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1.	Leifsdottir, Kristin, et al. (author) The cerebrospinal fluid proteome of preterm infants predicts neurodevelopmental outcome 2022 In: Frontiers in Pediatrics. - : Frontiers Media SA. - 2296-2360. ; 10 Journal article (peer-reviewed)abstract BackgroundSurvival rate increases for preterm infants, but long-term neurodevelopmental outcome predictors are lacking. Our primary aim was to determine whether a specific proteomic profile in cerebrospinal fluid (CSF) of preterm infants differs from that of term infants and to identify novel biomarkers of neurodevelopmental outcome in preterm infants. MethodsTwenty-seven preterm infants with median gestational age 27 w + 4 d and ten full-term infants were enrolled prospectively. Protein profiling of CSF were performed utilizing an antibody suspension bead array. The relative levels of 178 unique brain derived proteins and inflammatory mediators, selected from the Human Protein Atlas, were measured. ResultsThe CSF protein profile of preterm infants differed from that of term infants. Increased levels of brain specific proteins that are associated with neurodevelopment and neuroinflammatory pathways made up a distinct protein profile in the preterm infants. The most significant differences were seen in proteins involved in neurodevelopmental regulation and synaptic plasticity, as well as components of the innate immune system. Several proteins correlated with favorable outcome in preterm infants at 18-24 months corrected age. Among the proteins that provided strong predictors of outcome were vascular endothelial growth factor C, Neurocan core protein and seizure protein 6, all highly important in normal brain development. ConclusionOur data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome.
2.	Ahl, Rebecka, 1987-, et al. (author) β-Blocker after severe traumatic brain injury is associated with better long-term functional outcome : a matched case control study 2017 In: European Journal of Trauma and Emergency Surgery. - : Springer Berlin/Heidelberg. - 1863-9933 .- 1863-9941. ; 43:6, s. 783-789 Journal article (peer-reviewed)abstract PURPOSE: Severe traumatic brain injury (TBI) is the predominant cause of death and disability following trauma. Several studies have observed improved survival in TBI patients exposed to β-blockers, however, the effect on functional outcome is poorly documented.METHODS: Adult patients with severe TBI (head AIS ≥ 3) were identified from a prospectively collected TBI database over a 5-year period. Patients with neurosurgical ICU length of stay <48 h and those dying within 48 h of admission were excluded. Patients exposed to β-blockers ≤ 48 h after admission and who continued with treatment until discharge constituted β-blocked cases and were matched to non β-blocked controls using propensity score matching. The outcome of interest was Glasgow Outcome Scores (GOS), as a measure of functional outcome up to 12 months after injury. GOS ≤ 3 was considered a poor outcome. Bivariate analysis was deployed to determine differences between groups. Odds ratio and 95% CI were used to assess the effect of β-blockers on GOS.RESULTS: 362 patients met the inclusion criteria with 21% receiving β-blockers during admission. After propensity matching, 76 matched pairs were available for analysis. There were no statistical differences in any variables included in the analysis. Mean hospital length of stay was shorter in the β-blocked cases (18.0 vs. 26.8 days, p < 0.01). The risk of poor long-term functional outcome was more than doubled in non-β-blocked controls (OR 2.44, 95% CI 1.01-6.03, p = 0.03).CONCLUSION: Exposure to β-blockers in patients with severe TBI appears to improve functional outcome. Further prospective randomized trials are warranted.
3.	Al Nimer, Faiez, et al. (author) Comparative Assessment of the Prognostic Value of Biomarkers in Traumatic Brain Injury Reveals an Independent Role for Serum Levels of Neurofilament Light 2015 In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7 Journal article (peer-reviewed)abstract Traumatic brain injury (TBI) is a common cause of death and disability, worldwide. Early determination of injury severity is essential to improve care. Neurofilament light (NF-L) has been introduced as a marker of neuroaxonal injury in neuroinflammatory/-degenerative diseases. In this study we determined the predictive power of serum (s-) and cerebrospinal fluid (CSF-) NF-L levels towards outcome, and explored their potential correlation to diffuse axonal injury (DAI). A total of 182 patients suffering from TBI admitted to the neurointensive care unit at a level 1 trauma center were included. S-NF-L levels were acquired, together with S100B and neuron-specific enolase (NSE). CSF-NF-L was measured in a subcohort (n = 84) with ventriculostomies. Clinical and neuro-radiological parameters, including computerized tomography (CT) and magnetic resonance imaging, were included in the analyses. Outcome was assessed 6 to 12 months after injury using the Glasgow Outcome Score (1-5). In univariate proportional odds analyses mean s-NF-L, -S100B and -NSE levels presented a pseudo-R-2 Nagelkerke of 0.062, 0.214 and 0.074 in correlation to outcome, respectively. In a multivariate analysis, in addition to a model including core parameters (pseudo-R-2 0.33 towards outcome; Age, Glasgow Coma Scale, pupil response, Stockholm CT score, abbreviated injury severity score, S100B), S-NF-L yielded an extra 0.023 pseudo-R-2 and a significantly better model (p = 0.006) No correlation between DAI or CT assessed-intracranial damage and NF-L was found. Our study thus demonstrates that SNF-L correlates to TBI outcome, even if used in models with S100B, indicating an independent contribution to the prediction, perhaps by reflecting different pathophysiological processes, not possible to monitor using conventional neuroradiology. Although we did not find a predictive value of NF-L for DAI, this cannot be completely excluded. We suggest further
4.	Alam, Aftab, et al. (author) Modeling the Inflammatory Response of Traumatic Brain Injury Using Human Induced Pluripotent Stem Cell Derived Microglia 2023 In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 40:19-20, s. 2164-2173 Journal article (peer-reviewed)abstract The neuroinflammatory response after traumatic brain injury (TBI) is implicated as a key mediator of secondary injury in both the acute and chronic periods after primary injury. Microglia are the key innate immune cell in the central nervous system, responding to injury with the release of cytokines and chemokines. In this context, we aimed to characterize the downstream cytokine response of human induced pluripotent stem cell (iPSC)-derived microglia when stimulated with five separate cytokines identified after human TBI. The iPSC-derived microglia were exposed to interleukin (IL)-1 & beta;, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF) in the concentration ranges identified in clinical TBI studies. The downstream cytokine response was measured against a panel of 37 separate cytokines over a 72h time-course. The secretome revealed concentration-, time- and combined concentration and time-dependent downstream responses. TNF appeared to be the strongest inducer of downstream cytokine changes (51), followed by IL-1 & beta; (26) and IL-4 (19). IL-10 (11) and IL-6 (10) produced fewer responses. We also compare these responses with our previous studies of iPSC-derived neuronal and astrocyte cultures and the in vivo human TBI cytokine response. Notably, we found microglial culture to induce both a wider range of downstream cytokine responses and a greater fold change in concentration for those downstream responses, compared with astrocyte and neuronal cultures. In summary, we present a dataset for human microglial cytokine responses specific to the secretome found in the clinical context of TBI. This reductionist approach complements our previous datasets for astrocyte and neuronal responses and will provide a platform to enable future studies to unravel the complex neuroinflammatory network activated after TBI.
5.	Backman, Linda, et al. (author) Monthlong Intubated Patient with Life-Threatening COVID-19 and Cerebral Microbleeds Suffers Only Mild Cognitive Sequelae at 8-Month Follow-up : A Case Report 2022 In: Archives of clinical neuropsychology. - : Oxford University Press (OUP). - 0887-6177 .- 1873-5843. ; 37:2, s. 531-543 Journal article (peer-reviewed)abstract Objective: To elaborate on possible cognitive sequelae related to COVID-19, associated cerebrovascular injuries as well as the general consequences from intensive care. COVID-19 is known to have several, serious CNS-related consequences, but neuropsychological studies of severe COVID-19 are still rare.Methods: M., a 45-year-old man, who survived a severe COVID-19 disease course including Acute Respiratory Distress Syndrome (ARDS), cerebral microbleeds, and 35 days of mechanical ventilation, is described. We elaborate on M’s recovery and rehabilitation process from onset to the 8-month follow-up. The cognitive functions were evaluated with a comprehensive screening battery at 4 weeks after extubation and at the 8-month follow-up.Results: Following extubation, M. was delirious, reported visual hallucinations, and had severe sleeping difficulties. At about 3 months after COVID-19 onset, M. showed mild to moderate deficits on tests measuring processing speed, working memory, and attention. At assessments at 8 months, M. performed better, with results above average on tests measuring learning, memory, word fluency, and visuospatial functions. Minor deficits were still found regarding logical reasoning, attention, executive functioning, and processing speed. There were no lingering psychiatric symptoms. While M. had returned to a part-time job, he was not able to resume previous work-tasks.Conclusion: This case-study demonstrates possible cognitive deficits after severe COVID-19 and emphasizes the need of a neuropsychological follow-up, with tests sensitive to minor deficits. The main findings of this report provide some support that the long-term prognosis for cognition in severe COVID-19 may be hopeful.
6.	Darelid, Johan, et al. (author) An outbreak of Legionnaires’ Disease in a Swedish Hospital 1994 In: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 26:4, s. 417-425 Journal article (peer-reviewed)abstract We report a nosocomial outbreak of Legionella pneumophila serogroup (sg) 1 infection at the general hospital, Värnamo, Sweden. From December 1990 to February 1991, 28 patients and 3 staff fell ill with pneumonia and 3 died. L. pneumophila sg 1 together with several other Legionellae were isolated from the hot water supply to 17 of 20 hospital wards, probably being spread by aerosolization via shower nozzles. Raising the hospital's hot water temperature from 45°C to 65°C, together with heat disinfection of the shower equipment, arrested the outbreak within a week. Keeping the hot water temperature < 60°C without chlorination eliminated L. pneumophila from < 75% of the wards. During a period of 2 years after the outbreak we have diagnosed only 1 case of nosocomial legionellosis at the hospital despite an active surveillance program.
7.	Fletcher-Sandersjoo, Alexander, et al. (author) Stockholm score of lesion detection on computed tomography following mild traumatic brain injury (SELECT-TBI) : study protocol for a multicentre, retrospective, observational cohort study 2022 In: BMJ Open. - : BMJ. - 2044-6055. ; 12:9 Journal article (peer-reviewed)abstract Introduction Mild traumatic brain injury (mTBI) is one of the most common reasons for emergency department (ED) visits. A portion of patients with mTBI will develop an intracranial lesion that might require medical or surgical intervention. In these patients, swift diagnosis and management is paramount. Several guidelines have been developed to help direct patients with mTBI for head CT scanning, but they lack specificity, do not consider the interactions between risk factors and do not provide an individualised estimate of intracranial lesion risk. The aim of this study is to create a model that estimates individualised intracranial lesion risks in patients with mTBI who present to the ED. Methods and analysis This will be a retrospective cohort study conducted at ED hospitals in Stockholm, Sweden. Eligible patients are adults (>= 15 years) with mTBI who presented to the ED within 24 hours of injury and performed a CT scan. The primary outcome will be a traumatic lesion on head CT. The secondary outcomes will be any clinically significant lesion, defined as an intracranial finding that led to neurosurgical intervention, hospital admission >= 48 hours due to TBI or death due to TBI. Machine-learning models will be applied to create scores predicting the primary and secondary outcomes. An estimated 20 000 patients will be included. Ethics and dissemination The study has been approved by the Swedish Ethical Review Authority (Dnr: 2020-05728). The research findings will be disseminated through peer-reviewed scientific publications and presentations at international conferences.
8.	Fletcher-Sandersjöö, Alexander, et al. (author) Absolute Contusion Expansion Is Superior to Relative Expansion in Predicting Traumatic Brain Injury Outcomes : A Multi-Center Observational Cohort Study 2024 In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 41:5-6, s. 705-713 Journal article (peer-reviewed)abstract Contusion expansion (CE) is a potentially treatable outcome predictor in traumatic brain injury (TBI), and a suitable end-point for hemostatic therapy trials. However, there is no consensus on the definition of clinically relevant CE, both in terms of measurement criteria (absolute vs. relative volume increase) and cutoff values. In light of this, the aim of this study was to assess the predictive abilities of different CE definitions on outcome. We performed a multi-center observational cohort study of adults with moderate-to-severe TBI treated in an intensive care unit. The exposure of interest was CE, defined as the absolute and relative volume change between the first and second computed tomography scan. The primary outcome was the Glasgow Outcome Scale (GOS) at 6–12 months post-injury, dichotomized into unfavorable (GOS ≤3) or favorable (GOS ≥4). The secondary outcome was all-cause mortality. In total, 798 patients were included, with a median duration of 7.0 h between the first and second CT scan. The median absolute and relative CE was 1.5 mL (interquartile range [IQR] 0.1–8.3 mL) and 100% (IQR 10–530%), respectively. Both CE forms were independently associated with unfavorable GOS. Absolute CE outperformed relative CE in predicting both unfavorable GOS (area under the curve [AUC]: 0.65 vs. 0.60, p = 0.002) and all-cause mortality (AUC: 0.66 vs. 0.60, p = 0.003). For dichotomized CE, absolute cutoffs of 1–10 mL yielded the best results. We conclude that absolute CE demonstrates stronger outcome correlation than relative CE. In studies focusing on lesion progression in TBI, it may be advantageous to use absolute CE as the primary outcome metric. For dichotomized outcomes, cutoffs between 1 and 10 mL are suggested, depending on the desired sensitivity-specificity balance.
9.	Forssten, Maximilian Peter, 1996-, et al. (author) The Role of Glycerol-Containing Drugs in Cerebral Microdialysis : A Retrospective Study on the Effects of Intravenously Administered Glycerol 2019 In: Neurocritical Care. - : Humana Press. - 1541-6933 .- 1556-0961. ; 30:3, s. 590-600 Journal article (peer-reviewed)abstract BACKGROUND: Cerebral microdialysis (CMD) is a valuable tool for monitoring compounds in the cerebral extracellular fluid (ECF). Glycerol is one such compound which is regarded as a marker of cell membrane decomposition. Notably, in some acutely brain-injured patients, CMD-glycerol levels rise without any other apparent indication of cerebral deterioration. The aim of this study was to investigate whether this could be due to an association between CMD-glycerol levels and the administration of glycerol-containing drugs.METHODS: Microdialysis data were retrospectively retrieved from the hospital's intensive care unit patient data management system (PDMS). All patients who were monitored with CMD for ≥ 96 h were included. Administered drug doses were retrieved from the PDMS and converted to exact doses of glycerol. Cross-correlation analyses were performed between the free, metabolized as well as total administered dose of glycerol and the detrended and differenced CMD-glycerol concentration. These analyses were repeated for two sets of subgroups based upon the individual catheter's graphical trend and its location in relation to the lesion.RESULTS: There was no significant correlation between the differenced CMD-glycerol levels and drug-administered glycerol. Furthermore, there was no significant correlation between CMD-glycerol and catheter location or graphical trend. However, if the CMD-glycerol levels were detrended, significant but clinically non-relevant correlations were identified (maximum correlation coefficient of 0.1 (0.04-0.15, 95% CI) at a lag of 7 h using the total administered dose of glycerol).CONCLUSIONS: Glycerol-containing drugs routinely administered intravenously in the clinical setting appear to have a minimal and clinically insignificant effect on levels of glycerol in the cerebral ECF.
10.	Froese, Logan, et al. (author) The impact of sedative and vasopressor agents on cerebrovascular reactivity in severe traumatic brain injury 2023 In: Intensive Care Medicine Experimental. - : Springer. - 2197-425X. ; 11 Journal article (peer-reviewed)abstract Background: The aim of this study is to evaluate the impact of commonly administered sedatives (Propofol, Alfentanil, Fentanyl, and Midazolam) and vasopressor (Dobutamine, Ephedrine, Noradrenaline and Vasopressin) agents on cerebrovascular reactivity in moderate/severe TBI patients. Cerebrovascular reactivity, as a surrogate for cerebral autoregulation was assessed using the long pressure reactivity index (LPRx). We evaluated the data in two phases, first we assessed the minute-by-minute data relationships between different dosing amounts of continuous infusion agents and physiological variables using boxplots, multiple linear regression and ANOVA. Next, we assessed the relationship between continuous/bolus infusion agents and physiological variables, assessing pre-/post- dose of medication change in physiology using a Wilcoxon signed-ranked test. Finally, we evaluated sub-groups of data for each individual dose change per medication, focusing on key physiological thresholds and demographics.Results: Of the 475 patients with an average stay of 10 days resulting in over 3000 days of recorded information 367 (77.3%) were male with a median Glasgow coma score of 7 (4-9). The results of this retrospective observational study confirmed that the infusion of most administered agents do not impact cerebrovascular reactivity, which is confirmed by the multiple linear regression components having p value > 0.05. Incremental dose changes or bolus doses in these medications in general do not lead to significant changes in cerebrovascular reactivity (confirm by Wilcoxon signed-ranked p value > 0.05 for nearly all assessed relationships). Within the sub-group analysis that separated the data based on LPRx pre-dose, a significance between pre-/post-drug change in LPRx was seen, however this may be more of a result from patient state than drug impact.Conclusions: Overall, this study indicates that commonly administered agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity in TBI (nor do they impair cerebrovascular reactivity). Though further investigation in a larger and more diverse TBI patient population is required.
11.	Kiwanuka, Olivia, et al. (author) Long-term health-related quality of life after trauma with and without traumatic brain injury : a prospective cohort study 2023 In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1 Journal article (peer-reviewed)abstract To purpose was to assess and compare the health-related quality of life (HRQoL) and risk of depression two years after trauma, between patients with and without traumatic brain injury (TBI) in a mixed Swedish trauma cohort. In this prospective cohort study, TBI and non-TBI trauma patients included in the Swedish Trauma registry 2019 at a level II trauma center in Stockholm, Sweden, were contacted two years after admission. HRQoL was assessed with RAND-36 and EQ-5D-3L, and depression with Montgomery Åsberg depression Rating Scale self-report (MADRS-S). Abbreviated Injury Score (AIS) head was used to grade TBI severity, and American Society of Anesthesiologists (ASA) score was used to assess comorbidities. Data were compared using Chi-squared test, Mann Whitney U test and ordered logistic regression, and Bonferroni correction was applied. A total of 170 of 737 eligible patients were included. TBI was associated with higher scores in 5/8 domains of RAND-36 and 3/5 domains of EQ-5D (p < 0.05). No significant difference in MADRS-S. An AIS (head) of three or higher was associated with lower scores in five domains of RAND-36 and two domains of EQ-5D but not for MADRS-S. An ASA-score of three was associated with lower scores in all domains of both RAND-36 (p < 0.05, except mental health) and EQ-5D (p < 0.001, except anxiety/depression), but not for MADRS-S. In conclusion, patients without TBI reported a lower HRQoL than TBI patients two years after trauma. TBI severity assessed according to AIS (head) was associated with HRQoL, and ASA-score was found to be a predictor of HRQoL, emphasizing the importance of considering pre-injury health status when assessing outcomes in TBI patients.
12.	Lindblad, Caroline, et al. (author) Current state of high-fidelity multimodal monitoring in traumatic brain injury 2022 In: Acta Neurochirurgica. - : Springer Nature. - 0001-6268 .- 0942-0940. ; 164:12, s. 3091-3100 Research review (peer-reviewed)abstract Introduction Multimodality monitoring of patients with severe traumatic brain injury (TBI) is primarily performed in neurocritical care units to prevent secondary harmful brain insults and facilitate patient recovery. Several metrics are commonly monitored using both invasive and non-invasive techniques. The latest Brain Trauma Foundation guidelines from 2016 provide recommendations and thresholds for some of these. Still, high-level evidence for several metrics and thresholds is lacking. Methods Regarding invasive brain monitoring, intracranial pressure (ICP) forms the cornerstone, and pressures above 22 mmHg should be avoided. From ICP, cerebral perfusion pressure (CPP) (mean arterial pressure (MAP)-ICP) and pressure reactivity index (PRx) (a correlation between slow waves MAP and ICP as a surrogate for cerebrovascular reactivity) may be derived. In terms of regional monitoring, partial brain tissue oxygen pressure (PbtO(2)) is commonly used, and phase 3 studies are currently ongoing to determine its added effect to outcome together with ICP monitoring. Cerebral microdialysis (CMD) is another regional invasive modality to measure substances in the brain extracellular fluid. International consortiums have suggested thresholds and management strategies, in spite of lacking high-level evidence. Although invasive monitoring is generally safe, iatrogenic hemorrhages are reported in about 10% of cases, but these probably do not significantly affect long-term outcome. Non-invasive monitoring is relatively recent in the field of TBI care, and research is usually from single-center retrospective experiences. Near-infrared spectrometry (NIRS) measuring regional tissue saturation has been shown to be associated with outcome. Transcranial doppler (TCD) has several tentative utilities in TBI like measuring ICP and detecting vasospasm. Furthermore, serial sampling of biomarkers of brain injury in the blood can be used to detect secondary brain injury development. Conclusions In multimodal monitoring, the most important aspect is data interpretation, which requires knowledge of each metric's strengths and limitations. Combinations of several modalities might make it possible to discern specific pathologic states suitable for treatment. However, the cost-benefit should be considered as the incremental benefit of adding several metrics has a low level of evidence, thus warranting additional research.
13.	Lindblad, Caroline, et al. (author) Fluid proteomics of CSF and serum reveal important neuroinflammatory proteins in blood-brain barrier disruption and outcome prediction following severe traumatic brain injury : a prospective, observational study 2021 In: Critical Care. - : Springer Nature. - 1364-8535 .- 1466-609X. ; 25:1 Journal article (peer-reviewed)abstract Background: Severe traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption and a subsequent neuroinflammatory process. We aimed to perform a multiplex screening of brain enriched and inflammatory proteins in blood and cerebrospinal fluid (CSF) in order to study their role in BBB disruption, neuroinflammation and long-term functional outcome in TBI patients and healthy controls. Methods: We conducted a prospective, observational study on 90 severe TBI patients and 15 control subjects. Clinical outcome data, Glasgow Outcome Score, was collected after 6-12 months. We utilized a suspension bead antibody array analyzed on a FlexMap 3D Luminex platform to characterize 177 unique proteins in matched CSF and serum samples. In addition, we assessed BBB disruption using the CSF-serum albumin quotient (Q(A)), and performed Apolipoprotein E-genotyping as the latter has been linked to BBB function in the absence of trauma. We employed pathway-, cluster-, and proportional odds regression analyses. Key findings were validated in blood samples from an independent TBI cohort. Results: TBI patients had an upregulation of structural CNS and neuroinflammatory pathways in both CSF and serum. In total, 114 proteins correlated with Q(A), among which the top-correlated proteins were complement proteins. A cluster analysis revealed protein levels to be strongly associated with BBB integrity, but not carriage of the Apolipoprotein E4-variant. Among cluster-derived proteins, innate immune pathways were upregulated. Forty unique proteins emanated as novel independent predictors of clinical outcome, that individually explained similar to 10% additional model variance. Among proteins significantly different between TBI patients with intact or disrupted BBB, complement C9 in CSF (p = 0.014, Delta R-2 = 7.4%) and complement factor B in serum (p = 0.003, Delta R-2 = 9.2%) were independent outcome predictors also following step-down modelling. Conclusions: This represents the largest concomitant CSF and serum proteomic profiling study so far reported in TBI, providing substantial support to the notion that neuroinflammatory markers, including complement activation, predicts BBB disruption and long-term outcome. Individual proteins identified here could potentially serve to refine current biomarker modelling or represent novel treatment targets in severe TBI.
14.	Mohseni, Shahin, 1978-, et al. (author) The Effect of beta-blockade on Survival After Isolated Severe Traumatic Brain Injury 2015 In: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 39:8, s. 2076-2083 Journal article (peer-reviewed)abstract Several North American studies have observed survival benefit in patients exposed to beta-blockers following traumatic brain injury (TBI). The purpose of this study was to evaluate the effect of beta-blockade on mortality in a Swedish cohort of isolated severe TBI patients.The trauma registry of an urban academic trauma center was queried to identify patients with an isolated severe TBI between 1/2007 and 12/2011. Isolated severe TBI was defined as an intracranial injury with an Abbreviated Injury Scale (AIS) a parts per thousand yen3 excluding extra-cranial injuries AIS a parts per thousand yen3. Multivariable logistic regression analysis was used to determine the effect of beta-blocker exposure on mortality. Also, a subgroup analysis was performed to investigate the risk of mortality in patients on pre-admission beta-blocker versus not and the effect of specific type of beta-blocker on the overall outcome.Overall, 874 patients met the study criteria. Of these, 33 % (n = 287) were exposed to beta-blockers during their hospital admission. The exposed patients were older (62 +/- A 16 years vs. 49 +/- A 21 years, p < 0.001), and more severely injured based on their admission GCS, ISS, and head AIS scores (GCS a parts per thousand currency sign8: 32 % vs. 28 %, p = 0.007; ISS a parts per thousand yen16: 71 % vs. 59 %, p = 0.001; head AIS a parts per thousand yen4: 60 % vs. 45 %, p < 0.001). The crude mortality was higher in patients who did not receive beta-blockers (17 % vs. 11 %, p = 0.007) during their admission. After adjustment for significant confounders, the patients not exposed to beta-blockers had a 5-fold increased risk of in-hospital mortality (AOR 5.0, CI 95 % 2.7-8.5, p = 0.001). No difference in survival was noted in regards to the type of beta-blocker used. Subgroup analysis revealed a higher risk of mortality in patients naive to beta-blockers compared to those on pre-admission beta-blocker therapy (AOR 3.0 CI 95 % 1.2-7.1, p = 0.015).Beta-blocker exposure after isolated severe traumatic brain injury is associated with significantly improved survival. We also noted decreased mortality in patients on pre-admission beta-blocker therapy compared to patients naive to such treatment. Further prospective studies are warranted.
15.	Mondello, Stefania, et al. (author) Extracellular vesicles : pathogenetic, diagnostic and therapeutic value in traumatic brain injury 2018 In: Expert Review of Proteomics. - : Taylor & Francis. - 1478-9450 .- 1744-8387. ; 15:5, s. 451-461 Research review (peer-reviewed)abstract Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Accurate classification according to injury-specific and patient-specific characteristics is critical to help informed clinical decision-making and to the pursuit of precision medicine in TBI. Reliable biomarker signatures for improved TBI diagnostics are required but still an unmet need. Areas covered: Extracellular vesicles (EVs) represent a new class of biomarker candidates in TBI. These nano-sized vesicles have key roles in cell signaling profoundly impacting pathogenic pathways, progression and long-term sequelae of TBI. As such EVs might provide novel neurobiological insights, enhance our understanding of the molecular mechanisms underlying TBI pathophysiology and recovery, and serve as biomarker signatures and therapeutic targets and delivery systems. Expert commentary: EVs are fast gaining momentum in TBI research, paving the way for new transformative diagnostic and treatment approaches. Their potential to sort out TBI variability and active involvement in the mechanisms underpinning different clinical phenotypes point out unique opportunities for improved classification, risk-stratification ad intervention, harboring promise of predictive, personalized, and even preemptive therapeutic strategies. Although a great deal of progress has been made, substantial efforts are still required to ensure the needed rigorous validation and reproducibility for clinical implementation of EVs.
16.	Needham, Edward J, et al. (author) Complex Autoantibody Responses Occur following Moderate to Severe Traumatic Brain Injury. 2021 In: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 207:1, s. 90-100 Journal article (peer-reviewed)abstract Most of the variation in outcome following severe traumatic brain injury (TBI) remains unexplained by currently recognized prognostic factors. Neuroinflammation may account for some of this difference. We hypothesized that TBI generated variable autoantibody responses between individuals that would contribute to outcome. We developed a custom protein microarray to detect autoantibodies to both CNS and systemic Ags in serum from the acute-phase (the first 7 d), late (6-12 mo), and long-term (6-13 y) intervals after TBI in human patients. We identified two distinct patterns of immune response to TBI. The first was a broad response to the majority of Ags tested, predominantly IgM mediated in the acute phase, then IgG dominant at late and long-term time points. The second was responses to specific Ags, most frequently myelin-associated glycopeptide (MAG), which persisted for several months post-TBI but then subsequently resolved. Exploratory analyses suggested that patients with a greater acute IgM response experienced worse outcomes than predicted from current known risk factors, suggesting a direct or indirect role in worsening outcome. Furthermore, late persistence of anti-MAG IgM autoantibodies correlated with raised serum neurofilament light concentrations at these time points, suggesting an association with ongoing neurodegeneration over the first year postinjury. Our results show that autoantibody production occurs in some individuals following TBI, can persist for many years, and is associated with worse patient outcome. The complexity of responses means that conventional approaches based on measuring responses to single antigenic targets may be misleading.
17.	Olsson, Christian, et al. (author) No benefit of reduced heparinization in thoracic aortic operation with heparin-coated bypass circuits 2000 In: Annals of Thoracic Surgery. - 0003-4975 .- 1552-6259. ; 69:3, s. 743-749 Journal article (peer-reviewed)abstract BACKGROUND: Heparin coating of the cardiopulmonary bypass circuit attenuates inflammatory response and confer clinical benefits in cardiac operations. The positive effects may be amplified with reduced systemic heparin dosage. We studied markers of inflammation and coagulation in thoracic aortic operations with heparin-coated circuits and standard vs reduced systemic heparinization. METHODS: Thirty patients were randomized to standard (group S; 300 IU/kg initially; activated clotting times [ACT] > 480 seconds; 5,000 IU in prime; n = 16) or reduced (group R; 100 IU/kg initially; ACT > 250 seconds; 2,500 IU in prime; n = 14) dose systemic heparin. The following markers were analyzed perioperatively: (a) inflammatory response; acute phase cytokine interleukin-6, and granulocytic proteins myeloperoxidase and lactoferrin; (b) complement activation; factor C3a and the C5a-9 terminal complement complex [TCC]; and (c) coagulation; thrombin-antithrombin III complex. RESULTS: The clinical outcome did not differ between groups. Four (29%) patients in group R had a perioperative thromboembolic event. All studied markers were significantly elevated during and throughout cardiopulmonary bypass in both groups. Maximal values were higher in group R for all variables except for TCC. There were no statistically significant intergroup differences regarding markers of inflammation, complement activation, or coagulation activation. CONCLUSIONS: The blood trauma in thoracic aortic operation is extensive, as reflected by the elevation of the studied biochemical markers, even when heparin-coated cardiopulmonary bypass circuits are used. In this study, we did not detect any benefits, either biochemical or clinical, of reducing the dose of systemic heparin.
18.	Pietilä, Riikka, et al. (author) Molecular anatomy of adult mouse leptomeninges 2023 In: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 111:23 Journal article (peer-reviewed)abstract Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we iden-tify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arach-noid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
19.	Thelin, Eric (author) On biomarkers in traumatic brain injury 2015 Doctoral thesis (other academic/artistic)abstract Traumatic brain injury (TBI) is a common cause of death and disability. Unfortunately, TBI patients will be affected by secondary insults, such as hypoxia and increased intracranial pressure, which may lead to secondary brain injuries. Because of this, these patients are treated in specialized neuro-intensive care units (NICU) where the brain is monitored in order to prevent secondary lesion development. Cerebral monitoring is limited by its locality and more generalized markers to monitor the injured brain are warranted. Biomarkers have been introduced in the field of TBI, where they may be evaluated to examine potential pathophysiological processes. S100B, a primarily astrocytic protein, is the most studied serum biomarker in TBI, but other candidates exist. The aims of this thesis were to validate biomarkers toward long-term functional outcome, to evaluate the effect of biomarkers and a new global method of microdialysis in multimodal monitoring of NICU patients and in a translational methodology assess how biomarkers may facilitate in the damage analysis in a hypoxic-TBI animal model. In Paper I, a retrospective study including 265 NICU TBI patients, where S100B samples were acquired at admission and every 12 hours the first 48 hours after injury, we detected a significant, and independent, correlation between S100B levels and long-term functional outcome. The predictive capabilities increased sharply after 12 hours and remained high up to 36 hours after injury. S100B levels were only significantly correlated to pathology detected on computerized tomography (CT) and not to extracranial trauma. In Paper II, a retrospective study including 250 NICU TBI patients, we analyzed S100B samples acquired later than 48 hours after injury. We noted that secondary increases of S100B even as low as 0.05μg/L is sensitive and specific enough to detect radiological verified cerebral deteriorations, undetected by conventional monitoring. In Paper III, a prospective study including 14 NICU TBI patients, we monitored patients using microdialysis (MD) in flowing cerebrospinal fluid (CSF) for a more “global” overview of cerebral metabolism. We validated the method using conventional CSF samples, and found that the MD-CSF method yielded adequate results. Also, albeit a small sample size, we noted that lactate and pyruvate levels were significantly elevated in patients with an unfavorable outcome. In Paper IV, a retrospective study including 182 NICU TBI patients, we analyzed serum and CSF levels of Neurofilament light, a protein of axonal origin thus different from S100B. We showed that NFL levels significantly correlated independently to outcome, even in the presence of S100B. However, we could not correlate NFL levels to injuries visible on CT and magnetic resonance imaging (MRI). In Paper V, a preclinical study including 73 Sprague-Dawley rats, we analyzed how hypoxia exacerbates TBI. We detected increased neuronal death using immunohistochemistry and increased lesion size on MRI in the hypoxic animals compared to normoxic animals. A trend was found towards higher S100B levels in serum after 24 hours in the hypoxic group. Vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF1α) expressions were significantly increased in the normoxic group. In summary, the biomarker S100B provides important information towards long-term outcome, even more so than other known predictors of long-term outcome. Outcome prediction models including both S100B and NFL presents the highest explanatory variance, presumably by monitoring different pathophysiological processes. S100B is a valuable asset in the multimodal monitoring in order to detect secondary cerebral injuries and together with the MD-CSF technique; it could improve conventional NICU care with a more global approach. Hypoxic insults following TBI aggravate injury development and this pathophysiological process could presumably be monitored using S100B as an indicator of injury severity.
20.	Thelin, Eric Peter, et al. (author) Editorial : Monitoring pathophysiology in the injured brain 2018 In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9:MAR Journal article (peer-reviewed)
21.	Thelin, Eric Peter, et al. (author) Protein profiling in serum after traumatic brain injury in rats reveals potential injury markers 2018 In: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 340, s. 71-80 Journal article (peer-reviewed)abstract Introduction: The serum proteome following traumatic brain injury (TBI) could provide information for outcome prediction and injury monitoring. The aim with this affinity proteomic study was to identify serum proteins over time and between normoxic and hypoxic conditions in focal TBI. Material and methods: Sprague Dawley rats (n = 73) received a 3 mm deep controlled cortical impact ("severe injury"). Following injury, the rats inhaled either a normoxic (22% O-2) or hypoxic (11% O-2) air mixture for 30 min before resuscitation. The rats were sacrificed at day 1, 3, 7, 14 and 28 after trauma. A total of 204 antibodies targeting 143 unique proteins of interest in TBI research, were selected. The sample proteome was analyzed in a suspension bead array set-up. Comparative statistics and factor analysis were used to detect differences as well as variance in the data. Results: We found that complement factor 9 (C9), complement factor B (CFB) and aldolase c (ALDOC) were detected at higher levels the first days after trauma. In contrast, hypoxia inducing factor (HIF)1 alpha, amyloid precursor protein (APP) and WBSCR17 increased over the subsequent weeks. S100A9 levels were higher in hypoxic-compared to normoxic rats, together with a majority of the analyzed proteins, albeit few reached statistical significance. The principal component analysis revealed a variance in the data, highlighting clusters of proteins. Conclusions: Protein profiling of serum following TBI using an antibody based microarray revealed temporal changes of several proteins over an extended period of up to four weeks. Further studies are warranted to confirm our findings.
22.	Thelin, Eric Peter, et al. (author) S100B Is an Important Outcome Predictor in Traumatic Brain Injury 2013 In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 30:7, s. 519-528 Journal article (peer-reviewed)abstract The objective of the study was to examine how S100B, a biomarker of traumatic brain injury (TBI), contributes to outcome prediction after adjusting for known parameters, including age, Glasgow Coma Scale (GCS), pupil reaction, and computed tomography (CT) variables; to examine which parameters have the best correlation to elevated serum levels of S100B; and to investigate when to sample S100B to achieve the strongest association to outcome. This retrospective study included 265 patients with TBI admitted to the neurointensive care unit, Karolinska University Hospital Solna, Stockholm, Sweden. Univariate and multivariate proportional odds regressions were performed to determine parameters most closely related to outcome, and how S100B adds to prediction accuracy. Age (p < 0.0001), pupil reaction (p < 0.0001), and levels of S100B (p < 0.0001) had the strongest statistical correlation to outcome. The area under curve of S100B, the first 48 h after trauma, yielded an additional explained variance of 6.6% in excess of known outcome parameters, including age, GCS, pupil reaction, and CT variables, themselves exhibiting an explained variance of 29.3%. S100B adds substantial information regarding patient outcome, in excess of that provided by known parameters. Only CT variables were found to be significant predictors of increased levels of S100B in uni- and multivariate analysis. Early samples of S100B, within 12 h after trauma, appear to have little prognostic value, and S100B should likely be sampled 12-36 h following trauma to best enhance TBI outcome prediction.
23.	Thelin, Eric Peter, et al. (author) Serial sampling of serum protein biomarkers for monitoring human traumatic brain injury dynamics : A systematic review 2017 In: Frontiers in Neurology. - : Frontiers Media S.A.. - 1664-2295. ; 8 Research review (peer-reviewed)abstract Background: The proteins S100B, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and neurofilament light (NF-L) have been serially sampled in serum of patients suffering from traumatic brain injury (TBI) in order to assess injury severity and tissue fate. We review the current literature of serum level dynamics of these proteins following TBI and used the term "effective half-life" (t1/2) in order to describe the "fall" rate in serum.Materials and methods: Through searches on EMBASE, Medline, and Scopus, we looked for articles where these proteins had been serially sampled in serum in human TBI. We excluded animal studies, studies with only one presented sample and studies without neuroradiological examinations.Results: Following screening (10,389 papers), n = 122 papers were included. The proteins S100B (n = 66) and NSE (n = 27) were the two most frequent biomarkers that were serially sampled. For S100B in severe TBI, a majority of studies indicate a t1/2 of about 24 h, even if very early sampling in these patients reveals rapid decreases (1-2 h) though possibly of non-cerebral origin. In contrast, the t1/2 for NSE is comparably longer, ranging from 48 to 72 h in severe TBI cases. The protein GFAP (n = 18) appears to have t1/2 of about 24-48 h in severe TBI. The protein UCH-L1 (n = 9) presents a t1/2 around 7 h in mild TBI and about 10 h in severe. Frequent sampling of these proteins revealed different trajectories with persisting high serum levels, or secondary peaks, in patients with unfavorable outcome or in patients developing secondary detrimental events. Finally, NF-L (n = 2) only increased in the few studies available, suggesting a serum availability of >10 days. To date, automated assays are available for S100B and NSE making them faster and more practical to use.Conclusion: Serial sampling of brain-specific proteins in serum reveals different temporal trajectories that should be acknowledged. Proteins with shorter serum availability, like S100B, may be superior to proteins such as NF-L in detection of secondary harmful events when monitoring patients with TBI.
24.	Thelin, Eric, et al. (author) THE SENSITIVITY AND ROLE OF PROTEIN S100B IN DETECTING SECONDARY INJURIES AFTER TRAUMATIC BRAIN INJURY IN HUMANS 2011 In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 28:6, s. a55-A55 Journal article (peer-reviewed)abstract BACKGROUND: Patients suffering from traumatic brain injury (TBI) are often treated in specialized neuro-intensive care units (NICU) using multi-modal monitoring to detect harmful secondary insults such as increased intra cranial pressure. In addition to different monitoring devices. serum biomarkers have been shown to provide additional important information regarding the patient. Elevated serum levels of S100B have been detected following TBI. cerebral ischemia. spontaneous intra-cerebral hematomas and edema formation. S100B is known to correlate to outcome. Severe secondary cerebral injuries have been shown to correlate to secondary peaks in serum levels of S100B. Increases of more than 0.1mug/L are considered pathological. METHOD: 267 patients treated in the NICU for TBI with S100B samples obtained every 12 hours during a minimum of a 96-hour time period were included. Secondary increases of S100B after 48 hours following trauma were noted. All patients had at least 2 CT-scans and/or MRI scans performed. RESULTS: 67 secondary injuries during the NICU stay were detected using MRI or CT-scans. The most common lesions were diffuse is- chemic injuries (29). edema (13). cerebral infarctions (11) and intracerebral hematoma (5). Looking at secondary peaks of S100B in detecting radiological verifiable cerebral lesions during the NICU stay. a cut-off level of more than 0.5mug/L the specificity was 100% and sensitivity 8.9%. Decreasing the cut-off level to 0.1mug/L a specificity of 95.9% and sensitivity of 64.2% was obtained. while a cut-off level of 0.05mug/L presented a specificity of 92.7% and sensitivity of 92.5%. CONCLUSIONS: S100B is a sensitive marker for secondary cerebral injuries occurring in the NICU after TBI. A low cut-off point for the secondary peak of S100B (0.05 mug/L) increases sensitivity without any major deficit of specificity in detecting secondary injuries during the NICU stay.
25.	Thelin, Eric, et al. (author) The temporal profiles in serum concentrations of the biomarker S100B in the first 48 hours after traumatic brain injury correspond to outcome 2011 In: Journal of Neurotrauma. - : Mary Ann Liebert. - 0897-7151 .- 1557-9042. ; 28:5, s. A20-A20 Journal article (peer-reviewed)abstract Background: Traumatic brain injury (TBI) is one of the leading causes of death and disability. An early and accurate assessment of the affected patient suffering from TBI is important to promptly decide upon treatment strategies. Serum levels of the protein S100B are elevated in patients suffering from TBI, and has been proposed as a good addition to other clinical variables when calculating outcome. Different temporal patterns of the serum levels of S100B have been shown. The aim of this study was to analyze the different patterns, with a focus on outcome and other factors related to co-morbidity in patients suffering from TBI.Methods: In all, 265 patients suffering from TBI admitted to the neuro-intensive care unit, having three consecutive serum samples of S100B within the first 72 h after trauma were included.Results: S100B AUC, S100 peak serum level, and increasing serum levels of S100B significantly presence of traumatic subarachnoid hemorrhage, early cerebral ischemia and signs of increasing intracranial hematomas are statistically significant (p<0.05) to high and increasing levels of S100B. Using a multi-nomial logit regression analysis, increased age (p<0.01), early cerebral ischemia (p<0.05), and increased S100B AUC statistically significantly affected mortality (p<0.01).Conclusion: The temporal profile of S100B is unique for every patient after TBI, and statistically correlates with S100B AUC, one of the factors that correlates strongly with mortality and morbidity, and thereby may promptly provide the physician with an important tool in clinical decision-making.
26.	Wood, Sara, et al. (author) Predictors of intracranial hemorrhage in neonatal patients on extracorporeal membrane oxygenation 2023 In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1 Journal article (peer-reviewed)abstract Extracorporeal membrane oxygenation (ECMO) is a life-supportive treatment in neonatal patients with refractory lung and/or heart failure. Intracranial hemorrhage (ICH) is a severe complication and reliable predictors are warranted. The aims of this study were to explore the incidence and possible predictors of ICH in ECMO-treated neonatal patients. We performed a single-center retrospective observational cohort study. Patients aged <= 28 days treated with ECMO between 2010 and 2018 were included. Exclusion criteria were ICH, ischemic stroke, cerebrovascular malformation before ECMO initiation or detected within 12 h of admission, ECMO treatment < 12 h, or prior treatment with ECMO at another facility > 12 h. The primary outcome was a CT-verified ICH. Logistic regression models were employed to identify possible predictors of the primary outcome. Of the 223 patients included, 29 (13%) developed an ICH during ECMO treatment. Thirty-day mortality was 59% in the ICH group and 16% in the non-ICH group (p < 0.0001). Lower gestational age (p < 0.01, odds ratio (OR) 0.96; 95%CI 0.94-0.98), and higher pre-ECMO lactate levels (p = 0.017, OR 1.1; 95%CI 1.01-1.18) were independently associated with increased risk of ICH-development. In the clinical setting, identification of risk factors and multimodal neuromonitoring could help initiate steps that lower the risk of ICH in these patients.

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