Mitotic deacetylase complex (MiDAC) recognizes the HIV-1 core promoter to control activated viral gene expression.

The human immunodeficiency virus (HIV) integrates into the host genome forming latent cellular reservoirs that are an obstacle for cure or remission strategies. Viral transcription is the first step in the control of latency and depends upon the hijacking of the host cell RNA polymerase II (Pol II) machinery by the 5' HIV LTR. Consequently, "block and lock" or "shock and kill" strategies for an HIV cure depend upon a full understanding of HIV transcriptional control. The HIV trans-activating protein, Tat, controls HIV latency as part of a positive feed-forward loop that strongly activates HIV transcription. The recognition of the TATA box and adjacent sequences of HIV essential for Tat trans-activation (TASHET) of the core promoter by host cell pre-initiation complexes of HIV (PICH) has been shown to be necessary for Tat trans-activation, yet the protein composition of PICH has remained obscure. Here, DNA-affinity chromatography was employed to identify the mitotic deacetylase complex (MiDAC) as selectively recognizing TASHET. Using biophysical techniques, we show that the MiDAC subunit DNTTIP1 binds directly to TASHET, in part via its CTGC DNA motifs. Using co-immunoprecipitation assays, we show that DNTTIP1 interacts with MiDAC subunits MIDEAS and HDAC1/2. The Tat-interacting protein, NAT10, is also present in HIV-bound MiDAC. Gene silencing revealed a functional role for DNTTIP1, MIDEAS, and NAT10 in HIV expression in cellulo. Furthermore, point mutations in TASHET that prevent DNTTIP1 binding block the reactivation of HIV by latency reversing agents (LRA) that act via the P-TEFb/7SK axis. Our data reveal a key role for MiDAC subunits DNTTIP1, MIDEAS, as well as NAT10, in Tat-activated HIV transcription and latency. DNTTIP1, MIDEAS and NAT10 emerge as cell cycle-regulated host cell transcription factors that can control activated HIV gene expression, and as new drug targets for HIV cure strategies.

Lower levels of Th1 and Th2 cytokines in cerebrospinal fluid (CSF) at the time of initial CSF shunt placement in children are associated with subsequent shunt revision surgeries.

OBJECTIVE: We compare cytokine profiles at the time of initial CSF shunt placement between children who required no subsequent shunt revision surgeries and children requiring repeated CSF shunt revision surgeries for CSF shunt failure. We also describe the cytokine profiles across surgical episodes for children who undergo multiple subsequent revision surgeries. METHODS: This pilot study was nested within an ongoing prospective multicenter study collecting CSF samples and clinical data at the time of CSF shunt surgeries since August 2014. We selected cases where CSF was available for children who underwent an initial CSF shunt placement and had no subsequent shunt revision surgeries during >=24 months of follow-up (n = 7); as well as children who underwent an initial CSF shunt placement and then required repeated CSF shunt revision surgeries (n = 3). Levels of 92 human cytokines were measured using the Olink immunoassay and 41 human cytokines were measured using Luminex based bead array on CSF obtained at the time of each child's initial CSF shunt placement and were displayed in heat maps. RESULTS: Qualitatively similar profiles for the majority of cytokines were observed among the patients in each group in both Olink and Luminex assays. Lower levels of MCP-3, CASP-8, CD5, CXCL9, CXCL11, eotaxin, IFN-γ, IL-13, IP-10, and OSM at the time of initial surgery were noted in the children who went on to require multiple surgeries. Pro- and anti-inflammatory cytokines were selected a priori and shown across subsequent revision surgeries for the 3 patients. Cytokine patterns differed between patients, but within a given patient pro-inflammatory and anti-inflammatory cytokines acted in a parallel fashion, with the exception of IL-4. CONCLUSIONS: Heat maps of cytokine levels at the time of initial CSF shunt placement for each child undergoing only a single initial CSF shunt placement and for each child undergoing repeat CSF shunt revision surgeries demonstrated qualitatively similar profiles for the majority of cytokines. Lower levels of MCP-3, CASP-8, CD5, CXCL9, CXCL11, eotaxin, IFN-γ, IL-13, IP-10, and OSM at the time of initial surgery were noted in the children who went on to require multiple surgeries. Better stratification by patient age, etiology, and mechanism of failure is needed to develop a deeper understanding of the mechanism of inflammation in the development of hydrocephalus and response to shunting in children.

Mapping the Landscape of Equitable Access to Advanced Neurotechnologies in Canada.

Geographic, social, political, and economic factors shape access to advanced neurotechnologies, yet little previous research has explored the barriers, enablers, and areas of opportunity for equitable and meaningful access for diverse patient communities across Canada. We applied a mixed-mode approach involving semi-structured interviews and rating scale questions to consult with 24 medical experts who are involved in the care of patients who undergo functional neurosurgery targeting the brain. Seven major themes emerged from the qualitative analysis: Health care system, Neurotechnology features, Patient demographics, Target condition features, Ethics, Upstream barriers and enablers, and Areas of opportunity. Descriptive statistics of the Likert-scale responses suggest that interviewees perceive a disparity between the imperative of access to advanced neurotechnologies for people living in rural and remote areas and the likelihood of achieving such access. The results depict a complex picture of access to functional neurosurgery in Canada with pockets of excellence and a motivation to improve the availability of care for vulnerable populations through the expansion of distributed care models, improved health care system efficiencies, increasing funding and support for patient travel, and increasing awareness about and advocacy for advanced neurotechnologies.

Strategic and principled approach to the ethical challenges of epilepsy monitoring unit triage.

Electroencephalographic monitoring provides critical diagnostic and management information about patients with epilepsy and seizure mimics. Admission to an epilepsy monitoring unit (EMU) is the gold standard for such monitoring in major medical facilities worldwide. In many countries, access can be challenged by limited resources compared to need. Today, triaging admission to such units is generally approached by unwritten protocols that vary by institution. In the absence of explicit guidance, decisions can be ethically taxing and are easy to challenge. In an effort to address this gap, we propose a two-component approach to EMU triage that takes into account the unique landscape of epilepsy monitoring informed by triage literature from other areas of medicine. Through the strategic component, we focus on the EMU wait list management infrastructure at the institutional level. Through the principled component, we apply a combination of the ethical principles of prioritarianism, utilitarianism and justice to triage; and we use individual case examples to illustrate how they apply. The effective implementation of this approach to specific epilepsy centres will need to be customised to the nuances of different settings, including diverse practice patterns, patient populations and constraints on resource distribution, but the conceptual consolidation of its components can alleviate some of the pressures imposed by the complex decisions involved in EMU triage.

Clinician preferences for neurotechnologies in pediatric drug-resistant epilepsy: A discrete choice experiment.

OBJECTIVE: Novel and minimally invasive neurotechnologies offer the potential to reduce the burden of epilepsy while avoiding the risks of conventional resective surgery. Few neurotechnologies have been tested in randomized controlled trials with pediatric populations, leaving clinicians to face decisions about whether to recommend these treatments with insufficient evidence about the relevant risks and benefits. This study specifically explores the preferences of clinicians for treating pediatric drug-resistant epilepsy (DRE) with novel neurotechnologies. METHODS: A discrete-choice experiment (DCE) was designed to elicit the preferences of clinicians with experience in treating children with DRE using novel neurotechnological interventions. The preferences for six key attributes used when making treatment decisions (chances of clinically significant improvement in seizures, major and minor risks from intervention, availability of evidence, financial burden for the family, and access to the intervention) were estimated using a conditional logit model. The estimates from this model were then used to predict the adoption of existing novel neurotechnological interventions. RESULTS: Sixty-eight clinicians completed the survey: 33 neurosurgeons, 28 neurologists, and 7 other clinicians. Most clinicians were working in the United States (74%), and the remainder (26%) in Canada. All attributes, apart from the nearest location with access to the intervention, influenced preferences significantly. The chance of clinically significant improvement in seizures was the most positive influence on clinician preferences, but low-quality evidence and a higher risk of major complications could offset these preferences. Of the existing neurotechnological interventions, vagus nerve stimulation was predicted to have the highest likelihood of adoption; deep brain stimulation had the lowest likelihood of adoption. SIGNIFICANCE: The preferences of clinicians are drive primarily by the likelihood of achieving seizure freedom for their patients, but preferences for an intervention are largely eradicated if only low quality of evidence supporting the intervention is available. Until better evidence supporting the use of potentially effective, novel neurotechnologies becomes available, clinicians are likely to prefer more established treatments.

Neutrophils expressing lysyl oxidase-like 4 protein are present in colorectal cancer liver metastases resistant to anti-angiogenic therapy.

Colorectal cancer liver metastases (CRCLM) that present with a replacement histopathological growth pattern (HGP) are resistant to neoadjuvant anti-angiogenic therapy. Surrogate biomarkers are not available to preoperatively identify patients with these tumors. Here we identify differentially expressed genes between CRCLM with a replacement HGP and those with a desmoplastic HGP using RNA sequencing. We demonstrate that LOXL4 is transcriptionally upregulated in replacement HGP CRCLM compared with desmoplastic HGP CRCLM and the adjacent normal liver. Interestingly, lysyl oxidase-like 4 (LOXL4) protein was expressed by neutrophils present in the tumor microenvironment in replacement HGP CRCLM. We further demonstrate that LOXL4 expression is higher in circulating neutrophils of cancer patients compared with healthy control patients and its expression can be induced by stimulation with lipopolysaccharide and TNF-α. Our study is the first to show the expression of LOXL4 in neutrophils and reveals the potential for LOXL4-expressing neutrophils to support the replacement HGP phenotype and to serve as a surrogate biomarker for this subtype of CRCLM. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Immediate replacement of bone flap after craniotomy for empyema in children.

PURPOSE: Optimal management of the bone flap after craniotomy for intracranial infection has not been well defined in the pediatric population. This study reviewed the outcomes of a single Canadian center where immediate replacement of the bone flap was standard practice. METHODS: This is a retrospective study of all patients who underwent craniotomies for evacuation of epidural or subdural empyema at a single center from 1982 to 2018. Patients were identified using the prospective surgical database maintained by the Division of Pediatric Neurosurgery at BC Children's Hospital. Primary outcome was treatment failure, defined as reoperation at the site of initial surgery for removal of an infected bone flap or repeat drainage of empyema under the replaced bone flap. Secondary outcome was any reoperation for recurrent infection at any site. RESULTS: Twenty-four patients met the inclusion criteria with a minimum of 3-month follow-up from the index intervention. Treatment failure occurred in four patients (17%), all of whom required repeat surgery for further drainage of pus underlying the bone flap. Mean time to repeat surgery was 13 days. Any reoperation for recurrent infection at any site occurred in three patients. Seven out of 24 patients required a second surgery to evacuate empyema (29.2%). Age, sex, epidural or subdural location, osteomyelitis, and bone flap wash were not associated with the primary outcome of treatment failure. CONCLUSION: Immediate replacement of the bone flap in the surgical management of pediatric subdural or epidural empyema is reasonable. Replacing the flap at the time of first surgery avoids the morbidity and costs of a subsequent reconstructive operation.

Hydrocephalus treatment in patients with craniosynostosis: an analysis from the Hydrocephalus Clinical Research Network prospective registry.

OBJECTIVE: Hydrocephalus may be seen in patients with multisuture craniosynostosis and, less commonly, single-suture craniosynostosis. The optimal treatment for hydrocephalus in this population is unknown. In this study, the authors aimed to evaluate the success rate of ventriculoperitoneal shunt (VPS) treatment and endoscopic third ventriculostomy (ETV) both with and without choroid plexus cauterization (CPC) in patients with craniosynostosis. METHODS: Utilizing the Hydrocephalus Clinical Research Network (HCRN) Core Data Project (Registry), the authors identified all patients who underwent treatment for hydrocephalus associated with craniosynostosis. Descriptive statistics, demographics, and surgical outcomes were evaluated. RESULTS: In total, 42 patients underwent treatment for hydrocephalus associated with craniosynostosis. The median gestational age at birth was 39.0 weeks (IQR 38.0, 40.0); 55% were female and 60% were White. The median age at first craniosynostosis surgery was 0.6 years (IQR 0.3, 1.7), and at the first permanent hydrocephalus surgery it was 1.2 years (IQR 0.5, 2.5). Thirty-three patients (79%) had multiple different sutures fused, and 9 had a single suture: 3 unicoronal (7%), 3 sagittal (7%), 2 lambdoidal (5%), and 1 unknown (2%). Syndromes were identified in 38 patients (90%), with Crouzon syndrome being the most common (n = 16, 42%). Ten patients (28%) received permanent hydrocephalus surgery before the first craniosynostosis surgery. Twenty-eight patients (67%) underwent VPS treatment, with the remaining 14 (33%) undergoing ETV with or without CPC (ETV ± CPC). Within 12 months after initial hydrocephalus intervention, 14 patients (34%) required revision (8 VPS and 6 ETV ± CPC). At the most recent follow-up, 21 patients (50%) required a revision. The revision rate decreased as age increased. The overall infection rate was 5% (VPS 7%, 0% ETV ± CPC). CONCLUSIONS: This is the largest prospective study reported on children with craniosynostosis and hydrocephalus. Hydrocephalus in children with craniosynostosis most commonly occurs in syndromic patients and multisuture fusion. It is treated at varying ages; however, most patients undergo surgery for craniosynostosis prior to hydrocephalus treatment. While VPS treatment is performed more frequently, VPS and ETV are both reasonable options, with decreasing revision rates with increasing age, for the treatment of hydrocephalus associated with craniosynostosis.

Epilepsy through the eyes of the media: A paradox of positive reporting and challenges of access to advanced neurotechnology.

OBJECTIVE: Media coverage of disorders and medical advancements can impact public perception regarding the riskiness, effectiveness, and accessibility of treatment options. We studied that coverage for epilepsy with a focus on surgical interventions and emerging neurotechnologies. METHODS: Epilepsy-related English language articles published through 2019 were retrieved from online International news media with a circulation of 80,000 or above. We used directed content analysis of news articles to code content into a priori categories both to identify salient themes and to characterize their valence. RESULTS: One hundred forty-six unique articles matched our search terms. Overall, there was a steady increase in epilepsy reporting over time, with a majority of articles published with a positive tone. Neuromodulation was the focus of over 50% of all the articles in the time points analyzed. Vagus nerve stimulation (VNS) and deep-brain stimulation (DBS) were discussed more prominently than other types of neurotechnological interventions; VNS was the neurotechnological focus in 39% of the pediatric articles; resective surgery was the focus in 34% of adult articles. Access, support, and epilepsy literacy were the central themes in the context of ethical, legal, and social issues. SIGNIFICANCE: News media can influence the trust that the public places in science and medicine, and by extension, influences health policy. As innovations in neurotechnology for epilepsy emerge, understanding of individual and societal values is essential to their beneficial evolution and translation to care.

Readiness for First-In-Human Neuromodulatory Interventions.

BACKGROUND: Novel neurointerventions present innovative therapeutic approaches to a range of treatment-refractory disorders. We sought to characterize factors that inform and define translational readiness for first-in-human (FIH) neuromodulatory trials. METHODS: We used a two-part methodology involving a scoping review of the biomedical literature on the readiness of FIH trials for both neurological and non-neurological applications, and semi-structured interviews with stakeholders about decision-making for neuromodulation using magnetic resonance-guided focused ultrasound as a case example. RESULTS: One hundred and thirty factors relevant to FIH readiness were identified in the scoping review. Trial design, adequacy of preclinical evidence, and risk were ubiquitous across biotechnologies. Target organ, target function, and inadequacy of animal models were dominant in the neurointervention literature. Interview results on the relative importance of these factors reveal divergent values, priorities, and understandings both between patients and clinicians and between patients affected by different conditions. CONCLUSION: Readiness of neurotechnology for FIH trials is defined by a multitude of interacting factors that pertain to clinical and nonclinical priorities, perceptions, and values.

Cervical Spine Dysfunction Following Pediatric Sports-Related Head Trauma.

OBJECTIVE: To examine the prevalence of cervical spine injuries among children and adolescents referred with suspected and diagnosed sports-related concussion (SRC); and evaluate the effect of cervical spine dysfunction (CSD) on physician-documented clinical recovery following SRC. SETTING: A multidisciplinary pediatric concussion program. PARTICIPANTS: A total of 266 patients (6-19 years) referred with suspected SRC. DESIGN: A retrospective cohort study. MAIN MEASURES: CSD defined as neurological symptoms localized to the cervical spine or the presence of neck pain, headache, or dizziness and abnormal cervical spine examination findings; physician-documented clinical recovery. RESULTS: One patient was diagnosed with a T1 compression fracture. Of the 246 patients diagnosed with SRC, 80 (32.5%) met the clinical criteria for CSD including 4 patients with central cord neuropraxia and 1 with a spinal cord injury without radiographic abnormality (SCIWORA). Excluding patients with central cord neuropraxia OR SCIWORA, patients with SRC with CSD took longer to achieve physician-documented clinical recovery (28.5 days vs 17 days, P < .0001) and were 3.95 times more likely to experience delayed physician-documented clinical recovery (>4 weeks postinjury) compared with those without CSD. CONCLUSIONS: Patients with suspected and diagnosed SRC can present with a wide spectrum of coincident cervical spine injuries. Cervical spine dysfunction may be a risk factor for delayed clinical recovery.

Interhypothalamic adhesions in endoscopic third ventriculostomy.

INTRODUCTION: An interhypothalamic adhesion (IHA) is a gray mater-like band of tissue traversing across the third ventricle anterior to the mammillary bodies and is similar but distinct from an interthalamic adhesion. These rare anatomic anomalies can be detected with magnetic resonance imaging or, incidentally, during endoscopic ventricular surgery. METHODS: All cases of interhypothalamic adhesions visualized during endoscopic third ventriculotomy (ETV), outside of the myelomeningocele setting, were identified from two institutions. Retrospective chart and imaging reviews were conducted and compared to intraoperative videos and photos for all cases. IHA variables collected included the following size, location, multiplicity, and associated anatomic anomalies. RESULTS: Four cases of interhypothalamic adhesions were identified during ETV-all of which, either partially or completely, obscured access to the third ventricular floor. The IHAs in our cohort were duplicated in two patients, large (> 3 mm and severely obstructing access to the third ventricular floor) in three patients, and adherent to the floor of the third ventricle in three patients. All four patients had primary absence of the septum pellucidum. Previous reports found associations of IHAs with other congenital, particularly midline, abnormalities. The IHAs in our cohort affected the surgery in three of four cases including misdirecting the ventriculostomy and requiring retraction or division of the IHA. In no case was postoperative pituitary or hypothalamic dysfunction observed. CONCLUSIONS: Although interhypothalamic adhesions are rare, these anomalies must be recognized as they may hinder access to the third ventricular floor. IHAs may be large, multiple, or adherent to adjacent ventricular structures, they can misdirect or occlude the ventriculostomy or impart risk of bleeding and hypothalamic injury. Techniques for management of IHA include aborting the attempt, re-siting the ventriculostomy, or retracting or dividing the IHA, which enabled technically successful ETV in three of four patients in this series.

Fetal Repair of Open Neural Tube Defects: Ethical, Legal, and Social Issues.

Open neural tube defects or myelomeningoceles are a common congenital condition caused by failure of closure of the neural tube early in gestation, leading to a number of neurologic sequelae including paralysis, hindbrain herniation, hydrocephalus and neurogenic bowel and bladder dysfunction. Traditionally, the condition was treated by closure of the defect postnatally but a recently completed randomized controlled trial of prenatal versus postnatal closure demonstrated improved neurologic outcomes in the prenatal closure group. Fetal surgery, or more precisely maternal-fetal surgery, raises a number of ethical issues that we address including who the patient is, informed consent, surgical innovation and equipoise as well maternal assumption of risk. As the procedure becomes more widely adopted into practice, we suggest close monitoring of new fetal surgery centers, in order to ensure that the positive results of the trial are maintained without increased risk to both the mother and fetus.

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLS) play a major role in invasive joint destruction in rheumatoid arthritis (RA). This prodestructive phenotype has been shown to involve autocrine TGF-ß that triggers formation of matrix-degrading invadosomes through molecular mechanisms that are not fully elucidated. The platelet-derived growth factor (PDGF) receptor (PDGFR) family of receptor tyrosine kinases (RTK) has been shown to cooperate with TGF-ß in various pathological conditions. We therefore sought to determine whether RTK activity played a role in invadosome biogenesis. We demonstrated that, among the common RTKs, PDGFR-αß was specifically phosphorylated in FLS from RA patients. Phosphorylation of PDGFR-αß was also elevated in RA synovial tissues. Interference with PDGFR activation or PDGF neutralization inhibited invadosome formation in RA synoviocytes, indicating the presence of an autocrine PDGFR activation loop that involved endogenous PDGF. Among the PDGF-A-D isoforms, only PDGF-B was found both significantly elevated in FLS lines from RA patients, and related to high-invadosome forming cells. Addition of TGF-ß upregulated invadosome formation, PDGF-B mRNA expression, and phosphorylation of PDGFR. All of these functions were efficiently suppressed by TGF-ß neutralization or interference with the Smad/TßR1or PI3K/Akt pathway. Among the class 1 PI3K family proteins known to be expressed in RA synoviocytes, PI3Kα was selectively involved in PDGF-B expression, whereas both PI3Kα and PI3Kδ participated in invadosome formation. Our findings demonstrate that PDGFR is a critical RTK required for the prodestructive phenotype of RA synovial cells. They also provide evidence for an association between autocrine TGF-ß and PDGFR-mediated invadosome formation in RA synoviocytes that involves the production of PDGF-B induced by TGF-ß.

Non-surgical transient cerebellar mutism-case report and systematic review.

INTRODUCTION: Transient cerebellar mutism has been well recognized in literature as a complication of posterior fossa tumor resection. It is marked by profound impairment of fluency, articulation, and modulation of speech, irritability and autistic features and typically resolves within days to months. Underlying pathophysiology is debated, but currently unknown. METHODS: We present a case of a child with similar clinical findings after cerebellitis, demonstration of diffuse cerebellar signal changes, swelling, and protruding tonsils at the level of foramen magnum. DISCUSSION: To support the hypothesis that this clinical syndrome may occur in a non-surgical context, we present a review of literature of non-surgical transient cerebellar mutism.

Pre-Trauma Center Management of Intracranial Pressure in Severe Pediatric Traumatic Brain Injury.

OBJECTIVES: Pre-trauma center care is a critical component in severe pediatric traumatic brain injury (TBI). For geographically large trauma catchment areas, optimizing increased intracranial pressure (ICP) management may potentially improve outcomes. This retrospective study examined ICP management in nontrauma centers and during interfacility transport to the trauma center. METHODS: Charts from a pediatric level I trauma center were reviewed for admissions between 2008 and 2013. Patients with a Glasgow Coma Scale score of 8 or less, head Abbreviated Injury Scale score of 3 or higher, and requiring intubation at a nontrauma center were included. Exclusion criteria included head injury secondary to drowning, stroke, obstetrical complications, asphyxia, and afflicted head trauma (younger than 5 years). Trauma center charts contained coalesced data from first responders, nontrauma centers, and transport. RESULTS: Twenty-five patients (74%) had increased ICP upon admission at trauma center, 48% experienced ICPs greater than 20 cm H2O within 12 hours of admission, 12% required an urgent craniotomy, and 16% had herniation syndromes on neuroimaging. Pre-trauma center ICP management included osmotherapy and head-of-bed elevation. Sixty-four percent of patients with increased ICP at trauma center admission received pre-trauma center ICP management. CONCLUSIONS: Early increased ICP is a common presentation of severe pediatric TBI during pre-trauma center management. However, what constitutes optimal care remains unknown. Given the difficulties of diagnosing early increased ICP in this setting, prophylactic raising ICP-lowering strategies may be considered.

Transitioning in hydrocephalus: Current practices in Canadian Paediatric Neurosurgery centres.

INTRODUCTION: Advances in perinatal care in the developed world have resulted in more children living into adulthood with complex chronic health conditions. Transition is a process to improve and maximize the functional status of adolescents via the provision of adequate and appropriate health services in adulthood. This process is frequently disjointed, fragmented and inconsistent and inadequate transition increases morbidity, hospital admissions and urgent interventions. Ten thousand children are diagnosed with hydrocephalus annually in North America. Most survive to adulthood yet there are few transitioning programs and little research data on successful programs for this population. METHODS: An email survey of paediatric neurosurgical centres in Canada was carried out to establish current transition practices and attitudes for adolescents with hydrocephalus. Data were analyzed descriptively. RESULTS: Eleven out of 12 centres responded. The age of transition ranged from 16 to 18 years. Four centres have access to a dedicated Adult Hydrocephalus Clinic. Referral practices vary between centres and we highlight inconsistencies in care to this cohort of patients in Canada. There is little satisfaction among neurosurgeons with current transition arrangements in Canada. Several suggestions were made on how to improve this process. CONCLUSION: We recommend research into the needs of patients with hydrocephalus in order to formalize appropriate standards for transitioning patients with a view to developing national guidelines to standardize the transition process. This will require input from patients, families and the wider medical and allied health professional groups.

Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses.

The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be activated by different classes of inflammatory stimuli, namely, chemoattractants and growth factors. After stimulation with such agents, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the inducible phosphorylation of ERK occurring in response to these stimuli but had little or no effect on that of p38 MAPK or PI3K. Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF. Moreover, both TAK1 and the MEK/ERK module were found to influence inflammatory cytokine expression and release in fMLF- and GM-CSF-activated neutrophils, whereas the PI3K pathway influenced this response independently of TAK1. Besides cytokine production, other responses were found to be under TAK1 control in neutrophils stimulated with chemoattractants and/or GM-CSF, namely, delayed apoptosis and leukotriene biosynthesis. Our data further emphasize the central role of TAK1 in controlling signaling cascades and functional responses in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions.

National Perspectives on the Training of Neurosurgery Residents in Stereotactic Radiosurgery.

BACKGROUND: Despite the critical role played by neurosurgeons in performing radiosurgery, neurosurgery residents in Canada have limited exposure to radiosurgery during their training. A survey of neurosurgery residents and faculty along with radiation oncology faculty was conducted to analyze perspectives regarding incorporating formal radiosurgery training into the neurosurgery residency curriculum Methods: An online survey platform was employed. Descriptive statistics were used to summarize center and respondent characteristics. Categorical variables were compared using odds ratios and corresponding 95% confidence intervals. The chi-squared test was utilized to assess statistical significance. A value of p<0.05 was considered significant Results: The response rate was 31% (119/381); 87% (102/119) of respondents were from the neurosurgical specialty and 13% (17/119) from radiation oncology. Some 46% of residents (18/40) were "very uncomfortable" with radiosurgery techniques, and 57% of faculty (42/73) believed that dedicated radiosurgery training would be beneficial though impractical. No respondents felt that "no training" would be beneficial. A total of 46% of residents (19/41) felt that this training would be beneficial and that time should be taken away from other rotations, if needed, while 58% of faculty (42/73) and 75% (28/41) of residents believed that either 1 or 1-3 months of time dedicated to training in radiosurgery would suffice Conclusions: Canadian neurosurgeons are actively involved in radiosurgery. Despite residents anticipating a greater role for radiosurgery in their future, they are uncomfortable with the practice. With the indications for radiosurgery expanding, this training gap can have serious adverse consequences for patients. Considerations regarding the incorporation and optimal duration of dedicated radiosurgery training into the Canadian neurosurgery residency curriculum are necessary.