Imaging incidence and type in primary care patients with low back pain: a cross-sectional study on new referrals to an Australian specialist spinal surgical centre.

Introduction Low back pain (LBP) is common and a significant cause of morbidity. Many patients receive inappropriate imaging for LBP in primary care. Aim To explore the incidence and type of spinal imaging conducted for LBP patients referred from general practice for specialist surgical opinion, and evaluate whether imaging conformed to clinical guidelines. Methods Audit of a sequential cohort (n = 100) of new LBP patients referred from primary care for specialist opinion at a suburban Australian capital city independent Spinal Centre. Results In the 6 months before referral, 90% (95% CI 83-95%) of patients underwent spinal imaging. Imaging was performed in 95% of those who did and 79% of those who did not meet guidelines for radiological investigation. 35% of patients were inappropriately imaged and 3% inappropriately not imaged. Spinal computed tomography (CT) imaging was used in 52% of patients, magnetic resonance imaging (MRI) in 42% and image-guided lumbar spinal interventional procedures in 28%. Discussion Most patients with LBP referred for surgical opinion have diagnostic radiological investigations whether or not it is indicated by clinical guidelines. The more frequent use of spinal CT compared to MRI may be due to idiosyncrasies of the Australian Medicare Benefits Schedule (MBS) rebate system. The findings of this pilot study provide support for the changes recommended by the 2016 MBS Review Taskforce on LBP that permit GP access to subsidised lumbar MRI, while constraining access to lumbar CT, and provide novel data about spinal imaging and practice in this cohort of patients.

Using general practitioners with an extended role in spinal practice for the initial assessment of patients referred to spinal surgeons: preliminary experience and challenges.

AIM: To describe experience using general practitioners (GPs), with an extended role (GPwER) in spinal medicine, to expedite assessment, triage, and management of patients referred from primary care for specialist spinal surgical opinion. BACKGROUND: Low back and neck pain are common conditions in primary care. Indiscriminate or inappropriate referral to a spinal surgeon contributes to long waiting times. Previous attempts at triaging patients who really require a surgical opinion have used practice nurses, physiotherapists, clinical algorithms, and interdisciplinary screening clinics. METHODS: Within the setting of an independent spinal care centre, we have used GPs specially trained in spinal practice to expedite the assessment and triage of new referrals between 2015 and 2021. We reviewed feedback from a Patient Satisfaction Questionnaire and the postgraduate backgrounds, training, practice with regard to triage of new referrals, and experiences of the GPs who were recruited. FINDINGS: Six GPwER had a mean of 26 years of postgraduate experience before appointment (range 10-44 years). The first four GPwER, appointed between 2015 and 2018, underwent an ad hoc in-house, interdisciplinary training programme and saw 2994 new patients between 2016 and 2020. After GPwER, assessment in only 18.9% (range 12.6 to 22.7%) of these patients was a spinal surgical opinion deemed necessary. Waiting times to see the spinal surgeon remained at 6-8 weeks despite a three-fold annual increase (from 340 to 1058) in new referrals. A Patient Satisfaction Questionnaire revealed high levels of satisfaction with the performances of the GPwER across seven dimensions. A dedicated training programme was designed in 2020, and the last two appointees underwent 20 h of clinical teaching prior to practice. Initial experience using GPwER, here termed 'Spinal Clinicians', suggests they are efficient at screening for patients needing spinal surgical referral. Establishing a recognised training programme, assessment, and certification for these practitioners are the next challenges.

Clinical utility and reproducibility of surface electromyography in individuals with chronic low back pain: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Chronic low back pain (CLBP) is one of the most common disorders presenting in primary healthcare. Kinematic studies of low lumbar pelvic mobility allied with surface electromyography (sEMG) may assist in the assessment and management of CLBP. However, the applicability in the use of sEMG in the clinical setting remains uncertain. In this protocol, we aim to review the clinical utility and reproducibility of the sEMG component of these kinematic studies in patients with CLBP. METHODS AND ANALYSIS: This protocol was informed by the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) and results will be reported in line with the PRISMA. Searches will be conducted on PubMed, Scopus, Web of Science, Embase, CINAHL and Google Scholar databases, along with a comprehensive review of grey literature. Two reviewers will conduct the searches and independently screen them, according to title and abstract. Two independent reviewers will then assess the full-text versions of those selected articles and assess the risk of bias using the defined protocol inclusion criteria. The risk of bias within the studies included will be assessed via the Quality Assessment of Diagnostic Accuracy Studies tool, V.2 and the Grading of Recommendations Assessment, Development and Evaluation guidelines will be used to assess certainty of evidence for recommendations based on the risk of bias findings. Meta-analysis will be conducted where appropriate on groups of studies with low heterogeneity. In instances of higher heterogeneity, meta-synthesis will instead be completed, comparing results in terms of increased or decreased clinical utility and/or reproducibility of sEMG. ETHICS AND DISSEMINATION: Ethics approval was not required for this research. It is anticipated that the results will influence the use, interpretation and further development of sEMG in management and assessment of these patients. PROSPERO REGISTRATION NUMBER: CRD42021273936.

Imaging signatures of meningioma and low-grade glioma: a diffusion tensor, magnetization transfer and quantitative longitudinal relaxation time MRI study.

Differentiation of cerebral tumor pathology currently relies on interpretation of conventional structural MRI and in some cases histology. However, more advanced MRI methods may provide further insight into the organization of cerebral tumors and have the potential to aid diagnosis. The objective of this study was to use multimodal quantitative MRI to measure the imaging signatures of meningioma and low-grade glioma (LGG). Nine adults with meningioma and 11 with LGG were identified, and underwent standard structural, quantitative longitudinal relaxation time (T1) mapping, magnetization transfer and diffusion tensor MRI. Maps of mean (〈D〉), axial (λAX) and radial (λRAD) diffusivity, fractional anisotropy (FA), magnetization transfer ratio (MTR) and T1 were generated on a voxel-by-voxel basis. Using structural and echo-planar T2-weighted MRI, manual region-of-interest segmentation of brain tumor, edema, ipsilateral and contralateral normal-appearing white matter (NAWM) was performed. Differences in imaging signatures between the different tissue types, both absolute mean values and ratios relative to contralateral NAWM, were assessed using t-tests with statistical significance set at p<0.05. For both absolute mean values and ratios relative to contralateral NAWM, there were significant differences in 〈D〉, λAX, λRAD, FA, MTR and T1 between meningioma and LGG tumor tissue, respectively. Only T1 and FA differed significantly between edematous tissue associated with the two tumor types. These results suggest that multimodal MRI biomarkers are significantly different, particularly in tumor tissue, between meningioma and LGG. By using quantitative multimodal MRI it may be possible to identify tumor pathology non-invasively.

Human post-mortem synapse proteome integrity screening for proteomic studies of postsynaptic complexes.

BACKGROUND: Synapses are fundamental components of brain circuits and are disrupted in over 100 neurological and psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes and polygenic mutations converge on postsynaptic complexes in schizophrenia, autism and intellectual disability. Directly characterising human synapses and their multiprotein complexes from post-mortem tissue is essential to understanding disease mechanisms. However, multiprotein complexes have not been directly isolated from human synapses and the feasibility of their isolation from post-mortem tissue is unknown. RESULTS: Here we establish a screening assay and criteria to identify post-mortem brain samples containing well-preserved synapse proteomes, revealing that neocortex samples are best preserved. We also develop a rapid method for the isolation of synapse proteomes from human brain, allowing large numbers of post-mortem samples to be processed in a short time frame. We perform the first purification and proteomic mass spectrometry analysis of MAGUK Associated Signalling Complexes (MASC) from neurosurgical and post-mortem tissue and find genetic evidence for their involvement in over seventy human brain diseases. CONCLUSIONS: We have demonstrated that synaptic proteome integrity can be rapidly assessed from human post-mortem brain samples prior to its analysis with sophisticated proteomic methods. We have also shown that proteomics of synapse multiprotein complexes from well preserved post-mortem tissue is possible, obtaining structures highly similar to those isolated from biopsy tissue. Finally we have shown that MASC from human synapses are involved with over seventy brain disorders. These findings should have wide application in understanding the synaptic basis of psychiatric and other mental disorders.

The proteomic response in glioblastoma in young patients.

Increasing age is an important prognostic variable in glioblastoma (GBM). We have defined the proteomic response in GBM samples from 7 young patients (mean age 36 years) compared to peritumoural-control samples from 10 young patients (mean age 32 years). 2-Dimensional-gel-electrophoresis, image analysis, and protein identification (LC/MS) were performed. 68 proteins were significantly altered in young GBM samples with 29 proteins upregulated and 39 proteins downregulated. Over 50 proteins are described as altered in GBM for the first time. In a parallel analysis in old GBM (mean age 67 years), an excellent correlation could be demonstrated between the proteomic profile in young GBM and that in old GBM patients (r(2) = 0.95) with only 5 proteins altered significantly (p < 0.01). The proteomic response in young GBM patients highlighted alterations in protein-protein interactions in the immunoproteosome, NFkB signalling, and mitochondrial function and the same systems participated in the responses in old GBM patients.

Interactions among mitochondrial proteins altered in glioblastoma.

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change ≥ 2) and significantly altered in GBM (p ≤ 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein-protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology.

A test-retest fMRI dataset for motor, language and spatial attention functions.

BACKGROUND: Since its inception over twenty years ago, functional magnetic resonance imaging (fMRI) has been used in numerous studies probing neural underpinnings of human cognition. However, the between session variance of many tasks used in fMRI remains understudied. Such information is especially important in context of clinical applications. A test-retest dataset was acquired to validate fMRI tasks used in pre-surgical planning. In particular, five task-related fMRI time series (finger, foot and lip movement, overt verb generation, covert verb generation, overt word repetition, and landmark tasks) were used to investigate which protocols gave reliable single-subject results. Ten healthy participants in their fifties were scanned twice using an identical protocol 2-3 days apart. In addition to the fMRI sessions, high-angular resolution diffusion tensor MRI (DTI), and high-resolution 3D T1-weighted volume scans were acquired. FINDINGS: Reliability analyses of fMRI data showed that the motor and language tasks were reliable at the subject level while the landmark task was not, despite all paradigms showing expected activations at the group level. In addition, differences in reliability were found to be mostly related to the tasks themselves while task-by-motion interaction was the major confounding factor. CONCLUSIONS: Together, this dataset provides a unique opportunity to investigate the reliability of different fMRI tasks, as well as methods and algorithms used to analyze, de-noise and combine fMRI, DTI and structural T1-weighted volume data.

Overcoming fear and anxiety during awake resection of brain tumours: family support can be pivotal to a successful outcome.

Patient anxiety and fear about an awake craniotomy can affect the patient's choice about having an operation despite comprehensive pre-operative counselling. We report three cases in which a family member came into theatre during the procedure to support the patient during surgery. All three cases, which involved intra-operative cortical and subcortical stimulations and intra-operative patient testing, were successfully completed with major tumour resections and no post-operative complications. We suggest that family support should be considered in patients who have extreme fear and anxiety about awake surgery.

NICE guidance on the use of carmustine wafers in high grade gliomas: a national study on variation in practice.

BACKGROUND: Multidisciplinary team (MDT) working in oncology aims to improve outcomes for patients with cancer. One role is to ensure the implementation of best practice and National Institute for Health and Clinical Excellence (NICE) guidance. In this study, we have assessed the role of MDT in implementing the TA121 appraisal of the use of carmustine wafers in high grade gliomas. METHODS: 296 patients with high-grade glioma suitable for maximal resection were recruited from 17 Neurosurgical Centres. The number of patients treated with carmustine wafers and reasons for not using this were recorded. Complications at 48 hours post-operatively and at 6 weeks post-radiotherapy were recorded. RESULTS: 94/296 (32%) of suitable patients received carmustine wafers. In 55% of cases carmustine was not used due to either surgeon preference or a lack of an MDT decision. There was no increased complication rate with carmustine use at either 48 hours post-surgery or at 6 weeks post radiotherapy. Use of carmustine wafers did not decrease access to and use of chemoradiotherapy. CONCLUSIONS: One third of patients suitable for carmustine wafers received them. Their use was neither associated with more frequent complications, nor decreased use of chemoradiotherapy. Implementation of NICE TA121 Guidance is extremely variable in different MDTs across the United Kingdom.

Cognitive functioning in newly presenting patients with supratentorial intracranial tumors: is there a role for inspection time?

Quantifying the extent of cognitive dysfunction in patients with intracranial tumors is important to monitor treatment effects and assess patients' needs. Inspection time, a measure of the efficiency of visual information processing, was evaluated, and its usefulness in patients with intracranial tumors was compared with that of other widely used cognitive tests. Newly presenting inpatients with supratentorial intracranial tumors (n = 118) underwent preoperative assessment using inspection time and a number of other measures of cognitive function, mood, and functional status. The brain tumor cohort was compared with patients admitted for elective spinal surgery (n = 85) and a healthy control group (n = 80). Analysis of covariance was used to compare the performance of the 3 groups. The brain tumor cohort had significantly lower inspection time scores than the spinal surgery group (P = .005) and the healthy volunteer control group (P < .001). The effect size was moderate. There was a large effect size of participant group for the Rey Auditory Verbal Learning Test, Digit Symbol-Coding, and Verbal Fluency (P = .002). The performance of patients with brain tumors was significantly worse than that of both of the control groups. Inspection time was well-tolerated by patients with intracranial tumors. However, inspection time is neither as easy to perform nor as sensitive as some other measures of cognitive function. Although its lack of any motor speed or coordination requirements, conceptual simplicity, repeatability, and relative lack of learning effect make inspection time a potentially useful tool in clinical neuro-oncology, practical considerations will limit its use.

Preoperative quality of life in patients with degenerative spinal disorders: many are worse than patients with brain tumours and cancer.

BACKGROUND: This study compared prospectively the quality of life (QoL), function and mood of patients about to undergo surgery for either an intracranial supratentorial tumour or a spinal degenerative condition. The QoL scores were also compared to that of cohorts with a range of extracranial cancers. MATERIAL AND METHODS: The study took place in a Scottish NHS Neurosurgical Unit. Patients were assessed on the day prior to surgery for their QoL (European Organisation for Research and Treatment of Cancer (EORTC)-QLQ C30), mood status (Hospital Anxiety and Depression Score), Performance status (Karnosky Score, timed 10-m walk) and disability (Barthel Disability Index). All tests were performed by a single trained psychologist. RESULTS: Between 2007 and 2009, 101 patients with intracranial tumours, 75 age- and gender-matched patients with degenerative spinal disorders and 80 healthy adults were evaluated. There was no difference in the mood or disability scores between the two patient cohorts, but mood was significantly worse than a matched healthy cohort. The spinal cohort had significantly worse scores on the Karnovsky Scale, timed 10-m walk and for Global Health than those of the brain tumour cohort. They also had worse mean scores on all five functional scales, as well as six of the nine symptom/single-item scales, of the EORTC QLQ C30. SUMMARY: Patients with degenerative spinal disorders awaiting surgery on the NHS have significantly impaired QoL in multiple domains as well as other functional and mood disorders. Not only are their scores worse than a brain tumour cohort but they are also worse than many cancer cohorts described in the literature using the EORTC QLQ C30. These findings suggest that preoperative care, assessment and management of NHS patients with degenerative spinal disorders could be improved and that the EORTC QLQ C30 may be a useful tool for audit purposes in this cohort.

Surgical decompression for cerebral oedema in acute ischaemic stroke.

BACKGROUND: Large cerebral infarction has a high case fatality. Despite the use of conventional medical treatments such as hyperventilation, mannitol, diuretics, corticosteroids and barbiturates, the outcome of this condition remains poor. Decompressive surgery to relieve intracranial pressure is performed in some cases, although evidence of any clinical benefits has not been available until recently. This is an update of a Cochrane review first published in 2002. OBJECTIVES: To examine the effects of decompressive surgery in patients with massive acute ischaemic stroke complicated with cerebral oedema, and to judge whether decompressive surgery is effective in improving survival or survival free of severe disability. SEARCH METHODS: We searched the Cochrane Stroke Group's Trials Register (last searched October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 7), MEDLINE (1966 to October 2010), EMBASE (1980 to October 2010) and Science Citation Index (October 2010). We also searched the reference lists of all relevant articles. SELECTION CRITERIA: Randomised controlled studies of decompressive surgery plus medical treatment versus medical treatment alone in patients with clinically and radiologically confirmed cerebral infarcts complicated with cerebral oedema. DATA COLLECTION AND ANALYSIS: One author assessed the titles and retrieved the relevant studies. The same author extracted data, with discussion among all authors for clarification. Outcomes were death at the end of follow-up, death or disability defined as the modified Rankin Scale (mRS) > 3 at the end of follow-up, death or severe disability defined as mRS > 4 at 12 months and disability defined as mRS 4 or 5 at 12 months. The results are given using the Peto odds ratio (Peto OR) with 95% confidence intervals (CIs). MAIN RESULTS: We included three trials in this review, involving 134 patients who were 60 years of age or younger. The time window for the intervention was 30 hours from stroke onset in two studies and 96 hours in one study. All trials were stopped early. Surgical decompression reduced the risk of death at the end of follow-up (OR 0.19, 95% CI 0.09 to 0.37) and the risk of death or disability defined as mRS > 4 at 12 months (OR 0.26, 95% CI 0.13 to 0.51). Death or disability defined as mRS > 3 at the end of follow-up was no different between the treatment arms (OR 0.56, 95% CI 0.27 to 1.15). AUTHORS' CONCLUSIONS: Surgical decompression lowers the risk of death and death or severe disability defined as mRS > 4 in selected patients 60 years of age or younger with a massive hemispheric infarction and oedema. Optimum criteria for patient selection and for timing of decompressive surgery are yet to be defined. Since survival may be at the expense of substantial disability, surgery should be the treatment of choice only when it can be assumed, based on their preferences, that it is in the best interest of patients. Since all the trials were stopped early, an overestimation of the effect size cannot be excluded.

Advising potential recipients on the use of organs from donors with primary central nervous system tumors.

Deciding to use an organ from a donor with a primary central nervous system (CNS) tumor necessitates offsetting the risk of tumor transmission with the chances of survival if the patient waits for another offer of a transplant. Published data vary in the quoted risk of tumor transmission. We used data obtained by reviewing 246 UK recipients of organs taken from donors with CNS tumors and found no evidence of a difference in overall patient mortality for recipients of a kidney, liver, or cardiothoracic organ, compared with recipients of organs from donors without a CNS tumor. Recent publication of the UK experience of transplanting organs from CNS tumor donors found no transmission in 448 recipients of organs from 177 donors with a primary CNS tumor (Watson et al., Am J Transplant 2010; 10: 1437). This 0% transmission rate is associated with an upper 95% confidence interval limit of 1.5%. Using a series of assumptions of risk, we compared the risks of dying as a result of the transmission of a primary brain tumor with the risks of dying if not transplanted. On this basis, the use of kidneys from a donor with a primary CNS tumor provides a further 8 years of life over someone who waited for a donor who did not have a primary CNS tumor, in addition to the life years gained by the transplant itself. The benefits for the recipients of livers and cardiothoracic organs were less, but there was no disadvantage in the impact on life expectancy.

Characterization of the proteome, diseases and evolution of the human postsynaptic density.

We isolated the postsynaptic density from human neocortex (hPSD) and identified 1,461 proteins. hPSD mutations cause 133 neurological and psychiatric diseases and were enriched in cognitive, affective and motor phenotypes underpinned by sets of genes. Strong protein sequence conservation in mammalian lineages, particularly in hub proteins, indicates conserved function and organization in primate and rodent models. The hPSD is an important structure for nervous system disease and behavior.

Assessment of physiological parameters within glioblastomas in awake patients: a prospective clinical study.

OBJECT: Multiparametric brain monitoring probes now make it possible to measure cerebral physiology. This prospective clinical study was designed to evaluate the pathophysiological environment of tumoural and peritumoural tissue O(2), CO(2), pH, HCO(3)- and temperature of awake patients with glioblastoma. METHODS: A Neurotrend multiparametric sensor was placed using intraoperative image guidance into glioblastoma after biopsy under general anesthetic. Postoperative monitoring was then performed in awake patients. RESULTS: Twelve patients were recruited and monitoring was performed, and well tolerated in 9 for up to 22 hrs. Mean glioblastoma tumour values were: tissue oxygen pressure (PtiO(2)) 21.0 mmHg, standard deviation +/- 7.9; PtiCO(2) 60.2 +/- 17.2 mmHg; temperature 36.9 +/- 0.4 degrees C, pH 7.08 + 0.2; and HCO(3) 17.1 +/- 3.7. Mean peritumoural brain values in 5 patients were PtiO(2) 29.1 +/- 27.6 mmHg; PtiCO(2) 48.6 +/- 7.0 mmg; temperature 36.4 +/- 0.6 degrees C; pH 7.20 +/- 0.09 and HCO(3) 19.1 +/- 3.5. There were trends for the PtiO(2) to decrease with increasing brain depth. As glioblastoma PtiCO(2) levels decreased, pH increased. There were no relationships between either tumoural PtiO(2) and pH, or PtiO(2) and PtiCO(2), however there were large intra- and inter-tumoural variation in monitoring values. There were technical problems in some patients with the Neurotrend sensor that limited its application, and that compromised aspects of data collection and interpretation, particularly of PtiO(2). CONCLUSION: This study has shown that this novel approach to monitoring glioma pathophysiology is feasible and well tolerated by patients. The data, much of which is novel, contributes to the knowledge of glioblastoma pathophysiology. However, further study and clinical exploitation awaits the development of a more reliable multiparametric sensor.

Glioma cell death: cell-cell interactions and signalling networks.

The prognosis for patients with malignant gliomas is poor, but improvements may emerge from a better understanding of the pathophysiology of glioma signalling. Recent therapeutic developments have implicated lipid signalling in glioma cell death. Stress signalling in glioma cell death involves mitochondria and endoplasmic reticulum. Lipid mediators also signal via extrinsic pathways in glioma cell proliferation, migration and interaction with endothelial and microglial cells. Glioma cell death and tumour regression have been reported using polyunsaturated fatty acids in animal models, human ex vivo explants, glioma cell preparations and in clinical case reports involving intratumoral infusion. Cell death signalling was associated with generation of reactive oxygen intermediates and mitochondrial and other signalling pathways. In this review, evidence for mitochondrial responses to stress signals, including polyunsaturated fatty acids, peroxidizing agents and calcium is presented. Additionally, evidence for interaction of glioma cells with primary brain endothelial cells is described, modulating human glioma peroxidative signalling. Glioma responses to potential therapeutic agents should be analysed in systems reflecting tumour connectivity and CNS structural and functional integrity. Future insights may also be derived from studies of signalling in glioma-derived tumour stem cells.

The role of mitochondria in glioma pathophysiology.

It has long been recognised that malignant tumours favour aerobic glycolysis to generate ATP and contain abnormalities of the intrinsic, mitochondria-dependent, apoptotic pathway, suggesting the involvement of dysfunctional mitochondria in tumour pathophysiology. However, the mechanisms underlying such processes in gliomas are poorly understood. Few recent studies have evaluated mitochondrial ultrastructure and proteomics in the pathophysiology of malignant gliomas. However, aberrant energy metabolism has been reported in gliomas and mitochondrial dysfunction links to glioma apoptotic signalling have been observed. Mitochondrial structural abnormalities and dysfunction in malignant gliomas is a neglected area of research. Definition of abnormalities in mitochondrial proteomics, membrane potential regulation, energy metabolism and intrinsic apoptotic pathway signalling in gliomas may open novel therapeutic opportunities.