a direct result of TBI, including DNA methylation, histone modification, and changes in the levels of non-coding RNA. This review focuses on DNA methylation, its potential to alter the degree of injury, and the extent of recovery, including development of post-traumatic neurodegeneration, response to therapies, and the hereditable consequences of injury. The functional consequences of non-coding RNA and histone modifications are well described in the literature; however, the mechanism by which these three mechanisms interact are often overlooked. Here, we briefly describe the interaction of DNA methylation with the two other key epigenetic changes, and highlight key work being performed to understand the functional relevance of those mechanisms. The field of epigenetics is rapidly advancing as a result of the advent of less invasive and more versatile methods for measuring epigenetic proteins and their functional impact on cells; however, the evidence specific to TBI is limited. This review identifies several important outstanding questions that remain from the work already conducted, and highlights directions for the future

Loss of highwire Protects Against the Deleterious Effects of Traumatic Brain Injury in Drosophila Melanogaster.

Traumatic brain injury is a major global cause of death and disability. Axonal injury is a major underlying mechanism of TBI and could represent a major therapeutic target. We provide evidence that targeting the axonal death pathway known as Wallerian degeneration improves outcome in a Drosophila Melanogaster model of high impact trauma. This cell-autonomous neurodegenerative pathway is initiated following axon injury, and in Drosophila, involves activity of the E3 ubiquitin ligase highwire. We demonstrate that a loss-of-function mutation in the highwire gene rescues deleterious effects of a traumatic injury, including-improved functional outcomes, lifespan, survival of dopaminergic neurons, and retention of synaptic proteins. This data suggests that highwire represents a potential therapeutic target in traumatic injury

Injury programs shape glioblastoma

Glioblastoma is the most common and aggressive primary brain cancer in adults and is almost universally fatal due to its stark therapeutic resistance. During the past decade, although survival has not substantially improved, major advances have been made in our understanding of the underlying biology. It has become clear that these devastating tumors recapitulate features of neurodevelopmental hierarchies which are influenced by the microenvironment. Emerging evidence also highlights a prominent role for injury responses in steering cellular phenotypes and contributing to tumor heterogeneity. This review highlights how the interplay between injury and neurodevelopmental programs impacts on tumor growth, invasion, and treatment resistance, and discusses potential therapeutic considerations in view of these findings

The importance of expert feedback during endovascular simulator training

ObjectivesComplex endovascular skills are difficult to obtain in the clinical environment. Virtual reality (VR) simulator training is a valuable addition to current training curricula, but is there a benefit in the absence of expert trainers?MethodsEighteen endovascular novices performed a renal artery angioplasty/stenting (RAS) on the Vascular Interventional Surgical Trainer simulator. They were randomized into three groups: Group A (n = 6, control), no performance feedback; Group B (n = 6, nonexpert feedback), feedback after every procedure from a nonexpert facilitator; and Group C (n = 6, expert feedback), feedback after every procedure from a consultant vascular surgeon. Each trainee completed RAS six times. Simulator-measured performance metrics included procedural and fluoroscopy time, contrast volume, accuracy of balloon placement, and handling errors. Clinical errors were also measured by blinded video assessment. Data were analyzed using SPSS version 15.ResultsA clear learning curve was observed across the six trials. There were no significant differences between the three groups for the general performance metrics, but Group C made fewer errors than Groups A (P = .009) or B (P = .004). Video-based error assessment showed that Groups B and C performed better than Group A (P = .002 and P = .000, respectively).ConclusionVR simulator training for novices can significantly improve general performance in the absence of expert trainers. Procedure-specific qualitative metrics are improved with expert feedback, but nonexpert facilitators can also enhance the quality of training and may represent a valuable alternative to expert clinical faculty

Teaching handover in undergraduate education: an evidence-based multi-disciplinary approach

Poor standards of handover threaten patient safety and continuity of care, contributing significantly to morbidity and mortality. Handover practices has risen to the forefront of the patient safety agenda, with a call to develop and implement undergraduate handover modules into undergraduate healthcare education. Recent systematic reviews demonstrate a common failure of educational interventions to demonstrate a theoretical and pedagogical framework underpinning the delivery of education and method of assessment. The authors developed and piloted a multi-disciplinary evidence-based undergraduate handover training program to health care students studying at a UK university. The intervention was designed based on underpinning educational theories. It has been developed in a manner that supports dissemination and replication, with a model that is cost effective. The intervention was designed to assess learner reaction, attitudes and confidence, and knowledge and skills. This was achieved through a pre- and post-intervention attitude questionnaire, and an externally validated pre- and postintervention knowledge assessment. 46 undergraduate students participated, with a statistically significant increase in self-reported attitudes (p < 0.001) and knowledge (p < 0.001) following the handover intervention. Students participated from the disciplines of medicine, adult nursing, pharmacy, mental health nursing, paramedic practice and operating department practioners. This intervention serves as a significant resource for those looking to develop local interventions and stands as a truly multi-disciplinary approach to handover education, mirroring the clinical reality. The introduction of this handover intervention immediately improves the attitudes, knowledge and skills of undergraduate healthcare students. Future work should sample beyond the selected 6 professions, investigating the transference of outcomes to the workplace, as well as the impact on patient safety

Data-driven spatio-temporal modelling of glioblastoma

Mathematical oncology provides unique and invaluable insights into tumour growth on both the microscopic and macroscopic levels. This review presents state-of-the-art modelling techniques and focuses on their role in understanding glioblastoma, a malignant form of brain cancer. For each approach, we summarise the scope, drawbacks, and assets. We highlight the potential clinical applications of each modelling technique and discuss the connections between the mathematical models and the molecular and imaging data used to inform them. By doing so, we aim to prime cancer researchers with current and emerging computational tools for understanding tumour progression. Finally, by providing an in-depth picture of the different modelling techniques, we also aim to assist researchers who seek to build and develop their own models and the associated inference frameworks.Comment: 30 pages, 3 figures, 3 table

Twelve tips for undertaking a focused systematic review in medical education

The exponential growth of the systematic review methodology within health has been mirrored within medical education, allowing large numbers of publications on a topic to be synthesized to guide researchers and teachers. The robust, transparent and reproducible search methodologies employed offer scholarly rigor. The scope and scale of many reviews in education have only been matched by the size of the commitment needed to complete them and occasional lack of utility of reports. As such, we have noticed a growth in reviews across journals in the field that have questions that are more focused in scope. The authors propose 12 tips for performing a focused review in the right settings for the right reasons and discuss why such “focused reviews” may be more beneficial in those circumstances. Focused reviews allow researchers to formulate answers to specific local issues that have explicit utility of findings. Such reviews are equipped to identify what works for specific groups in specific circumstances and even question how and why this may occur. An additional impact of a focused approach can be a rapid turnaround. This article explains the purpose and benefits of focused review and provides guidance on how to produce them