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.

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.

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.

Human spinal cord tissue is an underutilised resource in degenerative cervical myelopathy: findings from a systematic review of human autopsies.

STUDY DESIGN: Systematic review. BACKGROUND: Although degenerative cervical myelopathy (DCM) is the most prevalent spinal cord condition worldwide, the pathophysiology remains poorly understood. Our objective was to evaluate existing histological findings of DCM on cadaveric human spinal cord tissue and explore their consistency with animal models. METHODS: MEDLINE and Embase were systematically searched (CRD42021281462) for primary research reporting on histological findings of DCM in human cadaveric spinal cord tissue. Data was extracted using a piloted proforma. Risk of bias was assessed using Joanna Briggs Institute critical appraisal tools. Findings were compared to a systematic review of animal models (Ahkter et al. 2020 Front Neurosci 14). RESULTS: The search yielded 4127 unique records. After abstract and full-text screening, 19 were included in the final analysis, reporting on 150 autopsies (71% male) with an average age at death of 67.3 years. All findings were based on haematoxylin and eosin (H&E) staining. The most commonly reported grey matter findings included neuronal loss and cavity formation. The most commonly reported white matter finding was demyelination. Axon loss, gliosis, necrosis and Schwann cell proliferation were also reported. Findings were consistent amongst cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. Cavitation was notably more prevalent in human autopsies compared to animal models. CONCLUSION: Few human spinal cord tissue studies have been performed. Neuronal loss, demyelination and cavitation were common findings. Investigating the biological basis of DCM is a critical research priority. Human spinal cord specimen may be an underutilised but complimentary approach.

Determinants of quality of life in degenerative cervical myelopathy: a systematic review.

BACKGROUND: Degenerative cervical myelopathy (DCM) is the most common cause of chronic, progressive spinal cord impairment worldwide. Patients experience substantial pain, functional neurological decline and disability. Health-related quality of life (HRQoL) appears to be particularly poor, even when compared to other chronic diseases. However, the determinants of HRQoL are poorly understood. The objective was to perform a systematic review of the determinants of quality of life of people with DCM. METHODS: A systematic search was conducted in MEDLINE and Embase following PRISMA 2020 guidelines (PROSPERO CRD42018115675). Full-text papers in English, exclusively studying DCM, published before 26 March 2020 were eligible for inclusion and were assessed using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias 2 (RoB 2) tool. Study sample characteristics, patient demographics, cohort type, HRQoL instrument utilised, HRQoL score, and relationships of HRQoL with other variables were qualitatively synthesised. RESULTS: A total of 1176 papers were identified; 77 papers and 13,572 patients were included in the final analysis. A total of 96% of papers studied surgical cohorts and 86% utilised the 36-Item Short Form Survey (SF-36) as a measure of HRQoL. HRQoL determinants were grouped into nine themes. The most common determinant to be assessed was surgical technique (38/77, 49%) and patient satisfaction and experience of pain (10/77, 13%). HRQoL appeared to improve after surgery. Pain was a negative predictor of HRQoL. CONCLUSION: Current data on the determinants of HRQoL in DCM are limited, contradictory and heterogeneous. Limitations of this systematic review include lack of distinction between DCM subtypes and heterogenous findings amongst the papers in which HRQoL is measured postoperatively or post-diagnosis. This highlights the need for greater standardisation in DCM research to allow further synthesis. Studies of greater precision are necessary to account for HRQoL being complex, multi-factorial and both time and context dependent.

Establishing mild, moderate and severe criteria for the myelopathy disability index in cervical spondylotic myelopathy.

AIM: Cervical Spondylotic Myelopathy (CSM) is a disabling condition arising from arthritic compression and consequent injury of the cervical spinal cord. Stratification of CSM severity has been useful to inform clinical practice and research analysis. In the UK the Myelopathy Disability Index (MDI) is a popular assessment tool and has been adopted by the British Spinal Registry. However, no categories of severity exist. Therefore, the aim of this study was to define categories of mild, moderate and severe. METHOD: An anchor-based analysis was carried out on previously collected data from a prospective observational cohort (N = 404) of patients with CSM scheduled for surgery and assessed pre-operatively and at 3, 12, 24 and 60 months post-operatively. Outcomes collected included the SF-36 version-1 quality of life measure, visual analogue scales for neck/arm/hand pain, MDI and Neck Disability Index (NDI). A Receiver Operating Curve (ROC) analysis, using the NDI for an anchor-based approach, was performed to identify MDI thresholds. RESULTS: Complete data was available for 404 patients (219 Men, 185 Women). The majority of patients underwent anterior surgery (284, 70.3%). ROC curves plotted to identify the thresholds from mild to moderate to severe disease, selected optimal thresholds of 4-5 (AUC 0.83) and 8-9 (AUC 0.87). These MDI categories were validated against domains of the SF36 and VAS scores with expected positive linear correlations. CONCLUSION: Categories of mild, moderate and severe CSM according to the MDI of 4-5 and 8-9 were established based on the NDI.

Development of a validated search filter for Ovid Embase for degenerative cervical myelopathy.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a recently proposed umbrella term for symptomatic cervical spinal cord compression secondary to degeneration of the spine. Currently literature searching for DCM is challenged by the inconsistent uptake of the term 'DCM' with many overlapping keywords and numerous synonyms. OBJECTIVES: Here, we adapt our previous Ovid medline search filter for the Ovid embase database, to support comprehensive literature searching. Both embase and medline are recommended as a minimum for systematic reviews. METHODS: References contained within embase identified in our prior study formed a 'development gold standard' reference database (N = 220). The search filter was adapted for embase and checked against the reference database. The filter was then validated against the 'validation gold standard'. RESULTS: A direct translation was not possible, as medline indexing for DCM and the keywords search field were not available in embase. We also used the 'focus' function to improve precision. The resulting search filter has 100% sensitivity in testing. DISCUSSION AND CONCLUSION: We have developed a validated search filter capable of retrieving DCM references in embase with high sensitivity. In the absence of consistent terminology and indexing, this will support more efficient and robust evidence synthesis in the field.

Hospitalisation for degenerative cervical myelopathy in England: insights from the National Health Service Hospital Episode Statistics 2012 to 2019.

PURPOSE: Degenerative cervical myelopathy (DCM) is the most common cause of adult spinal cord dysfunction worldwide. However, the current incidence of DCM is poorly understood. The Hospital Episode Statistics (HES) database contains details of all secondary care admissions across NHS hospitals in England. This study aimed to use HES data to characterise surgical activity for DCM in England. METHODS: The HES database was interrogated for all cases of DCM between 2012 and 2019. DCM cases were identified from 5 ICD-10 codes. Age-stratified values were collected for 'Finished Consultant Episodes' (FCEs), which correspond to a patient's hospital admission under a lead clinician. Data was analysed to explore current annual activity and longitudinal change. RESULTS: 34,903 FCEs with one or more of the five ICD-10 codes were identified, of which 18,733 (53.6%) were of working age (18-64 years). Mean incidence of DCM was 7.44 per 100,000 (SD ± 0.32). Overall incidence of DCM rose from 6.94 per 100,000 in 2012-2013 to 7.54 per 100,000 in 2018-2019. The highest incidence was seen in 2016-2017 (7.94 per 100,000). The median male number of FCEs per year (2919, IQR: 228) was consistently higher than the median female number of FCEs per year (2216, IQR: 326). The rates of both emergency admissions and planned admissions are rising. CONCLUSIONS: The incidence of hospitalisation for DCM in England is rising. Health care policymakers and providers must recognise the increasing burden of DCM and act to address both early diagnoses and access to treatment in future service provision plans.

Tremor as a symptom of degenerative cervical myelopathy: a systematic review.

BACKGROUND: AO Spine RECODE-DCM (Research objectives and common data elements for degenerative cervical myelopathy) has highlighted that the subjective disability reported by people living with DCM is much broader than routinely considered today by most professionals. This includes a description of tremor. The objective of this review was to study the incidence and possible aetiology of tremor in degenerative cervical myelopathy (DCM). METHODS: A systematic review registered in PROSPERO (CRD42020176905) was conducted in Embase and MEDLINE for papers studying tremor and DCM published on or before the 20th of July 2020. All manuscripts describing an association between tremor and DCM in humans were included. Articles relating to non-human animals, and those not available in English were excluded. An analysis was conducted in accordance with PRISMA and SWiM guidelines for systematic reviews. RESULTS: Out of a total of 4402 screened abstracts, we identified 7 case reports and series describing tremor in 9 DCM patients. Papers were divided into three groups for the discussion. The first group includes DCM correctly identified on presentation, with tremor as a described symptom. The second group includes cases where DCM was misdiagnosed, often as Parkinson's disease. The third group includes a single case with a previous history of DCM, presenting with an otherwise unexplained tremor. This grouping allows for the clustering of cases supporting various arguments for the association between tremor and DCM. CONCLUSION: DCM can be associated with tremor. The current evidence is restricted to case series. Further study is warranted to establish tremor prevalence, and its significance to assessment and management.

Degenerative cervical myelopathy education in UK medical schools: a national cross-sectional survey of medical students.

INTRODUCTION: Degenerative cervical myelopathy (DCM) is a common and progressive neurological condition caused by injury of the cervical spinal cord by degenerative spinal pathology. Delayed diagnosis leading to avoidable and irreversible disability is a major current problem limiting patient outcomes. Lack of sufficient representation of DCM in undergraduate and postgraduate medical curricula may contribute to poor recognition of DCM by non-specialist doctors. The objective of this study was to assess the DCM teaching provision in UK medical schools and the DCM knowledge of UK medical students. METHODS: UK medical students completed a web-based survey distributed nationally through university social media pages, university email bulletins and the national student network of Myelopathy.org. The survey comprised a 19-item questionnaire capturing data on student demographics, myelopathy teaching and myelopathy knowledge. Advertisements were repeated monthly over a 12-month recruitment period and participation was incentivised by entry into an Amazon voucher prize draw. Ethical approval for the study was granted by the Psychology Research Ethics Committee, University of Cambridge (PRE.2018.099). RESULTS: A total of 751 medical students from 32 British medical schools completed the survey. Medical students from all year groups participated. Most students (520; 72%) had not received any medical school teaching about DCM. When students had received DCM teaching, the duration of teaching was minimal (75% < 1 h). A total of 350 students (47%) reported conducting private study on DCM. Modal student self-rating of their own knowledge of DCM was 'terrible' (356; 47%). There was no correlation between a student's subjective rating of their knowledge and their answers to objective questions. A total of 723 (96%) of students expressed interest in learning more about DCM, with lectures the preferred format. CONCLUSIONS: DCM appears to be a neglected condition in medical education which has implications for clinical practice. However, student enthusiasm to undertake private study suggests future teaching interventions will be well-received. Future work is necessary to characterise the format of DCM teaching that is most effective and to subsequently measure how educational interventions translate into clinical benefits.

The effect of ageing on presentation, management and outcomes in degenerative cervical myelopathy: a systematic review.

OBJECTIVE: Degenerative cervical myelopathy (DCM) is a disabling neurological condition. The underlying degenerative changes are known to be more common with age, but the impact of age on clinical aspects of DCM has never been synthesised. The objective of this study is to determine whether age is a significant predictor in three domains-clinical presentation, surgical management and post-operative outcomes of DCM. METHODS: a systematic review of the Medline and Embase databases (inception to 12 December 2019), registered with PROSPERO (CRD42019162077) and reported in accordance with preferred reporting items of systematic reviews and meta-analysis (PRISMA) guidelines, was conducted. The inclusion criteria were full text articles in English, evaluating the impact of age on clinical aspects of DCM. RESULTS: the initial search yielded 2,420 citations, of which 206 articles were eventually included. Age was found to be a significant predictor in a variety of measures. Within the presentation domain, older patients have a worse pre-operative functional status. Within the management domain, older patients are more likely to undergo posterior surgery, with more levels decompressed. Within the outcomes domain, older patients have a worse post-operative functional status, but a similar amount of improvement in functional status. Because of heterogenous data reporting, meta-analysis was not possible. CONCLUSION: the current evidence demonstrates that age significantly influences the presentation, management and outcomes of DCM. Although older patients have worse health at all individual timepoints, they experience the same absolute benefit from surgery as younger patients. This finding is of particular relevance when considering the eligibility of older patients for surgery.

Systematic review of the impact of cannabinoids on neurobehavioral outcomes in preclinical models of traumatic and nontraumatic spinal cord injury.

STUDY DESIGN: Systematic review. OBJECTIVES: To evaluate the impact of cannabinoids on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI), with the aim of determining suitability for clinical trials involving SCI patients. METHODS: A systematic search was performed in MEDLINE and Embase databases, following registration with PROPSERO (CRD42019149671). Studies evaluating the impact of cannabinoids (agonists or antagonists) on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI were included. Data extracted from relevant studies, included sample characteristics, injury model, neurobehavioural outcomes assessed and study results. PRISMA guidelines were followed and the SYRCLE checklist was used to assess risk of bias. RESULTS: The search returned 8714 studies, 19 of which met our inclusion criteria. Sample sizes ranged from 23 to 390 animals. WIN 55,212-2 (n = 6) and AM 630 (n = 8) were the most used cannabinoid receptor agonist and antagonist respectively. Acute SCI models included traumatic injury (n = 16), ischaemia/reperfusion injury (n = 2), spinal cord cryoinjury (n = 1) and spinal cord ischaemia (n = 1). Assessment tools used assessed locomotor function, pain and anxiety. Cannabinoid receptor agonists resulted in statistically significant improvement in locomotor function in 9 out of 10 studies and pain outcomes in 6 out of 6 studies. CONCLUSION: Modulation of the endo-cannabinoid system has demonstrated significant improvement in both pain and locomotor function in pre-clinical SCI models; however, the risk of bias is unclear in all studies. These results may help to contextualise future translational clinical trials investigating whether cannabinoids can improve pain and locomotor function in SCI patients.

A scoping review of trials for cell-based therapies in human spinal cord injury.

INTRODUCTION: Spinal cord injury (SCI) is associated with significant and life-long disability. Yet, despite decades of research, no regenerative treatment has reached clinical practice. Cell-based therapies are one possible regenerative strategy beginning to transfer to human trials from a more extensive pre-clinical basis. METHODS: We therefore conducted a scoping review to synthesise all cell-based trials in SCI to consider the current state of the field and the cell transplant type or strategy with greatest promise. A search strategy of MEDLINE returned 1513 results. All clinical trials including adult human patients with acute or chronic, compete or incomplete SCI and a recorded ASIA score were sought. Exclusion criteria included non-traumatic SCI, paediatric patients and animal studies. A total of 43 studies, treating 1061 patients, were identified. Most trials evaluated cells from the bone marrow (22 papers, 660 patients) or the olfactory bulb (10 papers, 245 patients). RESULTS: Cell transplantation does appear to be safe, with no serious adverse effects being reported in the short-term. 86% of trials described efficacy as a primary outcome. However, varying degrees of outcome reporting prevented meta-analysis. No emerging cell type or technique was identified. The majority of trials, 53%, took place in developing countries, which may suggest more stringent regulatory requirements within Western countries. CONCLUSION: We believe cell-based transplantation translation remains in its infancy and that, although further robust clinical research is required, it is an important strategy to consider in the treatment of SCI.

Optimized inducible shRNA and CRISPR/Cas9 platforms for in vitro studies of human development using hPSCs.

Inducible loss of gene function experiments are necessary to uncover mechanisms underlying development, physiology and disease. However, current methods are complex, lack robustness and do not work in multiple cell types. Here we address these limitations by developing single-step optimized inducible gene knockdown or knockout (sOPTiKD or sOPTiKO) platforms. These are based on genetic engineering of human genomic safe harbors combined with an improved tetracycline-inducible system and CRISPR/Cas9 technology. We exemplify the efficacy of these methods in human pluripotent stem cells (hPSCs), and show that generation of sOPTiKD/KO hPSCs is simple, rapid and allows tightly controlled individual or multiplexed gene knockdown or knockout in hPSCs and in a wide variety of differentiated cells. Finally, we illustrate the general applicability of this approach by investigating the function of transcription factors (OCT4 and T), cell cycle regulators (cyclin D family members) and epigenetic modifiers (DPY30). Overall, sOPTiKD and sOPTiKO provide a unique opportunity for functional analyses in multiple cell types relevant for the study of human development.

Demographics, presentation and symptoms of patients with Klippel-Feil syndrome: analysis of a global patient-reported registry.

INTRODUCTION: Klippel-Feil syndrome (KFS) occurs due to failure of vertebral segmentation during development. Minimal research has been done to understand the prevalence of associated symptoms. Here, we report one of the largest collections of KFS patient data. METHODS: Data were obtained from the CoRDS registry. Participants with cervical fusions were categorized into Type I, II, or III based on the Samartzis criteria. Symptoms and comorbidities were assessed against type and location of fusion. RESULTS: Seventy-five patients (60F/14M/1 unknown) were identified and classified as: Type I, n = 21(28%); Type II, n = 15(20%); Type III, n = 39(52%). Cervical fusion by level were: OC-C1, n = 17(22.7%), C1-C2, n = 24(32%); C2-C3, n = 42(56%); C3-C4, n = 30(40%); C4-C5, n = 42(56%); C5-C6, n = 32(42.7%); C6-C7, n = 25(33.3%); C7-T1, n = 13(17.3%). 94.6% of patients reported current symptoms and the average age when symptoms began and worsened were 17.5 (± 13.4) and 27.6 (± 15.3), respectively. Patients reported to have a high number of comorbidities including spinal, neurological and others, a high frequency of general symptoms (e.g., fatigue, dizziness) and chronic symptoms (limited range of neck motion [LROM], neck/spine muscles soreness). Sprengel deformity was reported in 26.7%. Most patients reported having received medication and invasive/non-invasive procedures. Multilevel fusions (Samartzis II/III) were significantly associated with dizziness (p = 0.040), the presence of LROM (p = 0.022), and Sprengel deformity (p = 0.036). CONCLUSION: KFS is associated with a number of musculoskeletal and neurological symptoms. Fusions are more prevalent toward the center of the cervical region, and less common at the occipital/thoracic junction. Associated comorbidities including Sprengel deformity may be more common in KFS patients with multilevel cervical fusions. These slides can be retrieved under Electronic Supplementary Material.

Academic neurosurgery in the UK: present and future directions.

Academic neurosurgery encompasses basic science and clinical research efforts to better understand and treat diseases of relevance to neurosurgical practice, with the overall aim of improving treatment and outcome for patients. In this article, we provide an overview of the current and future directions of British academic neurosurgery. Training pathways are considered together with personal accounts of experiences of structured integrated clinical academic training and unstructured academic training. Life as an academic consultant is also described. Funding is explored, for the specialty as a whole and at the individual level. UK academic neurosurgical organisations are highlighted. Finally, the UK's international standing is considered.

A Novel Insight Into the Challenges of Diagnosing Degenerative Cervical Myelopathy Using Web-Based Symptom Checkers.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a common debilitating condition resulting from degeneration of the cervical spine. While decompressive surgery can halt disease progression, existing spinal cord damage is often permanent, leaving patients with lifelong disability. Early surgery improves the likelihood of recovery, yet the average time from the onset of symptoms to correct diagnosis is over 2 years. The majority of delays occur initially, before and within primary care, mainly due to a lack of recognition. Symptom checkers are widely used by patients before medical consultation and can be useful for preliminary triage and diagnosis. Lack of recognition of DCM by symptom checkers may contribute to the delay in diagnosis. OBJECTIVE: The aims of this study were to investigate whether Web-based symptom checkers were able to recognize relevant symptoms of DCM, to characterize the DCM differential they returned , and to evaluate the diagnostic performance of recognized DCM symptoms. METHODS: We pooled classical DCM symptoms from leading review articles. These symptoms were entered into the algorithms used by the top 20 symptom checker websites (N=4; Google Search). The most widely cited symptom checker, WebMD, was used to characterize the differential diagnosis for DCM symptoms. RESULTS: A total of 31 classical DCM symptoms were identified, of which 45% (14/31) listed DCM as a differential and 10% (3/31) placed DCM in the top third of the differential. The mean differential rank for motor symptoms was significantly better than that for arthritic symptoms (P=.01) and the average differential rank for all symptoms (P=.048). The symptom checker WebMD performed best at recognizing DCM, placing the condition nearer to the top of the differential list (mean rank of 5.6) than either Healthline (rank of 12.9, P=.02) or Healthtools.AARP (rank of 15.5, P=.001). On WebMD, only one combination of symptoms resulted in DCM as the primary differential: neck, shoulder, and arm pain with hand weakness. Moreover, 151 differential diagnoses for DCM symptoms were recorded on WebMD. Multiple sclerosis and peripheral neuropathy were the most common differentials, shortlisted for 52% (16/31) and 32% (10/31) of the DCM symptoms, respectively. CONCLUSIONS: DCM symptoms are poorly identified by Web-based symptom checkers, which leads to a large differential of many other common conditions. While a diagnosis becomes more likely as the number of symptoms increases, this represents more advanced disease and will not support much-needed earlier diagnosis. Symptom checkers remain an attractive concept with potential. Further research is required to support their optimization.

Development and validation of a MEDLINE search filter/hedge for degenerative cervical myelopathy.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a common condition with many unmet clinical needs. Pooled analysis of studies is an important tool for advancing medical understanding. This process starts with a systematic search of the literature. Identification of studies in DCM is challenged by a number of factors, including non-specific terminology and index terms. Search filters or HEDGEs, are search strings developed and validated to optimise medical literature searches. We aimed to develop a search filter for DCM for the MEDLINE database. METHODS: The diagnostic test assessment framework of a "development dataset" and seperate "validation dataset" was used. The development dataset was formed by hand searching four leading spinal journals (Spine, Journal of Neurosurgery Spine, Spinal Cord and Journal of Spinal Disorders and Techniques) in 2005 and 2010. The search filter was initially developed focusing on sensitivity and subsequently refined using NOT functions to improve specificity. One validation dataset was formed from DCM narrative and systematic review articles and the second, articles published in April of 1989, 1993, 1997, 2001, 2005, 2009, 2013 and 2017 retrieved via the search MeSH term 'Spine'. Metrics of sensitivity, specificity, precision and accuracy were used to test performance. RESULTS: Hand searching identified 77/1094 relevant articles for 2005 and 55/1199 for 2010. We developed a search hedge with 100% sensitivity and a precision of 30 and 29% for the 2005 and 2010 development datasets respectively. For the selected time periods, EXP Spine returned 2113 publications and 30 were considered relevant. The search filter identified all 30 relevant articles, with a specificity of 94% and precision of 20%. Of the 255 references listed in the narrative index reviews, 225 were indexed in MEDLINE and 165 (73%) were relevant articles. All relevant articles were identified and accuracy ranged from 67 to 97% over the three reviews. Of the 42 articles returned from 3 recent systematic reviews, all were identified by the filter. CONCLUSIONS: We have developed a highly sensitive hedge for the research of DCM. Whilst precision is similarly low as other hedges, this search filter can be used as an adjunct for DCM search strategies.