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Objectives: To compare brain injury biomarker release levels between two different cardiopulmonary bypass (CPB) flow rates in elective cardiac surgery and to explore differences in postoperative delirium between groups and associations between age, sex, CPB time, oxygen levels, and near-infrared spectroscopy, and biomarker levels., Design: A randomized controlled substudy trial SETTING: Sahlgrenska University Hospital, Sweden PARTICIPANTS: Forty patients undergoing elective cardiac surgery with CPB INTERVENTION: Patients were assigned at random to either a standard (2.4 L/min/m 2 ) or a high (2.9 L/min/m 2 ) CPB flow rate., Measurements and Main Results: Glial fibrillary acidic protein, neurofilament light chain, total-tau, and phosphorylated-tau217 were sampled in plasma before anesthesia induction, after 60 minutes on CPB, and at 30 minutes, 24 hours, and 72 hours post-CPB. Mixed models for repeated measures were used to analyze differences in biomarker levels between groups and to assess relationships, which showed no differences between the 2 flow rate groups. There also was no difference in the occurrence of delirium between the 2 groups. Associations were found between age and increased neurofilament light chain levels. Female sex, oxygen delivery >330 mL/min/m 2 , and near-infrared spectroscopy level >60% were associated with lower biomarker levels., Conclusions: An increased flow rate did not have any significant effects on biomarker levels compared to a standard flow rate. Several associations were identified between treatment characteristics and biomarker levels. No difference in delirium was seen., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests. M.A. reports compensation for lectures and advisory boards from Biogen, Genzyme, and Novartis. L.L. reports consultancy honoraria from XVIVO Perfusion AB. K.B. is a founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, that includes board membership. Supported by the Swedish Research Council (Grants 2017-00915 and 2022-00732), the Swedish Alzheimer Foundation (Grants AF-930351, AF-939721, AF-968270, and AF-994551), Hjärnfonden Sweden (Grants FO2017-0243 and ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF agreement (ALFGBG-715986 and ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495), the Alzheimer's Association 2022-2025 Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer, and the Kirsten and Freddy Johansen Foundation. K.B. reports serving as a consultant and on advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; serving on data monitoring committees for Julius Clinical and Novartis; and participating in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics. He is a cofounder of Brain Biomarker Solutions in Gothenburg AB. H.Z. declares a financial interest in Biomarker Solutions in Gothenburg AB, which includes board membership. He is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (2023-00356, 2022-01018, and 2019-02397), the European Union's Horizon Europe research and innovation program under Grant 101053962, Swedish State Support for Clinical Research (ALFGBG-71320), the Alzheimer Drug Discovery Foundation (201809-2016862), the AD Strategic Fund and the Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C, and ADSF-24-1284328-C), the Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (FO2022-0270), the European Union's Horizon 2020 research and innovation program under Marie Skłodowska-Curie Grant 860197, the European Union Joint Programme–Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). He has served on scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB. R.O.B. reports receiving institutional research grants from Bristol-Myers Squibb, Endomag, SkyLineDx, and NeraCare GmbH; receiving speaker's honoraria from Roche, Pfizer, and Pierre-Fabre; and serving on advisory boards for Amgen, BD/BARD, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, and Sanofi Genzyme; and is a shareholder in SATMEG Ventures AB., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study aims to analyze the risk factors for early postoperative brain injury in patients undergoing cardiovascular surgery and explore the predictive value of transcranial color Doppler (TCCD) and regional cerebral oxygen saturation (rSO 2 ) for detecting early postoperative brain injury in cardiovascular surgery patients., Methods: A total of 55 patients undergoing cardiovascular surgery with cardiopulmonary bypass in Changzhou No.2 The People's Hospital of Nanjing Medical University were included in this study. Neuron-specific enolase (NSE) concentration was measured 24 h after operation. Patients were divided into brain injury (NSE ≥ 16.3 ng/mL) and normal (0 < NSE < 16.3 ng/mL) groups according to the measured NSE concentration. The clinical outcomes between the two groups were compared, including decreased rSO 2 and cerebral blood flow (as measured by TCCD) levels. The risk factors of early postoperative brain injury were analyzed by multivariate logistic regression analysis, and the significant variables were analyzed by receiver operating characteristic (ROC) analysis., Results: A total of 50 patients were included in this study, with 20 patients in the brain injury group and 30 patients in the normal group. Cardiopulmonary bypass time (min) (107 ± 29 vs. 90 ± 28, P = 0.047) and aortic occlusion time (min) (111 (IQR 81-127) vs. 87 (IQR 72-116), P = 0.010) were significantly longer in the brain injury group than in the normal group. Patients in the brain injury group had greater decreased rSO 2 (%) (27.0 ± 7.3 vs. 17.5 ± 6.1, P < 0.001) and cerebral blood flow (%) (44.9 (IQR 37.8-69.2) vs. 29.1 (IQR 12.0-48.2), P = 0.004) levels. Multivariate logistic regression analysis suggested that decreased rSO 2 and cerebral blood flow levels, aortic occlusion time, and history of atrial fibrillation were independent risk factors for early postoperative brain injury (P < 0.05). ROC analysis reported that the best cutoff values for predicting early postoperative brain injury were 21.4% and 37.4% for decreased rSO 2 and cerebral blood flow levels, respectively (P < 0.05)., Conclusion: The decreased rSO 2 and cerebral blood flow levels, aorta occlusion time, and history of atrial fibrillation were independent risk factors for early postoperative brain injury. TCCD and rSO 2 could effectively monitor brain metabolism and cerebral blood flow and predict early postoperative brain injury., (© 2024. The Author(s).)

Background: Trauma-related deaths and posttraumatic sequelae are a global health concern, necessitating a deeper understanding of the pathophysiology to advance trauma therapy. Proteomics offers insights into identifying and analyzing plasma proteins associated with trauma and inflammatory conditions; however, current proteomic methods have limitations in accurately measuring low-abundance plasma proteins. This study compared plasma proteomics profiles of patients from different acute trauma subgroups to identify new therapeutic targets and devise better strategies for personalized medicine., Methods: This prospective observational single-center cohort study was conducted between August 2020 and September 2021 in the intensive care unit of Osaka University Hospital in Japan. Enrolling 59 consecutive patients with blunt trauma, we meticulously analyzed plasma proteomics profiles in participants with torso or head trauma, comparing them with those of controls (mild trauma). Using the Olink Explore 3072 instrument (Olink Proteomics AB, Uppsala, Sweden), we identified five endotypes (α-ε) via unsupervised hierarchical clustering., Results: The median time from injury to blood collection was 47 minutes [interquartile range, 36-64 minutes]. The torso trauma subgroup exhibited 26 unique proteins with significantly altered expression, while the head trauma subgroup showed 68 unique proteins with no overlap between the two. The identified endotypes included α (torso trauma, n = 8), β (young patients with brain injury, n = 5), γ (severe brain injury postsurgery, n = 8), δ (torso or brain trauma with mild hyperfibrinolysis, n = 18), and ε (minor trauma, n = 20). Patients with torso trauma showed changes in blood pressure, smooth muscle adaptation, hypermetabolism, and hypoxemia. Patients with traumatic brain injury had dysregulated blood coagulation and altered nerves regeneration and differentiation., Conclusion: This study identified unique plasma protein expression patterns in patients with torso trauma and traumatic brain injury, helping categorize five distinct endotypes. Our findings may offer new insights for clinicians, highlighting potential strategies for personalized medicine and improved trauma-related care., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Acute brain injury (ABI) remains one of the leading causes of death and disability world-wide. Its treatment is challenging due to the heterogeneity of the mechanisms involved and the variability among individuals. This systematic review aims at evaluating the impact of anti-histone treatments on outcomes in ABI patients and experimental animals and defining the trend of nucleosome levels in biological samples post injury. We performed a search in Pubmed/Medline and Embase databases for randomized controlled trials and cohort studies involving humans or experimental settings with various causes of ABI. We formulated the search using the PICO method, considering ABI patients or animal models as population (P), comparing pharmacological and non-pharmacological therapy targeting the nucleosome as Intervention (I) to standard of care or no treatment as Control (C). The outcome (O) was mortality or functional outcome in experimental animals and patients affected by ABI undergoing anti-NET treatments. We identified 28 studies from 1246 articles, of which 7 were experimental studies and 21 were human clinical studies. Among these studies, only four assessed the effect of anti-NET therapy on circulating markers. Three of them were preclinical and reported better outcome in the interventional arm compared to the control arm. All the studies observed a significant reduction in circulating NET-derived products. NETosis could be a target for new treatments. Monitoring NET markers in blood and cerebrospinal fluid might predict mortality and long-term outcomes. However, longitudinal studies and randomized controlled trials are warranted to fully evaluate their potential, as current evidence is limited.

Background: Prematurity-related brain injury is a common and serious complication that has long-term effects on the survival and development of affected infants. Currently, the roles of certain biomarkers such as the protein hydrolysis product SBDP145, melatonin, soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), high mobility group box 1 protein (HMGB1), and hypoxia-inducible factor 1-alpha (HIF-1α) in prematurity-related brain injury remain not fully elucidated. Our study aims to assess the significance of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in preterm infants with brain injury., Methods: 135 preterm infants admitted to our hospital from January 2020 to February 2022 were selected and divided into 78 cases in a prematurity-associated brain injury group, and 57 cases in another group of preterm infants without brain injury or other diseases according to the magnetic resonance imaging results. The levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in the two groups were analyzed. The serum concentrations of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in newborns with different severity of ventricular hemorrhage were observed, and the levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α in those with different severity of white matter brain injury were compared., Results: The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were significantly higher in the preterm combined brain injury group than in the preterm group, and melatonin levels were significantly lower than in the preterm group(P < 0.05). The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were higher in the moderate to severe group and melatonin levels were lower in the mild group of newborns with ventricular hemorrhage (P < 0.05). The levels of SBDP145, sLOX-1, HMGB1 and HIF-1α were higher in the moderate-severe group and melatonin levels were lower in the mild group in newborns with cerebral white matter injury (P < 0.05). The independent variables were SBDP145, melatonin, sLOX-1, HMGB1, HIF-1α, and the dependent variable was the prognosis of neonates with brain injury. Univariate logistic regression analysis and multivariate logistic regression analysis were performed. The results showed that the influencing factors of newborns with brain injury were SBDP145, melatonin, sLOX-1, HMGB1, HIF-1α., Conclusion: The levels of SBDP145, melatonin, sLOX-1, HMGB1 and HIF-1α were highly expressed in preterm newborns with brain injury, and the levels were higher when the condition of the newborns was more severe. These findings suggest the potential clinical utility of these biomarkers in predicting and monitoring brain injury in preterm infants, which could aid in early intervention and improve long-term outcomes., (© 2024. The Author(s).)

Objective: Critically ill patients, including those with brain injuries (BI), are frequently hospitalized in an intensive care unit (ICU). As with other critical states, an adequate stress response is essential for survival. Research on the hypothalamic-pituitary-adrenal gland (HPA) axis function in BI has primarily focused on assessing ACTH and cortisol levels. However, the immunological, metabolic, and hemodynamic effects of glucocorticoids (GCs) are mediated through the glucocorticoid receptor (GCR), a ubiquitously distributed intracellular receptor protein. Data on GCR-α expression and its signaling in acute BI injury are lacking., Methods: We designed a prospective observational study, carried out in one academic multi-disciplinary ICU. Forty-two critically ill patients with acute (BI)were included. These patients suffered from traumatic BI (N= 20), subarachnoid hemorrhage (N= 12), intracranial hemorrhage (N= 7), or ischemic stroke (N= 3). All patients were steroid-free. Twenty-four age and sex-matched healthy controls were used for comparison., Results: Expression of GCR-α and the glucocorticoid-inducible leucine zipper ( GILZ ), serum cortisol, interleukins (IL) 6, 8, 10 and TNF- α, and the BI biomarkers glial fibrillary acidic protein (GFAP) and total Tau were measured on ICU admission (within 48 hours) and 5-7 days from admission. Compared to healthy controls, in the critically ill patients with BI, GCR-α mRNA expression was significantly downregulated on admission, and after 5-7 days in the ICU (2.3-fold, p<0.05 and 2.6-fold, p<0.01, respectively). Even though GCR-α was downregulated, its downstream gene, GILZ , was expressed at the same levels as in normal controls on admission and was significantly upregulated 5-7 days following admission (2-fold, p<0.001). TNF-α levels were undetectable at both time-points. GCR-α expression levels inversely correlated with IL-6. The levels of cortisol and the BI biomarkers did not differ between the 2 time-points., Conclusions: We provide novel evidence on the downregulated expression and upregulated signaling of the ligand-binding and functionally active GCR-α isoform in the polymorphonuclear neutrophils (PMNs) of critically ill patients with BI. The increased GILZ expression indicates an increased GC sensitivity in the PMNs of BI critically ill patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lotsios, Vrettou, Poupouzas, Chalioti, Keskinidou, Pratikaki, Giannopoulou, Kotanidou, Vassiliadi, Dimopoulou and Vassiliou.)

Objective: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study., Research Design and Methods: Plasma amyloid-β-40, amyloid-β-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)-like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment., Results: Participants were 60 (range 44-74) years old with 38 (30-51) years' T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL; P < 0.001) and a 19.5% increase in the odds of impaired cognition (P < 0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (P < 0.001) but not poorer memory. Amyloid-β measures were not associated with study measures. A 1% increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (P < 0.0001)., Conclusions: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D because of its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/nonamyloid mechanisms., (© 2024 by the American Diabetes Association.)

Current guidelines suggest a target of partial pressure of carbon dioxide (PaCO 2 ) of 32-35 mmHg (mild hypocapnia) as tier 2 for the management of intracranial hypertension. However, the effects of mild hyperventilation on cerebrovascular dynamics are not completely elucidated. The aim of this study is to evaluate the changes of intracranial pressure (ICP), cerebral autoregulation (measured through pressure reactivity index, PRx), and regional cerebral oxygenation (rSO 2 ) parameters before and after induction of mild hyperventilation. Single center, observational study including patients with acute brain injury (ABI) admitted to the intensive care unit undergoing multimodal neuromonitoring and requiring titration of PaCO 2 values to mild hypocapnia as tier 2 for the management of intracranial hypertension. Twenty-five patients were included in this study (40% female), median age 64.7 years (Interquartile Range, IQR = 45.9-73.2). Median Glasgow Coma Scale was 6 (IQR = 3-11). After mild hyperventilation, PaCO 2 values decreased (from 42 (39-44) to 34 (32-34) mmHg, p < 0.0001), ICP and PRx significantly decreased (from 25.4 (24.1-26.4) to 17.5 (16-21.2) mmHg, p < 0.0001, and from 0.32 (0.1-0.52) to 0.12 (-0.03-0.23), p < 0.0001). rSO 2 was statistically but not clinically significantly reduced (from 60% (56-64) to 59% (54-61), p < 0.0001), but the arterial component of rSO 2 (ΔO 2 Hbi, changes in concentration of oxygenated hemoglobin of the total rSO 2 ) decreased from 3.83 (3-6.2) μM.cm to 1.6 (0.5-3.1) μM.cm, p = 0.0001. Mild hyperventilation can reduce ICP and improve cerebral autoregulation, with minimal clinical effects on cerebral oxygenation. However, the arterial component of rSO 2 was importantly reduced. Multimodal neuromonitoring is essential when titrating PaCO 2 values for ICP management., (© 2024. The Author(s).)

Acquired brain injury is an urgent situation that requires rapid diagnosis and treatment. Magnetic resonance imaging (MRI) and computed tomography (CT) are required for accurate diagnosis. However, these methods are costly and require substantial infrastructure and specialized staff. Circulatory biomarkers of acute brain injury may help in the management of patients with acute cerebrovascular events and prevent poor outcome and mortality. The purpose of this review is to provide an overview of the development of potential biomarkers of brain damage to increase diagnostic possibilities. For this purpose, we searched the PubMed database of studies on the diagnostic potential of brain injury biomarkers. We also accessed information from Clinicaltrials.gov to identify any clinical trials of biomarker measurements for the diagnosis of brain damage. In total, we present 41 proteins, enzymes and hormones that have been considered as biomarkers for brain injury, of which 20 have been studied in clinical trials. Several microRNAs have also emerged as potential clinical biomarkers for early diagnosis. Combining multiple biomarkers in a panel, along with other parameters, is yielding promising outcomes., (© 2024. The Author(s).)

Postoperative neurological dysfunction (PND) is one of the most common complications after a total aortic arch replacement (TAAR). Electrical impedance tomography (EIT) monitoring of cerebral hypoxia injury during TAAR is a promising technique for preventing the occurrence of PND. This study aimed to explore the feasibility of electrical impedance tomography (EIT) for warning of potential brain injury during total aortic arch replacement (TAAR) through building the correlation between EIT extracted parameters and variation of neurological biomarkers in serum. Patients with Stanford type A aortic dissection and requiring TAAR who were admitted between December 2021 to March 2022 were included. A 16-electrode EIT system was adopted to monitor each patient's cerebral impedance intraoperatively. Five parameters of EIT signals regarding to the hypothermic circulatory arrest (HCA) period were extracted. Meanwhile, concentration of four neurological biomarkers in serum were measured regarding to time before and right after surgery, 12 h, 24 h and 48 h after surgery. The correlation between EIT parameters and variation of serum biomarkers were analyzed. A total of 57 TAAR patients were recruited. The correlation between EIT parameters and variation of biomarkers were stronger for patients with postoperative neurological dysfunction (PND(+)) than those without postoperative neurological dysfunction (PND(-)) in general. Particularly, variation of S100B after surgery had significantly moderate correlation with two parameters regarding to the difference of impedance between left and right brain which were MRAI abs and TRAI abs (0.500 and 0.485 with p < 0.05, respectively). In addition, significantly strong correlations were seen between variation of S100B at 24 h and the difference of average resistivity value before and after HCA phase (ΔARV HCA ), the slope of electrical impedance during HCA (k HCA ) and MRAI abs (0.758, 0.758 and 0.743 with p < 0.05, respectively) for patients with abnormal S100B level before surgery. Strong correlations were seen between variation of TAU after surgery and ΔARV HCA , k HCA and the time integral of electrical impedance for half flow of perfusion (TARV HP ) (0.770, 0.794 and 0.818 with p < 0.01, respectively) for patients with abnormal TAU level before surgery. Another two significantly moderate correlations were found between TRAI abs and variation of GFAP at 12 h and 24 h (0.521 and 0.521 with p < 0.05, respectively) for patients with a normal GFAP serum level before surgery. The correlations between EIT parameters and serum level of neurological biomarkers were significant in patients with PND, especially for MRAI abs and TRAI abs , indicating that EIT may become a powerful assistant for providing a real-time warning of brain injury during TAAR from physiological perspective and useful guidance for intensive care units., (© 2024. The Author(s).)

Introduction: Neurological impairment is a big concern in the development of patients with congenital heart defects (CHD). A number of neuromarkers have been studied in search of a diagnostic or prognostic marker for brain injury during the vulnerable perioperative period. Our aim was to assess two novel neuromarkers, myelin basic protein (MBP) and protein Tau (pTau), as diagnostic markers for brain injury in perioperative period in children with CHD., Methods: Forty patients were enrolled and dichotomized based on peripheric oxygen saturation in cyanotic and non-cyanotic group. Blood samples were collected preoperative, after the induction of anesthesia, and in postoperative day 1. Neuromarker concentrations were measured using commercially available ELISA kits., Results: Neuromarkers' values were increased postoperative, with statistical significance reached only in non-cyanotic group (p < 0.0001). A significant positive correlation was observed between preoperatory MBP and albumin level, hemoglobin level, height, and weight of patients. Association with cerebral saturations were analyzed by a coefficient defined as ≥ 20% reduction in cerebral saturation measured by near-infrared spectroscopy during perioperative period. An acceptable predicting model was observed with pTau in cyanotic group (AUC = 0.7)., Conclusion: We evaluated MBP and pTau as potential biomarkers of brain injury in children with CHD undergoing cardiac surgery. Elevated postoperative pTau and MBP concentrations were observed in both groups. Elevated pTau values were associated with perioperative hypoxemia., (© 2023. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

In this two-center prospective cohort study of children on ECMO, we assessed a panel of plasma brain injury biomarkers using exploratory factor analysis (EFA) to evaluate their interplay and association with outcomes. Biomarker concentrations were measured daily for the first 3 days of ECMO support in 95 participants. Unfavorable composite outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category > 2 with decline ≥ 1 point from baseline. EFA grouped 11 biomarkers into three factors. Factor 1 comprised markers of cellular brain injury (NSE, BDNF, GFAP, S100β, MCP1, VILIP-1, neurogranin); Factor 2 comprised markers related to vascular processes (vWF, PDGFRβ, NPTX1); and Factor 3 comprised the BDNF/MMP-9 cellular pathway. Multivariable logistic models demonstrated that higher Factor 1 and 2 scores were associated with higher odds of unfavorable outcome (adjusted OR 2.88 [1.61, 5.66] and 1.89 [1.12, 3.43], respectively). Conversely, higher Factor 3 scores were associated with lower odds of unfavorable outcome (adjusted OR 0.54 [0.31, 0.88]), which is biologically plausible given the role of BDNF in neuroplasticity. Application of EFA on plasma brain injury biomarkers in children on ECMO yielded grouping of biomarkers into three factors that were significantly associated with unfavorable outcome, suggesting future potential as prognostic instruments., (© 2024. The Author(s).)

Neonatal brain injury (NBI) is a critical condition for preterm neonates with potential long-term adverse neurodevelopmental outcomes. This prospective longitudinal case-control study aimed at investigating the levels and prognostic value of serum neuron-specific enolase (NSE) during the first 3 days of life in preterm neonates (<34 weeks) that later developed brain injury in the form of either periventricular leukomalacia (PVL) or intraventricular hemorrhage (IVH) during their hospitalization. Participants were recruited from one neonatal intensive care unit, and on the basis of birth weight and gestational age, we matched each case ( n = 29) with a neonate who had a normal head ultrasound scan ( n = 29). We report that serum NSE levels during the first three days of life do not differ significantly between control and preterm neonates with NBI. Nevertheless, subgroup analysis revealed that neonates with IVH had significantly higher concentrations of serum NSE in comparison to controls and neonates with PVL on the third day of life ( p = 0.014 and p = 0.033, respectively). The same pattern on the levels of NSE on the third day of life was also observed between (a) neonates with IVH and all other neonates (PVL and control; p = 0.003), (b) neonates with II-IV degree IVH and all other neonates ( p = 0.003), and (c) between control and the five ( n = 5) neonates that died from the case group ( p = 0.023). We conclude that NSE could be an effective and useful biomarker on the third day of life for the identification of preterm neonates at high risk of developing severe forms of IVH.

Background: Acute brain injury (ABI) remains common after extracorporeal cardiopulmonary resuscitation (ECPR). Using a large international multicenter cohort, we investigated the impact of peri-cannulation arterial oxygen (PaO 2 ) and carbon dioxide (PaCO 2 ) on ABI occurrence., Methods: We retrospectively analyzed adult (≥18 years old) ECPR patients in the Extracorporeal Life Support Organization registry from 1/2009 through 12/2020. Composite ABI included ischemic stroke, intracranial hemorrhage (ICH), seizures, and brain death. The registry collects 2 blood gas data pre- (6 hours) and post- (24 hours) cannulation. Blood gas parameters were classified as: hypoxia (<60mm Hg), normoxia (60-119mm Hg), and mild (120-199mm Hg), moderate (200-299mm Hg), and severe hyperoxia (≥300mm Hg); hypocarbia (<35mm Hg), normocarbia (35-44mm Hg), mild (45-54mm Hg) and severe hypercarbia (≥55mm Hg). Missing values were handled using multiple imputation. Multivariable logistic regression analysis was used to assess the relationship of PaO 2 and PaCO 2 with ABI., Results: Of 3,125 patients with ECPR intervention (median age=58, 69% male), 488 (16%) experienced ABI (7% ischemic stroke; 3% ICH). In multivariable analysis, on-ECMO moderate (aOR=1.42, 95%CI: 1.02-1.97) and severe hyperoxia (aOR=1.59, 95%CI: 1.20-2.10) were associated with composite ABI. Additionally, severe hyperoxia was associated with ischemic stroke (aOR=1.63, 95%CI: 1.11-2.40), ICH (aOR=1.92, 95%CI: 1.08-3.40), and in-hospital mortality (aOR=1.58, 95%CI: 1.21-2.06). Mild hypercarbia pre-ECMO was protective of composite ABI (aOR=0.61, 95%CI: 0.44-0.84) and ischemic stroke (aOR=0.56, 95%CI: 0.35-0.89)., Conclusions: Early severe hyperoxia (≥300mm Hg) on ECMO was a significant risk factor for ABI and mortality. Careful consideration should be given in early oxygen delivery in ECPR patients who are at risk of reperfusion injury., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: EEG is widely used for prediction of neurologic outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explored the association between EEG and neurofilament light (NfL) as a marker of neuroaxonal injury, evaluated whether highly malignant EEG patterns are reflected by high NfL levels, and explored the association of EEG backgrounds and EEG discharges with NfL., Methods: We performed a post hoc analysis of the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours postarrest. Patients who awoke or died prior to 36 hours postarrest were excluded. EEG experts blinded to clinical information classified EEG background, amount of discharges, and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NfL after trial completion. The highest available concentration at 48 or 72 hours postarrest was used., Results: A total of 262/939 patients with EEG and NfL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NfL levels than patients with malignant patterns and NfL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI 1.4-6.1 and 6.5-26.2, respectively; effect size 0.47; p < 0.001). Both background and the amount of discharges were independently strongly associated with NfL levels ( p < 0.001). The EEG background had a stronger association with NfL levels than EEG discharges (R 2 = 0.30 and R 2 = 0.10, respectively). NfL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression, and suppression, respectively: 2.26-18.06, 3.91-41.71, and 5.74-41.74; effect size 0.30; p < 0.001 for all). NfL levels did not differ between suppression and burst suppression. Superimposed discharges were only associated with higher NfL levels if the EEG background was continuous., Discussion: Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NfL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NfL may be useful to better identify patients misclassified by single methods., Trial Registration Information: ClinicalTrials.gov NCT01020916., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA., Methods: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation., Results: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures., Interpretation: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403., (© 2022 American Neurological Association.)

Trimethylamine-N-oxide (TMAO), an intestinal flora metabolite of choline, may aggravate atherosclerosis by inducing a chronic inflammatory response and thereby promoting the occurrence of cerebrovascular diseases. Knowledge about the influence of TMAO-related inflammatory response on the pathological process of acute stroke is limited. This study was designed to explore the effects of TMAO on neuroinflammation, brain injury severity, and long-term neurologic function in mice with acute intracerebral hemorrhage (ICH). We fed mice with either a regular chow diet or a chow diet supplemented with 1.2% choline pre- and post-ICH. In this study, we measured serum levels of TMAO with ultrahigh-performance liquid chromatography-tandem mass spectrometry at 24 h and 72 h post-ICH. The expression level of P38-mitogen-protein kinase (P38-MAPK), myeloid differentiation factor 88 (MyD88), high-mobility group box1 protein (HMGB1), and interleukin-1 β (IL-1 β ) around hematoma was examined by western blotting at 24 h. Microglial and astrocyte activation and neutrophil infiltration were examined at 72 h. The lesion was examined on days 3 and 28. Neurologic deficits were examined for 28 days. A long-term choline diet significantly increased serum levels of TMAO compared with a regular diet at 24 h and 72 h after sham operation or ICH. Choline diet-induced high serum levels of TMAO did not enhance the expression of P38-MAPK, MyD88, HMGB1, or IL-1 β at 24 h. However, it did increase the number of activated microglia and astrocytes around the hematoma at 72 h. Contrary to our expectations, it did not aggravate acute or long-term histologic damage or neurologic deficits after ICH. In summary, choline diet-induced high serum levels of TMAO increased the cellular inflammatory response probably by activating microglia and astrocytes. However, it did not aggravate brain injury or worsen long-term neurologic deficits. Although TMAO might be a potential risk factor for cerebrovascular diseases, this exploratory study did not support that TMAO is a promising target for ICH therapy., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Caizhen Li et al.)

The inflammatory response to acute brain injuries is a key contributor to subsequent outcome. The study of local central nervous system inflammatory responses is hindered by raised intracranial pressure precluding cerebrospinal fluid sampling by lumbar puncture. External ventricular drains are sited in some acute brain injury patients to divert cerebrospinal fluid and thus reduce intracranial pressure, and represent a potential route to safely gather large volumes of cerebrospinal fluid for immunological studies. In this manuscript we show that mononuclear cells can be isolated from cerebrospinal fluid collected from external ventricular drains, and that the large volumes of cerebrospinal fluid available yield sufficient mononuclear cells to allow cryopreservation. Prolonged storage of cerebrospinal fluid in the external ventricular drain collection bag can alter the phenotype of cells recovered, but the predicted effect of this can be estimated for a given flow cytometry panel by assessing the changes in peripheral blood mononuclear cells exposed to the same conditions. The described method will allow clinical studies of acute brain injuries to investigate the immunological processes occurring within the central nervous system compartment, rather than relying on changes in the peripheral circulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Mounting evidence suggests the synaptic vesicle glycoprotein 2A (SV2A) targeted by levetiracetam may contribute to epileptogenesis. Levetiracetam has shown anti-inflammatory, antioxidant, neuroprotective, and possible antiepileptogenic effects in brain injury and seizure/epilepsy models, and a phase 2 study has signaled a possible clinical antiepileptogenic effect. Brivaracetam shows greater affinity and specificity for SV2A than levetiracetam and broader preclinical antiseizure effects. Thus, we assessed the antiepileptogenic/disease-modifying potential of brivaracetam in an etiologically realistic rat posttraumatic epilepsy model optimized for efficient drug testing. Brivaracetam delivery protocols were designed to maintain clinical moderate-to-high plasma levels in young (5-week-old) male Sprague-Dawley rats for 4 weeks. Treatment protocols were rapidly screened in 4-week experiments using small groups of animals to ensure against rigorous testing of futile treatment protocols. The antiepileptogenic effects of brivaracetam treatment initiated 30 minutes, 4 hours, and 8 hours after rostral parasagittal fluid percussion injury (rpFPI) were then compared with vehicle-treated controls in a fully powered blind and randomized 16-week validation. Seizures were evaluated by video-electrocorticography using a 5-electrode epidural montage. Endpoint measures included incidence, frequency, duration, and spread of seizures. Group sizes and recording durations were supported by published power analyses. Three months after treatment ended, rats treated with brivaracetam starting at 4 hours post-FPI (the best-performing protocol) experienced a 38% decrease in overall incidence of seizures, 59% decrease in seizure frequency, 67% decrease in time spent seizing, and a 45% decrease in the proportion of spreading seizures that was independent of duration-based seizure definition. Thus, brivaracetam shows both antiepileptogenic and disease-modifying properties after rpFPI. SIGNIFICANCE STATEMENT: The rpFPI model, which likely incorporates epileptogenic mechanisms operating after human head injury, can be used to efficiently screen investigational treatment protocols and assess antiepileptogenic/disease-modifying effects. Our studies 1) support a role for SV2A in epileptogenesis, 2) suggest that brivaracetam and other drugs targeting SV2A should be considered for human clinical trials of prevention of post-traumatic epilepsy after head injury, and 3) provide data to inform the design of treatment protocols for clinical trials., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes., Methods: Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs-including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs-including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID-19 vs. controls and (b) men vs. women., Results: Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p < 0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women., Conclusion: The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women., (© 2021. The Author(s).)

Background/aim: Postnatal corticosteroids are commonly used to treat bronchopulmonary dysplasia (BPD). We aimed to show whether S100 calcium-binding B (S100B), neuron-specific enolase (NSE), Tau protein or microtubule-associated protein tau (MAPT), and glial fibrillary acid protein (GFAP) levels would provide any evidence of early neurological damage in premature infants receiving postnatal low dose dexamethasone therapy for BPD treatment., Materials and Methods: In this cohort study, 136 preterm infants diagnosed with BPD at ≤32 weeks of gestation formed the study group, and 64 preterm infants formed the control group. NSE, S100B, GFAP, and MAPT levels were first measured before the postnatal corticosteroid treatment in both the patient and the control group on the 28th day and, for a second time, after treatment termination in the patient group., Results: There were significant differences between the measured GFAP, MAPT, and NSE values of the BPD and control groups on the 28th day, whereas there was no significant difference between the measured S100B values of the two groups. There were a statistically significant difference between the NSE values measured on the 28th day and after the treatment within the BPD group, whereas no significant difference existed between the GFAP, MAPT, and S100B values., Conclusion: NSE levels, which indicate brain damage in the early period, increased in preterm babies with BPD who had been administered postnatal dexamethasone., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Bedside detection and early treatment of lasting cerebral ischemia may improve outcome after out-of-hospital cardiac arrest (OHCA). This feasibility study explores the possibilities to use microdialysis (MD) for continuous monitoring of cerebral energy metabolism by analyzing the draining cerebral venous blood. Eighteen comatose patients were continuously monitored with jugular bulb and radial artery (reference) MD following resuscitation. Median time from cardiac arrest to MD was 300 min (IQR 230-390) with median monitoring time 60 h (IQR 40-81). The lactate/pyruvate ratio in cerebral venous blood was increased during the first 20 h after OHCA, and significant differences in time-averaged mean MD metabolites between jugular venous and artery measurements, were documented (p < 0.02). In patients with unfavorable outcome (72%), cerebral venous lactate and pyruvate levels remained elevated during the study period. In conclusion, the study indicates that jugular bulb microdialysis (JBM) is feasible and safe. Biochemical signs of lasting ischemia and mitochondrial dysfunction are frequent and associated with unfavorable outcome. The technique may be used in comatose OHCA patients to monitor biochemical variables reflecting ongoing brain damage and support individualized treatment early after resuscitation., (© 2021. The Author(s).)

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines-many associated with worse outcomes-occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood-brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling., Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E)., Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes., Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

Pituitary tumors and subsequent treatment with endoscopic transsphenoidal surgery (ETSS) may cause injury to suprasellar structures, causing long-term fatigue and neurocognitive impairment. A method to quantify brain injury after ETSS is not available. In this prospective, exploratory study of patients undergoing ETSS for pituitary tumors, a novel approach to detect possible neuronal damage is presented. Plasma concentrations of brain injury biomarkers (glial fibrillary acidic protein [GFAP], tau, and neurofilament light [NFL]) were measured the day before surgery, immediately after surgery, at day 1 and 5, and at 6 and 12 months after surgery, using enzyme-linked immunosorbent assays. The association between the increase of biomarkers with preoperative tumor extension and postoperative patient-perceived fatigue was evaluated. Suprasellar tumor extension was assessed from MRI scans, and self-perceived fatigue was assessed using the Multidimensional Fatigue Inventory before and 6 months after surgery. Thirty-five patients were included in the analysis. Compared to baseline, GFAP showed a maximal increase at day 1 after surgery (p = 0.0005), tau peaked postoperatively on the day of surgery (p = 0.019), and NFL reached its maximum at day 5 after surgery (p < 0.0001). The increase in GFAP correlated with preoperative chiasmal compression (p = 0.020). The increase in tau was correlated with preoperative chiasmal (p = 0.011) and hypothalamus compression (p = 0.016), and fatigue score 6 months after surgery (p = 0.016). In conclusion, the concentrations of brain injury biomarkers in blood increased after ETSS for pituitary tumors. The results indicate that postoperative plasma GFAP and tau might reflect astroglial and neuronal damage after ETSS., Competing Interests: Declaration of Competing Interest T S has received lecture fees from Abbott. G J has served as consultant for Shire and Astra Zeneca, and has received lecture fees from Eli Lilly, Ipsen, Novartis, Novo Nordisk, Merck Serono, Otsuka, and Pfizer. D S O has served as a consultant for Ipsen, Pfizer, NovoNordisk and Sandoz, and has received research grants from Sandoz. K B has served as a consultant or on advisory boards for Alector, Biogen, CogRx, Lilly, MagQu, Novartis, and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. H Z has served on scientific advisory boards for Roche Diagnostics, Samumed, Wave, and CogRx; has given lectures for symposia sponsored by Biogen and Alzecure; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. None of the above is related to the work presented in this paper. All other authors have no relevant disclosures., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Hyperbilirubinemia is a common disease in the neonatal period, and hyperbilirubinemia may cause brain damage. Therefore, prevention and diagnosis and management of hyperbilirubinemia is very important, and vitamin D may affect bilirubin levels. To evaluate the relationship between neonatal hyperbilirubinemia and vitamin D levels., Method: The China National Knowledge Infrastructure, VIP, Wanfang, Chinese Biology Medicine Disc, PubMed, Web of Science, Cochrane Library, and Embase databases as well as clinical trial registries in China and the United States were searched for relevant studies from inception to September 2020 without restrictions on language, population, or year. The studies was screened by two reviewers independently, the data were extracted, and the risk of bias of the included studies was evaluated using the NOS. A meta-analysis was conducted on the included studies using Stata11 software., Results: Six case-control studies were included, and the methodological quality of the studies was high (grade A). The studies included 690 newborns; more than 409 were diagnosed with hyperbilirubinemia. The means and standard deviations were calculated. Meta-analysis results showed that neonatal vitamin D levels were 7.1 ng/ml lower among infants with hyperbilirubinemia than among healthy newborn levels (z = 6.95, 95% CI 9.10 ~ 5.09, P < 0.05). Subgroup analysis was conducted based on whether the bilirubin levels were concentrated in the 15 to 20 mg/dl range. Vitamin D level of infants with hyperbilirubinemia (the bilirubin levels were concentrated in the 15 to 20 mg/dl range) was 9.52 ng/ml (Z = 15.55, 95% CI-10.72~-8.32, P<0.05) lower than that of healthy infants. The bilirubin levels in four cases were not concentrated in the 15-20 mg/dl range. The results showed that the vitamin D level of hyperbilirubinemia (The bilirubin levels were not concentrated in the 15-20 mg/dl range) neonates were 5.35 ng/ml lower than that of healthy neonates (Z = 6.43, 95% CI-6.98~-3.72, P<0.05)., Conclusion: Vitamin D levels were observed to be lower in neonates with hyperbilirubinemia as compared to term neonates without hyperbilirubinemia in this study. This can possibly suggest that neonates with lower vitamin D levels are at higher risk for developing hyperbilirubinemia., Competing Interests: The authors have declared that no competing interests exist.

Importance: Circulating levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) are important in the course of brain injury in adults, but longitudinal postnatal circulating levels in preterm infants have not been investigated., Objectives: To examine postnatal longitudinal serum levels of NfL and GFAP in preterm infants during the first 15 weeks of life and to explore possible associations between these biomarkers, neonatal morbidities, and neurodevelopmental outcomes at 2 years., Design, Setting, and Participants: This cohort study used data from 3 clinical studies, including 221 infants born before 32 weeks gestational age (GA) from 1999 to 2015; neurodevelopmental outcomes were evaluated in 120 infants. Data were collected at tertiary-level neonatal intensive care units in Gothenburg, Lund, and Uppsala, Sweden. Data analysis was conducted from January to October 2020., Exposure: Preterm birth., Main Outcomes and Measures: Serum NfL and GFAP levels, retinopathy of prematurity (ROP), intraventricular hemorrhage, and Bayley Scales of Infant Development II and III at 2 years of age, analyzed by multivariate logistic regression measured by odds ratio (OR), and receiver operating characteristic curve (ROC) analysis. Area under the curve (AUC) was also measured., Results: The 221 included infants (108 [48.9%] girls) had a mean (SD) GA at birth of 26.5 (2.1) weeks and a mean (SD) birth weight of 896 (301) grams. NfL levels increased after birth, remaining high during the first 4 weeks of life before declining to continuously low levels by postnatal age 12 weeks (median [range] NfL level at birth: 58.8 [11.5-1371.3] ng/L; 1 wk: 83.5 [14.1-952.2] ng/L; 4 wk: 24.4 [7.0-306.0] ng/L; 12 wk: 9.1 [3.7-57.0] ng/L). In a binary logistic regression model adjusted for GA at birth, birth weight SD score, Apgar status at 5 minutes, and mode of delivery, the NfL AUC at weeks 2 to 4 was independently associated with any ROP (OR, 4.79; 95% CI, 2.17-10.56; P < .001). In an exploratory analysis adjusted for GA at birth and sex, NfL AUC at weeks 2 to 4 was independently associated with unfavorable neurodevelopmental outcomes at 2 years corrected age (OR per 10-unit NfL increase, 1.07; 95% CI, 1.02-1.13; P = .01). Longitudinal GFAP levels were not significantly associated with neonatal morbidity or neurodevelopmental outcome., Conclusions and Relevance: In this study, high NfL levels during the first weeks of life were associated with ROP and poor neurodevelopmental outcomes at 2 years of age. Associations between NfL and later neurovascular development in infants born prematurely should be investigated further.

Previous experiments demonstrated improved outcome following prolonged cerebral ischemia given controlled brain reperfusion using extracorporeal circulation. The current study further investigates this. Young adult pigs were exposed to 30 min of global normothermic cerebral ischemia, achieved through intrathoracic clamping of cerebral arteries, followed by 20 min of isolated mechanical brain reperfusion. Leukocyte-filtered blood was delivered by a roller-pump at fixed pressure and flow. One experimental group additionally had a custom-made buffer solution delivered at 1:8 ratio with the blood. Hemodynamics including intracranial pressure were monitored. Blood gases were from peripheral arteries and the sagittal sinus, and intraparenchymal brain microdialysis was performed. The brains were examined by a neuropathologist. The group with the added buffer showed lower intracranial pressure as well as decreased intraparenchymal glycerol and less signs of excitotoxicity and ischemia, although histology revealed similar degrees of injury. A customized mechanical reperfusion improves multiple parameters after prolonged normothermic global cerebral ischemia. Graphical Abstract The current study investigates if it possible to improve neurological outcomes following prolonged global brain ischemia. The results indicate that a customized mechanical reperfusion protocol can attenuate neurological injury.

Mechanical ventilation is the cornerstone of the Intensive Care Unit. However, it has been associated with many negative consequences. Recently, ventilator-induced brain injury has been reported in rodents under injurious ventilation settings. Our group wanted to explore the extent of brain injury after 50 h of mechanical ventilation, sedation and physical immobility, quantifying hippocampal apoptosis and inflammation, in a normal-lung porcine study. After 50 h of lung-protective mechanical ventilation, sedation and immobility, greater levels of hippocampal apoptosis and neuroinflammation were clearly observed in the mechanically ventilated group, in comparison to a never-ventilated group. Markers in the serum for astrocyte damage and neuronal damage were also higher in the mechanically ventilated group. Therefore, our study demonstrated that considerable hippocampal insult can be observed after 50 h of lung-protective mechanical ventilation, sedation and physical immobility.

Effects of treatment-associated variables on cerebrovascular autoregulation (CA) in acute brain injury patients remain unclear. As deficient CA is associated with worse outcomes and ideas about CA-steered management are emerging, this question is relevant. We investigated effects of norepinephrine and propofol infusion rates and hemoglobin concentration on dynamic measurements of cerebrovascular reactivity as surrogate for CA. A retrospective analysis of 91 traumatic brain injury (TBI) and 13 stroke patients admitted to the intensive care unit (ICU) of the Leuven University Hospitals was performed. Low-resolution autoregulation index (LAx) and high-frequency pressure reactivity index (PRx) were calculated as measurements of cerebrovascular reactivity. Data was binned into 5-, 15-, and 60-min intervals. Bivariate time-series analysis using lagged cross-correlations were calculated after pre-whitening and differencing. Linear mixed models evaluated effects of age, gender, cardiovascular risk, brain comorbidity, Glasgow Coma Scale (GCS), pupil reactivity, and type of injury. Median dose of norepinephrine, propofol and hemoglobin concentration was 7.8 μg/kg/h (Q1 3.6-Q3 13.8), 3 mg/kg/h (Q1 1.9-Q3 4.3), and 9.2 g·dL -1 (Q1 8.2-Q3 10.5), respectively. Mean cross-correlations for 24 lags were close to zero and not significant for all variables. No significant differences as function of age, gender, cardiovascular risk, brain comorbidity, GCS, pupil reactivity, and type of injury were found. Dynamic intracranial pressure-based measurements of cerebrovascular reactivity in acute brain injured patients are not affected by gradually adjusted norepinephrine or propofol infusion rates or slow changes in hemoglobin concentration within the typical ranges during ICU admission. Future trials on cerebrovascular reactivity-steered management and treatment of CA impairment may not have to take these variables into account.

Diabetic brain is a serious complication of diabetes, and it is associated with oxidative stress and neuronal injury. This study investigated the protective effect of melatonin (MLT) on diabetes-induced brain injury. A rat model of type 2 diabetes mellitus was produced by intraperitoneal injection of nicotinamide 100 mg/kg, followed by intraperitoneal injection of streptozotocin 55 mg/kg. The diabetic rats were orally administered MLT 10 mg/kg of body weight for 15 days. MLT remarkably downregulated serum glucose levels. It also improved levels of the lipid peroxidation product 4-hydroxynonenal, improved levels of antioxidants including glutathione, glutathione peroxidase and glutathione reductase in the brains of the diabetic rats, and this is indicative of the antioxidant potential of MLT. MLT also prevented increase in homocysteine, amyloid-β42 and tau levels in diabetic rats, and this suggests that it can reduce the risk of dementia. This is associated with reduction in the levels of the dopamine, serotonin, and glutamate and is indicative of the regulatory effect of MLT on neurotransmitters. Treatment with MLT improved diabetes-induced structural alteration in the hippocampus and cerebral cortex. MLT significantly reduced caspase-3 and Bax as well as significantly increase Bcl-2 protein and GFAP-positive astrocytes indicating its anti-apoptotic effect. MLT showed remarkable ameliorative effect against biochemical and molecular alterations in the brains of diabetic rats most likely through its antioxidant property., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group ( P <0.0001). Histology showed less neuronal degeneration in the cortex ( P <0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus ( P =0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation ( P <0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release ( P <0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.

Background: Pneumococcal meningitis (PM) remains a global public health concern and affects all age groups. If acquired during infancy or childhood, permanent neurofunctional deficits including cognitive impairment, cerebral palsy, and secondary epilepsy are typical sequelae of neuronal injury. Determination of patients at risk for the development of brain injury and subsequent neurofunctional sequelae could help to identify patients for focused management. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released upon neuronal injury into the cerebrospinal fluid (CSF) and blood. As little is known about the course of neurofilament release in the course of PM, we measured CSF and serum NfL levels longitudinally in experimental PM (ePM)., Methods: Eleven-day-old infant Wistar rats were infected intracisternally with Streptococcus pneumoniae and treated with ceftriaxone. At 18 and 42 h post-infection (hpi), the blood and CSF were sampled for NfL measurements by a single molecule array technology. Inflammatory cytokines and MMP-9 in CSF were quantified by magnetic bead multiplex assay (Luminex®) and by gel zymography, respectively., Results: In ePM, CSF and serum NfL levels started to increase at 18 hpi and were 26- and 3.5-fold increased, respectively, compared to mock-infected animals at 42 hpi (p < 0.0001). CSF and serum NfL correlated at 18 hpi (p < 0.05, r = 0.4716) and 42 hpi (p < 0.0001, r = 0.8179). Both CSF and serum NfL at 42 hpi strongly correlated with CSF levels of IL-1β, TNF-α, and IL-6 and of MMP-9 depending on their individual kinetics., Conclusion: Current results demonstrate that during the peak inflammatory phase of ePM, NfL levels in CSF and serum are the highest among CNS disease models studied so far. Given the strong correlation of CSF versus serum NfL, and its CNS-specific signal character, longitudinal measurements to monitor the course of PM could be performed based on blood sample tests, i.e., without the need of repetitive spinal taps. We conclude that NfL in the serum should be evaluated as a biomarker in PM.

Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs-miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128-were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival.

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood-brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.

The identification of precision blood biomarkers which can accurately indicate damage to brain tissue could yield molecular diagnostics with the potential to improve how we detect and treat neurological pathologies. However, a majority of candidate blood biomarkers for neurological damage that are studied today are proteins which were arbitrarily proposed several decades before the advent of high-throughput omic techniques, and it is unclear whether they represent the best possible targets relative to the remainder of the human proteome. Here, we leveraged mRNA expression data generated from nearly 12,000 human specimens to algorithmically evaluate over 17,000 protein-coding genes in terms of their potential to produce blood biomarkers for neurological damage based on their expression profiles both across the body and within the brain. The circulating levels of proteins associated with the top-ranked genes were then measured in blood sampled from a diverse cohort of patients diagnosed with a variety of acute and chronic neurological disorders, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, Alzheimer's disease, and multiple sclerosis, and evaluated for their diagnostic performance. Our analysis identifies several previously unexplored candidate blood biomarkers of neurological damage with possible clinical utility, many of which whose presence in blood is likely linked to specific cell-level pathologic processes. Furthermore, our findings also suggest that many frequently cited previously proposed blood biomarkers exhibit expression profiles which could limit their diagnostic efficacy., Competing Interests: The authors declare no competing interest.

In predicting outcomes in patients with acute brain injury, current practice focuses special attention on neuron-specific proteins that reliably reflect the severity of the lesion. Further studies of molecular markers and their specificity and sensitivity could contribute to broadening the understanding of pathophysiological, diagnostic, and prognostic methods, which is vital to reducing the mortality and disability associated with these critical conditions. The purpose of this study was to assess the biomarkers of brain lesions and their correlative relations with the integral Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) in predicting severity and treatment outcomes in patients with acute neuropathologies. Ninety patients were examined, including those with traumatic brain lesions (16.6%, n = 15), hemorrhagic stroke (52.2%, n = 47), and ischemic stroke (31.1%, n = 28). Patients were classified into two groups according to the outcome of the disease: those who survived (group I, 57.8%, n = 52) and those who died (group II, 42.2%, n = 38). In comparison with the survivors, the group of patients who died demonstrated an initial increase in neuron-specific enolase (NSE) by 1.23 and S100 by 6.45 times, and in dynamics by 1.5 and 7.4 times. A significant correlation with NIHSS and GCS was determined for NSE (r = 0.1149; P = 0.3073 and r = -0.0758; P = 0.5011) and for S100 (r = 0.3243; P = 0.0031 and r = -0.2661; P = 0.0163). The receiver operating characteristic (ROC) curves were 0.828 for S100 and 0.712 for NSE. The degree of sensitivity and specificity of the markers was studied. Increased levels of S100 and NSE correlated with NIHSS and GCS, with sensitivity of 80.77 and 63.46% and specificity of 42.11 and 73.68%, respectively, and were predictive of adverse disease outcome. The survival analysis showed that early detection of these biomarkers enables the timely prognostication of the progression of secondary brain injury and aids in implementing treatment.

Chronic restraint stress (CRS) induces insulin-resistant hyperglycemia by inducing injury to the brain neurons in the nucleus tractus solitarius (NTS). However, the CRS mice did not suffer from hypoglycemia. In this study, mice of both CRS and NTS mechanical injury models were induced to investigate whether impaired glucose metabolism has changed upon the extension of the survival time after modeling. Body weight, food and water intake, fasting blood glucose, glucose tolerance, and glucose metabolism related to blood hormone levels were monitored for 12 weeks following the induction of injury. The mice were also administered with insulin intraperitoneally, and the blood glucose and glucagon levels were measured and compared to those in the control mice administered with saline. The results showed that the body weights of CRS-hyperglycemic mice were significantly higher than those in the control group, while the body weights of NTS mechanically injured mice were significantly lower than those in the control group. The food and water intake of both CRS-hyperglycemic and NTS mechanically injured mice were significantly more than those in the control groups. Although the levels of fasting blood glucose and resting serum hormone in the injured mice have returned to normal levels, the utilization of glucose and hypoglycemic counterregulation (the response that raises the blood glucose levels) was impaired in either CRS-hyperglycemic or NTS mechanically injured mice. The blood glucagon levels following insulin administration showed abnormal increase. These findings suggest that the CRS-induced NTS injury resulted not only in early insulin-resistant hyperglycemia but also impaired the ability to raise blood glucose and glucagon levels when blood glucose levels plummet in the later stage.

Background: Hypotension and/or hypocapnia might increase general anesthesia (GA)-related neuromorbidity in infants, but safe levels of perioperative blood pressure are poorly defined. Serum protein S100b has been used as screening, monitoring, and prediction tool in the management of patients with traumatic brain injury. Using an animal model, we investigated serum S100b as an acute biomarker of cerebral hypoperfusion and cerebral cell dysfunction during hypotension, hypocapnia, or combined hypotension/hypocapnia during GA., Methods: Fifty-seven sevoflurane-midazolam anesthetized piglets aged 4 to 6 weeks were randomly allocated to control (n=9), hypotension (n=18), hypocapnia (n=20), or combined hypotension and hypocapnia (n=10). Hypotension (target mean arterial blood pressure: 35 to 38 or 27 to 30 mm Hg) was induced by blood withdrawal and nitroprusside infusion, and hypocapnia by hyperventilation (target PaCO2: 28 to 30 and 23 to 25 mm Hg). Serum S100b and albumin were measured at baseline, before and 60 minutes after the interventions, and following 60-minute recovery., Results: Serum S100b concentrations decreased over time (P=0.001), but there was no difference in S100b between control piglets and those exposed to hypotension, hypocapnea, or a combination of the both (P=0.105). Albumin decreased in all 4 groups (P=0.001)., Conclusion: S100b did not increase following 60 minutes of systemic hypotension and/or hypocapnia during GA in piglets. In this setting, the use of S100b as a biomarker of cerebral cell tissue dysfunction cannot be supported.

Ischemic stroke provokes an inflammatory response concurrent with both sympathetic nervous system activation and hyperglycemia. Currently, their crosstalk and consequences in stroke outcomes are of clinical attraction. We have provided experimental evidence showing the suppressive effects of the nonselective β-adrenoreceptor antagonist propranolol on hyperglycemia, inflammation, and brain injury in a rat model experiencing cerebral ischemia. Pretreatment with propranolol protected against postischemic brain infarction, edema, and apoptosis. The neuroprotection caused by propranolol was accompanied by a reduction in fasting glucose, fasting insulin, glucose tolerance impairment, plasma C-reactive protein, plasma free fatty acids, plasma corticosterone, brain oxidative stress, and brain inflammation. Pretreatment with insulin alleviated-while glucose augmented-postischemic brain injury and inflammation. Additionally, the impairment of insulin signaling in the gastrocnemius muscles was noted in rats with cerebral ischemia, with propranolol improving the impairment by reducing oxidative stress and tumor necrosis factor-α signaling. The anti-inflammatory effects of propranolol were further demonstrated in isoproterenol-stimulated BV2 and RAW264.7 cells through its ability to decrease cytokine production. Despite their potential benefits, stroke-associated hyperglycemia and inflammation are commonly linked with harmful consequences. Our findings provide new insight into the anti-inflammatory, neuroprotective, and hypoglycemic mechanisms of propranolol in combating neurodegenerative diseases, such as stroke.

We investigated the role of dynamic changes of serum levels S100B protein in brain injury and poor outcome of sepsis. This is a prospective cohort study designed to include 104 adult patients with sepsis who are admitted to ICU from Jan 2015 to Aug 2016. Sepsis was defined as sepsis 3.0. Patients with a GCS score of <15, or at least one positive CAM-ICU score were thought to have brain dysfunction. 59 patients were diagnosed with SAE and the rest 45 patients were diagnosed with non-SAE. Serum S100B was measured on day 1 and 3 after ICU admission. Primary outcomes included brain dysfunction and 28-day/180-day mortality. The SAE group showed a significantly higher APACHE II score, SOFA scores, length of ICU stay, 28-day and 180-day mortality, serum S100B levels on day 1 and day 3. S100B levels on day 1 of 0.226 μg/L were diagnostic for SAE with 80.0% specificity and 66.1% sensitivity, and the area under (AUC) the curve was 0.728, S100B levels on day 3 of 0.144 μg/L were diagnostic for SAE with 84.44% specificity and 69.49% sensitivity, and the AUC was 0.819. In addition, the AUC for S100B on day 3 for predicting 180-day mortality was larger than for S100B on day 1 (0.731 vs. 0.611). Multiple logistic regression analysis showed that S100B3 (p = 0.001) but not S100B1 (p = 0.927) were independently correlated with SAE. Kaplan-Meier survival analysis showed that patients with S100B levels higher than 0.144 μg/L had a lower probability of survival at day 180. There were more patients with encephalopathy and a higher 28-day or 180-day mortality in the ΔS100B + group than in the ΔS100B- group. Multiple logistic regression analysis showed that SAE and IL-6 on day 3 were independently correlated with S100B dynamic increase. These findings suggest that elevated serum S100B levels on day 3 and the dynamic changes of serum S100B levels from day three to one were more associated with brain dysfunction and mortality than that on day 1 in patients with sepsis.

Objective : To evaluate the effects of isolated impaired fasting glucose (IIFG) on brain injury in patients undergoing cardiopulmonary bypass (CPB) surgery. Methods : Patients with rheumatic heart valve disease who underwent elective mitral valve replacement were included and divided into control and IIFG groups. Pre-, intra-, and postoperative blood glucose levels, serum insulin levels, insulin resistance index (HOMA-IR), lactic acid levels, and neuron-specific enolase (NSE) and S100B levels were measured. The cerebral oxygen extraction ratio (OER) was calculated. Cognitive function was assessed via the Mini-Mental State Examination (MMSE). Results : HOMA-IR levels were higher in the IIFG group than the control group 30 min after the beginning of CPB, at the termination of CPB, and 2 h after the termination of CPB. Cerebral OER and lactic acid increased intraoperatively in both groups, especially in the IIFG group. NSE and S100B levels were higher in the IIFG group than in the control group at the termination of CPB, 2 h after the termination of CPB, and at 24 h postoperatively. The MMSE scores did not significantly differ between the two groups. Delirium occurred in two patients in the IIFG group, and one in the control group. No other signs and symptoms of brain injuries were detected in either group. Conclusions : The increased postoperative NSE and S100B levels in the IIFG group compared with controls may be associated with severe insulin resistance and stress hyperglycemia. However, the IIFG group did not have clinical manifestations of brain injuries, including cognitive impairment.

Introduction: Children with CHD who undergo cardiopulmonary bypass are at an increased risk of acute kidney injury. This study evaluated the association of end-organ specific injury plasma biomarkers for brain: glial fibrillary acidic protein and heart: Galectin 3, soluble suppression of tumorgenicity 2, and N-terminal pro b-type natriuretic peptide with acute kidney injury in children undergoing cardiopulmonary bypass., Materials and Methods: We enrolled consecutive children undergoing cardiac surgery with cardiopulmonary bypass. Blood samples were collected pre-bypass in the operating room and in the immediate post-operative period. Acute kidney injury was defined as a rise of serum creatinine ≥50% from pre-operative baseline within 7 days after surgery., Results: Overall, 162 children (mean age 4.05 years, sd 5.28 years) were enrolled. Post-operative acute kidney injury developed in 55 (34%) children. Post-operative plasma glial fibrillary acidic protein levels were significantly higher in patients with acute kidney injury (median 0.154 (inter-quartile range 0.059-0.31) ng/ml) compared to those without acute kidney injury (median 0.056 (inter-quartile range 0.001-0.125) ng/ml) (p = 0.043). After adjustment for age, weight, and The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category, each natural log increase in post-operative glial fibrillary acidic protein was significantly associated with a higher risk for subsequent acute kidney injury (adjusted odds ratio glial fibrillary acidic protein 1.25; 95% confidence interval 1.01-1.59). Pre/post-operative levels of galectin 3, soluble suppression of tumorgenicity 2, and N-terminal pro b-type natriuretic peptide did not significantly differ between patients with and without acute kidney injury., Conclusions: Higher plasma glial fibrillary acidic protein levels measured in the immediate post-operative period were independently associated with subsequent acute kidney injury in children after cardiopulmonary bypass. Elevated glial fibrillary acidic protein likely reflects intraoperative brain injury which may occur in the context of acute kidney injury-associated end-organ dysfunction.

Objective : Although extensively studied in children, the safety and tolerability of ketone supplementation in adults is unclear, particularly in the acute brain injury population. The purpose of this study was to examine the feasibility and safety of inducing ketosis using an enteric ketogenic formulation and determine its impact on intracranial and cerebral perfusion pressures and metabolic parameters. Methods : Prospective interventional Phase II trial of ventilated critically ill patients with acute brain injury administered a ketogenic feed over a 6 day period. Results : 20 patients were recruited, 5 females and 15 males, 3 with stroke, 2 with subarachnoid haemorrhage and 15 with traumatic brain injury. Feeds were well tolerated with 19 patients completing study. There was a significant increase in both plasma beta-hydroxybutyrate and acetoacetate from 0.24± 0.31 mmol/l and 0.19 ± 0.16 mmol/l to 0.61 ± 0.53 mmol/l (p =0.0005) and 0.52 ± 0.40 mmol/l (p<0.0001) respectively over the 6 day period. Total daily Ketocal ® caloric intake was positively correlated with plasma beta-hydroxybutyrate concentrations (p=0.0011). There was no significant correlation between the cerebral hypertension and cerebral hypoperfusion indices and plasma ketone concentrations. In 95% of patients there were no clinically significant changes in acid/base status over the 6 days with pH remaining within normal range. Conclusion : In patients with acute brain injury, an enterally administered ketogenic formulation increased plasma ketone concentrations, was well tolerated, did not impact on cerebral hemodynamics and can be safely administered.Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN12616000332426) Abbreviations : BHB: betahydroxybutyrate; AcAc: acetoacetate; ABI: acute brain injury; TBI: traumatic brain injury; CSF: cerebrospinal fluid; SAH: subarachnoid injury; CVA: cerebrovascular accidents; ICP: intracranial pressure; CPP: cerebral perfusion pressure; ICU: intensive care unit; EVD: external ventricular device; CHI: cerebral hypoperfusion index; IHI: intracranial hypertension index; GCS: Glasgow Coma Scale.

Traumatic brain injury (TBI) is a worldwide public health concern due to increasing mortality, affecting around 10 million patients per year. A wide variety of clinical presentations are a function of the magnitude of injury and the anatomical perturbation of the brain parenchyma, supporting structures, and cerebral vasculature, with subsequent alteration of the blood-brain barrier. These disturbances correspond with the evolution of intracerebral hemorrhage and clinical outcomes. The associated hemostatic alterations associated with TBI are caused by the disruption of the delicate balance between bleeding and thrombosis formation, which can exacerbate initial injury. TBI-associated coagulopathy is a function of a cross-talk between coagulation and inflammation, with varying influences on the immunomodulation and regulation of coagulation that occur on platelets and the endothelium of injured TBI patients. In addition to the severity of initial injury, the following factors modulate the hemocoagulative response to TBI: time from the onset of injury to treatment, age, gender, catecholamine secretion, platelet dysfunction, endotheliopathy, premorbid anticoagulation, fibrinolysis, tissue factor, and activated protein C contribution. All these entities are intertwined and influence the pathologic evolution of TBI. These factors have implications for therapeutic options such as the choice of blood components for transfusion and hemostatic agents such as tranexamic acid. Monitoring hemostatic changes of TBI patients requires an understanding of these interactions between immunology and coagulation, which can be discerned by point-of-care viscoelastic testing with specific limitations. This review considers the implications of these interrelated influences on the evaluation of coagulopathy in TBI., Competing Interests: In the past, Marc Maegele has received speaker's fees and travel payments from Abbott, Laboratories, AstraZeneca, Bayer, Biotest, CSL Behring, LFB Biomedicaments (France), Portola Inc., and TEM International/IL Werfen. Mark Walsh receives research grants from Haemonetics Inc., Braintree, MA, and is on the Speaker's Bureau for Portola Inc., San Francisco, CA., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Problem: Exposure to intrauterine inflammation (IUI) has been shown to induce fetal brain injury and increase the risk of acquiring a neurobehavioral disorder. The trafficking of the inflammatory mediator, lipopolysaccharide (LPS), in the pregnant female reproductive tract in the setting of IUI and the precise mechanisms by which inflammation induces fetal brain injury are not fully understood., Method of Study: FITC-labeled LPS was utilized to induce IUI on E15, tissues were collected, and fluorescence was visualized via the Spectrum IVIS. Embryo transfer was utilized to create divergent maternal and fetal genotypes. Wild-type (WT) embryos were transferred into TLR4-/- pseudopregnant dams (TLR4-/- mat /WT fet ). On E15, TLR4-/- mat /WT fet dams or their WT controls (WT mat /WT fet ) received an intrauterine injection of LPS or phosphate-buffered saline (PBS). Endotoxin and IL-6 levels were assessed in amniotic fluid, and cytokine expression was measured via QPCR., Results: Lipopolysaccharide trafficked to the uterus, fetal membranes, placenta, and the fetus and was undetectable in other tissues. Endotoxin was present in the amniotic fluid of all animals exposed to LPS. However, the immune response was blunted in TLR4-/- mat /WT fet compared with WT controls., Conclusion: Intrauterine administered LPS is capable of accessing the entire feto-placental unit with or without a functional maternal TLR4. Thus, bacteria or bacterial byproducts in the uterus may negatively impact fetal development regardless of the maternal genotype or endotoxin response. Despite the blunted immune response in the TLR4-deficient dams, an inflammatory response is still ignited in the amniotic cavity and may negatively impact the fetus., (© 2019 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Background: S100B and neuron-specific enolase (NSE) have been widely studied in diverse neurocritical pathologies, being recognized as the most promising biomarkers for brain injury assessment. However, their role in intracerebral hemorrhage (ICH) has not been widely analyzed., Methods: This was an observational prospective cohort study of patients with ICH admitted to a neurocritical care unit. Blood samples were collected on admission and at 24 hours, 48 hours, and 72 hours. Patient outcomes were assessed at 6 months after the event., Results: Thirty-six patients with ICH were included in the study. The mortality rate was 36%. Nonsurvivors had higher S100B values than survivors at admission, 24 hours, and 48 hours (P < 0.05). Likewise, S100B levels were higher in patients with poor outcomes (modified Rankin Scale [mRS] score >4) compared with those with good outcome (mRS score ≤3) in the 24-hour, 48-hour, and 72-hour samples. Receiver operating characteristic (ROC) curve analysis showed that S100B at admission, 24 hours, and 48 hours can discriminate between patients who survive and those who die as a consequence of ICH. The 48-hour sample (area under the ROC curve, 0.817; P = 0.003) reached the best values for sensitivity (75%) and specificity (80%); cutoff, 0.250 μg/L. For 6-month functional outcome, S100B protein could differentiate between groups at 24, 48, and 72 hours. The S100B 24-hour sample had the best values for sensitivity (82.6%) and specificity (72.7%), with a cutoff of 0.202 μg/L. We found no clear relationship between NSE values and clinical characteristics., Conclusions: S100B protein acts as early predictor of mortality and functional outcome in patients with ICH. This biomarker measurement can provide additional information beyond clinical and radiologic findings to guide physicians in the management of these patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)