Imaging evaluation of a proposed 3D generative model for MRI to CT translation in the lumbar spine.

BACKGROUND CONTEXT: A computed tomography (CT) and magnetic resonance imaging (MRI) are used routinely in the radiologic evaluation and surgical planning of patients with lumbar spine pathology, with the modalities being complimentary. We have developed a deep learning algorithm which can produce 3D lumbar spine CT images from MRI data alone. This has the potential to reduce radiation to the patient as well as burden on the health care system. PURPOSE: The purpose of this study is to evaluate the accuracy of the synthetic lumbar spine CT images produced using our deep learning model. STUDY DESIGN: A training set of 400 unpaired CTs and 400 unpaired MRI scans of the lumbar spine was used to train a supervised 3D cycle-Gan model. Evaluators performed a set of clinically relevant measurements on 20 matched synthetic CTs and true CTs. These measurements were then compared to assess the accuracy of the synthetic CTs. PATIENT SAMPLE: The evaluation data set consisted of 20 patients who had CT and MRI scans performed within a 30-day period of each other. All patient data was deidentified. Notable exclusions included artefact from patient motion, metallic implants or any intervention performed in the 30 day intervening period. OUTCOME MEASURES: The outcome measured was the mean difference in measurements performed by the group of evaluators between real CT and synthetic CTs in terms of absolute and relative error. METHODS: Data from the 20 MRI scans was supplied to our deep learning model which produced 20 "synthetic CT" scans. This formed the evaluation data set. Four clinical evaluators consisting of neurosurgeons and radiologists performed a set of 24 clinically relevant measurements on matched synthetic CT and true CTs in 20 patients. A test set of measurements were performed prior to commencing data collection to identify any significant interobserver variation in measurement technique. RESULTS: The measurements performed in the sagittal plane were all within 10% relative error with the majority within 5% relative error. The pedicle measurements performed in the axial plane were considerably less accurate with a relative error of up to 34%. CONCLUSIONS: The computer generated synthetic CTs demonstrated a high level of accuracy for the measurements performed in-plane to the original MRIs used for synthesis. The measurements performed on the axial reconstructed images were less accurate, attributable to the images being synthesized from nonvolumetric routine sagittal T1-weighted MRI sequences. It is hypothesized that if axial sequences or volumetric data were input into the algorithm these measurements would have improved accuracy.

GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma.

BACKGROUND: Aggressive primary brain tumors such as glioblastoma are uniquely challenging to treat. The intracranial location poses barriers to therapy, and the potential for severe toxicity. Effective treatments for primary brain tumors are limited, and 5-year survival rates remain poor. Immune checkpoint inhibitor therapy has transformed treatment of some other cancers but has yet to significantly benefit patients with glioblastoma. Early phase trials of chimeric antigen receptor (CAR) T-cell therapy in patients with glioblastoma have demonstrated that this approach is safe and feasible, but with limited evidence of its effectiveness. The choices of appropriate target antigens for CAR-T-cell therapy also remain limited. METHODS: We profiled an extensive biobank of patients' biopsy tissues and patient-derived early passage glioma neural stem cell lines for GD2 expression using immunomicroscopy and flow cytometry. We then employed an approved clinical manufacturing process to make CAR- T cells from patients with peripheral blood of glioblastoma and diffuse midline glioma and characterized their phenotype and function in vitro. Finally, we tested intravenously administered CAR-T cells in an aggressive intracranial xenograft model of glioblastoma and used multicolor flow cytometry, multicolor whole-tissue immunofluorescence and next-generation RNA sequencing to uncover markers associated with effective tumor control. RESULTS: Here we show that the tumor-associated antigen GD2 is highly and consistently expressed in primary glioblastoma tissue removed at surgery. Moreover, despite patients with glioblastoma having perturbations in their immune system, highly functional GD2-specific CAR-T cells can be produced from their peripheral T cells using an approved clinical manufacturing process. Finally, after intravenous administration, GD2-CAR-T cells effectively infiltrated the brain and controlled tumor growth in an aggressive orthotopic xenograft model of glioblastoma. Tumor control was further improved using CAR-T cells manufactured with a clinical retroviral vector encoding an interleukin-15 transgene alongside the GD2-specific CAR. These CAR-T cells achieved a striking 50% complete response rate by bioluminescence imaging in established intracranial tumors. CONCLUSIONS: Targeting GD2 using a clinically deployed CAR-T-cell therapy has a sound scientific and clinical rationale as a treatment for glioblastoma and other aggressive primary brain tumors.

Systematic Analysis of Publication Bias in Neurosurgery Meta-Analyses.

BACKGROUND: Statistically significant positive results are more likely to be published than negative or insignificant outcomes. This phenomenon, also termed publication bias, can skew the interpretation of meta-analyses. The widespread presence of publication bias in the biomedical literature has led to the development of various statistical approaches, such as the visual inspection of funnel plots, Begg test, and Egger test, to assess and account for it. OBJECTIVE: To determine how well publication bias is assessed for in meta-analyses of the neurosurgical literature. METHODS: A systematic search for meta-analyses from the top neurosurgery journals was conducted. Data relevant to the presence, assessment, and adjustments for publication bias were extracted. RESULTS: The search yielded 190 articles. Most of the articles (n = 108, 56.8%) were assessed for publication bias, of which 40 (37.0%) found evidence for publication bias whereas 61 (56.5%) did not. In the former case, only 11 (27.5%) made corrections for the bias using the trim-and-fill method, whereas 29 (72.5%) made no correction. Thus, 111 meta-analyses (58.4%) either did not assess for publication bias or, if assessed to be present, did not adjust for it. CONCLUSION: Taken together, these results indicate that publication bias remains largely unaccounted for in neurosurgical meta-analyses.

Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma.

Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.

The O-Arm as an Additional Tool to Confirm Optimal Ventricular Tip Position-A Technical Note.

BACKGROUND: Ventricular catheter placement can be a challenging procedure when treating patients with slit ventricles, despite the use of a neuronavigation system. METHODS: We report the case of 3 patients with idiopathic intracranial hypertension who had required revision of their ventricular catheter due to malpositioning, despite initial placement using neuronavigation. Owing to the absence of intraoperative computed tomography in our center, we used the O-arm imaging system to confirm placement of the optimal ventricular tip position intraoperatively. RESULTS: Optimal ventricular drain position was achieved in all 3 patients. CONCLUSIONS: This short technical note describes an easy technique for using the O-arm to confirm the optimal ventricular drain position.

Can We Geographically Validate a Natural Language Processing Algorithm for Automated Detection of Incidental Durotomy Across Three Independent Cohorts From Two Continents?

BACKGROUND: Incidental durotomy is an intraoperative complication in spine surgery that can lead to postoperative complications, increased length of stay, and higher healthcare costs. Natural language processing (NLP) is an artificial intelligence method that assists in understanding free-text notes that may be useful in the automated surveillance of adverse events in orthopaedic surgery. A previously developed NLP algorithm is highly accurate in the detection of incidental durotomy on internal validation and external validation in an independent cohort from the same country. External validation in a cohort with linguistic differences is required to assess the transportability of the developed algorithm, referred to geographical validation. Ideally, the performance of a prediction model, the NLP algorithm, is constant across geographic regions to ensure reproducibility and model validity. QUESTION/PURPOSE: Can we geographically validate an NLP algorithm for the automated detection of incidental durotomy across three independent cohorts from two continents? METHODS: Patients 18 years or older undergoing a primary procedure of (thoraco)lumbar spine surgery were included. In Massachusetts, between January 2000 and June 2018, 1000 patients were included from two academic and three community medical centers. In Maryland, between July 2016 and November 2018, 1279 patients were included from one academic center, and in Australia, between January 2010 and December 2019, 944 patients were included from one academic center. The authors retrospectively studied the free-text operative notes of included patients for the primary outcome that was defined as intraoperative durotomy. Incidental durotomy occurred in 9% (93 of 1000), 8% (108 of 1279), and 6% (58 of 944) of the patients, respectively, in the Massachusetts, Maryland, and Australia cohorts. No missing reports were observed. Three datasets (Massachusetts, Australian, and combined Massachusetts and Australian) were divided into training and holdout test sets in an 80:20 ratio. An extreme gradient boosting (an efficient and flexible tree-based algorithm) NLP algorithm was individually trained on each training set, and the performance of the three NLP algorithms (respectively American, Australian, and combined) was assessed by discrimination via area under the receiver operating characteristic curves (AUC-ROC; this measures the model's ability to distinguish patients who obtained the outcomes from those who did not), calibration metrics (which plot the predicted and the observed probabilities) and Brier score (a composite of discrimination and calibration). In addition, the sensitivity (true positives, recall), specificity (true negatives), positive predictive value (also known as precision), negative predictive value, F1-score (composite of precision and recall), positive likelihood ratio, and negative likelihood ratio were calculated. RESULTS: The combined NLP algorithm (the combined Massachusetts and Australian data) achieved excellent performance on independent testing data from Australia (AUC-ROC 0.97 [95% confidence interval 0.87 to 0.99]), Massachusetts (AUC-ROC 0.99 [95% CI 0.80 to 0.99]) and Maryland (AUC-ROC 0.95 [95% CI 0.93 to 0.97]). The NLP developed based on the Massachusetts cohort had excellent performance in the Maryland cohort (AUC-ROC 0.97 [95% CI 0.95 to 0.99]) but worse performance in the Australian cohort (AUC-ROC 0.74 [95% CI 0.70 to 0.77]). CONCLUSION: We demonstrated the clinical utility and reproducibility of an NLP algorithm with combined datasets retaining excellent performance in individual countries relative to algorithms developed in the same country alone for detection of incidental durotomy. Further multi-institutional, international collaborations can facilitate the creation of universal NLP algorithms that improve the quality and safety of orthopaedic surgery globally. The combined NLP algorithm has been incorporated into a freely accessible web application that can be found at https://sorg-apps.shinyapps.io/nlp_incidental_durotomy/ . Clinicians and researchers can use the tool to help incorporate the model in evaluating spine registries or quality and safety departments to automate detection of incidental durotomy and optimize prevention efforts. LEVEL OF EVIDENCE: Level III, diagnostic study.

The effectiveness of prophylactic antibiotics and betadine skin preparation on cranial cutaneous Cutibacterium acnes - A prospective study.

BACKGROUND: Cutibacterium acnes, formerly known as Propionibacterium acnes, is increasingly recognized as a cause of surgical site infection and implant failure despite the use of prophylactic antibiotics and antiseptic surgical preparations. The aim of this study was to investigate whether C. acnes persists in the dermal layer of the skin after standard perioperative antibiotics and skin prepping with alcoholic betadine solution in consecutive patients undergoing a craniotomy. METHODS: A single centre prospective observational study was performed at Flinders Medical Centre. Adult patients undergoing a cranial neurosurgical intervention between October 2019 to March 2021 were eligible for inclusion. After administration of standard preoperative antibiotics (Cefazolin), three swabs were taken for each patient: one before prepping the skin with alcoholic betadine, one after prepping the skin and a dermal swab once the skin was incised. RESULTS: 73 patients were included. Cutibacterium acnes cultures were positive in 61 patients of the "pre-prep" group (83.6%), 12 (16.4%) in the "post-prep" group, and 53 (72.6%) were from dermal swabs There was a significant reduction of positive cultures of the skin after surgical preparation was applied (p < 0.00001). There was a non-significant reduction of positive cultures in the dermal swabs after skin preparation (p = 0.068) CONCLUSIONS: Cutibacterium acnes persists within the dermis of the scalp despite standard prophylactic measures using alcoholic betadine solution and cefazolin.

Long-term adherence of human brain cells in vitro is enhanced by charged amine-based plasma polymer coatings.

Advances in cellular reprogramming have radically increased the use of patient-derived cells for neurological research in vitro. However, adherence of human neurons on tissue cultureware is unreliable over the extended periods required for electrophysiological maturation. Adherence issues are particularly prominent for transferable glass coverslips, hindering imaging and electrophysiological assays. Here, we assessed thin-film plasma polymer treatments, polymeric factors, and extracellular matrix coatings for extending the adherence of human neuronal cultures on glass. We find that positive-charged, amine-based plasma polymers improve the adherence of a range of human brain cells. Diaminopropane (DAP) treatment with laminin-based coating optimally supports long-term maturation of fundamental ion channel properties and synaptic activity of human neurons. As proof of concept, we demonstrated that DAP-treated glass is ideal for live imaging, patch-clamping, and optogenetics. A DAP-treated glass surface reduces the technical variability of human neuronal models and enhances electrophysiological maturation, allowing more reliable discoveries of treatments for neurological and psychiatric disorders.

3D-printed microplate inserts for long term high-resolution imaging of live brain organoids.

BACKGROUND: Organoids are a reliable model used in the study of human brain development and under pathological conditions. However, current methods for brain organoid culture generate tissues that range from 0.5 to 2 mm of size, which need to be constantly agitated to allow proper oxygenation. The culture conditions are, therefore, not suitable for whole-brain organoid live imaging, required to study developmental processes and disease progression within physiologically relevant time frames (i.e. days, weeks, months). RESULTS: Here we designed 3D-printed microplate inserts adaptable to standard 24 multi-well plates, which allow the growth of multiple organoids in pre-defined and fixed XYZ coordinates. This innovation facilitates high-resolution imaging of whole-cerebral organoids, allowing precise assessment of organoid growth and morphology, as well as cell tracking within the organoids, over long periods. We applied this technology to track neocortex development through neuronal progenitors in brain organoids, as well as the movement of patient-derived glioblastoma stem cells within healthy brain organoids. CONCLUSIONS: This new bioengineering platform constitutes a significant advance that permits long term detailed analysis of whole-brain organoids using multimodal inverted fluorescence microscopy.

A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma.

Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6-9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.

A deep convolutional neural network for segmentation of whole-slide pathology images identifies novel tumour cell-perivascular niche interactions that are associated with poor survival in glioblastoma.

BACKGROUND: Glioblastoma is the most aggressive type of brain cancer with high-levels of intra- and inter-tumour heterogeneity that contribute to its rapid growth and invasion within the brain. However, a spatial characterisation of gene signatures and the cell types expressing these in different tumour locations is still lacking. METHODS: We have used a deep convolutional neural network (DCNN) as a semantic segmentation model to segment seven different tumour regions including leading edge (LE), infiltrating tumour (IT), cellular tumour (CT), cellular tumour microvascular proliferation (CTmvp), cellular tumour pseudopalisading region around necrosis (CTpan), cellular tumour perinecrotic zones (CTpnz) and cellular tumour necrosis (CTne) in digitised glioblastoma histopathological slides from The Cancer Genome Atlas (TCGA). Correlation analysis between segmentation results from tumour images together with matched RNA expression data was performed to identify genetic signatures that are specific to different tumour regions. RESULTS: We found that spatially resolved gene signatures were strongly correlated with survival in patients with defined genetic mutations. Further in silico cell ontology analysis along with single-cell RNA sequencing data from resected glioblastoma tissue samples showed that these tumour regions had different gene signatures, whose expression was driven by different cell types in the regional tumour microenvironment. Our results further pointed to a key role for interactions between microglia/pericytes/monocytes and tumour cells that occur in the IT and CTmvp regions, which may contribute to poor patient survival. CONCLUSIONS: This work identified key histopathological features that correlate with patient survival and detected spatially associated genetic signatures that contribute to tumour-stroma interactions and which should be investigated as new targets in glioblastoma. The source codes and datasets used are available in GitHub: https://github.com/amin20/GBM_WSSM .

SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion.

High-throughput RNA sequencing (RNA-seq) and dedicated bioinformatics pipelines have synergized to identify an expansive repertoire of unique circular RNAs (circRNAs), exceeding 100,000 variants. While the vast majority of these circRNAs comprise canonical exonic and intronic sequences, microexons (MEs)-which occur in 30% of functional mRNA transcripts-have been entirely overlooked. CircRNAs which contain these known MEs (ME-circRNAs) could be identified with commonly utilized circRNA prediction pipelines, CIRCexplorer2 and CIRI2, but were not previously recognized as ME-circRNAs. In addition, when employing a bespoke bioinformatics pipeline for identifying RNA chimeras, called Hyb, we could also identify over 2000 ME-circRNAs which contain novel MEs at their backsplice junctions, that are uncalled by either CIRCexplorer2 or CIRI2. Analysis of circRNA-seq datasets from gliomas of varying clinical grades compared with matched control tissue has shown circRNAs have potential as prognostic markers for stratifying tumor from healthy tissue. Furthermore, the abundance of microexon-containing circRNAs (ME-circRNAs) between tumor and normal tissues is correlated with the expression of a splicing associated factor, Serine/arginine repetitive matrix 4 (SRRM4). Overexpressing SRRM4, known for regulating ME inclusion in mRNAs critical for neural differentiation, in human HEK293 cells resulted in the biogenesis of over 2000 novel ME-circRNAs, including ME-circEIF4G3, and changes in the abundance of many canonical circRNAs, including circSETDB2 and circLBRA. This shows SRRM4, in which its expression is correlated with poor prognosis in gliomas, acts as a bona fide circRNA biogenesis factor. Given the known roles of MEs and circRNAs in oncogenesis, the identification of these previously unrecognized ME-circRNAs further increases the complexity and functional purview of this non-coding RNA family.

Endothelial, pericyte and tumor cell expression in glioblastoma identifies fibroblast activation protein (FAP) as an excellent target for immunotherapy.

OBJECTIVES: Targeted immunotherapies such as chimeric antigen receptor (CAR)-T cells are emerging as attractive treatment options for glioblastoma, but rely on identification of a suitable tumor antigen. We validated a new target antigen for glioblastoma, fibroblast activation protein (FAP), by undertaking a detailed expression study of human samples. METHODS: Glioblastoma and normal tissues were assessed using immunostaining, supported by analyses of published transcriptomic datasets. Short-term cultures of glioma neural stem (GNS) cells were compared to cultures of healthy astrocytes and neurons using flow cytometry. Glioblastoma tissues were dissociated and analysed by high-parameter flow cytometry and single-cell transcriptomics (scRNAseq). RESULTS: Compared to normal brain, FAP was overexpressed at the gene and protein level in a large percentage of glioblastoma tissues, with highest levels of expression associated with poorer prognosis. FAP was also overexpressed in several paediatric brain cancers. FAP was commonly expressed by cultured GNS cells but absent from normal neurons and astrocytes. Within glioblastoma tissues, the strongest expression of FAP was around blood vessels. In fact, almost every tumor vessel was highlighted by FAP expression, whereas normal tissue vessels and cultured endothelial cells (ECs) lacked expression. Single-cell analyses of dissociated tumors facilitated a detailed characterisation of the main cellular components of the glioblastoma microenvironment and revealed that vessel-localised FAP is because of expression on both ECs and pericytes. CONCLUSION: Fibroblast activation protein is expressed by multiple cell types within glioblastoma, highlighting it as an ideal immunotherapy antigen to target destruction of both tumor cells and their supporting vascular network.

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma.

Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM.

The benefit of delayed reassessment post high-volume CSF removal in the diagnosis of shunt-responsive idiopathic normal-pressure hydrocephalus.

The principle aim of the study was to demonstrate the value of performing delayed reassessment in the diagnosis of idiopathic normal-pressure hydrocephalus (iNPH) and selection of suitable candidates for ventriculoperitoneal shunting (VPS). Thirty-one consecutive patients underwent the NPH protocol at the Flinders Medical Centre between March 2017 and November 2018. The protocol involved mobility and cognitive testing with reassessment post high-volume cerebrospinal fluid (CSF) removal at 24 h and 48 h. The Assessment of Quality of Life 6D (AQoL-6D) questionnaire and International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF) were completed and repeated again at 6 weeks and 6 months post shunting. Results were analysed to determine the significance of delayed reassessment. Twenty patients (64.5%) underwent insertion of a VPS on the basis of objective improvements and specific criteria. Of these, 6 patients (30%) were shunted based on delayed reassessment at 48 h post CSF removal. Continued improvements were seen for all mobility and cognitive tests from baseline to 48 h post CSF removal. At 6 weeks and 6 months post shunting, there was an overall mean improvement in AQoL-6D and ICIQ-UI SF for the cohort and the improvement was also observed in the subgroup of patients who met shunt criteria at 48 h post CSF removal. In the diagnosis of shunt-responsive idiopathic normal-pressure hydrocephalus, delayed reassessment post CSF removal improves sensitivity and is therefore important.

The use of antiepileptic medication in early post traumatic seizure prophylaxis at a single institution.

BACKGROUND: Current international guidelines for traumatic brain injury (TBI) recommend the use of phenytoin for the prevention of early post traumatic seizures (PTS) when the benefits are thought to outweigh the risks. In practice however, alternative antiepileptic drugs (AEDs) such as levetiracetam and valproate are being used as they are believed to have a more favourable risk profile. This is despite there being insufficient evidence to support their efficacy. The purpose of this study was to identify which AED was prescribed to patients presenting with a TBI at a single institution, and to determine the rate of early PTSs. METHODS: This was a retrospective case-note review study done at the Flinders Medical Centre including patients admitted from May 2013 to June 2017. All patients with traumatic intracranial haematomas were included. Patients were excluded if they had seizures prior to presentation to hospital or died within 24 h of injury. The primary outcomes were rate of early PTSs and the type of prophylactic AED prescribed. RESULTS: During this study period, 610 patients presented with a mild, moderate or severe traumatic brain injury. Overall, 16% of patients were prescribed an AED, with more than 90% of these patients being prescribed levetiracetam. Overall, the rate of early PTSs for patients prescribed AEDs was 2.9% compared with 3.5% for patients not prescribed AEDs (OR 0.83 CI 0.24-2.85 p = 1). CONCLUSIONS: This study showed that levetiracetam was the most commonly prescribed AED. It also demonstrated no statistically significant difference in the rate of early PTSs in patients with TBI, with or without prophylactic AEDs. This is in keeping with other contemporary studies, and therefore the routine administration of prophylactic AEDs may need to be re-examined.

Dose-Dependent Effects of Statins for Patients with Aneurysmal Subarachnoid Hemorrhage: Meta-Regression Analysis.

OBJECTIVE: The study uses meta-regression analysis to quantify the dose-dependent effects of statin pharmacotherapy on vasospasm, delayed ischemic neurologic deficits (DIND), and mortality in aneurysmal subarachnoid hemorrhage. METHODS: Prospective, retrospective observational studies, and randomized controlled trials (RCTs) were retrieved by a systematic database search. Summary estimates were expressed as absolute risk (AR) for a given statin dose or control (placebo). Meta-regression using inverse variance weighting and robust variance estimation was performed to assess the effect of statin dose on transformed AR in a random effects model. Dose-dependence of predicted AR with 95% confidence interval (CI) was recovered by using Miller's Freeman-Tukey inverse. RESULTS: The database search and study selection criteria yielded 18 studies (2594 patients) for analysis. These included 12 RCTs, 4 retrospective observational studies, and 2 prospective observational studies. Twelve studies investigated simvastatin, whereas the remaining studies investigated atorvastatin, pravastatin, or pitavastatin, with simvastatin-equivalent doses ranging from 20 to 80 mg. Meta-regression revealed dose-dependent reductions in Freeman-Tukey-transformed AR of vasospasm (slope coefficient -0.00404, 95% CI -0.00720 to -0.00087; P = 0.0321), DIND (slope coefficient -0.00316, 95% CI -0.00586 to -0.00047; P = 0.0392), and mortality (slope coefficient -0.00345, 95% CI -0.00623 to -0.00067; P = 0.0352). CONCLUSIONS: The present meta-regression provides weak evidence for dose-dependent reductions in vasospasm, DIND and mortality associated with acute statin use after aneurysmal subarachnoid hemorrhage. However, the analysis was limited by substantial heterogeneity among individual studies. Greater dosing strategies are a potential consideration for future RCTs.

Recurrence of chest wall hydatid cyst disease involving the thoracic spine in an Australian patient.

Hydatid disease involving the spine is a relatively uncommon occurrence. The cestode Echinococcus granulosus is the primary pathogen associated with hydatid disease and most patients present with signs and symptoms of spinal cord compression depending on the location of the spinal involvement. We present a rare case of recurrent hydatid disease with extensive hemithorax involvement, including the thoracic spine, associated with spinal cord compression. This case highlights the role of staged and minimally invasive spine surgery in spinal hydatid disease with spinal cord compression, the importance of ongoing medical treatment and long term follow-up.

Spontaneous atlantoaxial subluxation associated with tonsillitis.

Atlantoaxial subluxation is a rare condition and requires a high index of suspicion to diagnose and treat in order to avoid long-term sequelae. Here, we present a case of late presentation of a nontraumatic rotatory subluxation of the atlantoaxial joint or atlantoaxial rotatory subluxation. A 17-year-old girl presented 3 months after the onset of nonspecific upper limb sensory symptoms which eventually settled spontaneously. Initial conservative management by the general practitioner had no effect. Computed tomography scanning revealed a Type 1 dislocation with rotatory fixation and with <3 mm anterior displacement of the atlas. The management of Type 1 subluxations is usually conservative with bed rest, oral nonsteroidal anti-inflammatory drugs, muscle relaxants, reduction (if required) and immobilization with a soft collar. This patient, however, required more invasive management due to the late presentation and slightly greater fixed deformity. As the subluxation could not be reduced with active manipulation, Gardner-Wells tongs with traction were applied. She then progressed to a pinned HALO, cyber neck support and subsequently an aspen collar which was eventually weaned off over a few weeks. The outcome and radiologic alignment at follow-up was satisfactory.