Post-traumatic hypoxia exacerbates neurological deficit, neuroinflammation and cerebral metabolism in rats with diffuse traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. In this study, we investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Rats were examined for behavioral and sensorimotor deficits, increased brain production of inflammatory cytokines, formation of cerebral edema, changes in brain metabolism and enlargement of the lateral ventricles.</p> <p>Methods</p> <p>Adult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O₂/88% N₂) or normoxic (22% O₂/78% N₂) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique.</p> <p>Results</p> <p>TAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels.</p> <p>Conclusion</p> <p>Altogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction.</p

Concussion-Related Biomarker Variations in Retired Rugby Players and Implications for Neurodegenerative Disease Risk: The UK Rugby Health Study

The health and well-being of retired rugby union and league players, particularly regarding the long-term effects of concussions, are of major concern. Concussion has been identified as a major risk factor for neurodegenerative diseases, such as Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS), in athletes engaged in contact sports. This study aimed to assess differences in specific biomarkers between UK-based retired rugby players with a history of concussion and a non-contact sports group, focusing on biomarkers associated with Alzheimer’s, ALS, and CTE. We randomly selected a sample of male retired rugby or non-contact sport athletes (n = 56). The mean age was 41.84 ± 6.44, and the mean years since retirement from the sport was 7.76 ± 6.69 for participants with a history of substantial concussions (>5 concussions in their career) (n = 30). The mean age was 45.75 ± 11.52, and the mean years since retirement was 6.75 ± 4.64 for the healthy controls (n = 26). Serum biomarkers (t-tau, RBP-4, SAA, Nf-L, and retinol), plasma cytokines, and biomarkers associated with serum-derived exosomes (Aβ42, p-tau181, p-tau217, and p-tau231) were analyzed using validated commercial ELISA assays. The results of the selected biomarkers were compared between the two groups. Biomarkers including t-tau and p-tau181 were significantly elevated in the history of the substantial concussion group compared to the non-contact sports group (t-tau: p < 0.01; p-tau181: p < 0.05). Although between-group differences in p-tau217, p-tau231, SAA, Nf-L, retinol, and Aβ42 were not significantly different, there was a trend for higher levels of Aβ42, p-tau217, and p-tau231 in the concussed group. Interestingly, the serum-derived exosome sizes were significantly larger (p < 0.01), and serum RBP-4 levels were significantly reduced (p < 0.05) in the highly concussed group. These findings indicate that retired athletes with a history of multiple concussions during their careers have altered serum measurements of exosome size, t-tau, p-tau181, and RBP-4. These biomarkers should be explored further for the prediction of future neurodegenerative outcomes, including ALS, in those with a history of concussion

Global, regional, and national estimates of the population at increased risk of severe COVID-19 due to underlying health conditions in 2020: a modelling study

Background: The risk of severe COVID-19 if an individual becomes infected is known to be higher in older individuals and those with underlying health conditions. Understanding the number of individuals at increased risk of severe COVID-19 and how this varies between countries should inform the design of possible strategies to shield or vaccinate those at highest risk. Methods: We estimated the number of individuals at increased risk of severe disease (defined as those with at least one condition listed as “at increased risk of severe COVID-19” in current guidelines) by age (5-year age groups), sex, and country for 188 countries using prevalence data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 and UN population estimates for 2020. The list of underlying conditions relevant to COVID-19 was determined by mapping the conditions listed in GBD 2017 to those listed in guidelines published by WHO and public health agencies in the UK and the USA. We analysed data from two large multimorbidity studies to determine appropriate adjustment factors for clustering and multimorbidity. To help interpretation of the degree of risk among those at increased risk, we also estimated the number of individuals at high risk (defined as those that would require hospital admission if infected) using age-specific infection–hospitalisation ratios for COVID-19 estimated for mainland China and making adjustments to reflect country-specific differences in the prevalence of underlying conditions and frailty. We assumed males were twice at likely as females to be at high risk. We also calculated the number of individuals without an underlying condition that could be considered at increased risk because of their age, using minimum ages from 50 to 70 years. We generated uncertainty intervals (UIs) for our estimates by running low and high scenarios using the lower and upper 95% confidence limits for country population size, disease prevalences, multimorbidity fractions, and infection–hospitalisation ratios, and plausible low and high estimates for the degree of clustering, informed by multimorbidity studies. Findings: We estimated that 1·7 billion (UI 1·0–2·4) people, comprising 22% (UI 15–28) of the global population, have at least one underlying condition that puts them at increased risk of severe COVID-19 if infected (ranging from &lt;5% of those younger than 20 years to &gt;66% of those aged 70 years or older). We estimated that 349 million (186–787) people (4% [3–9] of the global population) are at high risk of severe COVID-19 and would require hospital admission if infected (ranging from &lt;1% of those younger than 20 years to approximately 20% of those aged 70 years or older). We estimated 6% (3–12) of males to be at high risk compared with 3% (2–7) of females. The share of the population at increased risk was highest in countries with older populations, African countries with high HIV/AIDS prevalence, and small island nations with high diabetes prevalence. Estimates of the number of individuals at increased risk were most sensitive to the prevalence of chronic kidney disease, diabetes, cardiovascular disease, and chronic respiratory disease. Interpretation: About one in five individuals worldwide could be at increased risk of severe COVID-19, should they become infected, due to underlying health conditions, but this risk varies considerably by age. Our estimates are uncertain, and focus on underlying conditions rather than other risk factors such as ethnicity, socioeconomic deprivation, and obesity, but provide a starting point for considering the number of individuals that might need to be shielded or vaccinated as the global pandemic unfolds. Funding: UK Department for International Development, Wellcome Trust, Health Data Research UK, Medical Research Council, and National Institute for Health Research

Practical considerations for measuring the effective reproductive number, Rt.

Estimation of the effective reproductive number Rt is important for detecting changes in disease transmission over time. During the Coronavirus Disease 2019 (COVID-19) pandemic, policy makers and public health officials are using Rt to assess the effectiveness of interventions and to inform policy. However, estimation of Rt from available data presents several challenges, with critical implications for the interpretation of the course of the pandemic. The purpose of this document is to summarize these challenges, illustrate them with examples from synthetic data, and, where possible, make recommendations. For near real-time estimation of Rt, we recommend the approach of Cori and colleagues, which uses data from before time t and empirical estimates of the distribution of time between infections. Methods that require data from after time t, such as Wallinga and Teunis, are conceptually and methodologically less suited for near real-time estimation, but may be appropriate for retrospective analyses of how individuals infected at different time points contributed to the spread. We advise caution when using methods derived from the approach of Bettencourt and Ribeiro, as the resulting Rt estimates may be biased if the underlying structural assumptions are not met. Two key challenges common to all approaches are accurate specification of the generation interval and reconstruction of the time series of new infections from observations occurring long after the moment of transmission. Naive approaches for dealing with observation delays, such as subtracting delays sampled from a distribution, can introduce bias. We provide suggestions for how to mitigate this and other technical challenges and highlight open problems in Rt estimation

Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery A Randomized Clinical Trial and Systematic Review

Importance: small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm.Objective: to evaluate the clinical effectiveness of a perioperative, cardiac output–guided hemodynamic therapy algorithm.Design, setting, and participants: OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014.Interventions: patients were randomly assigned to a cardiac output–guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366).Main outcomes and measures: the primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care–free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay.Results: baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, ?0.3% to 13.9%]; P?=?.07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]).Conclusions and relevance: in a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output–guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rate

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

Blast-Induced Neurotrauma Results in Spatially Distinct Gray Matter Alteration Alongside Hormonal Alteration: A Preliminary Investigation

Blast-induced neurotrauma (BINT) frequently occurs during military training and deployment and has been linked to long-term neuropsychological and neurocognitive changes, and changes in brain structure. As military personnel experience frequent exposures to stress, BINT may negatively influence stress coping abilities. This study aimed to determine the effects of BINT on gray matter volume and hormonal alteration. Participants were Canadian Armed Forces personnel and veterans with a history of BINT (n = 12), and first responder controls (n = 8), recruited due to their characteristic occupational stress professions. Whole saliva was collected via passive drool on the morning of testing and analyzed for testosterone (pg/mL), cortisol (μg/dL), and testosterone/cortisol (T/C) ratio. Voxel-based morphometry was performed to compare gray matter (GM) volume, alongside measurement of cortical thickness and subcortical volumes. Saliva analyses revealed distinct alterations following BINT, with significantly elevated testosterone and T/C ratio. Widespread and largely symmetric loci of reduced GM were found specific to BINT, particularly in the temporal gyrus, precuneus, and thalamus. These findings suggest that BINT affects hypothalamic-pituitary-adrenal and -gonadal axis function, and causes anatomically-specific GM loss, which were not observed in a comparator group with similar occupational stressors. These findings support BINT as a unique injury with distinct structural and endocrine consequences

Blast-Induced Neurotrauma Results in Spatially Distinct Gray Matter Alteration Alongside Hormonal Alteration: A Preliminary Investigation

Blast-induced neurotrauma (BINT) frequently occurs during military training and deployment and has been linked to long-term neuropsychological and neurocognitive changes, and changes in brain structure. As military personnel experience frequent exposures to stress, BINT may negatively influence stress coping abilities. This study aimed to determine the effects of BINT on gray matter volume and hormonal alteration. Participants were Canadian Armed Forces personnel and veterans with a history of BINT (n = 12), and first responder controls (n = 8), recruited due to their characteristic occupational stress professions. Whole saliva was collected via passive drool on the morning of testing and analyzed for testosterone (pg/mL), cortisol (μg/dL), and testosterone/cortisol (T/C) ratio. Voxel-based morphometry was performed to compare gray matter (GM) volume, alongside measurement of cortical thickness and subcortical volumes. Saliva analyses revealed distinct alterations following BINT, with significantly elevated testosterone and T/C ratio. Widespread and largely symmetric loci of reduced GM were found specific to BINT, particularly in the temporal gyrus, precuneus, and thalamus. These findings suggest that BINT affects hypothalamic–pituitary–adrenal and –gonadal axis function, and causes anatomically-specific GM loss, which were not observed in a comparator group with similar occupational stressors. These findings support BINT as a unique injury with distinct structural and endocrine consequences