Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

Human spinal cord tissue is an underutilised resource in degenerative cervical myelopathy: findings from a systematic review of human autopsies.

STUDY DESIGN: Systematic review. BACKGROUND: Although degenerative cervical myelopathy (DCM) is the most prevalent spinal cord condition worldwide, the pathophysiology remains poorly understood. Our objective was to evaluate existing histological findings of DCM on cadaveric human spinal cord tissue and explore their consistency with animal models. METHODS: MEDLINE and Embase were systematically searched (CRD42021281462) for primary research reporting on histological findings of DCM in human cadaveric spinal cord tissue. Data was extracted using a piloted proforma. Risk of bias was assessed using Joanna Briggs Institute critical appraisal tools. Findings were compared to a systematic review of animal models (Ahkter et al. 2020 Front Neurosci 14). RESULTS: The search yielded 4127 unique records. After abstract and full-text screening, 19 were included in the final analysis, reporting on 150 autopsies (71% male) with an average age at death of 67.3 years. All findings were based on haematoxylin and eosin (H&E) staining. The most commonly reported grey matter findings included neuronal loss and cavity formation. The most commonly reported white matter finding was demyelination. Axon loss, gliosis, necrosis and Schwann cell proliferation were also reported. Findings were consistent amongst cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament. Cavitation was notably more prevalent in human autopsies compared to animal models. CONCLUSION: Few human spinal cord tissue studies have been performed. Neuronal loss, demyelination and cavitation were common findings. Investigating the biological basis of DCM is a critical research priority. Human spinal cord specimen may be an underutilised but complimentary approach.

Motivations, barriers, and social media: a qualitative study of uptake of women into neurosurgery.

OBJECTIVE: To explore how social media could be utilised to influence an individual's motivation to pursue a neurosurgical career, an emerging topic area. The focus of this study was on women interested in neurosurgery. SUMMARY BACKGROUND DATA: Women are significantly under-represented in neurosurgery. 18% of all neurosurgeons - including 8% of consultants - are women. Most previous studies have used quantitative methods that are not best suited to gaining an in-depth understanding of the barriers that women face in pursuing a career in neurosurgery, or what would enable more women to go into the speciality. METHODS: In this qualitative study, individual semi-structured interviews were conducted until data saturation was achieved. Participants were women pre-neurosurgical trainees. The interview data was examined through a thematic analysis involving open and axial coding. RESULTS: Thirty women participated in the study. Four overarching themes were identified: (1) mentorship, (2) testimony from other women doing neurosurgery, (3) social media as a means of increasing interest in neurosurgery as a career choice, and (4) real-life exposure to the speciality. CONCLUSION: There is scope to further improve uptake of women into neurosurgical training in the UK. Motivations and barriers to women pursuing neurosurgery should be addressed openly through early experience, role models and mentorship. Social media can help facilitate these opportunities, disseminate information and inspiration, and has the potential to undo societal biases.

Personal protective equipment and infection prevention and control: a national survey of UK medical students and interim foundation doctors during the COVID-19 pandemic.

BACKGROUND: The adequacy of personal protective equipment (PPE) and infection prevention and control (IPC) training in UK medical students and interim Foundation Year 1 (FiY1) doctors during the COVID-19 pandemic is unknown, as is its impact on COVID-19-related anxiety. METHODS: Cross-sectional, multi-centre study analysing self-reported adequacy of PPE and IPC training and correlation to a modified pandemic anxiety scale. Participants were current medical students and FiY1 doctors in the UK. Data were collected by an online survey. RESULTS: Participants reported that they received insufficient PPE information (43%) and IPC training (56%). Significantly, fewer participants identifying as women or BAME/mixed ethnicity reported receiving sufficient PPE information, compared with those identifying as men and White British/White Other, respectively. COVID-19-related anxiety was significantly higher in those without sufficient reported PPE or IPC training, in women compared with men, and in FiY1 doctors compared with medical students. CONCLUSIONS: With medical students currently volunteering in and imminently returning to hospitals in an educational capacity, levels of self-reported PPE and IPC training are sub-optimal. Better training is paramount to avoid harm to patients and healthcare professionals and to reduce COVID-19-related anxiety among medical students and FiY1 doctors.

Physical restraint and the protection of the human rights of immigration detainees in hospitals.

Immigration detainees, like prisoners, are entitled to the same standard of healthcare as non-detained patients. When hospital attendance or admission is required, the priority for custodial staff (who for purposes of this article we refer to as 'escorts') is to prevent absconding. For that reason, they may wish to use physical restraints, such as handcuffs, and remain with the detainee at all times. This can be degrading for the patient and breach their human rights. Clinicians have professional obligations to all their patients and must object to any restraint methods that risk damaging the patient's right to confidentiality, treatment, health or the therapeutic relationship itself. The starting presumption is that restraints ought not to be used during treatment and only in the most exceptional cases ought escorts to be present during clinical examination or treatment.

Risk assessment in pT1 colorectal cancer.

Colorectal cancer (CRC) is a common malignancy worldwide and tumour stage is closely related to clinical outcome. A small but significant proportion of submucosal-invasive (ie, pT1) CRC are associated with regional lymph node metastases (LNM) and a worse prognosis. The likelihood of LNM in pT1 CRC needs to be balanced against the operative risk and costs of surgical resection when determining the best patient management. A wide range of histopathological and clinical factors may affect LNM risk in this setting. This script provides a comprehensive overview of the tumour and patient-associated features that have been linked to LNM risk in pT1 CRC. Some of the features are well established within the literature and are included in published guidelines, while others are novel and emerging in nature. Odds ratios for LNM that are associated with key predictive features are provided where appropriate, and published models developed as an aid to the calculation of LNM risk are discussed.

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses.

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1-11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.

Ageing is associated with maladaptive immune response and worse outcome after traumatic brain injury.

Traumatic brain injury is increasingly common in older individuals. Older age is one of the strongest predictors for poor prognosis after brain trauma, a phenomenon driven by the presence of extra-cranial comorbidities as well as pre-existent pathologies associated with cognitive impairment and brain volume loss (such as cerebrovascular disease or age-related neurodegeneration). Furthermore, ageing is associated with a dysregulated immune response, which includes attenuated responses to infection and vaccination, and a failure to resolve inflammation leading to chronic inflammatory states. In traumatic brain injury, where the immune response is imperative for the clearance of cellular debris and survey of the injured milieu, an appropriate self-limiting response is vital to promote recovery. Currently, our understanding of age-related factors that contribute to the outcome is limited; but a more complete understanding is essential for the development of tailored therapeutic strategies to mitigate the consequences of traumatic brain injury. Here we show greater functional deficits, white matter abnormalities and worse long-term outcomes in aged compared with young C57BL/6J mice after either moderate or severe traumatic brain injury. These effects are associated with altered systemic, meningeal and brain tissue immune response. Importantly, the impaired acute systemic immune response in the mice was similar to the findings observed in our clinical cohort. Traumatic brain-injured patient cohort over 70 years of age showed lower monocyte and lymphocyte counts compared with those under 45 years. In mice, traumatic brain injury was associated with alterations in peripheral immune subsets, which differed in aged compared with adult mice. There was a significant increase in transcription of immune and inflammatory genes in the meninges post-traumatic brain injury, including monocyte/leucocyte-recruiting chemokines. Immune cells were recruited to the region of the dural injury, with a significantly higher number of CD11b+ myeloid cells in aged compared with the adult mice. In brain tissue, when compared with the young adult mice, we observed a more pronounced and widespread reactive astrogliosis 1 month after trauma in aged mice, sustained by an early and persistent induction of proinflammatory astrocytic state. These findings provide important insights regarding age-related exacerbation of neurological damage after brain trauma.

Hosting an Educational Careers Day Within the Virtual Paradigm: The Neurology and Neurosurgery Interest Group Experience.

INTRODUCTION:  To explore our experience of hosting the 10th Annual Neurology and Neurosurgery Interest Group-Society of British Neurological Surgeons (NANSIG-SBNS) Neurosurgery Careers Day, held virtually for the first time. METHODS:  Reflective feedback and review of an international, virtual neurosurgery careers day. The authors reflect on the logistics of organizing the event, and the pre- and post-event feedback provided by delegates. Recommendations have been made on how to successfully host a virtual event. The key themes that permeated the event have been outlined and discussed in the context of the feedback received. RESULTS:  The event was attended by 231 delegates from 20 countries worldwide. Knowledge of neurosurgery as a career and the application process increased after attending the careers day (4.27/5 to 4.51/5, p=0.003 and 3.12/5 to 4.31/5, p<0.001 respectively). The key themes identified from the event include attendance, networking, and education. Qualitative feedback was positive and indicated a positive perception of the careers day. CONCLUSIONS:  The future of educational events is unclear, and a hybrid approach is recommended to retain the benefits of the online space when in-person events eventually return.

Splenic Infarct Due to a Patent Foramen Ovale and Paradoxical Emboli Post-COVID-19 Infection: A Case Study.

Hypercoagulability is now a recognized complication of COVID-19 infection. Despite this, splenic infarction remains rare and is often found incidentally, radiologically, or at autopsy. We report a case of symptomatic splenic infarction with superimposed infection, secondary to COVID-19-induced hypercoagulability in a young patient with paradoxical emboli due to an undiagnosed patent foramen ovale (PFO). This multifactorial case should prompt a level of suspicion of the patient with unexplained abdominal pain and recent COVID-19 infection.

Use of Wide-Awake Local Anaesthetic No Tourniquet (WALANT) in upper limb and hand surgery: A systematic review protocol.

INTRODUCTION: Wide Awake Local Anaesthetic No Tourniquet (WALANT) technique has been developed to eliminate tourniquet pain during upper limb and hand surgery whilst also improving utilisation of operating theatre time and inpatient stay, however inconclusive data still limits the techniques uptake. Here presents a protocol for a systematic review to collate findings to produce conclusive data on efficacy of WALANT. METHODS: This systematic review will be registered a priori. All study designs defined by the Oxford Centre for Evidence-Based Medicine will be included in the search. "WALANT" in "upper limb" and "hand" surgery will be investigated as per the devised search strategy. 18 electronic databases will be searched, including PubMed, Medline and Embase in addition to a Grey literature search. Two independent teams of 3 researchers will screen all relevant titles, abstracts and subsequent full texts for suitability. Data will be extrapolated and entered into a preformatted database for analysis. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and presented at both national and international conferences within the field of plastic and orthopaedic surgery. This review aims to inform surgical practice and policy.

Oxidation of Nb(110): atomic structure of the NbO layer and its influence on further oxidation.

NbO terminated Nb(110) and its oxidation are examined by scanning tunneling microscopy and spectroscopy (STS). The oxide structures are strongly influenced by the structural and electronic properties of the underlying NbO substrate. The NbO is terminated by one-dimensional few-nanometer nanocrystals, which form an ordered pattern. High-resolution STS measurements reveal that the nanocrystals and the regions between the nanocrystals exhibit different electronic characters. Low-dosage oxidation, sufficient for sub-monolayer coverage of the NbO, with subsequent UHV annealing results in the formation of resolved sub-nanometer clusters, positioned in-between the nanocrystals. Higher dosage oxidation results in the formation of a closed Nb2O5-y layer, which is confirmed by X-ray photoelectron spectroscopy measurements. The pentoxide is amorphous at the atomic-scale. However, large scale (tens of nanometers) structures are observed with their symmetry matching that of the underlying nanocrystals.

Cell Senescence and Cerebral Small Vessel Disease in the Brains of People Aged 80 Years and Older.

Cerebral small vessel disease (cSVD) in penetrating arteries is a major cause of age-related morbidity. Cellular senescence is a molecular process targeted by novel senolytic drugs. We quantified senescence in penetrating arteries and tested whether myocyte senescence was associated with cSVD. We immunolabeled subcortical white matter of older persons (age 80-96 years, n = 60) with minimal AD, using antibodies to 2 established senescence markers (H3K9me3, γH2AX) and a myocyte marker (hSMM). Within the walls of penetrating arteries (20-300 µm), we quantified senescence-associated heterochromatic foci (SAHF)-positive nuclei, cell density (nuclei/µm2), and sclerotic index (SI). Senescent-appearing mural cells were present in small arteries of all cases. cSVD cases exhibited a lower proportion of senescent-appearing cells and lower area fraction (AF%) of SAHF-positive nuclei compared to controls (p = 0.014, 0.016, respectively). cSVD severity and SI both correlated negatively with AF% (p = 0.013, 0.002, respectively). Mural cell density was lower (p < 0.001) and SI higher (p < 0.001) in cSVD, relative to controls. In conclusion, senescent myocyte-like cells were universal in penetrating arteries of an AD-free cohort aged 80 years and older. Senescent-appearing nuclei were more common in persons aged 80 years and older without cSVD compared to cSVD cases, indicating caution in senolytic drug prescribing. Myocyte senescence and cSVD may represent alternative vessel fates in the aging human brain.

Quantifying the Performance of P-Type Transparent Conducting Oxides by Experimental Methods.

Screening for potential new materials with experimental and theoretical methods has led to the discovery of many promising candidate materials for p-type transparent conducting oxides. It is difficult to reliably assess a good p-type transparent conducting oxide (TCO) from limited information available at an early experimental stage. In this paper we discuss the influence of sample thickness on simple transmission measurements and how the sample thickness can skew the commonly used figure of merit of TCOs and their estimated band gap. We discuss this using copper-deficient CuCrO 2 as an example, as it was already shown to be a good p-type TCO grown at low temperatures. We outline a modified figure of merit reducing thickness-dependent errors, as well as how modern ab initio screening methods can be used to augment experimental methods to assess new materials for potential applications as p-type TCOs, p-channel transparent thin film transistors, and selective contacts in solar cells.

Decoupling the refractive index from the electrical properties of transparent conducting oxides via periodic superlattices.

We demonstrate an alternative approach to tuning the refractive index of materials. Current methodologies for tuning the refractive index of a material often result in undesirable changes to the structural or optoelectronic properties. By artificially layering a transparent conducting oxide with a lower refractive index material the overall film retains a desirable conductivity and mobility while acting optically as an effective medium with a modified refractive index. Calculations indicate that, with our refractive index change of 0.2, a significant reduction of reflective losses could be obtained by the utilisation of these structures in optoelectronic devices. Beyond this, periodic superlattice structures present a solution to decouple physical properties where the underlying electronic interaction is governed by different length scales.