Heterogeneous Spine Loss in Layer 5 Cortical Neurons after Spinal Cord Injury

A large thoracic spinal cord injury disconnects the hindlimb (HL) sensory-motor cortex from its target, the lumbar spinal cord. The fate of the synaptic structures of the axotomized cortical neurons is not well studied. We evaluated the density of spines on axotomized corticospinal neurons at 3, 7, and 21 days after the injury in adult mice expressing yellow fluorescence protein in a subset of layer 5 neurons. Spine density of the dendritic segment proximal to the soma (in layer 5) declined as early as 3 days after injury, far preceding the onset of somatic atrophy. In the distal segment (in layer 2/3), spine loss was slower and less severe than in the proximal segment. Axotomy of corticospinal axons in the brainstem (pyramidotomy) induced a comparable reduction of spine density, demonstrating that the loss is not restricted to the neurons axotomized in the thoracic spinal cord. Surprisingly, in both forms of injury, the spine density of putative non-axotomized layer 5 neurons was reduced as well. The spine loss may reflect fast rearrangements of cortical circuits after axotomy, for example, by a disconnection of HL cortical neurons from synaptic inputs that no longer provide useful informatio

Back seat driving: hindlimb corticospinal neurons assume forelimb control following ischaemic stroke

Whereas large injuries to the brain lead to considerable irreversible functional impairments, smaller strokes or traumatic lesions are often associated with good recovery. This recovery occurs spontaneously, and there is ample evidence from preclinical studies to suggest that adjacent undamaged areas (also known as peri-infarct regions) of the cortex ‘take over' control of the disrupted functions. In rodents, sprouting of axons and dendrites has been observed in this region following stroke, while reduced inhibition from horizontal or callosal connections, or plastic changes in subcortical connections, could also occur. The exact mechanisms underlying functional recovery after small- to medium-sized strokes remain undetermined but are of utmost importance for understanding the human situation and for designing effective treatments and rehabilitation strategies. In the present study, we selectively destroyed large parts of the forelimb motor and premotor cortex of adult rats with an ischaemic injury. A behavioural test requiring highly skilled, cortically controlled forelimb movements showed that some animals recovered well from this lesion whereas others did not. To investigate the reasons behind these differences, we used anterograde and retrograde tracing techniques and intracortical microstimulation. Retrograde tracing from the cervical spinal cord showed a correlation between the number of cervically projecting corticospinal neurons present in the hindlimb sensory-motor cortex and good behavioural recovery. Anterograde tracing from the hindlimb sensory-motor cortex also showed a positive correlation between the degree of functional recovery and the sprouting of neurons from this region into the cervical spinal cord. Finally, intracortical microstimulation confirmed the positive correlation between rewiring of the hindlimb sensory-motor cortex and the degree of forelimb motor recovery. In conclusion, these experiments suggest that following stroke to the forelimb motor cortex, cells in the hindlimb sensory-motor area reorganize and become functionally connected to the cervical spinal cord. These new connections, probably in collaboration with surviving forelimb neurons and more complex indirect connections via the brainstem, play an important role for the recovery of cortically controlled behaviours like skilled forelimb reachin

Rewiring of the corticospinal tract in the adult rat after unilateral stroke and anti-Nogo-A therapy

The adult CNS has limited potential for functional recovery after structural lesions. Lindau et al. report that a blocking antibody to the neurite-growth inhibitory protein Nogo-A improved functional recovery in a rat sensorimotor cortex stroke model. The functional recovery was accompanied by increased corticospinal innervation from the contralateral corte

Current provision of myelopathy education in medical schools in the UK: protocol for a national medical student survey

Introduction: Degenerative cervical myelopathy (DCM) is a common, disabling and progressive neurological condition triggered by chronic compression of the cervical spinal cord by surrounding degenerative changes. Early diagnosis and specialist management are essential to reduce disability, yet time to diagnosis is typically prolonged. Lack of sufficient representation of DCM in undergraduate and postgraduate medical curricula may contribute to the poor recognition of DCM by non-specialist doctors in clinical practice. In this study, our objective, therefore, is to assess DCM teaching provision in medical schools throughout the UK and to assess the impact of teaching on the DCM knowledge of UK medical students. Methods and analysis: A 19-item questionnaire capturing data on medical student demographics, myelopathy teaching and myelopathy knowledge was designed. Ethical approval was granted by the Psychology Research Ethics Committee, University of Cambridge. An online survey was hosted on Myelopathy.org, an international myelopathy charity. Students studying at a UK medical school are eligible for inclusion. The survey is advertised nationally through university social media pages, university email bulletins and the national student network of Myelopathy.org. Advertisements are scheduled monthly over a 12-month recruitment period. Participation is incentivised by entering consenting participants of completed surveys to an Amazon voucher prize draw. Responses are anonymised using participant-chosen unique identifier codes. A participant information sheet followed by an explicit survey question captures participant informed consent. Regular updates on the progress of the study will be published on Myelopathy.org. Ethics and Dissemination: Ethical approval for the study was granted by the Psychology Research Ethics Committee, University of Cambridge (PRE.2018.099). The findings of the study described in this protocol, and all other related work, will be submitted for publication in a peer-reviewed journal and will be presented at scientific conferences

Estimation of Energy Expenditure in Wheelchair-Bound Spinal Cord Injured Individuals Using Inertial Measurement Units

A healthy lifestyle reduces the risk of cardio-vascular disease. As wheelchair-bound individuals with spinal cord injury (SCI) are challenged in their activities, promoting and coaching an active lifestyle is especially relevant. Although there are many commercial activity trackers available for the able-bodied population, including those providing feedback about energy expenditure (EE), activity trackers for the SCI population are largely lacking, or are limited to a small set of activities performed in controlled settings. The aims of the present study were to develop and validate an algorithm based on inertial measurement unit (IMU) data to continuously monitor EE in wheelchair-bound individuals with a SCI, and to establish reference activity values for a healthy lifestyle in this population. For this purpose, EE was measured in 30 subjects each wearing four IMUs during 12 different physical activities, randomly selected from a list of 24 activities of daily living. The proposed algorithm consists of three parts: resting EE estimation based on multi-linear regression, an activity classification using a k-nearest-neighbors algorithm, and EE estimation based on artificial neural networks (ANNs). The mean absolute estimation error for the ANN-based algorithm was 14.4% compared to indirect calorimeter measurements. Based on reference values from the literature and the data collected within this study, we recommend wheeling 3 km per day for a healthy lifestyle in wheelchair-bound SCI individuals. Combining the proposed algorithm with a recommendation for physical activity provides a powerful tool for the promotion of an active lifestyle in the SCI population, thereby reducing the risk for secondary diseases

Notes on the distribution and status of small carnivores in Gabon

The distribution and status of small carnivore species in Gabon have never been comprehensively assessed. We collated data from general wildlife surveys, camera-trap and transect studies and analyses of bushmeat consumption and trade, to map their country-wide occurrence and assess current exploitation levels. Records of Common Slender Mongoose Herpestes sanguineus and Cameroon Cusimanse Crossarchus platycephalus represent the first confirmation of their occurrence in Gabon. Cameroon Cusimanse was believed to extend into north-east Gabon, but the Slender Mongoose records extend its known range well outside that previously suspected. We furthermore extended the known range for Egyptian Mongoose Herpestes ichneumon. Crested Genet Genetta cristata has also been proposed to occur in Gabon but our records were not suited to evaluating this possibility given the difficulties of separation from Servaline Genet G. servalina. Most species appear to be distributed widely across the country. While several are commonly recorded in hunter catch and bushmeat markets, they form only a small proportion (3.4% and 3.1%, respectively) of all bushmeat records. However, in proximity to settlements, small carnivore exploitation, for bushmeat and use of body parts in traditional ceremonies, appears to have adverse effects on species richness and abundance

Targeting patient recovery priorities in degenerative cervical myelopathy:design and rationale for the RECEDE-Myelopathy trial-study protocol

Introduction: Degenerative cervical myelopathy (DCM) is a common and disabling condition of symptomatic cervical spinal cord compression secondary to degenerative changes in spinal structures leading to a mechanical stress injury of the spinal cord. RECEDE-Myelopathy aims to test the disease-modulating activity of the phosphodiesterase 3/phosphodiesterase 4 inhibitor Ibudilast as an adjuvant to surgical decompression in DCM. Methods and analysis: RECEDE-Myelopathy is a multicentre, double-blind, randomised, placebo-controlled trial. Participants will be randomised to receive either 60-100 mg Ibudilast or placebo starting within 10 weeks prior to surgery and continuing for 24 weeks after surgery for a maximum of 34 weeks. Adults with DCM, who have a modified Japanese Orthopaedic Association (mJOA) score 8-14 inclusive and are scheduled for their first decompressive surgery are eligible for inclusion. The coprimary endpoints are pain measured on a visual analogue scale and physical function measured by the mJOA score at 6 months after surgery. Clinical assessments will be undertaken preoperatively, postoperatively and 3, 6 and 12 months after surgery. We hypothesise that adjuvant therapy with Ibudilast leads to a meaningful and additional improvement in either pain or function, as compared with standard routine care. Study design: Clinical trial protocol V.2.2 October 2020. Ethics and dissemination: Ethical approval has been obtained from HRA - Wales. The results will be presented at an international and national scientific conferences and in a peer-reviewed journals.Trial registration number: ISRCTN Number: ISRCTN16682024.</p

RE-CODE DCM (REsearch Objectives and Common Data Elements for Degenerative Cervical Myelopathy): A Consensus Process to Improve Research Efficiency in DCM, Through Establishment of a Standardized Dataset for Clinical Research and the Definition of the Research Priorities.

Study Design: Mixed-method consensus process. Objectives: Degenerative cervical myelopathy (DCM) is a common and disabling condition that arises when mechanical stress damages the spinal cord as a result of degenerative changes in the surrounding spinal structures. RECODE-DCM (REsearch Objectives and Common Data Elements for Degenerative Cervical Myelopathy) aims to improve efficient use of health care resources within the field of DCM by using a multi-stakeholder partnership to define the DCM research priorities, to develop a minimum dataset for DCM clinical studies, and confirm a definition of DCM. Methods: This requires a multi-stakeholder partnership and multiple parallel consensus development processes. It will be conducted via 4 phases, adhering to the guidance set out by the COMET (Core Outcomes in Effectiveness Trials) and JLA (James Lind Alliance) initiatives. Phase 1 will consist of preliminary work to inform online Delphi processes (Phase 2) and a consensus meeting (Phase 3). Following the findings of the consensus meeting, a synthesis of relevant measurement instruments will be compiled and assessed as per the COSMIN (Consensus-based Standards for the Selection of Health Measurement Instruments) criteria, to allow recommendations to be made on how to measure agreed data points. Phase 4 will monitor and promote the use of eventual recommendations. Conclusions: RECODE-DCM sets out to establish for the first time an index term, minimum dataset, and research priorities together. Our aim is to reduce waste of health care resources in the future by using patient priorities to inform the scope of future DCM research activities. The consistent use of a standard dataset in DCM clinical studies, audit, and clinical surveillance will facilitate pooled analysis of future data and, ultimately, a deeper understanding of DCM.AM is funded by a Clinician Scientist Fellowship (NIHR-CS-2017-17-010) from the UK National Institute for Health Research (NIHR) and supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Research in the senior author’s laboratory is supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. MRNK is supported by a NIHR Clinician Scientist Award, CS-2015-15-023

Lived Experience-Centred Word Clouds May Improve Research Uncertainty Gathering in Priority Setting Partnerships

INTRODUCTION: AO Spine RECODE-DCM was a multi-stakeholder priority setting partnership (PSP) to define the top ten research priorities for degenerative cervical myelopathy (DCM). Priorities were generated and iteratively refined using a series of surveys administered to surgeons, other healthcare professionals (oHCP) and people with DCM (PwDCM). The aim of this work was to utilise word clouds to enable the perspectives of people with the condition to be heard earlier in the PSP process than is traditionally the case. The objective was to evaluate the added value of word clouds in the process of defining research uncertainties in National Institute for Health Research (NIHR) James Lind Alliance (JLA) Priority Setting Partnerships. METHODS: Patient-generated word clouds were created for the four survey subsections of the AO Spine RECODE-DCM PSP: diagnosis, treatment, long-term management and other issues. These were then evaluated as a nested methodological study. Word-clouds were created and iteratively refined by an online support group of people with DCM, before being curated by the RECODE-DCM management committee and expert healthcare professional representatives. The final word clouds were embedded within the surveys administered at random to 50% of participants. DCM research uncertainties suggested by participants were compared pre- and post-word cloud presentation. RESULTS: A total of 215 (50.9%) participants were randomised to the word cloud stream, including 118 (55%) spinal surgeons, 52 (24%) PwDCM and 45 (21%) oHCP. Participants submitted 434 additional uncertainties after word cloud review: word count was lower and more uniform across each survey subsections compared to pre-word cloud uncertainties. Twenty-three (32%) of the final 74 PSP summary questions did not have a post-word cloud contribution and no summary question was formed exclusively on post-word cloud uncertainties. There were differences in mapping of pre- and post-word cloud uncertainties to summary questions, with greater mapping of post-word cloud uncertainties to the number 1 research question priority: raising awareness. Five of the final summary questions were more likely to map to the research uncertainties suggested by participants after having reviewed the word clouds. CONCLUSIONS: Word clouds may increase the perspective of underrepresented stakeholders in the research question gathering stage of priority setting partnerships. This may help steer the process towards research questions that are of highest priority for people with the condition

Point-of-care testing in paediatric settings in the UK and Ireland: A cross-sectional study

Background: Point-of-care testing (POCT) is diagnostic testing performed at or near to the site of the patient. Understanding the current capacity, and scope, of POCT in this setting is essential in order to respond to new research evidence which may lead to wide implementation. Methods: A cross-sectional online survey study of POCT use was conducted between 6th January and 2nd February 2020 on behalf of two United Kingdom (UK) and Ireland-based paediatric research networks (Paediatric Emergency Research UK and Ireland, and General and Adolescent Paediatric Research UK and Ireland). Results: In total 91/109 (83.5%) sites responded, with some respondents providing details for multiple units on their site based on network membership (139 units in total). The most commonly performed POCT were blood sugar (137/139; 98.6%), urinalysis (134/139; 96.4%) and blood gas analysis (132/139; 95%). The use of POCT for Influenza/Respiratory Syncytial Virus (RSV) (45/139; 32.4%, 41/139; 29.5%), C-Reactive Protein (CRP) (13/139; 9.4%), Procalcitonin (PCT) (2/139; 1.4%) and Group A Streptococcus (5/139; 3.6%) and was relatively low. Obstacles to the introduction of new POCT included resources and infrastructure to support test performance and quality assurance. Conclusion: This survey demonstrates significant consensus in POCT practice in the UK and Ireland but highlights specific inequity in newer biomarkers, some which do not have support from national guidance. A clear strategy to overcome the key obstacles of funding, evidence base, and standardising variation will be essential if there is a drive toward increasing implementation of POCT