All Publications


  • Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses. Brain : a journal of neurology Needham, E. J., Ren, A. L., Digby, R. J., Norton, E. J., Ebrahimi, S., Outtrim, J. G., Chatfield, D. A., Manktelow, A. E., Leibowitz, M. M., Newcombe, V. F., Doffinger, R., Barcenas-Morales, G., Fonseca, C., Taussig, M. J., Burnstein, R. M., Samanta, R. J., Dunai, C., Sithole, N., Ashton, N. J., Zetterberg, H., Gisslén, M., Edén, A., Marklund, E., Openshaw, P. J., Dunning, J., Griffiths, M. J., Cavanagh, J., Breen, G., Irani, S. R., Elmer, A., Kingston, N., Summers, C., Bradley, J. R., Taams, L. S., Michael, B. D., Bullmore, E. T., Smith, K. G., Lyons, P. A., Coles, A. J., Menon, D. K. 2022

    Abstract

    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 hospitalisation, 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 characterised 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.

    View details for DOI 10.1093/brain/awac321

    View details for PubMedID 36065116

  • Immunometabolism, a new therapeutic development for immunotherapies of high-grade gliomas: a narrative review. Chinese clinical oncology Wu, J. Y., Ren, A. L., Lim, M. 2022; 11 (4): 26

    Abstract

    Immunotherapy has yielded significant improvements in survival for many cancer types, but its impact on glioblastoma (GBM) has been relatively muted. There is a growing interest in understanding the role of cancer metabolism and its role in tumor growth and therapeutic response. Thus, it is equally important to consider the clinical implications of immune cell metabolism on cancer progression and implications for therapeutic development. Our objective is to present new developments in immunometabolic research that are relevant to immunotherapy development for high-grade gliomas.A literature search and review was conducted, regarding original research articles studying metabolic pathways of immune cells in high-grade gliomas. Searches were conducted in PubMed and Embase databases on May 15 and June 13, 2022. English-language original research articles were selected and prioritized based on their inclusion of findings related to metabolic changes in myeloid and lymphoid cells in the glioma tumor microenvironment.There are many metabolic mechanisms by which immune cells in high-grade gliomas, like GBM, contribute to tumor growth and persistence via immunosuppression and high therapeutic resistance. There are also several ways that metabolic optimization has already been shown to improve immunotherapies already in clinical trials or in use, including dendritic cell vaccines and chimeric antigen receptor T cells.The implications of immunometabolic research presented here should be taken into consideration in future research and immunotherapy development of high-grade gliomas for our best chances at improving patient survival.

    View details for DOI 10.21037/cco-22-58

    View details for PubMedID 36098097

  • Health Care Resource Utilization in Management of Opioid-Naive Patients With Newly Diagnosed Neck Pain. JAMA network open Jin, M. C., Jensen, M., Zhou, Z., Rodrigues, A., Ren, A., Barros Guinle, M. I., Veeravagu, A., Zygourakis, C. C., Desai, A. M., Ratliff, J. K. 2022; 5 (7): e2222062

    Abstract

    Importance: Research has uncovered heterogeneity and inefficiencies in the management of idiopathic low back pain, but few studies have examined longitudinal care patterns following newly diagnosed neck pain.Objective: To understand health care utilization in patients with new-onset idiopathic neck pain.Design, Setting, and Participants: This cross-sectional study used nationally sourced longitudinal data from the IBM Watson Health MarketScan claims database (2007-2016). Participants included adult patients with newly diagnosed neck pain, no recent opioid use, and at least 1 year of continuous postdiagnosis follow-up. Exclusion criteria included prior or concomitant diagnosis of traumatic cervical disc dislocation, vertebral fractures, myelopathy, and/or cancer. Only patients with at least 1 year of prediagnosis lookback were included. Data analysis was performed from January 2021 to January 2022.Main Outcomes and Measures: The primary outcome of interest was 1-year postdiagnosis health care expenditures, including costs, opioid use, and health care service utilization. Early services were those received within 30 days of diagnosis. Multivariable regression models and regression-adjusted statistics were used.Results: In total, 679 030 patients (310 665 men [45.6%]) met the inclusion criteria, of whom 7858 (1.2%) underwent surgery within 1 year of diagnosis. The mean (SD) age was 44.62 (14.87) years among nonsurgical patients and 49.69 (9.53) years among surgical patients. Adjusting for demographics and comorbidities, 1-year regression-adjusted health care costs were $24 267.55 per surgical patient and $515.69 per nonsurgical patient. Across all health care services, $95 379 949 was accounted for by nonsurgical patients undergoing early imaging who did not receive any additional conservative therapy or epidural steroid injections, for a mean (SD) of $477.53 ($1375.60) per patient and median (IQR) of $120.60 ($20.70-$452.37) per patient. On average, patients not undergoing surgery, physical therapy, chiropractic manipulative therapy, or epidural steroid injection, who underwent either early advanced imaging (magnetic resonance imaging or computed tomography) or both early advanced and radiographic imaging, accumulated significantly elevated health care costs ($850.69 and $1181.67, respectively). Early conservative therapy was independently associated with 24.8% (95% CI, 23.5%-26.2%) lower health care costs.Conclusions and Relevance: In this cross-sectional study, early imaging without subsequent intervention was associated with significantly increased health care spending among patients with newly diagnosed idiopathic neck pain. Early conservative therapy was associated with lower costs, even with increased frequency of therapeutic services, and may have reduced long-term care inefficiency.

    View details for DOI 10.1001/jamanetworkopen.2022.22062

    View details for PubMedID 35816312

  • Neurological update: COVID-19. Journal of neurology Ren, A. L., Digby, R. J., Needham, E. J. 2021; 268 (11): 4379-4387

    Abstract

    Coronavirus Disease 2019 is predominantly a disorder of the respiratory system, but neurological complications have been recognised since early in the pandemic. The major pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease, immunologically mediated neurological disorders and the detrimental effects of critical illness on the nervous system. It is still unclear whether direct invasion of the nervous system by the Severe Acute Respiratory Syndrome Coronavirus 2 occurs; given the vast numbers of people infected at this point, this uncertainty suggests that nervous system infection is unlikely to represent a significant issue if it occurs at all. In this review, we explore what has been learnt about the neurological complications of COVID-19 over the course of the pandemic, and by which mechanisms these complications most commonly occur.

    View details for DOI 10.1007/s00415-021-10581-y

    View details for PubMedID 33929617

    View details for PubMedCentralID PMC8085652