Pathophysiology and therapeutic strategies for the treatment of traumatic brain injury: investigating the role of erythropoietin

Traumatic brain injury (TBI) is a leading cause of death and disability in the industrialised world, and predominantly strikes young people in the prime of their lives. Diffuse brain injury may derive from numerous mechanisms, such as rapid rotation, acceleration/deceleration of the head, or a traumatic impact, often resulting in diffuse axonal injury (DAI) which has been reported to occur in up to 70% of all TBI patients. Characterised by damage in the vulnerable white matter tracts of the brain, DAI is a debilitating injury that may often go unnoticed in imaging due to the lack of overt tissue damage. Patients who suffer DAI also frequently present with respiratory impairment due to associated chest injury, TBI-induced loss of respiratory control, or cerebral hypoperfusion, with this resulting in decreased oxygen flow to the brain (termed hypoxia) worsening outcomes for patients clinically. In order to elucidate the contribution of post-traumatic hypoxia in heightening neuropathology and prolonging recovery, this study employed a rat model of diffuse traumatic brain injury (TAI) both with and without post-traumatic hypoxia, with outcomes assessed spanning a behavioural to a cellular level to determine which aspects of injury were the most vulnerable to exacerbation by hypoxia. This study also sought to determine the ability of the potential neuroprotective drug erythropoietin (EPO) to ameliorate the deleterious consequences of TAI with and without hypoxia, with thorough investigation of EPO’s actions in alleviating behavioural and cognitive dysfunction, through to mitigating tissue and cellular damage, minimising inflammation, and examination of the intracellular signalling pathways used by EPO to confer neuroprotection. In this study, post-traumatic hypoxia was found to critically worsen axonal pathology, heighten neuroinflammation, and contribute to poor behavioural outcomes when compared to rats undergoing TAI alone. When administered EPO, rats subjected to the combination of TAI and hypoxia were found to have markedly improved behavioural and cognitive performance, attenuated white matter damage, striking resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammatory responses, with these results coinciding with enhanced expression of EPO’s cognate receptor EPOR. Fascinatingly, many of these changes occurred after a single injection of EPO, providing compelling evidence of EPO’s ability as a neuroprotective agent. Interestingly, few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO’s neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic

Pathophysiology and therapeutic strategies for the treatment of traumatic brain injury: investigating the role of erythropoietin

Traumatic brain injury (TBI) is a leading cause of death and disability in the industrialised world, and predominantly strikes young people in the prime of their lives. Diffuse brain injury may derive from numerous mechanisms, such as rapid rotation, acceleration/deceleration of the head, or a traumatic impact, often resulting in diffuse axonal injury (DAI) which has been reported to occur in up to 70% of all TBI patients. Characterised by damage in the vulnerable white matter tracts of the brain, DAI is a debilitating injury that may often go unnoticed in imaging due to the lack of overt tissue damage. Patients who suffer DAI also frequently present with respiratory impairment due to associated chest injury, TBI-induced loss of respiratory control, or cerebral hypoperfusion, with this resulting in decreased oxygen flow to the brain (termed hypoxia) worsening outcomes for patients clinically. In order to elucidate the contribution of post-traumatic hypoxia in heightening neuropathology and prolonging recovery, this study employed a rat model of diffuse traumatic brain injury (TAI) both with and without post-traumatic hypoxia, with outcomes assessed spanning a behavioural to a cellular level to determine which aspects of injury were the most vulnerable to exacerbation by hypoxia. This study also sought to determine the ability of the potential neuroprotective drug erythropoietin (EPO) to ameliorate the deleterious consequences of TAI with and without hypoxia, with thorough investigation of EPO’s actions in alleviating behavioural and cognitive dysfunction, through to mitigating tissue and cellular damage, minimising inflammation, and examination of the intracellular signalling pathways used by EPO to confer neuroprotection. In this study, post-traumatic hypoxia was found to critically worsen axonal pathology, heighten neuroinflammation, and contribute to poor behavioural outcomes when compared to rats undergoing TAI alone. When administered EPO, rats subjected to the combination of TAI and hypoxia were found to have markedly improved behavioural and cognitive performance, attenuated white matter damage, striking resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammatory responses, with these results coinciding with enhanced expression of EPO’s cognate receptor EPOR. Fascinatingly, many of these changes occurred after a single injection of EPO, providing compelling evidence of EPO’s ability as a neuroprotective agent. Interestingly, few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO’s neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic

Guilty Molecules, Guilty Minds? The Conflicting Roles of the Innate Immune Response to Traumatic Brain Injury

Traumatic brain injury (TBI) is a complex disease in the most complex organ of the body, whose victims endure lifelong debilitating physical, emotional, and psychosocial consequences. Despite advances in clinical care, there is no effective neuroprotective therapy for TBI, with almost every compound showing promise experimentally having disappointing results in the clinic. The complex and highly interrelated innate immune responses govern both the beneficial and deleterious molecular consequences of TBI and are present as an attractive therapeutic target. This paper discusses the positive, negative, and often conflicting roles of the innate immune response to TBI in both an experimental and clinical settings and highlights recent advances in the search for therapeutic candidates for the treatment of TBI

Genomic reconstruction of the SARS-CoV-2 epidemic in England

AbstractThe evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.</jats:p

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Critical care admission following elective surgery was not associated with survival benefit: prospective analysis of data from 27 countries

This was an investigator initiated study funded by Nestle Health Sciences through an unrestricted research grant, and by a National Institute for Health Research (UK) Professorship held by RP. The study was sponsored by Queen Mary University of London