Neuropsychological and Neuroimaging Outcomes Following Moderate to Severe Paediatric Traumatic Brain Injury in South Africa

Paediatric traumatic brain injury (pTBI) is a leading cause of mortality and disability. South Africa is predicted to have a high pTBI rate and an adverse socioeconomic environment for recovery. Despite this, few studies have investigated the neuropsychological and/or neuroimaging outcomes of pTBI in South Africa. The study was designed as a capacity-building exercise to demonstrate the successful collection of data from different sites involved in a developing international collaboration. The aims were therefore to 1) provide a detailed description of the premorbid factors and neuropsychological and neuroimaging outcomes of a sample of South African children with moderate to severe pTBI, and 2) investigate the barriers to the successful implementation of neuropsychological and neuroimaging research in this population. Five patients with severe pTBI were enrolled during the 6-month recruitment window. These participants presented with 6-month post-TBI outcomes that ranged from mild neuropsychological deficits and no visible abnormalities on neuroimaging to severe neuropsychological deficits and evidence of multifocal pathology on imaging. There was a relatively high occurrence of adverse developmental, socioeconomic, and neuropsychological histories, which will need to be considered when selecting an appropriate control group or combining with other populations in a potential future multicentre study. Additional strategies will also be required to improve recruitment and increase the rate of successful imaging. Changes may need to be made to the neuropsychology assessment so as not to disadvantage this population, for example avoiding tests that are reliant on sequencing the alphabet. In conclusion, the study's findings will help to improve the likelihood of the much-needed large-scale research in this at-risk and understudied South African population

On-field identification and management of concussion in amateur rugby union

Background: Rugby is a popular team sport and due to its contact nature carries a relatively high potential for injury, including concussion. Moreover, it is estimated that as much as 50% of concussions are not reported due to a variety of reasons, including not considering the injury to be sufficiently serious or not wanting to miss game time. Objectives: The aim of this brief review was to investigate and summarise current best practice for on-field identification and on-field management of concussion in amateur rugby. Methods: PubMed and ClinicalKey were searched between September and December 2014 for articles in the five years preceding the search dates. The latest versions of the Consensus Statement for Concussion in Sports and World Rugby's concussion guidelines were also consulted. Results: Based on this search strategy, eight systematic reviews, one physician information article and four patient guidelines were investigated. Four reviews specifically described an "action plan" for on-field evaluation and management. Education of key stakeholders could reduce the number of unreported concussions. Once identified or suspected, concussions should be managed according to best practice procedures, which include removing the player from play immediately and consulting a medical doctor. If a medical doctor is not immediately available on the field tools such as the BokSmart on-field pocket "Concussion Guide", and World Rugby's "Pocket Concussion Recognition Tool", are freely available online. Conclusion: Stakeholder education (including players, parents, teachers, coaches, referees, spouses) on both the on-field identification and management of concussions could reduce under-reporting and improve the overall management of concussed rugby players

“It was only a mild concussion”: Exploring the description of sports concussion in online news articles

Background/aims Concussion is widely discussed in online sports news articles, but the terms used to report this injury vary. This study aimed to use a systematic search strategy and explore the description of sports concussion in online sports news articles. Methods A systematic approach was employed to obtain online articles related to sports concussion from four sports associated with concussion (hockey, football, soccer, and rugby). Included articles were evaluated for the descriptors used in relation to concussion and possible consequences associated with concussion. Data was analysed to determine trends between each sport as well between the countries of origin of the articles. Results From 200 articles retrieved, 153 were included for analysis. The terms "Head injury" (30.1%) and "Brain injury" (20.9%) were most used to describe a concussive injury, and the most frequently mentioned consequence of concussion was "Chronic Traumatic Encephalopathy" (15%). Modifiers which potentially play down the importance of the injury were noted in 9.8% of the articles, with journalists the primary source of these terms. Conclusions The variability in reporting of concussion by online news articles may limit the transmission of correct concussion information to the public. To improve the consistency of this reporting, the "Media Concussion Checklist" was developed

Genome-Wide Functional Profiling Identifies Genes and Processes Important for Zinc-Limited Growth of Saccharomyces cerevisiae

Zinc is an essential nutrient because it is a required cofactor for many enzymes and transcription factors. To discover genes and processes in yeast that are required for growth when zinc is limiting, we used genome-wide functional profiling. Mixed pools of ∼4,600 deletion mutants were inoculated into zinc-replete and zinc-limiting media. These cells were grown for several generations, and the prevalence of each mutant in the pool was then determined by microarray analysis. As a result, we identified more than 400 different genes required for optimal growth under zinc-limiting conditions. Among these were several targets of the Zap1 zinc-responsive transcription factor. Their importance is consistent with their up-regulation by Zap1 in low zinc. We also identified genes that implicate Zap1-independent processes as important. These include endoplasmic reticulum function, oxidative stress resistance, vesicular trafficking, peroxisome biogenesis, and chromatin modification. Our studies also indicated the critical role of macroautophagy in low zinc growth. Finally, as a result of our analysis, we discovered a previously unknown role for the ICE2 gene in maintaining ER zinc homeostasis. Thus, functional profiling has provided many new insights into genes and processes that are needed for cells to thrive under the stress of zinc deficiency

High Throughput Confocal Screen of 1,727 Compounds to Identify Novel Regulators of Primary Cilia Structure

PhD thesisThe primary cilium is a singular microtubule-based cell organelle present on most quiescent eukaryotic cell types and is required for numerous signalling pathways. Primary cilia length and incidence have been reported to be altered by many mechanical and chemical stimuli. Furthermore, a group of diseases termed ciliopathies are associated with genetic disruption to primary cilia. Alterations in primary cilia structure have been associated with modified cell signalling events, of which the hedgehog signalling pathway is the most well established as having a ciliary link. The aim of this thesis project was to identify compounds that regulate primary cilia expression in healthy chondrocytes, and in turn to investigate the effect of altered cilia structure on cilia function. It is envisaged that this will support future work to use cilia modifying compounds as potential ‘ciliotherapies’ for the treatment of established ciliopathies and diseases with a ciliary component. A high throughput screen was optimised and executed to enable the unbiased investigation of the effect of 1,727 compounds on cilia expression and structure. Primary bovine articular chondrocytes were utilised; an ideal cell model for the interrogation of primary cilia structure due to their high expression of flat lying cilia in vitro 2D culture. Compound treatment of a confluent monolayer culture was uniformly performed using liquid handling robotics, followed by cellular fixation and immunofluorescent labelling. Nuclei, F-actin and the cilia axoneme components acetylated-α-tubulin and polyglutamylated tubulin were labelled and imaged with automated 3D confocal microscopy. High content image analysis of the 552,960 images generated in first pass screen collected data on over 60 cellular parameters. The data was stored in a database of compound effect with accompanying z-score matrix. From the full library, 233 (13.5%) compounds were identified as altering either cilia length and/or incidence. Using hierarchical clustering, six phenotypic clusters were found amongst these compounds. A cluster of 68 compounds causing an increase in cilia length with a predominantly ciliary specific effect were validated in cells isolated from two additional animals. The 22 validated compounds were carried forward for investigation in a human chondrocyte cell line. The viability of the 22 candidate compounds was tested in a human chondrocyte cell line, of which 16 compounds were found to maintain cell number. Of the viable compounds, 15 increased primary cilia length in the human cells, replicating the effects seen in bovine. The impact of this cilia elongation on subsequent cilia function, specifically on hedgehog signalling was examined by RT-PCR, with ligand induction of the pathway. Although effects were inconsistent, across all compounds there was a trend towards an inhibition to Gli1 induction with the addition of Ihh ligand. These studies identified a robust group of candidate compounds that induced primary cilia elongation in multiple biological replicates using chondrocytes from both bovine and human sources. Although cilia elongation in healthy cells did not cause a consistent effect on ligand-induced hedgehog signalling, these compounds may have future potential as novel ‘ciliotherapies’ to correct cilia dysfunction

The association between COMT rs4680 and 5-HTTLPR genotypes and concussion history in South African rugby union players

The objective was to investigate the relationship between Catechol-O-methyltransferase (COMT) rs4680 and serotonin-transporter-linked polymorphic region (5-HTTLPR) genotypes with concussion history and personality traits. Rugby players (“all levels”: n = 303), from high schools (“junior”, n = 137), senior amateur, and professional teams (“senior”, n = 166), completed a self-reported concussion history questionnaire, Cloninger’s Tridimensional Personality Questionnaire, and donated a DNA sample. Participants were allocated into control (non-concussed, n = 140), case (all) (previous suspected or diagnosed concussions, n = 163), or case (diagnosed only) (previous diagnosed concussion, n = 140) groups. COMT rs4680 Val/Val genotypes were over-represented in controls in all levels (P = 0.013, OR:2.00, 95% CI:1.15–3.57) and in juniors (P = 0.003, OR:3.57, 95% CI:1.45–9.09). Junior Val/Val participants displayed increased “anticipatory worry” (P = 0.023). The 5-HTTLPR low expressing group was under-represented in controls when all levels were considered (P = 0.032; OR:2.02, 95% CI:1.05–3.90) and in juniors (P = 0.021; OR:3.36, 95% CI:1.16–9.72). Junior 5-HTTLPR low and intermediate expressing groups displayed decreased “harm avoidance” (P = 0.009), “anticipatory worry” (P = 0.041), and “fear of uncertainty” (P < 0.001). This study provides preliminary indications that personality associated genetic variants can influence concussion in rugby.The South African National Research Foundation (A.V.S., grant number 90942), (M.P., grant numbers 93416:2015, 85534:2015). The South African National Research Foundation and the University of Cape Town funded S.A. and S.M.http://www.tandfonline.com/loi/rjsp202019-10-01hj2017Sports Medicin