The pathology of lumbosacral lipomas:macroscopic and microscopic disparity have implications for embryogenesis and mode of clinical deterioration

AIMS: Lumbosacral lipomas (LSL) are congenital disorders of the terminal spinal cord region that have the potential to cause significant spinal cord dysfunction in children. They are of unknown embryogenesis with variable clinical presentation and natural history. It is unclear whether the spinal cord dysfunction reflects a primary developmental dysplasia or whether it occurs secondarily to mechanical traction (spinal cord tethering) with growth. Whilst different anatomical subtypes are recognised and classified according to radiological criteria, these subtypes correlate poorly with clinical prognosis. We have undertaken an analysis of surgical specimens in order to describe the spectrum of histological changes that occur and have correlated the histology with the anatomical type of LSL to determine if there are distinct histological sub-types. METHODS AND RESULTS: The histopathology was reviewed of 64 patients who had undergone surgical resection of LSL. The presence of additional tissues and cells types were recorded. LSLs were classified from pre-operative MRI scans according to Chapman classification. 95% of the specimens consisted predominantly of mature adipocytes with all containing thickened bands of connective tissue and peripheral nerve fibres. 91% of samples contained ectatic blood vessels with thickened walls, whilst 22% contained CNS glial tissue. Additional tissue was identified of both mesodermal and neuroectodermal origin. CONCLUSIONS: Our analysis highlights the heterogeneity of tissue types within all samples, not reflected in the nomenclature. The diversity of tissue types, consistent across all subtypes, challenges currently held notions regarding the embryogenesis of LSLs and the assumption that clinical deterioration is simply due to tethering. This article is protected by copyright. All rights reserved

Impact of COVID-19 pandemic on surgical neuro-oncology multi-disciplinary team decision making: a national survey (COVID-CNSMDT Study).

OBJECTIVES: Pressures on healthcare systems due to COVID-19 has impacted patients without COVID-19 with surgery disproportionally affected. This study aims to understand the impact on the initial management of patients with brain tumours by measuring changes to normal multidisciplinary team (MDT) decision making. DESIGN: A prospective survey performed in UK neurosurgical units performed from 23 March 2020 until 24 April 2020. SETTING: Regional neurosurgical units outside London (as the pandemic was more advanced at time of study). PARTICIPANTS: Representatives from all units were invited to collect data on new patients discussed at their MDT meetings during the study period. Each unit decided if management decision for each patient had changed due to COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures included number of patients where the decision to undergo surgery changed compared with standard management usually offered by that MDT. Secondary outcome measures included changes in surgical extent, numbers referred to MDT, number of patients denied surgery not receiving any treatment and reasons for any variation across the UK. RESULTS: 18 units (75%) provided information from 80 MDT meetings that discussed 1221 patients. 10.7% of patients had their management changed-the majority (68%) did not undergo surgery and more than half of this group not undergoing surgery had no active treatment. There was marked variation across the UK (0%-28% change in management). Units that did not change management could maintain capacity with dedicated oncology lists. Low volume units were less affected. CONCLUSION: COVID-19 has had an impact on patients requiring surgery for malignant brain tumours, with patients receiving different treatments-most commonly not receiving surgery or any treatment at all. The variations show dedicated cancer operating lists may mitigate these pressures. STUDY REGISTRATION: This study was registered with the Royal College of Surgeons of England's COVID-19 Research Group (https://www.rcseng.ac.uk/coronavirus/rcs-covid-research-group/)

The contribution of advisory committees and public involvement to large studies: case study

Background: Many large studies have complex advisory committee structures, yet there is no empirical evidence regarding their optimal composition, scope and contribution. The aim of this study was to inform the committee and advice infrastructure for future research studies. Methods: In the context of a five-year study funded by the UK National Institute for Health Research, three advisory committees were formed. In addition, advice was obtained from individual experts. All recommendations received in the start-up phase (first seven months) of the study were recorded, along with the decision about implementation of the recommendation. A particular focus was on the impact of public involvement. Results: A total of 172 recommendations were made, including 70 from 20 individual experts. The recommendations were grouped into five emergent themes: Scientific, Pragmatic, Resources, Committee and Collaboration. Most recommendations related to strengthening existing components or adding new components to the study protocol. Very few recommendations either proposed removing study components or contradicted other recommendations. Three 'implementation criteria' were identified: scientific value, pragmatic feasibility, and paradigmatic consistency. 103 (60%) of recommendations were implemented and 25 (15%) were not implemented. The benefits identified by the research team were improved quality and confidence, and the costs were increased cognitive demands, protocol revision time, and slower progress. Conclusions: The findings are discussed in the context of the wider literature on public involvement in research. Six recommendations are identified. First, have a clear rationale for each advisory committee expressed as terms of reference, and consider the best balance between committees and individual consultation with experts. Second, an early concern of committees is inter-committee communication, so consider cross-representation and copying minutes between committees. Third, match the scope of advisory committees to the study, with a less complex advisory structure for studies with more finalised designs. Fourth, public involvement has a mixed impact, and relies on relationships of trust, which take time to develop. Fifth, carefully consider the match between the scientific paradigm applied in the study and the contribution of different types of knowledge and expertise, and how this will impact on possibilities for taking on advice. Finally, responding to recommendations uses up research team resources, and the costs can be reduced by using the three implementation criteria

Functional characteristics of nitric oxide receptor isoforms

Physiologically, nitric oxide (NO) signal transduction occurs through activation of guanylyl cyclase (GC)-coupled receptors, which catalyse cGMP formation. The accumulation of cyclic guanosine 3'-5' monophosphate (cGMP) engages a number of downstream targets to trigger various biological effects, and is ultimately degraded by phosphodiesterases. Unlike with many neurotransmitter receptors, knowledge of the functional characteristics of the NO receptors is limited. The aim of the present research was to begin to address this deficiency by examining the kinetics of the activation of the native receptor and of heterologously-expressed receptor isoforms in intact cells or cell lysates. In cells from a brain region that is enriched in the NO-cGMP signalling pathway, namely the striatum, NO-evoked cGMP accumulation was located in a neuronal subpopulation and the receptor activity displayed a rapidly-desensitizing profile similar to that found previously in cerebellar astrocytes. To determine if this pattern of activity is peculiar to particular receptors, the two known heterodimeric isoforms, α1β1 and α2β1, were expressed in COS-7 cells. NO was applied in fixed concentrations using a recently-developed method based on balancing NO release from a donor with NO inactivation by red blood cells. The two isoforms were highly sensitive to NO, half-maximal cGMP accumulation occurring at concentrations of about 1 nM in both cases. Furthermore, the NO-evoked activity of both receptors desensitized with very similar kinetics. To circumvent limitations of the method for NO delivery used in the initial experiments, particularly problems of haemolysis, a new technique, in which a chemical NO scavenger was substituted for the red blood cells, was evaluated and found to be superior in several respects. The new method was used to determine the kinetic parameters of the receptor purified from bovine lung and, for comparison, cell lysates containing the two isoforms. Half-maximal activity in all cases required about 1 nM NO. In addition, the Hill slopes were close to 1, questioning a previous conclusion that receptor activation requires binding of more than one NO molecule per receptor. Contrasting with another previous study which suggested that membrane association sensitizes the receptor to NO, comparison of cytosolic and membrane preparations of two different tissues (cerebellum and platelets) revealed that their sensitivities to NO were indistinguishable when studied using fixed concentrations