Cost-effectiveness of surgery for degenerative cervical myelopathy in the United Kingdom.

PURPOSE: Degenerative cervical myelopathy (DCM) is the commonest cause of adult spinal cord dysfunction worldwide, for which surgery is the mainstay of treatment. At present, there is limited literature on the costs associated with the surgical management of DCM, and none from the United Kingdom (UK). This study aimed to evaluate the cost-effectiveness of DCM surgery within the National Health Service, UK. MATERIALS AND METHODS: Incidence of DCM was identified from the Hospital Episode Statistics (HES) database for a single year using five ICD-10 diagnostic codes to represent DCM. Health Resource Group (HRG) data was used to estimate the mean incremental surgery (treatment) costs compared to non-surgical care, and the incremental effect (quality adjusted life year (QALY) gain) was based on data from a previous study. A cost per QALY value of <£30,000/QALY (GBP) was considered acceptable and cost-effective, as per the National Institute for Health and Clinical Excellence (NICE) guidance. A sensitivity analysis was undertaken (±5%, ±10% and ±20%) to account for variance in both the cost of admission and QALY gain. RESULTS: The total number of admissions for DCM in 2018 was 4,218. Mean age was 62 years, with 54% of admissions being of working age (18-65 years). The overall estimated cost of admissions for DCM was £38,871,534 for the year. The mean incremental (per patient) cost of surgical management of DCM was estimated to be £9,216 (ranged £2,358 to £9,304), with a QALY gain of 0.64, giving an estimated cost per QALY value of £14,399/QALY. Varying the QALY gain by ±20%, resulted in cost/QALY figures between £12,000 (+20%) and £17,999 (-20%). CONCLUSIONS: Surgery is estimated to be a cost-effective treatment of DCM amongst the UK population.

The significance of metabolic disease in degenerative cervical myelopathy: a systematic review.

Introduction: Degenerative cervical myelopathy (DCM) is a form of chronic spinal cord injury, with a natural history of potential for progression over time. Whilst driven by mechanical stress on the spinal cord from degenerative and congenital pathology, the neurological phenotype of DCM is likely to be modified by multiple systemic factors. The role of metabolic factors is therefore of interest, particularly given that ischaemia is considered a key pathological mechanism of spinal cord injury. The objective was therefore to synthesise current evidence on the effect of metabolism on DCM susceptibility, severity, and surgical outcomes. Methods: A systematic review in MEDLINE and Embase was conducted following PRISMA guidelines. Full-text papers in English, with a focus on DCM and metabolism, including diabetes, cardiovascular disease, anaemia, and lipid profile, were eligible for inclusion. Risk of methodological bias was assessed using the Joanna Briggs Institute (JBI) critical assessment tools. Quality assessments were performed using the GRADE assessment tool. Patient demographics, metabolic factors and the relationships between metabolism and spinal cord disease, spinal column disease and post-operative outcomes were assessed. Results: In total, 8,523 papers were identified, of which 57 met criteria for inclusion in the final analysis. A total of 91% (52/57) of included papers assessed the effects of diabetes in relation to DCM, of which 85% (44/52) reported an association with poor surgical outcomes; 42% of papers (24/57) discussed the association between cardiovascular health and DCM, of which 88% (21/24) reported a significant association. Overall, DCM patients with diabetes or cardiovascular disease experienced greater perioperative morbidity and poorer neurological recovery. They were also more likely to have comorbidities such as obesity and hyperlipidaemia. Conclusion: Metabolic factors appear to be associated with surgical outcomes in DCM. However, evidence for a more specific role in DCM susceptibility and severity is uncertain. The pathophysiology and natural history of DCM are critical research priorities; the role of metabolism is therefore a key area for future research focus. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021268814.

Degenerative Thoracic Myelopathy: A Scoping Review of Epidemiology, Genetics, and Pathogenesis.

STUDY DESIGN: Literature Review. OBJECTIVE: Myelopathy affecting the thoracic spinal cord can arise secondary to several aetiologies which have similar presentation and management. Consequently, there are many uncertainties in this area, including optimal terminology and definitions. Recent collaborative cervical spinal research has led to the proposal and subsequent community adoption of the name degenerative cervical myelopathy(DCM), which has facilitated the establishment of internationally-agreed research priorities for DCM. We put forward the case for the introduction of the term degenerative thoracic myelopathy(DTM) and degenerative spinal myelopathy(DSM) as an umbrella term for both DCM and DTM. METHODS: Following PRISMA guidelines, a systematic literature search was performed to identify degenerative thoracic myelopathy literature in Embase and MEDLINE. RESULTS: Conditions encompassed within DTM include thoracic spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, calcification of ligaments, hypertrophy of ligaments, degenerative disc disease, thoracic osteoarthritis, intervertebral disc herniation, and posterior osteophytosis. The classic presentation includes girdle pain, gait disturbance, leg weakness, sensory disturbance, and bladder or bowel dysfunction, often with associated back pain. Surgical management is typically favoured with post-surgical outcomes dependent on many factors, including the causative pathology, and presence of additional stenosis. CONCLUSION: The clinical entities encompassed by the term DTM are interrelated, can manifest concurrently, and present similarly. Building on the consensus adoption of DCM in the cervical spine and the recent proposal of degenerative cervical radiculopathy(DCR), extending this common nomenclature framework to the terms degenerative spinal myelopathy and degenerative thoracic myelopathy will help improve recognition and communication.

Brain MRI changes in degenerative cervical myelopathy: a systematic review.

BACKGROUND: Degenerative cervical myelopathy (DCM) is the most common cause of adult spinal cord dysfunction globally. Associated neurological symptoms and signs have historically been explained by pathobiology within the cervical spine. However, recent advances in imaging have shed light on numerous brain changes in patients with DCM, and it is hypothesised that these changes contribute to DCM pathogenesis. The aetiology, significance, and distribution of these supraspinal changes is currently unknown. The objective was therefore to synthesise all current evidence on brain changes in DCM. METHODS: A systematic review was performed. Cross-sectional and longitudinal studies with magnetic resonance imaging on a cohort of patients with DCM were eligible. PRISMA guidelines were followed. MEDLINE and Embase were searched to 28th August 2023. Duplicate title/abstract screening, data extraction and risk of bias assessments were conducted. A qualitative synthesis of the literature is presented as per the Synthesis Without Meta-Analysis (SWiM) reporting guideline. The review was registered with PROSPERO (ID: CRD42022298538). FINDINGS: Of the 2014 studies that were screened, 47 studies were identified that used MRI to investigate brain changes in DCM. In total, 1500 patients with DCM were included in the synthesis, with a mean age of 53 years. Brain alterations on MRI were associated with DCM both before and after surgery, particularly within the sensorimotor network, visual network, default mode network, thalamus and cerebellum. Associations were commonly reported between brain MRI alterations and clinical measures, particularly the Japanese orthopaedic association (JOA) score. Risk of bias of included studies was low to moderate. INTERPRETATION: The rapidly expanding literature provides mounting evidence for brain changes in DCM. We have identified key structures and pathways that are altered, although there remains uncertainty regarding the directionality and clinical significance of these changes. Future studies with greater sample sizes, more detailed phenotyping and longer follow-up are now needed. FUNDING: ODM is supported by an Academic Clinical Fellowship at the University of Cambridge. BMD is supported by an NIHR Clinical Doctoral Fellowship at the University of Cambridge (NIHR300696). VFJN is supported by an NIHR Rosetrees Trust Advanced Fellowship (NIHR302544). This project was supported by an award from the Rosetrees Foundation with the Storygate Trust (A2844).

The incidence and impact of 'Tandem Neurotrauma'.

Introduction: The epidemiology and prognosis of the isolated traumatic brain injury (TBI) and spinal cord injury (SCI) are well studied. However, the knowledge of the impact of concurrent neurotrauma is very limited. Research questions: To characterize the longitudinal incidence of concurrent TBI and SCI and to investigate their combined impact on clinical care and outcomes, compared to a comparative but isolated SCI or TBI. Materials and methods: Data from 167,793 patients in the Trauma Audit and Research Network (TARN) registry collected in England and Wales between 2008 and 2018 were analysed. Tandem neurotrauma was defined as patients with concurrent TBI and SCI. The patient with isolated TBI or SCI was matched to the patient with tandem neurotrauma using propensity scores. Results: The incidence of tandem neurotrauma increased tenfold between 2008 and 2018, from 0.21 to 2.21 per 100,000 person-years. Patients in the tandem neurotrauma group were more likely to require multiple surgeries, ICU admission, longer ICU and hospital LOS, higher 30-day mortality, and were more likely to be transferred to acute hospitals and rehabilitation or suffer death at discharge, compared to patients with isolated TBI. Likewise, individuals with tandem neurotrauma compared to those with isolated SCI had a higher tendency to receive more than one surgery, ICU admission, longer LOS for ICU and higher mortality either at 30-day follow-up or at discharge. Discussion and conclusions: The incidence of tandem neurotrauma has increased steadily during the past decade. Its occurrence leads to greater mortality and care requirements, particularly when compared to TBI alone. Further investigations are warranted to improve outcomes in tandem neurotrauma.

Is the type and/or co-existence of degenerative spinal pathology associated with the occurrence of degenerative cervical myelopathy? A single centre retrospective analysis of individuals with MRI defined cervical cord compression.

BACKGROUND: Degenerative cervical myelopathy (DCM) arises from spinal degenerative changes injuring the cervical spinal cord. Most cord compression is incidental, referred to as asymptomatic spinal cord compression (ASCC). How and why ASCC differs from DCM is poorly understood. In this paper, we study a local cohort to identify specific types and groups of degenerative pathology more likely associated with DCM than ASCC. METHODS: This study was a retrospective cohort analysis (IRB Approval ID: PRN10455). The frequency of degenerative findings between those with ASCC and DCM patients were compared using network analysis, hierarchical clustering, and comparison to existing literature to identify potential subgroups in a local cohort (N = 155) with MRI-defined cervical spinal cord compression. Quantitative measures of spinal cord compression (MSCC and MCC) were used to confirm their relevance. RESULTS: ELF (8.7 %, 95 % CI 3.8-13.6 % vs 35.7 %, 95 % CI 27.4-44.0 %) Congenital Stenosis (3.9 %, 95 % CI 0.6-7.3 % vs 25.0 %, 95 % CI 17.5-32.5 %), and OPLL (0.0 %, 95 % CI 0.0-0.0 % vs 3.6 %, 95 % CI 0.3-6.8 %) were more likely in patients with DCM. Comparative network analysis indicated loss of lordosis was associated with ASCC, whilst ELF with DCM. Hierarchical Cluster Analysis indicated four sub-groups: multi-level disc disease with ELF, single-level disc disease without loss of lordosis and OPLL with DCM, and single-level disc disease with loss of lordosis with ASCC. Quantitative measures of cord compression were higher in groups associated with DCM, but similar in patients with single-level disc disease and loss of lordosis. CONCLUSIONS: This study identified four subgroups based on degenerative pathology requiring further investigation.

A single centre service evaluation of degenerative cervical and thoracic myelopathy.

BACKGROUND: Degenerative cervical myelopathy (DCM) and degenerative thoracic myelopathy (DTM) present with leg, bladder and bowel symptoms. If imaging confirms spinal cord compression both conditions are usually managed surgically. Surgical timing is important in patient management as it affects post-operative recovery and long-term outcomes. This service evaluation aims to explore whether that patients with DTM are more likely to be treated urgently than those with DCM and to examine whether any differences in management are justified. METHODS: A retrospective service evaluation was registered and approved by the Cambridge University Hospitals NHS Foundation Trust (CUH) Clinical Audit Department (Clinical Project ID4455 PRN10455). All patients who had undergone surgery for DTM at CUH from January 2015 until April 2022 were included. Comparison was made to a cohort of DCM patients who underwent surgery at CUH from June 2016 to January 2019. Data analysis was conducted in R. RESULTS: A total of 130 DCM patients and 78 DTM patients were included. Our DCM and DTM patient cohorts had comparable demographics, but DTM patients had fewer spinal levels affected. Despite equivalent disease severity, DTM patients had a shorter time to diagnosis, shorter wait for surgery and were more likely to be operated on as an emergency case. CONCLUSIONS: Despite comparable demographics and pathophysiology, DTM was diagnosed and managed more quickly than DCM. Better defined diagnostic pathways for degenerative spinal myelopathy may hold opportunities to optimise diagnosis and management, ensuring consistent high quality, efficient and equitable care.

Toward Shared Decision-Making in Degenerative Cervical Myelopathy: Protocol for a Mixed Methods Study.

BACKGROUND: Health care decisions are a critical determinant in the evolution of chronic illness. In shared decision-making (SDM), patients and clinicians work collaboratively to reach evidence-based health decisions that align with individual circumstances, values, and preferences. This personalized approach to clinical care likely has substantial benefits in the oversight of degenerative cervical myelopathy (DCM), a type of nontraumatic spinal cord injury. Its chronicity, heterogeneous clinical presentation, complex management, and variable disease course engenders an imperative for a patient-centric approach that accounts for each patient's unique needs and priorities. Inadequate patient knowledge about the condition and an incomplete understanding of the critical decision points that arise during the course of care currently hinder the fruitful participation of health care providers and patients in SDM. This study protocol presents the rationale for deploying SDM for DCM and delineates the groundwork required to achieve this. OBJECTIVE: The study's primary outcome is the development of a comprehensive checklist to be implemented upon diagnosis that provides patients with essential information necessary to support their informed decision-making. This is known as a core information set (CIS). The secondary outcome is the creation of a detailed process map that provides a diagrammatic representation of the global care workflows and cognitive processes involved in DCM care. Characterizing the critical decision points along a patient's journey will allow for an effective exploration of SDM tools for routine clinical practice to enhance patient-centered care and improve clinical outcomes. METHODS: Both CISs and process maps are coproduced iteratively through a collaborative process involving the input and consensus of key stakeholders. This will be facilitated by Myelopathy.org, a global DCM charity, through its Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy community. To develop the CIS, a 3-round, web-based Delphi process will be used, starting with a baseline list of information items derived from a recent scoping review of educational materials in DCM, patient interviews, and a qualitative survey of professionals. A priori criteria for achieving consensus are specified. The process map will be developed iteratively using semistructured interviews with patients and professionals and validated by key stakeholders. RESULTS: Recruitment for the Delphi consensus study began in April 2023. The pilot-testing of process map interview participants started simultaneously, with the formulation of an initial baseline map underway. CONCLUSIONS: This protocol marks the first attempt to provide a starting point for investigating SDM in DCM. The primary work centers on developing an educational tool for use in diagnosis to enable enhanced onward decision-making. The wider objective is to aid stakeholders in developing SDM tools by identifying critical decision junctures in DCM care. Through these approaches, we aim to provide an exhaustive launchpad for formulating SDM tools in the wider DCM community. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46809.

The impact of phosphodiesterase inhibition on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review.

Study design: Systematic review. Objective: The objective of this study was to evaluate the impact of phosphodiesterase (PDE) inhibitors on neurobehavioral outcomes in preclinical models of traumatic and non-traumatic spinal cord injury (SCI). Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was registered with PROSPERO (CRD42019150639). Searches were performed in MEDLINE and Embase. Studies were included if they evaluated the impact of PDE inhibitors on neurobehavioral outcomes in preclinical models of traumatic or non-traumatic SCI. Data were extracted from relevant studies, including sample characteristics, injury model, and neurobehavioral assessment and outcomes. Risk of bias was assessed using the SYRCLE checklist. Results: The search yielded a total of 1,679 studies, of which 22 met inclusion criteria. Sample sizes ranged from 11 to 144 animals. PDE inhibitors used include rolipram (n = 16), cilostazol (n = 4), roflumilast (n = 1), and PDE4-I (n = 1). The injury models used were traumatic SCI (n = 18), spinal cord ischemia (n = 3), and degenerative cervical myelopathy (n = 1). The most commonly assessed outcome measures were Basso, Beattie, Bresnahan (BBB) locomotor score (n = 13), and grid walking (n = 7). Of the 22 papers that met the final inclusion criteria, 12 showed a significant improvement in neurobehavioral outcomes following the use of PDE inhibitors, four papers had mixed findings and six found PDE inhibitors to be ineffective in improving neurobehavioral recovery following an SCI. Notably, these findings were broadly consistent across different PDE inhibitors and spinal cord injury models. Conclusion: In preclinical models of traumatic and non-traumatic SCI, the administration of PDE inhibitors appeared to be associated with statistically significant improvements in neurobehavioral outcomes in a majority of included studies. However, the evidence was inconsistent with a high risk of bias. This review provides a foundation to aid the interpretation of subsequent clinical trials of PDE inhibitors in spinal cord injury. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150639, identifier: CRD42019150639.

Secondary analysis of a James Lind Alliance priority setting partnership to facilitate knowledge translation in degenerative cervical myelopathy (DCM): insights from AO Spine RECODE-DCM.

OBJECTIVES: To explore whether a James Lind Alliance Priority Setting Partnership could provide insights on knowledge translation within the field of degenerative cervical myelopathy (DCM). DESIGN: Secondary analysis of a James Lind Alliance Priority Setting Partnership process for DCM. PARTICIPANTS AND SETTING: DCM stake holders, including spinal surgeons, people with myelopathy and other healthcare professionals, were surveyed internationally. Research suggestions submitted by stakeholders but considered answered were identified. Sampling characteristics of respondents were compared with the overall cohort to identify subgroups underserved by current knowledge translation. RESULTS: The survey was completed by 423 individuals from 68 different countries. A total of 22% of participants submitted research suggestions that were considered 'answered'. There was a significant difference between responses from different stakeholder groups (p<0.005). Spinal surgeons were the group which was most likely to submit an 'answered' research question. Respondents from South America were also most likely to submit 'answered' questions, when compared with other regions. However, there was no significant difference between responses from different stakeholder regions (p=0.4). CONCLUSIONS: Knowledge translation challenges exist within DCM. This practical approach to measuring knowledge translation may offer a more responsive assessment to guide interventions, complementing existing metrics.

Electrophysiological In Vitro Study of Long-Range Signal Transmission by Astrocytic Networks.

Astrocytes are diverse brain cells that form large networks communicating via gap junctions and chemical transmitters. Despite recent advances, the functions of astrocytic networks in information processing in the brain are not fully understood. In culture, brain slices, and in vivo, astrocytes, and neurons grow in tight association, making it challenging to establish whether signals that spread within astrocytic networks communicate with neuronal groups at distant sites, or whether astrocytes solely respond to their local environments. A multi-electrode array (MEA)-based device called AstroMEA is designed to separate neuronal and astrocytic networks, thus allowing to study the transfer of chemical and/or electrical signals transmitted via astrocytic networks capable of changing neuronal electrical behavior. AstroMEA demonstrates that cortical astrocytic networks can induce a significant upregulation in the firing frequency of neurons in response to a theta-burst charge-balanced biphasic current stimulation (5 pulses of 100 Hz × 10 with 200 ms intervals, 2 s total duration) of a separate neuronal-astrocytic group in the absence of direct neuronal contact. This result corroborates the view of astrocytic networks as a parallel mechanism of signal transmission in the brain that is separate from the neuronal connectome. Translationally, it highlights the importance of astrocytic network protection as a treatment target.

Osteopathy in the Early Diagnosis and Management of Degenerative Cervical Myelopathy: National Survey.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a common and disabling neurodegenerative condition. Surgical decompression is the only evidence-based treatment to halt disease progression; however, diagnosis and access to timely treatment are often delayed, which contribute to significant disability and dependence. Supporting early diagnosis and access to timely treatment is a critical priority. Exploring these challenges, Myelopathy.org has observed that people with DCM may seek osteopathy care for their symptoms, both before and after diagnosis. OBJECTIVE: This study aimed to describe the current interaction between osteopaths and people with DCM and understand how this may be targeted to enhance the DCM diagnostic pathway. METHODS: Registered osteopaths in the United Kingdom completed a web-based survey hosted by the Institute of Osteopathy, as part of their institute's 2021 census. Responses were collected from February to May 2021. Demographic information about the respondents was captured, including age, gender, and ethnicity. Professional information captured included the year of qualification; region of practice; type of practice; and number of undiagnosed, operated diagnosed, and unoperated diagnosed DCM cases encountered per year. The completion of the survey was voluntary; however, a prize draw incentive was offered to participants. RESULTS: The demographics were heterogenous for the 547 practitioners who completed the survey. There was representation from a wide range of demographic groups, including the level of experience, gender, age, and the region of United Kingdom. At least 68.9% (377/547) of osteopaths reported encounters with DCM each year. Osteopaths most frequently encountered patients with undiagnosed DCM, with a mean of 3 patient encounters per year. This compares to 2 encounters per year with patients with diagnosed DCM. The level of practitioner experience was positively correlated with the detection of undiagnosed DCM (P<.005). The influence of practitioner experience was corroborated by a subgroup analysis looking at the relationship between practitioner age on the detection of undiagnosed DCM. Osteopaths older than 54 years encountered an average of 4.2 cases per year, whereas those younger than 35 years detected 2.9 cases per year. Osteopaths in private clinics reported encounters with a greater mean number (4.4) of undiagnosed DCM cases per year than osteopaths in other clinic types (3.0). CONCLUSIONS: Osteopaths reported that they frequently consult people with DCM, including those suspected to have undiagnosed or presurgical DCM. Given this concentrated presentation of early DCM and a workforce professionally trained to examine musculoskeletal disease, osteopaths could have an important role in accelerating access to timely treatment. We included a decision support tool and specialist referral template as a tool to support onward care.

Transcription factor combinations that define human astrocyte identity encode significant variation of maturity and function.

Increasing evidence indicates that cellular identity can be reduced to the distinct gene regulatory networks controlled by transcription factors (TFs). However, redundancy exists in these states as different combinations of TFs can induce broadly similar cell types. We previously demonstrated that by overcoming gene silencing, it is possible to deterministically reprogram human pluripotent stem cells directly into cell types of various lineages. In the present study we leverage the consistency and precision of our approach to explore four different TF combinations encoding astrocyte identity, based on previously published reports. Analysis of the resulting induced astrocytes (iAs) demonstrated that all four cassettes generate cells with the typical morphology of in vitro astrocytes, which expressed astrocyte-specific markers. The transcriptional profiles of all four iAs clustered tightly together and displayed similarities with mature human astrocytes, although maturity levels differed between cells. Importantly, we found that the TF cassettes induced iAs with distinct differences with regards to their cytokine response and calcium signaling. In vivo transplantation of selected iAs into immunocompromised rat brains demonstrated long term stability and integration. In conclusion, all four TF combinations were able to induce stable astrocyte-like cells that were morphologically similar but showed subtle differences with respect to their transcriptome. These subtle differences translated into distinct differences with regards to cell function, that could be related to maturation state and/or regional identity of the resulting cells. This insight opens an opportunity to precision-engineer cells to meet functional requirements, for example, in the context of therapeutic cell transplantation.

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.

Life expectancy in patients with degenerative cervical myelopathy is currently reduced but can be restored with timely treatment.

PURPOSE: Degenerative cervical myelopathy is a progressive slow-motion spinal cord injury. Surgery is the mainstay of treatment. Baseline disability predicts surgical recovery; therefore, timely treatment is critical to restoring function. However, current challenges mean most patients present with advanced disease and are instead left with life changing disabilities. While short-term mortality is rarely reported, the long-term effects of this on life expectancy are unknown, including whether function could be modifiable with timely treatment. This article investigates the effect of DCM on life expectancy. METHODS: The survival of patients from an observational study of patients undergoing surgery from 1994 to 2007 was compared to their expected survival using a gender- and aged -matched cohort. Comparisons were made by one sample log-rank test and standardised mortality ratios. Factors associated with survival were explored using a Cox regression analysis, including disease severity. RESULTS: A total of 357 patients were included in the analysis. After a median follow-up of 15.3 years, 135 of 349 patients had died; 114.7 deaths would have been expected. The DCM cohort had an increased risk of death compared to the non-DCM cohort (standardised mortality ratio 1.18 [95% CI: 1.02-1.34]. Age at operation 1.08 (95% CI: 1.07 to 1.1, p < 0.001) and severe DCM 1.6 (95% CI: 1.06 to 2.3, p = 0.02) were associated with worse survival (N = 287). In those surviving at least 2 years after surgery, only severe DCM was associated with conditional survival (HR 1.6, 95% CI 1.04 2.4, p = 0.03). CONCLUSION: Life expectancy is reduced in those undergoing surgery for DCM. This is driven by premature mortality among those left with severe disability. As disability can be reduced with timely treatment, these findings reinforce the need for collective and global action to raise awareness of DCM and enable early diagnosis.

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.

Functional neurological restoration of amputated peripheral nerve using biohybrid regenerative bioelectronics.

The development of neural interfaces with superior biocompatibility and improved tissue integration is vital for treating and restoring neurological functions in the nervous system. A critical factor is to increase the resolution for mapping neuronal inputs onto implants. For this purpose, we have developed a new category of neural interface comprising induced pluripotent stem cell (iPSC)-derived myocytes as biological targets for peripheral nerve inputs that are grafted onto a flexible electrode arrays. We show long-term survival and functional integration of a biohybrid device carrying human iPSC-derived cells with the forearm nerve bundle of freely moving rats, following 4 weeks of implantation. By improving the tissue-electronics interface with an intermediate cell layer, we have demonstrated enhanced resolution and electrical recording in vivo as a first step toward restorative therapies using regenerative bioelectronics.

Targeting earlier diagnosis: What symptoms come first in Degenerative Cervical Myelopathy?

BACKGROUND: Degenerative cervical myelopathy (DCM) is a common and disabling condition. Early effective treatment is limited by late diagnosis. Conventional descriptions of DCM focus on motor and sensory limb disability, however, recent work suggests the true impact is much broader. This study aimed to characterise the symptomatic presentation of DCM from the perspective of people with DCM and determine whether any of the reported symptoms, or groups of symptoms, were associated with early diagnosis. METHODS: An internet survey was developed, using an established list of patient-reported effects. Participants (N = 171) were recruited from an online community of people with DCM. Respondents selected their current symptoms and primary presenting symptom. The relationship of symptoms and their relationship to time to diagnosis were explored. This included symptoms not commonly measured today, termed 'non-conventional' symptoms. RESULTS: All listed symptoms were experienced by >10% of respondents, with poor balance being the most commonly reported (84.2%). Non-conventional symptoms accounted for 39.7% of symptomatic burden. 55.4% of the symptoms were reported as an initial symptom, with neck pain the most common (13.5%). Non-conventional symptoms accounted for 11.1% of initial symptoms. 79.5% of the respondents were diagnosed late (>6 months). Heavy legs was the only initial symptom associated with early diagnosis. CONCLUSIONS: A comprehensive description of the self-reported effects of DCM has been established, including the prevalence of symptoms at disease presentation. The experience of DCM is broader than suggested by conventional descriptions and further exploration of non-conventional symptoms may support earlier diagnosis.

Massively parallel characterization of CRISPR activator efficacy in human induced pluripotent stem cells and neurons.

CRISPR activation (CRISPRa) is an important tool to perturb transcription, but its effectiveness varies between target genes. We employ human pluripotent stem cells with thousands of randomly integrated barcoded reporters to assess epigenetic features that influence CRISPRa efficacy. Basal expression levels are influenced by genomic context and dramatically change during differentiation to neurons. Gene activation by dCas9-VPR is successful in most genomic contexts, including developmentally repressed regions, and activation level is anti-correlated with basal gene expression, whereas dCas9-p300 is ineffective in stem cells. Certain chromatin states, such as bivalent chromatin, are particularly sensitive to dCas9-VPR, whereas constitutive heterochromatin is less responsive. We validate these rules at endogenous genes and show that activation of certain genes elicits a change in the stem cell transcriptome, sometimes showing features of differentiated cells. Our data provide rules to predict CRISPRa outcome and highlight its utility to screen for factors driving stem cell differentiation.