The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing

Bringing together coproduction and community participatory research approaches: Using first person reflective narrative to explore coproduction and community involvement in mental health research

Background A growing literature explores the coproduction of research knowledge. Barriers to coproduction in mental health research have been identified, especially for the people from marginalized communities. There is an established body of participatory research that has potential to inform coproduction in mental health research. Objectives To explore and articulate how learning from community participatory approaches to research enable barriers to knowledge coproduction to be overcome in mental health research. Setting An evaluation of a primary care mental health service, led by an experienced survivor researcher, supported by a health service researcher and involving a team of community co‐researchers. Design Cycles of reflective writing (first‐person narrative) by the authors, and feedback from the co‐researcher team, on their experiences of undertaking the evaluation were used to explore the ways in which community actors, including those from marginalized communities, might be meaningfully involved in producing research knowledge about mental health services. Results A space was created where community co‐researchers, including those from traditionally marginalized communities, felt safe and empowered to move beyond essentialized “service user” identities and bring a range of skills and expertise to the evaluation. There was meaningful rebalancing of power between traditional university and community roles, although the issues around leadership remained complex and more could be done to explore how our different experiences of race and mental health shape the research we do. Conclusions Potential was demonstrated for participatory research approaches to inform coproduction of knowledge in mental health research that fully reflects the diversity of identity and experience

Embedding patient and public involvement: managing tacit and explicit expectations

Background: Evidencing well-planned and implemented patient and public involvement (PPI) in a research project is increasingly required in funding bids and dissemination activities. There is a tacit expectation that involving people with experience of the condition under study will improve the integrity and quality of the research. This expectation remains largely unproblematised and unchallenged. Objective: To critically evaluate the implementation of PPI activity, including co-research in a programme of research exploring ways to enhance the independence of people with dementia. Design: Using critical cases we make visible and explicate theoretical and moral challenges of PPI. Results: Case 1 explores the challenges of undertaking multiple PPI roles in the same study making explicit different responsibilities of being a co-applicant, PPI advisory member and a co-researcher. Case 2 explores tensions which arose when working with carer co-researchers during data collection; here the co-researcher’s wish to offer support and advice to research participants, a moral imperative, was in conflict with assumptions about the role of the objective interviewer. Case 3 defines and examines co-research data coding and interpretation activities undertaken with people with dementia; reporting the theoretical outputs of the activity and questioning whether this was co-researcher analysis or PPI validation. Conclusion: PPI activity can empower individual PPI volunteers and improve relevance and quality of research but it is a complex activity which is socially constructed in flexible ways with variable outcomes. It cannot be assumed to be simple or universal panacea for increasing the relevance and accessibility of research to the public

Integrating isotopes and documentary evidence : dietary patterns in a late medieval and early modern mining community, Sweden

We would like to thank the Archaeological Research Laboratory, Stockholm University, Sweden and the Tandem Laboratory (Ångström Laboratory), Uppsala University, Sweden, for undertaking the analyses of stable nitrogen and carbon isotopes in both human and animal collagen samples. Also, thanks to Elin Ahlin Sundman for providing the δ13C and δ15N values for animal references from Västerås. This research (Bäckström’s PhD employment at Lund University, Sweden) was supported by the Berit Wallenberg Foundation (BWS 2010.0176) and Jakob and Johan Söderberg’s foundation. The ‘Sala project’ (excavations and analyses) has been funded by Riksens Clenodium, Jernkontoret, Birgit and Gad Rausing’s Foundation, SAU’s Research Foundation, the Royal Physiographic Society of Lund, Berit Wallenbergs Foundation, Åke Wibergs Foundation, Lars Hiertas Memory, Helge Ax:son Johnson’s Foundation and The Royal Swedish Academy of Sciences.Peer reviewedPublisher PD

From Motion to Emotion : Accelerometer Data Predict Subjective Experience of Music

Music is often discussed to be emotional because it reflects expressive movements in audible form. Thus, a valid approach to measure musical emotion could be to assess movement stimulated by music. In two experiments we evaluated the discriminative power of mobile-device generated acceleration data produced by free movement during music listening for the prediction of ratings on the Geneva Emotion Music Scales (GEMS-9). The quality of prediction for different dimensions of GEMS varied between experiments for tenderness (R12(first experiment) = 0.50, R22(second experiment) = 0.39), nostalgia (R12 = 0.42, R22 = 0.30), wonder (R12 = 0.25, R22 = 0.34), sadness (R12 = 0.24, R22 = 0.35), peacefulness (R12 = 0.20, R22 = 0.35) and joy (R12 = 0.19, R22 = 0.33) and transcendence (R12 = 0.14, R22 = 0.00). For others like power (R12 = 0.42, R22 = 0.49) and tension (R12 = 0.28, R22 = 0.27) results could be almost reproduced. Furthermore, we extracted two principle components from GEMS ratings, one representing arousal and the other one valence of the experienced feeling. Both qualities, arousal and valence, could be predicted by acceleration data, indicating, that they provide information on the quantity and quality of experience. On the one hand, these findings show how music-evoked movement patterns relate to music-evoked feelings. On the other hand, they contribute to integrate findings from the field of embodied music cognition into music recommender systems

Using the value creation framework to capture knowledge co-creation and pathways to impact in a transnational community of practice in autism education

Although theories around Communities of Practice have gained significant ground in recent years and have become an important focus for organizational development, there is a gap in studies that investigate what members gain from participation in these communities. This paper explains how the value creation framework was implemented in a transnational research and development project in autism education by examining cycles of value creation and drawing on two types of data identified by Wenger and colleagues. The value creation framework is a theoretically driven framework to assess social learning in communities. Participants involved in the learning space were co-researchers engaged in a process of investigating, sharing and reflecting on their practice. The paper discusses the methodological challenges and strengths of using the value creation framework, with a particular focus on how insights and interactions led to subsequent changes in the practice of the participants. This work has the potential to make an important contribution to methods and analysis in assessing social learning and pathways to impact in participatory research and development projects more broadly

Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats

Background: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. Methodology/Principal Findings: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Coadministration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when th

Sub region-specific modulation of synchronous neuronal burst firing after a kainic acid insult in organotypic hippocampal cultures

<p>Abstract</p> <p>Background</p> <p>Excitotoxicity occurs in a number of pathogenic states including stroke and epilepsy. The adaptations of neuronal circuits in response to such insults may be expected to play an underlying role in pathogenesis. Synchronous neuronal firing can be induced in isolated hippocampal slices and involves all regions of this structure, thereby providing a measure of circuit activity. The effect of an excitotoxic insult (kainic acid, KA) on Mg²⁺-free-induced synchronized neuronal firing was tested in organotypic hippocampal culture by measuring extracellular field activity in CA1 and CA3.</p> <p>Results</p> <p>Within 24 hrs of the insult regional specific changes in neuronal firing patterns were evident as: (i) a dramatic <it>reduction </it>in the ability of CA3 to generate firing; and (ii) a contrasting <it>increase </it>in the frequency and duration of synchronized neuronal firing events in CA1. Two distinct processes underlie the increased propensity of CA1 to generate synchronized burst firing; a lack of ability of the CA3 region to 'pace' CA1 resulting in an increased frequency of synchronized events; and a change in the 'intrinsic' properties limited to the CA1 region, which is responsible for increased event duration. Neuronal quantification using NeuN immunoflurescent staining and stereological confocal microscopy revealed no significant cell loss in hippocampal sub regions, suggesting that changes in the properties of neurons within this region were responsible for the KA-mediated excitability changes.</p> <p>Conclusion</p> <p>These results provide novel insight into adaptation of hippocampal circuits following excitotoxic injury. KA-mediated disruption of the interplay between CA3 and CA1 clearly increases the propensity to synchronized firing in CA1.</p

Enhancing Participatory Strategies With Designerly Ways for Sociolegal Impact: Lessons From Research Aimed at Making Hate Crime Visible

This paper draws the attention of impact-curious sociolegal researchers to the potential of participatory research strategies; and proposes that the effectiveness of those strategies can be enhanced by the introduction of ‘designerly ways’. It explores and evidences this proposition through the multi-country Facing All the Facts project which aimed to support and accelerate the process of making hate crime conceptually and empirically visible in Europe. The paper concludes that by pursuing the designerly strategy of making experiences, perceptions and expectations around hate crime reporting and recording visible and tangible in artefacts (formal graphics and collaborative prototypes), the project activities generated structured-yet-free spaces in which publics/stakeholders could more effectively participate in practical, critical and imaginative discussion about how things are, and how they might be; and that this has improved the relevance and rigour of the research, and its ability to generate meaningful change (‘impact’)