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PURPOSE To examine whether nurse-led stroke aftercare is beneficial for long-term psychosocial outcome of community-dwelling persons with stroke. MATERIALS AND METHODS Comparative effectiveness research design in which a prospective stroke aftercare cohort (n = 87) was compared to care-as-usual (n = 363) at six- and 12-months post stroke. Changes over time in cognitive and emotional problems experienced in daily life, fatigue and stroke impact on daily life were examined for stroke aftercare only. Multilevel modelling was used to compare stroke aftercare to care-as-usual concerning anxiety and depression symptoms, social participation and quality of life, over time. RESULTS Sample characteristics did not differ between cohorts except for stroke type and on average, more severe stroke in the stroke aftercare cohort (p < 0.05). Following stroke aftercare, anxiety and emotional problems decreased significantly (p < 0.05), whereas care-as-usual remained stable over time in terms of anxiety. No significant changes over time were observed on the other outcome domains. CONCLUSIONS Nurse-led stroke aftercare showed to be beneficial for emotional well-being in comparison to care-as-usual. Providing psychoeducation and emotional support seem effective elements but adding other therapeutic elements such as self-management strategies might increase the effectiveness of nurse-led stroke aftercare.Implications for rehabilitationRoutine stroke follow-up care should pay attention to psychosocial and emotional outcome in a systematic manner, in addition to secondary prevention.Healthcare professionals such as (specialized) nurses are needed to appropriately address the hidden cognitive and emotional consequences of stroke.Providing psychoeducation and emotional support in stroke aftercare diminish insecurities and worries in community-dwelling persons with stroke, leading to better outcomes.

PURPOSE: (1) To explore the course of participation from two months up to four years after stroke, and (2) to examine if adaptive and maladaptive psychological factors and mood measured at two months after stroke are determinants of the course of participation during this period.MATERIALS AND METHODS: Prospective cohort study in which 369 individuals with stroke were assessed at stroke onset, two months, six months, one year, two years and three to four years after stroke. The Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-Participation) restrictions subscale was used to measure participation. Psychological factors were clustered into adaptive (proactive coping, self-efficacy, extraversion and optimism) and maladaptive (passive coping, neuroticism and pessimism) psychological factors. The Hospital Anxiety and Depression Scale was used to assess mood.RESULTS: Although improvements in participation were observed up to one year after stroke, considerable long-term restrictions in social and physical domains persisted. More mood problems and less adaptive psychological factors were independent determinants of worse participation up to four years after stroke.CONCLUSIONS: Participation improves in the first 12 months after stroke and stabilizes afterwards. Mood problems and less adaptive psychological factors negatively influence the course of participation over time up to four years after stroke. Implications for rehabilitation Follow-up assessments after stroke should not only focus on cognitive and motor impairment, but also encompass screening on mood problems and adaptive psychological factors. Implementation of a routine follow-up assessment one year after stroke can be beneficial as restrictions in participation are unlikely to diminish spontaneously from then onwards.

Background: Adverse neurological events during extracorporeal membrane oxygenation (ECMO) are common and may be associated with devastating consequences. Close monitoring, early identification and prompt intervention can mitigate early and late neurological morbidity. Neuromonitoring and neurocognitive/neurodevelopmental follow-up are critically important to optimize outcomes in both adults and children. Objective: To assess current practice of neuromonitoring during ECMO and neurocognitive/neurodevelopmental follow-up after ECMO across Europe and to inform the development of neuromonitoring and follow-up guidelines. Methods: The EuroELSO Neurological Monitoring and Outcome Working Group conducted an electronic, web-based, multi-institutional, multinational survey in Europe. Results: Of the 211 European ECMO centres (including non-ELSO centres) identified and approached in 23 countries, 133 (63%) responded. Of these, 43% reported routine neuromonitoring during ECMO for all patients, 35% indicated selective use, and 22% practiced bedside clinical examination alone. The reported neuromonitoring modalities were NIRS ( n = 88, 66.2%), electroencephalography ( n = 52, 39.1%), transcranial Doppler ( n = 38, 28.5%) and brain injury biomarkers ( n = 33, 24.8%). Paediatric centres (67%) reported using cranial ultrasound, though the frequency of monitoring varied widely. Before hospital discharge following ECMO, 50 (37.6%) reported routine neurological assessment and 22 (16.5%) routinely performed neuroimaging with more paediatric centres offering neurological assessment (65%) as compared to adult centres (20%). Only 15 (11.2%) had a structured longitudinal follow-up pathway (defined followup at regular intervals), while 99 (74.4%) had no follow-up programme. The majority ( n = 96, 72.2%) agreed that there should be a longitudinal structured follow-up for ECMO survivors. Conclusions: This survey demonstrated significant variability in the use of different neuromonitoring modalities during and after ECMO. The perceived importance of neuromonitoring and follow-up was noted to be very high with agreement for a longitudinal structured follow-up programme, particularly in paediatric patients. Scientific society endorsed guidelines and minimum standards should be developed to inform local protocols.

Aim: To determine the ability of serum glial fibrillary acidic protein (GFAp) and tau protein to predict neurological outcome after out-of-hospital cardiac arrest (OHCA). Methods: We measured plasma concentrations of GFAp and tau of patients included in the previously published COMACARE trial (NCT02698917) on intensive care unit admission and at 24, 48, and 72 h after OHCA, and compared them to neuron specific enolase (NSE). NSE concentrations were determined already during the original trial. We defined unfavourable outcome as a cerebral performance category (CPC) score of 3-5 six months after OHCA. We determined the prognostic accuracy of GFAp and tau using the receiver operating characteristic curve and area under the curve (AUROC). Results: Overall, 39/112 (35%) patients had unfavourable outcomes. Over time, both markers were evidently higher in the unfavourable outcome group (p < 0.001). At 48 h, the median (interquartile range) GFAp concentration was 1514 (886-4995) in the unfavourable versus 238 (135-463) pg/ ml in the favourable outcome group (p < 0.001). The corresponding tau concentrations were 99.6 (14.5-352) and 3.0 (2.2-4.8) pg/ml (p < 0.001). AUROCs at 48 and 72 h were 0.91 (95% confidence interval 0.85-0.97) and 0.91 (0.85-0.96) for GFAp and 0.93 (0.86-0.99) and 0.95 (0.89-1.00) for tau. Corresponding AUROCs for NSE were 0.86 (0.79-0.94) and 0.90 (0.82-0.97). The difference between the prognostic accuracies of GFAp or tau and NSE were not statistically significant. Conclusions: At 48 and 72 h, serum both GFAp and tau demonstrated excellent accuracy in predicting outcomes after OHCA but were not superior to NSE. Clinical trial registration: NCT02698917 (https://www.clinicaltrials.gov/ct2/show/NCT02698917).

Objective: Self-regulation, participation and health-related quality of life are important rehabilitation outcomes. The aim of this study was to explore associations between these outcomes in a multi-diagnostic and heterogenic group of former rehabilitation patients.Methods: This cross-sectional survey used the Self-Regulation Assessment (SeRA), Utrecht Scale for Evaluation of Rehabilitation-participation (USERParticipation) and the Patient-Reported-Outcome-Measurement-System (PROMIS) ability and PROMIS satisfaction with participation in social roles, and the EuroQol-5L-5D and PROMIS-10 Global Health. Regression analyses, controlling for demographic and condition-related factors, were performed.Results: Respondents (n = 563) had a mean age of 56.5 (standard deviation (SD) 12.7) years. The largest diagnostic groups were chronic pain disorder and brain injury. In addition to demographic and condition-related factors, self-regulation subscales explained 0–15% of the variance in participation outcome scores, and 0–22% of the variance in HRQoL outcome scores. Self-regulation subscales explained up to 22% of the variance in satisfaction subscales of participation (USER-Participation and PROMIS) and the mental health subscale of the PROMIS-10. Self-regulation subscales explained up to 11% of the restriction and frequency subscales of participation (USER-Participation) and the physical health subscale of the PROMIS-10.Conclusion: Self-regulation is more strongly associated with outcomes such as satisfaction with participation and mental health compared with outcomes such as restrictions in participation and physical health. LAY ABSTRACTThis article provide insights into the assocations between self-regulation, participation and health-related quality of life. This was studied in a rehabilitation population. Diagnostic groups included were: brain injury, chronic pain disorder, spinal cord injury, neurological and neuromuscular disorder, musculoskeletal disorder and oncology. We found that persons with higher levels of self-regulation, experience more satisfaction with their functioning in the community and experience less mental health problems. Also, when persons have trust in themselves, they tend to have less mental health problems and are more satisfied in their daily life.

Background Brain injury and neurodevelopmental impairment remain a concern in children with complex congenital heart disease (CHD). A practice guideline on neuromonitoring, neuroimaging, and neurodevelopmental follow-up in CHD patients undergoing cardiopulmonary bypass surgery is lacking. The aim of this survey was to systematically evaluate the current practice in centers across Europe. Methods An online-based structured survey was sent to pediatric cardiac surgical centers across Europe between April 2019 and June 2020. Results were summarized by descriptive statistics. Results Valid responses were received by 25 European centers, of which 23 completed the questionnaire to the last page. Near-infrared spectroscopy was the most commonly used neuromonitoring modality used in 64, 80, and 72% preoperatively, intraoperatively, and postoperatively, respectively. Neuroimaging was most commonly performed by means of cranial ultrasound in 96 and 84% preoperatively and postoperatively, respectively. Magnetic resonance imaging was obtained in 72 and 44% preoperatively and postoperatively, respectively, but was predominantly reserved for clinically symptomatic patients (preoperatively 67%, postoperatively 64%). Neurodevelopmental follow-up was implemented in 40% of centers and planned in 24%. Conclusions Heterogeneity in perioperative neuromonitoring and neuroimaging practice in CHD in centers across Europe is large. The need for neurodevelopmental follow-up has been recognized. A clear practice guideline is urgently needed. Impact There is large heterogeneity in neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices among European centers caring for neonates with complex congenital heart disease. This study provides a systematic evaluation of the current neuromonitoring, neuroimaging, and neurodevelopmental follow-up practice in Europe. The results of this survey may serve as the basis for developing a clear practice guideline that could help to early detect and prevent neurological and neurodevelopmental sequelae in neonates with complex congenital heart disease.

Purpose: Ample evidence exists on the relationship between bicycle injuries and craniofacial fractures. However, as the mechanism behind these injuries is often multifactorial, the presence of associated injuries (AIs) in this study population requires further examination. We hypothesized that patients with craniofacial fracture injured in bicycle accidents are at high risk of sustaining severe AIs, especially those of the head and neck region. Patients and Methods: The investigators performed a retrospective study on all patients with bicyclerelated craniofacial fracture admitted to a tertiary trauma centre during 2013 to 2018. The predictor variable was defined as any type of craniofacial fracture. The outcome variable was defined as any kind of AI. Other study variables included demographic and injury-related parameters. Variables were analyzed using bivariate and Firth's logistic regression analyses. Results: A total of 407 patients were included in the analysis. Our results revealed that AIs were present in 150 (36.9%) patients; there were multiple AIs in 47 cases. Traumatic brain injuries followed by upper limb injuries were the most frequent AIs. Severe head and neck injuries were present in 20.1% of all patients with craniofacial fracture. AIs were observed in 57.4% of patients with combined midfacial fractures (P < .001). Helmet use had a protective effect against traumatic brain injuries (P < .001). Conclusions: Our results suggest that AIs are relatively common in this specific patient population. Close co-operation in multidisciplinary trauma centers allowing comprehensive evaluation and treatment can be recommended for patients with bicycle-related craniofacial fracture. (C) 2021 American Association of Oral and Maxillofacial Surgeons.

ObjectiveEstablish if serial, multichannel video electroencephalography (EEG) in preterm infants can accurately predict 2-year neurodevelopmental outcome.Design and patientsEEGs were recorded at three time points over the neonatal course for infants SettingNeonatal intensive care unit at Cork University Maternity Hospital, Ireland.Main outcome measuresBayley Scales of Infant Development III at 2 years’ corrected age.ResultsSixty-seven infants were prospectively enrolled in the study and 57 had follow-up available (median GA 28.9 weeks (IQR 26.5–30.4)). Forty had normal outcome, 17 had abnormal outcome/died. All EEG time points were individually predictive of abnormal outcome; however, the 35-week EEG performed best. The area under the receiver operating characteristic curve (AUC) for this time point was 0.91 (95% CI 0.83 to 1), pConclusionMultichannel EEG is a strong predictor of 2-year outcome in preterm infants particularly when recorded around 35 weeks’ PMA. Infants at high risk of brain injury may benefit from early postnatal EEG recording which, if normal, is reassuring. Postnatal clinical complications can contribute to poor outcome; therefore, we state that a later EEG around 35 weeks has a role to play in prognostication.

Encephalopathy of prematurity (EoP) is a common cause of long‐term neurodevelopmental morbidity in extreme preterm infants. Diffuse white matter injury (dWMI) is currently the most commonly observed form of EoP. Impaired maturation of oligodendrocytes (OLs) is the main underlying pathophysiological mechanism. No therapies are currently available to combat dWMI. Intranasal application of mesenchymal stem cells (MSCs) is a promising therapeutic option to boost neuroregeneration after injury. Here, we developed a double‐hit dWMI mouse model and investigated the therapeutic potential of intranasal MSC therapy. Postnatal systemic inflammation and hypoxia‐ischemia led to transient deficits in cortical myelination and OL maturation, functional deficits and neuroinflammation. Intranasal MSCs migrated dispersedly into the injured brain and potently improved myelination and functional outcome, dampened cerebral inflammationand rescued OL maturation after dWMI. Cocultures of MSCs with primary microglia or OLs show that MSCs secrete factors that directly promote OL maturation and dampen neuroinflammation. We show that MSCs adapt their secretome after ex vivo exposure to dWMI milieu and identified several factors including IGF1, EGF, LIF, and IL11 that potently boost OL maturation. Additionally, we showed that MSC‐treated dWMI brains express different levels of these beneficial secreted factors. In conclusion, the combination of postnatal systemic inflammation and hypoxia‐ischemia leads to a pattern of developmental brain abnormalities that mimics the clinical situation. Intranasal delivery of MSCs, that secrete several beneficial factors in situ, is a promising strategy to restore myelination after dWMI and subsequently improve the neurodevelopmental outcome of extreme preterm infants in the future., Main Points Intranasal MSC therapy potently restores myelination after encephalopathy of prematurity.MSCs modify their secretome in situ to support OL maturation by upregulating valuable, beneficial growth factors and/or anti‐inflammatory cytokines.

Extremely low frequency electromagnetic stimulation (ELF-EMS) has been considered as a neuroprotective therapy for ischemic stroke based on its capacity to induce nitric oxide (NO) signaling. Here, we examined whether ELF-EMS reduces ischemic stroke volume by stimulating cerebral collateral perfusion. Moreover, the pathway responsible for ELF-EMS-induced NO production was investigated. ELF-EMS diminished infarct growth following experimental stroke in collateral-rich C57BL/6 mice, but not in collateral-scarce BALB/c mice, suggesting that decreased lesion sizes after ELF-EMS results from improved collateral blood flow. In vitro analysis demonstrated that ELF-EMS increased endothelial NO levels by stimulating the Akt-/eNOS pathway. Furthermore, ELF-EMS augmented perfusion in the hind limb of healthy mice, which was mediated by enhanced Akt-/eNOS signaling. In healthy C57BL/6 mouse brains, ELF-EMS treatment increased cerebral blood flow in a NOS-dependent manner, whereas no improvement in cerebrovascular perfusion was observed in collateral-sparse BALB/c mice. In addition, ELF-EMS enhanced cerebral blood flow in both the contra- and ipsilateral hemispheres of C57BL/6 mice subjected to experimental ischemic stroke. In conclusion, we showed that ELF-EMS enhances (cerebro)vascular perfusion by stimulating NO production, indicating that ELF-EMS could be an attractive therapeutic strategy for acute ischemic stroke by improving cerebral collateral blood flow.

Involvement of the cerebellum in the pathophysiology of hypoxic‐ischemic encephalopathy (HIE) in preterm infants is increasingly recognized. We aimed to assess the neuroprotective potential of intravenously administered multipotent adult progenitor cells (MAPCs) in the preterm cerebellum. Instrumented preterm ovine fetuses were subjected to transient global hypoxia‐ischemia (HI) by 25 minutes of umbilical cord occlusion at 0.7 of gestation. After reperfusion, two doses of MAPCs were administered intravenously. MAPCs are a plastic adherent bone‐marrow‐derived population of adult progenitor cells with neuroprotective potency in experimental and clinical studies. Global HI caused marked cortical injury in the cerebellum, histologically indicated by disruption of cortical strata, impeded Purkinje cell development, and decreased dendritic arborization. Furthermore, global HI induced histopathological microgliosis, hypomyelination, and disruption of white matter organization. MAPC treatment significantly prevented cortical injury and region‐specifically attenuated white matter injury in the cerebellum following global HI. Diffusion tensor imaging (DTI) detected HI‐induced injury and MAPC neuroprotection in the preterm cerebellum. This study has demonstrated in a preclinical large animal model that early systemic MAPC therapy improved structural injury of the preterm cerebellum following global HI. Microstructural improvement was detectable with DTI. These findings support the potential of MAPC therapy for the treatment of HIE and the added clinical value of DTI for the detection of cerebellar injury and the evaluation of cell‐based therapy., Systemic multipotent adult progenitor cells protected the preterm cerebellum in a preclinical animal model of perinatal asphyxia. Diffusion tensor imaging detected cerebellar injury and repair underlining the added clinical value of this imaging technique.

Congenital heart defects (CHD) is one of the most common types of birth defects. Thanks to advances in surgical techniques and intensive care, the majority of children with severe forms of CHD survive into adulthood. However, this increase in survival comes with a cost. CHD survivors have neurological functioning at the bottom of the normal range. A large spectrum of central nervous system dysmaturation leads to the deficits seen in critical CHD. The heart develops early during gestation, and CHD has a profound effect on fetal brain development for the remainder of gestation. Term infants with critical CHD are born with an immature brain, which is highly susceptible to hypoxic-ischemic injuries. Perioperative blood flow disturbances due to the CHD and the use of cardiopulmonary bypass or circulatory arrest during surgery cause additional neurological injuries. Innate patient factors, such as genetic syndromes and preterm birth, and postoperative complications play a larger role in neurological injury than perioperative factors. Strategies to reduce the disability burden in critical CHD survivors are urgently needed.

Background: Ischemic stroke is a devastating disease without a cure. The available treatments for ischemic stroke, thrombolysis by tissue plasminogen activator, and thrombectomy are suitable only to a fraction of patients and thus novel therapeutic approaches are urgently needed. The neuroinflammatory responses elicited secondary to the ischemic attack further aggravate the stroke-induced neuronal damage. It has been demonstrated that these responses are regulated at the level of non-coding RNAs, especially miRNAs.Methods: We utilized lentiviral vectors to overexpress miR-669c in BV2 microglial cells in order to modulate their polarization. To detect whether the modulation of microglial activation by miR-669c provides protection in a mouse model of transient focal ischemic stroke, miR-669c overexpression was driven by a lentiviral vector injected into the striatum prior to induction of ischemic stroke.Results: Here, we demonstrate that miR-669c-3p, a member of chromosome 2 miRNA cluster (C2MC), is induced upon hypoxic and excitotoxic conditions in vitro and in two different in vivo models of stroke. Rather than directly regulating the neuronal survival in vitro, miR-669c is capable of attenuating the microglial proinflammatory activation in vitro and inducing the expression of microglial alternative activation markers arginase 1 (Arg1), chitinase-like 3 (Ym1), and peroxisome proliferator-activated receptor gamma (PPAR-γ). Intracerebral overexpression of miR-669c significantly decreased the ischemia-induced cell death and ameliorated the stroke-induced neurological deficits both at 1 and 3 days post injury (dpi). Albeit miR-669c overexpression failed to alter the overall Iba1 protein immunoreactivity, it significantly elevated Arg1 levels in the ischemic brain and increased colocalization of Arg1 and Iba1. Moreover, miR-669c overexpression under cerebral ischemia influenced several morphological characteristics of Iba1 positive cells. We further demonstrate the myeloid differentiation primary response gene 88 (MyD88) transcript as a direct target for miR-669c-3p in vitro and show reduced levels of MyD88 in miR-669c overexpressing ischemic brains in vivo.Conclusions: Collectively, our data provide the evidence that miR-669c-3p is protective in a mouse model of ischemic stroke through enhancement of the alternative microglial/macrophage activation and inhibition of MyD88 signaling. Our results accentuate the importance of controlling miRNA-regulated responses for the therapeutic benefit in conditions of stroke and neuroinflammation.

Cerebral metabolism is tightly regulated and fundamental for healthy neurological function. There is increasing evidence that alterations in this metabolism may be a precursor and early biomarker of later stage disease processes. Proton magnetic resonance spectroscopy (1H-MRS) is a powerful tool to non-invasively assess tissue metabolites and has many applications for studying the normal and diseased brain. However, the technique has limitations including low spatial and temporal resolution, difficulties in discriminating overlapping peaks, and challenges in assessing metabolic flux rather than steady-state concentrations. Hyperpolarized carbon-13 magnetic resonance imaging is an emerging clinical technique that may overcome some of these spatial and temporal limitations, providing novel insights into neurometabolism in both health and in pathological processes such as glioma, stroke and multiple sclerosis. This review will explore the growing body of pre-clinical data that demonstrates a potential role for the technique in assessing metabolism in the central nervous system. There are now a number of clinical studies being undertaken in this area and this review will present the emerging clinical data as well as the potential future applications of hyperpolarized 13C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.

The conventional assessment of preterm somatosensory functions using averaged cortical responses to electrical stimulation ignores the characteristic components of preterm somatosensory evoked responses (SERs). Our study aimed to systematically evaluate the occurrence and development of SERs after tactile stimulus in preterm infants. We analysed SERs performed during 45 electroencephalograms (EEGs) from 29 infants at the mean post-menstrual age of 30.7 weeks. Altogether 2,087 SERs were identified visually at single trial level from unfiltered signals capturing also their slowest components. We observed salient SERs with a high amplitude slow component at a high success rate after hand (95%) and foot (83%) stimuli. There was a clear developmental change in both the slow wave and the higher frequency components of the SERs. Infants with intraventricular haemorrhage (IVH; eleven infants) had initially normal SERs, but those with bilateral IVH later showed a developmental decrease in the ipsilateral SER occurrence after 30 weeks of post-menstrual age. Our study shows that tactile stimulus applied at bedside elicits salient SERs with a large slow component and an overriding fast oscillation, which are specific to the preterm period. Prior experimental research indicates that such SERs allow studying both subplate and cortical functions. Our present findings further suggest that they might offer a window to the emergence of neurodevelopmental sequalae after major structural brain lesions and, hence, an additional tool for both research and clinical neurophysiological evaluation of infants before term age.

Background The rapidly increasing number of elderly (≥ 65 years old) with TBI is accompanied by substantial medical and economic consequences. An ASDH is the most common injury in elderly with TBI and the surgical versus conservative treatment of this patient group remains an important clinical dilemma. Current BTF guidelines are not based on high-quality evidence and compliance is low, allowing for large international treatment variation. The RESET-ASDH trial is an international multicenter RCT on the (cost-)effectiveness of early neurosurgical hematoma evacuation versus initial conservative treatment in elderly with a t-ASDH Methods In total, 300 patients will be recruited from 17 Belgian and Dutch trauma centers. Patients ≥ 65 years with at first presentation a GCS ≥ 9 and a t-ASDH > 10 mm or a t-ASDH 5 mm, or a GCS Discussion The study results will be implemented after publication and presented on international conferences. Depending on the trial results, the current Brain Trauma Foundation guidelines will either be substantiated by high-quality evidence or will have to be altered. Trial registration Nederlands Trial Register (NTR), Trial NL9012. ClinicalTrials.gov, Trial NCT04648436.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by cognitive, affective, and motor dysfunction. The main pathophysiological mechanisms are chronic neuroinflammation, hyper-phosphorylated tau (p-tau) accumulation and neurodegeneration. CTE is mostly caused by exposure to multiple mild traumatic brain injuries, placing people participating in, for example, high contact sports at increased risk. Currently, CTE can solely be diagnosed post mortem based on the spatial pattern of tau-accumulation. Herein, we review candidate imaging and molecular biomarkers for their sensitivity and specificity and we look whether these are sufficient for reliable ante mortem diagnosis. Of the imaging biomarkers, PET appears to have the best potential. Candidate fluid biomarkers consist of genes and proteins found in brain derived extracellular vesicles, as well as cerebrospinal fluid (CSF) p-tau levels. However, neither these biomarkers nor the imaging biomarkers have the discriminatory power to differentiate between CTE and other tauopathies, highlighting the need for further validation. Future research could incorporate machine learning methodologies to differentiate between the tau accumulation patterns detected by PET/fMRI in Alzheimer's and CTE patients. Additionally, proteomic and metabolomic profiling of CSF and plasma associated with chronic mild traumatic brain injuries could highlight potential biomarkers for identifying at risk patients.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by cognitive, affective, and motor dysfunction. The main pathophysiological mechanisms are chronic neuroinflammation, hyper-phosphorylated tau (p-tau) accumulation and neurodegeneration. CTE is mostly caused by exposure to multiple mild traumatic brain injuries, placing people participating in, for example, high contact sports at increased risk. Currently, CTE can solely be diagnosed post mortem based on the spatial pattern of tau-accumulation. Herein, we review candidate imaging and molecular biomarkers for their sensitivity and specificity and we look whether these are sufficient for reliable ante mortem diagnosis. Of the imaging biomarkers, PET appears to have the best potential. Candidate fluid biomarkers consist of genes and proteins found in brain derived extracellular vesicles, as well as cerebrospinal fluid (CSF) p-tau levels. However, neither these biomarkers nor the imaging biomarkers have the discriminatory power to differentiate between CTE and other tauopathies, highlighting the need for further validation. Future research could incorporate machine learning methodologies to differentiate between the tau accumulation patterns detected by PET/fMRI in Alzheimer's and CTE patients. Additionally, proteomic and metabolomic profiling of CSF and plasma associated with chronic mild traumatic brain injuries could highlight potential biomarkers for identifying at risk patients.

ObjectiveTo explore experiences of recovery after physical trauma and identify long-term needs for posthospital care.Design, participants and settingA qualitative study was conducted consisting of seven online focus groups among working-age adults who sustained their injury between 9 months and 5 years ago. Trauma patients discharged from a level 1 trauma centre in the Netherlands were divided into three groups based on the type of their physical trauma (monotrauma, polytrauma and traumatic brain injury). Group interviews were transcribed verbatim, and thematic analysis was conducted.ResultsDespite differences in type and severity of their injuries, participants all struggled with the impact that trauma had on various aspects of their lives. They experienced recovery as an unpredictable and inconstant process aimed at resuming a meaningful life. Work was often perceived as an important part of recovery, though the value attributed to work could change over time. Participants struggled to bring the difficulties they encountered in their daily lives and at work to the attention of healthcare professionals (HCPs). While posthospital care needs varied between and across groups, all people stressed the need for flexible access to person-centred, multidisciplinary care and support after hospital discharge.ConclusionsThis study reveals that people with a broad variety of injury experience recovery as a process towards resuming a meaningful life and report the need to expand trauma care to include comprehensive support to live well long term. Person-centred care might be helpful to enable HCPs to take people’s individual long-term needs and life situations into account. Furthermore, providing timely access to coordinated, multidisciplinary care after discharge is advocated. Integrated care models that span a network of multidisciplinary support around the person may help align existing services and may facilitate easy and timely access to the most suitable support for injured people and their loved ones.

Objective: There is a growing body of research aimed at identifying biological markers that could indicate traumatic cerebral deaths such as traumatic brain damage in the postmortem period. In the event of astrocytic and neuronal injury, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are released into cerebrospinal fluid and blood. In the postmortem identification of traumatic brain injury, the present research explores the ability of GFAP and UCH-L1. Methods: Cerebrospinal fluid and blood samples were obtained from medicolegal autopsies, 17 cases with severe head trauma, 9 cases with the non-lethal head trauma group and 18 control cases. UCH-L1 and GFAP levels in postmortem cerebrospinal fluid and serum were determined from an enzyme-linked immunosorbent assay (ELISA). Results: GFAP level in cerebrospinal fluid and serum was 2.68±0.67 ng/ml and 0.79±0.92 ng/ml in the lethal head trauma group, 2.74±0.64 ng/ml and 1.05±0.68 ng/ml the non-lethal head trauma group and 2.49±0.55 ng/ml and 1.05±0.89 ng/ml in the control group, respectively. UCH-L1 level in cerebrospinal fluid and serum was 3.02±0.68 ng/ml and 2.69±0.77 ng/ml in the lethal head trauma group, 3.34±0.70 ng/ml and 2.59±0.65 ng/ml the non-lethal head trauma group and 3.28±0.33 ng/ml and 2.74±0.34 ng/ml in the control group, respectively. Elevated cerebrospinal fluid and serum UCH-L1 and GFAP levels were observed in all cases, although absence of statistically significant difference between the trauma and control groups (p>0.05). Conclusion: Further studies are needed to assess whether postmortem serum and CSF GFAP and UCH-L1 concentrations increase regardless of the cause of death.

Recent years have seen the emergence of the S100 calcium-binding protein B (S100B) biomarker used in the initial management of minor traumatic brain injury (TBI) patients. S100B has been found to reduce cerebral computed tomography (CT-C) scans and was recently implemented in the Scandinavian Neurotrauma Committee (SNC) guidelines. In a clinical setup, we retrospectively investigated the use of the S100B biomarker in relation to the SNC guidelines in the respective year before and after implementation. Accordingly, minor TBI patients with the International Classification of Diseases, Tenth Revision diagnostic code of S06.0 commotio cerebri were included in 2018 (n = 786) and 2019 (n = 709) for comparison of emergency department time (EDT) and CT-Cs. In 2019, we included all patients with an S100B sample (n = 547; 348/199 male:female; median age, 52 years). We found an S100B sensitivity of 92% and negative predictive value (NPV) of 99% (cutoff, 0.10 mu g/L) regardless of SNC guideline compliance. With strict SNC guideline management, sensitivity and NPV increased to 100%, even at a 0.20-mu g/L cutoff that increased the specificity from 49% to 76%. After S100B implementation, we found the median EDT to significantly increase from 196 min (interquartile range [IQR] = 127-289) in 2018 to 216 min (IQR = 134.0-309.5) in 2019 (p = 0.0148), which may have resulted from poor guideline compliance (53.9%). Contrarily, the proportion of CT-C scanned patients decreased from 70% to 56.3% equal to a relative 27.5% decrease of scanned patients (p < 0.0001). Conclusively, our study supported the safe and efficient clinical use of the S100B biomarker, albeit with a minor EDT increase. S100B combination with the SNC guidelines improved clinical potential.

ispartof: ACTA ANAESTHESIOLOGICA BELGICA vol:72 pages:45-53 status: published

Circulating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and a GFP BM chimeric approach, we found neuroprotection and a lack of significant motor deficits marked by reduced monocyte/macrophage cortical infiltration and an increased number of arginase-1(+) cells in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to antiinflammatory that included increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocytes/macrophages. In Epha4-BM-deficient mice, cortical-isolated GFP(+) monocytes/macrophages displayed a phenotypic shift from a classical to an intermediate subtype, which displayed reduced Ly6c(hi) concomitant with increased Ly6c(lo)- and Tie2-expressing populations. Furthermore, clodronate liposome-mediated monocyte depletion mimicked these effects in WT mice but resulted in attenuation of phenotype in Epha4-BM-deficient mice. This demonstrates that monocyte polarization not overall recruitment dictates neural tissue damage. Thus, coordination of monocyte proinflammatory phenotypic state by Epha4 is a key regulatory step mediating brain injury. Center for Engineered Health; National Institute of Neurological Disorders and Stroke of the NIH [NS121103] Published version We acknowledge The Center for Engineered Health for grant support and Mellissa Markus for flow cytometry support. The graphical abstract was created with BioRender.com. This work was supported by National Institute of Neurological Disorders and Stroke of the NIH grants NS121103 (to MHT).

Purpose Chronic traumatic encephalopathy refers to a neurodegenerative disease resulting from repetitive head injury of participants in contact sports. Similar to other neurodegenerative diseases, neuroinflammation is thought to play a role in the onset and progression of the disease. Limited knowledge is available regarding the neuroinflammatory consequences of repetitive head injury in currently active contact sports athletes. PET imaging of the 18-kDa translocator protein (TSPO) allows quantification of microglial activation in vivo, a marker of neuroinflammation. Methods Eleven rank A kickboxers and 11 age-matched controls underwent TSPO PET using [11C]-PK11195, anatomical MRI, diffusion tensor imaging, and neuropsychological testing. Relevant imaging parameters were derived and correlated with the outcomes of the neuropsychological testing. Results On a group level, no statistically significant differences were detected in non-displaceable binding potential (BPND) using PET. Individually, 3 kickboxers showed increased BPNDs in widespread regions of the brain without a correlation with other modalities. Increased FA was observed in the superior corona radiata bilaterally. DTI parameters in other regions did not differ between groups. Conclusion Despite negative results on a group level, individual results suggest that neuroinflammation may be present as a consequence of repetitive head injury in active kickboxers. Future studies using a longitudinal design may determine whether the observed TSPO upregulation is related to the future development of neuropsychiatric symptoms.

Purpose The aim of this study was to compare the pre-hospital treatment of major trauma patients with similar injury patterns in Germany and the Netherlands. Patients and methods This matched-pairs analysis is based on the TraumaRegister DGU (R). The authors compared major trauma patients (ISS >= 16) from 2009 to 2015 treated in Dutch and German Level 1 trauma centers (TC). Endpoints were the pre-hospital times and interventions performed until hospital admission. Additional endpoints included hospital mortality, 24-h mortality and standardized mortality ratio (SMR) which was calculated using the Revised Injury Severity Classification, version II (RISC II). Patients were matched by age, gender, injury pattern, vital status on-scene and involvement into a traffic accident. Three subgroups were formed according to the mode of transportation and level of care provided during transport: Ambulance/Physician, Helicopter/Physician and Ambulance/Emergency Medical Technician. Results Patients were matched into 1094 pairs. German patients arrived at the TC after a mean pre-hospital time of 65.6 (+/- 29.6) min while Dutch patients arrived after 61.4 (+/- 28.7) min. Pre-hospital intubation rate was slightly higher in the Netherlands (44.1% GER vs 50.5% NL). Chest tubes were placed in 3.0% of German patients and 8.3% of Dutch patients. 63.5% of the German patients received analgesia/sedation which was below the rate of Dutch patients (71.1%). The hospital mortality was for 17.6% for German patients and 19.8% for Dutch patients. The SMR was about 1.0 for both groups. Conclusion Multiple differences and some similarities in the treatment of major trauma patients with similar injury patterns were found but no clinically relevant differences in the chosen outcome parameters could be observed.

The circadian rhythm is driven by a master clock within the suprachiasmatic nucleus which regulates the rhythmic secretion of melatonin. Bmal1 coordinates the rhythmic expression of transcriptome and regulates biological activities, involved in cell metabolism and aging. However, the role of Bmal1 in cellular- survival, signaling, its interaction with intracellular proteins, and how melatonin regulates its expression is largely unclear. Here we observed that melatonin increases the expression of Bmal1 and both melatonin and Bmal1 increase cellular survival after oxygen glucose deprivation (OGD) while the inhibition of Bmal1 resulted in the decreased cellular survival without affecting neuroprotective effects of melatonin. By using a planar surface immunoassay for PI3K/AKT signaling pathway components, we revealed that both melatonin and Bmal1 increased phosphorylation of AKT, ERK-1/2, PDK1, mTOR, PTEN, GSK-3αβ, and p70S6K. In contrast, inhibition of Bmal1 resulted in decreased phosphorylation of these proteins, which the effect of melatonin on these signaling molecules was not affected by the absence of Bmal1. Besides, the inhibition of PI3K/AKT decreased Bmal1 expression and the effect of melatonin on Bmal1 after both OGD in vitro and focal cerebral ischemia in vivo. Our data demonstrate that melatonin controls the expression of Bmal1 via PI3K/AKT signaling, and Bmal1 plays critical roles in cellular survival via activation of survival kinases.

Visual agnosia and Balint’s syndrome are complex neurological disorders of the higher visual system that can have a remarkable impact on individuals’ lives. Rehabilitation of these individuals is important to enable participation in everyday activities despite the impairment. However, the literature about the rehabilitation of these disorders is virtually silent. Therefore, the aim of this systematic review is to give an overview of available literature describing treatment approaches and their effectiveness with regard to these disorders. The search engines Psychinfo, Amed, and Medline were used, resulting in 22 articles meeting the criteria for inclusion. Only articles describing acquired disorders were considered. These articles revealed that there is some information available on the major subtypes of visual agnosia as well as on Balint’s syndrome which practising clinicians can consult for guidance. With regard to the type of rehabilitation, compensatory strategies have proven to be beneficial in most of the cases. Restorative training on the other hand has produced mixed results. Concluding, although still scarce, a scientific foundation about the rehabilitation of visual agnosia and Balint’s syndrome is evolving. The available approaches give valuable information that can be built upon in the future.

AimThe aim of the present study was to identify possible facilitators and barriers that differently positioned relatives are facing when being actively involved in the rehabilitation process of patients with traumatic brain injury.DesignA qualitative secondary analysis of data from a qualitative study.MethodsData comprised participant observations and semi‐structured interviews with relatives of patients with traumatic brain injury. Data were analysed using a qualitative content analysis.ResultsThree exemplary cases illustrate how relatives’ differential and unequal resources function as facilitators and barriers. Facilitators for involvement are as follows: participating in nursing care situations, the possibility for being present during hospitalization, the relationship with the providers, experience with illness, dedication and proactivity. Contrary, being reactive, non‐participating in nursing care situations, unable to express own wants and needs, and minimal flexibility from workplace are barriers to involvement.

Objective: To investigate the concomitant effects of two patient-directed interventions for post-stroke depressive symptoms on caregivers’ well-being. Design: Secondary analyses of the results of a randomized controlled trial. Subjects: Fifty caregivers of stroke patients receiving outpatient rehabilitation. Interventions: Stroke patients and their caregivers were randomly allocated to either cognitive-behavioural therapy augmented with movement or occupational therapy ( n = 23) or computerized cognitive training ( n = 27) to alleviate depressive symptoms in patients. Main measures: Emotional burden (Involvement Evaluation Questionnaire), practical burden (Caregiver Strain Index), mental health (General Health Questionnaire) and emotional complaints (Hospital Anxiety and Depression Scale). Results: Caregivers of patients who received cognitive-behavioural therapy reported significantly higher mental health levels (mean difference (MD) = 1.78, 95% confidence interval (CI) = 0.43–3.13, P = 0.01) and less worrying about patients’ well-being (MD = 1.9, 95% CI = 0.56–3.24, P Conclusion: The results suggest that augmented cognitive-behavioural therapy aimed at improving patients’ emotional, behavioural and social functioning positively affects some aspects of caregivers’ well-being.

Glucocorticoid-induced (GC) and hypoxia-induced transcriptional responses play an important role in tissue homeostasis and in the regulation of cellular responses to stress and inflammation. Evidence exists that there is an important crosstalk between both GC and hypoxia effects. Hypoxia is a pathophysiological condition to which cells respond quickly in order to prevent metabolic shutdown and death. The hypoxia inducible factors (HIFs) are the master regulators of oxygen homeostasis and are responsible for the ability of cells to cope with low oxygen levels. Maladaptive responses of HIFs contribute to a variety of pathological conditions including acute mountain sickness (AMS), inflammation and neonatal hypoxia-induced brain injury. Synthetic GCs which are analogous to the naturally occurring steroid hormones (cortisol in humans, corticosterone in rodents), have been used for decades as anti-inflammatory drugs for treating pathological conditions which are linked to hypoxia (i.e. asthma, ischemic injury). In this review, we investigate the crosstalk between the glucocorticoid receptor (GR), and HIFs. We discuss possible mechanisms by which GR and HIF influence one another, in vitro and in vivo, and the therapeutic effects of GCs on HIF-mediated diseases.

AimsIntracerebral hemorrhage (ICH) is a known risk factor for the development of acute symptomatic as well as late unprovoked seizures. The underlying pathophysiology of post-ICH seizures is incompletely understood and there are no reliable predictive biomarkers. An animal model to study post-ICH seizures is currently lacking. The aim of this study was to investigate (1) the occurrence of seizures and interictal epileptiform activity in the ICH rat collagenase model using long-term video-EEG monitoring (VEM) and (2) whether seizure occurrence was associated with interictal epileptiform activity and histological features.MethodsMale Sprague-Dawley rats were implanted with epidural electrodes. After 1 week of baseline VEM, collagenase was injected in left striatum to induce an ICH. VEM was continued for 180 days to assess the occurrence of post-ICH seizures and interictal epileptiform activity (spikes and epileptiform discharges). At the end of the experiment, animals were euthanized for histological characterization of the hemorrhagic lesion, using cresyl violet, Prussian blue and immunofluorescence staining.ResultsAcute symptomatic seizures occurred in 4/12 animals between 46 and 80 h after ICH induction. Late unprovoked seizures were present in 2/12 animals and started at 90 and 103 days post-ICH. Animals with late unprovoked seizures did not have acute symptomatic seizures. All electrographic seizures were accompanied by clear behavioral changes. Interictal spikes and epileptiform discharges were observed in all animals but occurred more frequently in rats with late seizures (p = 0.019 and p < 0.001, respectively). Animals with acute symptomatic seizures had more extended hemorrhagic lesions and hemosiderin deposits in the piriform cortex.ConclusionBoth acute symptomatic and late unprovoked seizures were observed in the rat collagenase model. Interictal epileptiform activity was more frequently seen in animals with late seizures. Rats with acute symptomatic seizures showed more extensive lesions and hemosiderin deposits in the piriform cortex. This model could be used to further explore possible biomarkers for epileptogenesis.

Background Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. Methods Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. Results Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. Conclusions We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI. Impact Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy. Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown. In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death. Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.

Chorioamnionitis is a major risk factor for preterm birth and an independent risk factor for postnatal morbidity for which currently successful therapies are lacking. Emerging evidence indicates that the timing and duration of intra-amniotic infections are crucial determinants for the stage of developmental injury at birth. Insight into the dynamical changes of organ injury after the onset of chorioamnionitis revealed novel therapeutic windows of opportunity. Importantly, successful development and implementation of therapies in clinical care is currently impeded by a lack of diagnostic tools for early (prenatal) detection and surveillance of intra-amniotic infections. In the current study we questioned whether an intra-amniotic infection could be accurately diagnosed by a specific volatile organic compound (VOC) profile in exhaled breath of pregnant sheep. For this purpose pregnant Texel ewes were inoculated intra-amniotically with Ureaplasma parvum and serial collections of exhaled breath were performed for 6 days. Ureaplasma parvum infection induced a distinct VOC-signature in expired breath of pregnant sheep that was significantly different between day 0 and 1 vs. day 5 and 6. Based on a profile of only 15 discriminatory volatiles, animals could correctly be classified as either infected (day 5 and 6) or not (day 0 and 1) with a sensitivity of 83% and a specificity of 71% and an area under the curve of 0.93. Chemical identification of these distinct VOCs revealed the presence of a lipid peroxidation marker nonanal and various hydrocarbons including n-undecane and n-dodecane. These data indicate that intra-amniotic infections can be detected by VOC analyses of exhaled breath and might provide insight into temporal dynamics of intra-amniotic infection and its underlying pathways. In particular, several of these volatiles are associated with enhanced oxidative stress and undecane and dodecane have been reported as predictive biomarker of spontaneous preterm birth in humans. Applying VOC analysis for the early detection of intra-amniotic infections will lead to appropriate surveillance of these high-risk pregnancies, thereby facilitating appropriate clinical course of action including early treatment of preventative measures for pre-maturity-associated morbidities.

Background Helicopter Emergency Medical Services (HEMS) respond to serious trauma and medical emergencies. Geographical disparity and the regionalisation of trauma systems can complicate accurate HEMS dispatch. We sought to evaluate HEMS dispatch sensitivity in older trauma patients by analysing critical care interventions and conveyance in a well-established trauma system. Methods All trauma patients aged ≥65 years that were attended by the Air Ambulance Kent Surrey Sussex over a 6-year period from 1 July 2013 to 30 June 2019 were included. Patient characteristics, critical care interventions and hospital disposition were stratified by dispatch type (immediate, interrogate and crew request). Results 1321 trauma patients aged ≥65 were included. Median age was 75 years [IQR 69–89]. HEMS dispatch was by immediate (32.0%), interrogation (43.5%) and at the request of ambulance clinicians (24.5%). Older age was associated with a longer dispatch interval and was significantly longer in the crew request category (37 min [34–39]) compared to immediate dispatch (6 min [5–6] (p = .001). Dispatch by crew request was common in patients with falls 2 m more often resulted in immediate dispatch (p = .001). Immediate dispatch to isolated head injured patients often resulted in pre-hospital emergency anaesthesia (PHEA) (39%). However, over a third of head injured patients attended after dispatch by crew request received PHEA (36%) and a large proportion were triaged to major trauma centres (69%). Conclusions Many patients who do not fulfil the criteria for immediate HEMS dispatch need advanced clinical interventions and subsequent tertiary level care at a major trauma centre. Further studies should evaluate if HEMS activation criteria, nuanced by age-dependant triggers for mechanism and physiological parameters, optimise dispatch sensitivity and HEMS utilisation.

BackgroundMultiple clinical conditions are associated with cerebral hypoxia/ischaemia and thereby an increased risk of hypoxic-ischaemic brain injury. Cerebral near-infrared spectroscopy monitoring (NIRS) is a tool to monitor brain oxygenation and perfusion, and the clinical uptake of NIRS has expanded over recent years. Specifically, NIRS is used in the neonatal, paediatric, and adult perioperative and intensive care settings. However, the available literature suggests that clinical benefits and harms of cerebral NIRS monitoring are uncertain. As rates of clinically significant hypoxic-ischaemic brain injuries are typically low, it is difficult for randomised clinical trials to capture a sufficiently large number of events to evaluate the clinical effect of cerebral NIRS monitoring, when focusing on specific clinical settings. The aim of this systematic review will be to evaluate the benefits and harms of clinical care with access to cerebral NIRS monitoring versus clinical care without cerebral NIRS monitoring in children and adults across all clinical settings.MethodsWe will conduct a systematic review with meta-analysis and trial sequential analysis. We will only include randomised clinical trials. The primary outcomes are all-cause mortality, moderate or severe persistent cognitive or neurological deficit, and proportion of participants with one or more serious adverse events. We will search CENTRAL, EMBASE, MEDLINE, and the Science Citation Index Expanded from their inception and onwards. Two reviewers will independently screen all citations, full-text articles, and extract data. The risk of bias will be appraised using the Cochrane risk of bias tool version 2.0. If feasible, we will conduct both random-effects meta-analysis and fixed-effect meta-analysis of outcome data. Additional analysis will be conducted to explore the potential sources of heterogeneity (e.g. risk of bias, clinical setting).DiscussionAs we include trials across multiple clinical settings, there is an increased probability of reaching a sufficient information size. However, heterogeneity between the included trials may impair our ability to interpret results to specific clinical settings. In this situation, we may have to depend on subgroup analyses with inherent increased risks of type I and II errors.Systematic review registrationPROSPEROCRD42020202986. This systematic review protocol has been submitted for registration in the International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/prospero) on the 12th of October 2020 and published on the 12th of November 2020 (registration IDCRD42020202986).

Objectives: In this study, we aimed to investigate whether the positive union effect caused by head trauma could be transferred between individuals. Materials and methods: Seventy-two male rats with an average weight of 375 g were used in this study and divided into four groups including 18 in each group. Group 1 consisted of serum donor rats that were exposed to head trauma, while Group 2 consisted of study rats with long bone fractures that were given the serum obtained from the rats in Group 1, Group 3 included control rats with isolated long bone fractures, and Group 4 included control rats with both head trauma and long bone fractures. For radiological evaluation, the ratio of the width of the callus to the width of the neighboring diaphysis was considered as the callus-to- diaphyseal ratio in the study and control groups. Histopathological and radiological evaluations was made on Days 10, 20, and 30. Results: In evaluation of the radiological data regarding the callus- to-diaphyseal ratio, Group 3 was found to have significantly lower radiological values than Group 4 on Day 10 (p=0.006). Group 2 had significantly higher values than Group 3 (p=0.02). On Day 20, Group 2 exhibited significantly higher radiological values than Group 3 (p=0.004), but lower than Group 4 (p=0.032). As for Day 30, Group 2 exhibited significantly higher radiological values than Group 3, but lower than Group 4 (p=0.001). In the evaluation of the Huo scores obtained for histopathological evaluation, there was no significant difference among the groups on Days 10, 20, and 30 (p=0.295, p=0.569, and p=0.729, respectively). Conclusion: Our study results suggest that the osteoinductive effect after head trauma can be transmitted between individuals by means of serum transfer.

Infants with moderate and severe neonatal encephalopathy (NE) frequently suffer from long-term adverse outcomes. We hypothesize that the urinary metabolome of newborns with NE reflects the evolution of injury patterns observed with magnetic resonance imaging (MRI).

Purpose of review To discuss recent findings relevant to optimizing blood pressure targets in adult, postcardiac arrest (PCA) patients and whether to tailor these based on specific patient, cardiac arrest or treatment characteristics. Recent findings Observational data suggest that mean arterial pressure (MAP) below 65-75 mmHg in PCA patients is associated with worse outcome. A higher MAP could be beneficial in patients with chronic hypertension who more frequently have a right shift of the cerebral autoregulation curve. Two recent randomized pilot trials compared lower and higher MAP targets during PCA care and found no significant effect on biomarkers of neurological injury. The haemodynamic interventions in those studies did not use any cerebral perfusion endpoints beyond a static MAP targets during ICU stay. Individualized, dynamic MAP targets based on assessments of cerebral perfusion and tailored to the specifics of the patient, cardiac arrest circumstances and treatment responses may be more conducive to improved outcomes. Pilot data suggest that near infrared spectroscopy monitoring may be used to determine the cerebral autoregulatory capacity and an optimal MAP, but this approach is yet to be tested in clinical trials. Current evidence suggests targeting a MAP of at least 65-75 mmHg in PCA patients. Future studies should focus on whether certain patient groups could benefit from higher and dynamic MAP targets.

With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study’s objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1–13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1–13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (HT+V; n = 7); (iii) HT + Melatonin (HT+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after HI. Comparing HT+M to HT, aEEG scores recovered more quickly by 19 h (p 2) compared to HT (123.8 cells/mm2) (p = 0.0003) and HT+V (97.5 cells/mm2) compared to HT (p = 0.012). Localized protection was seen in white matter for HT+M versus HT (p = 0.036) and internal capsule for HT+M compared to HT (p = 0.001) and HT+V versus HT (p = 0.006). Therapeutic melatonin levels (15–30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.