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.NIHR Clinical Doctoral Research Fellowship

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

Study designSystematic review.ObjectiveThe 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).MethodsA 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.ResultsThe 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.ConclusionIn 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 registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150639, identifier: CRD42019150639

Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland

Background: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. Methods: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (<135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration >10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. Results: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. Conclusions: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care

Trends in research grant applications and outcomes among medical students in the United Kingdom: a national self-reported cross-sectional survey

Background Research funding disparities contribute to clinical academic workforce inequalities. Hence, our study explores the association between student demographics and research grant application rates and outcomes among UK medical students. Methods This is a national multicentre cross-sectional survey of UK medical students in the 2020–21 academic year. Multiple zero-inflated negative binomial regression and generalized linear model (binomial distribution; logit link) were utilized to investigate the association between student demographics, number of grant applications submitted, and successful grant applications (yes or no). P-values less than a Bonferroni-corrected significance level of 0.05/36 = 0.0014 were considered to be statistically significant. Results A total of 1528 students participated from 36 medical schools. One hundred fifty-one respondents (9.9%) had applied for research grants. Black students submitted applications 2.90 times more often than white students [Incident rate ratio (IRR): 2.90, 95% confidence interval (CI): 1.37–6.16], with no ethnic disparity in the odds of successful applications. Gender did not influence application rates significantly (P = .248), but women were 4.61 times more likely to secure a grant than men [odds ratio: 4.61, 95% CI: 2.04–10.4]. Being a PubMed-indexed author was associated with increased grant application submission rates [IRR: 3.61, 95% CI: 2.20– 5.92] while conducting more research was associated with greater odds of securing a grant [odds ratio: 1.42, 95% CI: 1.17– 1.73]. Conclusion Although black students submitted more applications, ethnicity did not influence success rates. Gender did not influence application rates, but women were more successful. These findings underscore the need for strategies supporting women and underrepresented students for continued academic achievement after graduation. Key Messages What is already known on this topic Research funding for post-PhD researchers is believed to be a major driver of gender and ethnic inequalities in the clinical academic workforce. Students who receive research grants are more likely to receive postgraduate research grants. What this study adds Black students applied for more research grants than white students, but there were no ethnic differences in the odds of securing a grant. There were no gender differences in the research grant application rates. However, female students had greater odds of securing research grants compared to male students. How this study might affect research, practice or policy Medical schools should incorporate grant writing skills into the undergraduate research curriculum. Also, to sustain women’s academic success post medical school, the NIHR and affiliates should provide research award extensions and childcare support for women when required

Prognostic factors in patients with metastatic spinal cord compression secondary to lung cancer—A retrospective UK single-centre study

Purpose: Metastatic spinal cord compression (MSCC) is a severe complication of cancer that can lead to irreversible neurological impairment, necessitating prompt recognition and intervention. This retrospective, single-centre study aimed to determine the prognostic factors and survival rates among patients presenting with MSCC secondary to lung cancer. Methods and Materials: We identified 74 patients with epidural metastases-related spinal cord compression and a history of lung cancer through the electronic database of Medway Maritime Hospital in the United Kingdom (UK), spanning the period from April 2016 to September 2021. Among them, 39 were below 55 years old, while 35 were aged 55 years or older; 24 patients were diagnosed with small cell lung cancer (SCLC), and 50 patients had non-small cell lung cancer (NSCLC). Results: The median overall survival (OS) was 5.5 months, with 52 out of 74 patients dying within 6 months of diagnosis with MSCC. For the entire cohort, the statistically significant variables on multi-variate analysis were cancer type (NSCLC had improved OS), the number of involved vertebrae (one to two vertebrae involvement had improved OS), and the time taken to develop motor deficits (≤10 days to develop motor deficits had worsened OS). For the NSCLC cohort, the statistically significant variables on multivariate analysis were molecular alterations (patients with epidermal growth factor receptor (EGFR) mutation), pre-treatment ambulatory status, Eastern Cooperative Oncology Group (ECOG) performance status, and the time taken to develop motor deficits. Conclusions: Within the entire cohort, patients diagnosed with NSCLC and spinal metastases affecting one to two vertebrae exhibited enhanced OS. Within the NSCLC subgroup, those with EGFR mutations who were ambulatory and possessed an ECOG performance status of 1–2 demonstrated improved OS. In both the entire cohort and the NSCLC subgroup, the development of motor deficits within a period of ≤10 days was associated with poor OS

Prognostic Factors in Patients with Metastatic Spinal Cord Compression Secondary to Lung Cancer—A Retrospective UK Single-Centre Study

Purpose: Metastatic spinal cord compression (MSCC) is a severe complication of cancer that can lead to irreversible neurological impairment, necessitating prompt recognition and intervention. This retrospective, single-centre study aimed to determine the prognostic factors and survival rates among patients presenting with MSCC secondary to lung cancer. Methods and Materials: We identified 74 patients with epidural metastases-related spinal cord compression and a history of lung cancer through the electronic database of Medway Maritime Hospital in the United Kingdom (UK), spanning the period from April 2016 to September 2021. Among them, 39 were below 55 years old, while 35 were aged 55 years or older; 24 patients were diagnosed with small cell lung cancer (SCLC), and 50 patients had non-small cell lung cancer (NSCLC). Results: The median overall survival (OS) was 5.5 months, with 52 out of 74 patients dying within 6 months of diagnosis with MSCC. For the entire cohort, the statistically significant variables on multi-variate analysis were cancer type (NSCLC had improved OS), the number of involved vertebrae (one to two vertebrae involvement had improved OS), and the time taken to develop motor deficits (≤10 days to develop motor deficits had worsened OS). For the NSCLC cohort, the statistically significant variables on multivariate analysis were molecular alterations (patients with epidermal growth factor receptor (EGFR) mutation), pre-treatment ambulatory status, Eastern Cooperative Oncology Group (ECOG) performance status, and the time taken to develop motor deficits. Conclusions: Within the entire cohort, patients diagnosed with NSCLC and spinal metastases affecting one to two vertebrae exhibited enhanced OS. Within the NSCLC subgroup, those with EGFR mutations who were ambulatory and possessed an ECOG performance status of 1–2 demonstrated improved OS. In both the entire cohort and the NSCLC subgroup, the development of motor deficits within a period of ≤10 days was associated with poor OS

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

Peer reviewed: TrueAcknowledgements: We gratefully acknowledge support from the Cambridge NIHR Brain Injury MedTech Cooperative.Study designSystematic review.ObjectiveThe 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).MethodsA 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.ResultsThe 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.ConclusionIn 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 registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=150639, identifier: CRD42019150639.</jats:sec

Predictors of self-reported research productivity amongst medical students in the United Kingdom: a national cross-sectional survey

Abstract Background The number of academic clinicians in the UK is declining and there are demographic inequalities in the clinical-academic workforce. Increased research productivity by medical students is believed to reduce future attrition in the clinical-academic workforce. Thus, this study investigated the association between student demographics and research productivity amongst UK medical students. Methods This is a national multicentre cross-sectional study of UK medical students in the 2020/21 academic year. We appointed one student representative per medical school, and they disseminated a 42-item online questionnaire over nine weeks, through departmental emails and social media advertisements. The outcome measures were: (i) publications (yes/no) (ii) number of publications (iii) number of first-authored publications (iv) abstract presentation (yes/no). We utilised multiple logistic and zero-inflated Poisson regression analyses to test for associations between the outcome measures and predictor variables at a 5% significance level. Results There are 41 medical schools in the UK. We received 1573 responses from 36 UK medical schools. We failed to recruit student representatives from three newly formed medical schools, whilst two medical schools prohibited us from sending the survey to their students. Women had lower odds of having a publication (OR: 0.53, 95% CI: 0.33–0.85) and on average had fewer first-author publications than men (IRR: 0.57, 95% CI: 0.37–0.89). Compared to white students, mixed-ethnicity students had greater odds of having a publication (OR: 3.06, 95% CI: 1.67–5.59), an abstract presentation (OR: 2.12, 95% CI: 1.37–3.26), and on average had a greater number of publications (IRR: 1.87, 95% CI: 1.02–3.43). On average, students who attended independent UK secondary schools had a higher rate of first-author publications compared to those that attended state secondary schools (IRR: 1.97, 95% CI: 1.23–3.15). Conclusion Our data suggest that there are gender, ethnic and socioeconomic inequalities in research productivity among UK medical students. To tackle this, and potentially improve diversity in clinical academia, we recommend that medical schools should facilitate targeted high quality research mentorship, funding and training, especially for under-represented-in-medicine students