Brain Injury Research Articles

Blood-brain barrier disruption following brain injury: Implications for clinical practice.

The blood-brain barrier (BBB) plays a critical role in regulating the exchange of substances between peripheral blood and the central nervous system and in maintaining the stability of the neurovascular unit in neurological diseases. To guide clinical treatment and basic research on BBB protection following brain injury, this manuscript reviews how BBB disruption develops and influences neural recovery after stroke and traumatic brain injury (TBI). By summarizing the pathological mechanisms of BBB damage, we underscore the critical role of promoting BBB repair in managing brain injury. We also emphasize the potential for personalized and precise therapeutic strategies and the need for continued research and innovation. From this, broadening insights into the mechanisms of BBB disruption and repair could pave the way for breakthroughs in the treatment of brain injury-related diseases.

Bibliometric Analysis of Studies on Delirium in Critical Care

Background Delirium leads to prolongation in intensive care unit (ICU) and hospital length of stay and an increase in ICU costs and mortality. As a result of this, the number of studies on delirium in ICUs has recently increased significantly, and many articles have been published. Objectives The aim of this study was to evaluate the articles related to “delirium” in “critical care” field in the Web of Science database and the first hundred most cited articles on this subject. Methods The Web of Science database was searched for articles relevant to “delirium” in the critical care medicine field published between 1980 and 2024. Text analytics and network models used in bibliometric mapping were used for prolific authors, annual trend, citation, and countries. Results In our study, it was determined that a total of 1834 articles in the field of delirium in critical care medicine were included. It was determined that the annual citation average was 42.79 and the H-index value was 134. There is a general upward trend over the years, and it was observed that it has intensified in the last 5 to 6 years. With the Reference Spectroscopy analysis, it was determined that the most intensively cited studies on delirium were the studies of 2013 and 2010. The distribution of keywords in recent years has focused on analgosedation, acute brain injury, older patient, COVID-19, and fragility. When examined for the top 100 cited articles, it was seen that mobilization, guidelines, pain, activities of daily living, anesthesia, sedation, and haloperidol have become prominent in recent years. Conclusion In recent years, there has been a noticeable increase in the volume of research focusing on delirium studies within the field of critical care medicine. Staying current with trends, incorporating findings from frequently cited studies, and customizing interventions to suit modern difficulties can all improve the quality of care offered to critically ill patients and lead to better outcomes.

From Controversy to Consensus: Neurogenesis and Neuroplasticity

More and more research in recent years has focused on neurogenesis and neuroplasticity. The hippocampus is a key location of adult neurogenesis. Because this part of the brain is regulated by environmental variables, it must be mentioned the therapeutic potential for neurodegenerative illnesses and brain injuries. Furthermore, this information challenges the historical concept of a static brain and tries to demonstrate its flexibility, adaptability, and possibility for regeneration. Those mechanisms which are found in a variety of mammalian species, including humans, are important when it comes to adaptive learning and memory, thus providing insights into cognitive well-being and mental health. The discovery of the brain's dynamic nature represented by new neurons, marks a shift in the field of neurology with far-reaching potentials. This paper highlights the significant potential of adult neurogenesis when it comes to clinical applications such as Alz-heimer’s disease.

Unraveling the Emerging Niche Role of Extracellular Vesicles (EVs) in Traumatic Brain Injury (TBI).

Extracellular vesicles or exosomes, often known as EVs, have acquired significant attention in the investigations of traumatic brain injury (TBI) and have a distinct advantage in actively researching the fundamental mechanisms underlying various clinical symptoms and diagnosing the wide range of traumatic brain injury cases. The mesenchymal stem cells (MSCs) can produce and release exosomes, which offer therapeutic benefits. Exosomes are tiny membranous vesicles produced by various cellular entities originating from endosomes. Several studies have reported that administering MSC-derived exosomes through intravenous infusions improves neurological recovery and promotes neuroplasticity in rats with traumatic brain damage. The therapeutic advantages of exosomes can be attributed to the microRNAs (miRNAs), which are small non-coding regulatory RNAs that significantly impact the regulation of posttranscriptional genes. Exosome-based therapies, which do not involve cells, have lately gained interest as a potential breakthrough in enhancing neuroplasticity and accelerating neurological recovery for various brain injuries and neurodegenerative diseases. This article explores the benefits and drawbacks of exosome treatment for traumatic brain injury while emphasizing the latest advancements in this field with clinical significance.

Impact of Trauma Verification Level on Management and Outcomes of Combined Traumatic Brain and Solid Organ Injuries: An NTDB Retrospective Review.

Level-I and level-II trauma centers are required to offer equivalent resources since "The Orange Book." This study evaluates differences between level-I and level-II management of solid organ injury (SOI) with traumatic brain injury (TBI). We conducted a retrospective review of the National Trauma Data Banks from 2013 to 2021 of adult (≥18years), blunt trauma patients with both TBI and SOI treated at level-I or level-II trauma centers. 48,479 TBI and SOI patients were identified, 32,611 (67.3%) at level-I centers. Unadjusted incidence of laparotomy was higher at level I (14.5% vs 11.7%, P < 0.001), and angiography rates were similar (3.3% vs 3.4%, P 0.717). Sub-group analysis of stable patients (SBP ≥100) showed an increase in nonoperative management at level II (87.3% vs 88.7%, P < 0.001) and decrease in laparotomy (9.9% vs 8.3%, P < 0.001). On logistic regression (LR), severe TBI, high-grade SOI, and level I trauma status were predictors of laparotomy. Logistic regression showed mild/moderate TBI with high-grade SOI and level II were associated with use of angiography. Unadjusted mortality rates were slightly different (14.8% vs 13.4%, P < 0.001), but there was no association with trauma level on LR. Nonoperative management was seen more at level-II centers with laparotomy at level I. Subgroup analysis showed no difference in mortality in trauma levels. Matched patients for level I and II showed no statistical difference in management. Patients were treated similarly at both levels with similar outcomes and mortality.

2-Acetylacteoside improves recovery after ischemic stroke by promoting neurogenesis via the PI3K/Akt pathway

Ischemic stroke induces adult neurogenesis in the subventricular zone (SVZ), even in elderly patients. Harnessing of this neuroregenerative response presents the therapeutic potential for post-stroke recovery. We found that phenylethanoid glycosides (PhGs) derived from Cistanche deserticola aid neural repair after stroke by promoting neurogenesis. Among these, 2-acetylacteoside had the most potent on the proliferation of neural stem cells (NSCs) in vitro. Furthermore, 2-acetylacteoside was shown to alleviate neural dysfunction by increase neurogenesis both in vivo and in vitro. RNA-sequencing analysis highlighted differentially expressed genes within the PI3K/Akt signaling pathway. The candidate target Akt was validated as being regulated by 2-acetylacteoside, which, in turn, enhanced the proliferation and differentiation of cultured NSCs after oxygen-glucose deprivation/reoxygenation (OGD/R), as evidenced by western blot analysis. Subsequent analysis using cultured NSCs from adult subventricular zones (SVZ) confirmed that 2-acetylacteoside enhanced the expression of phosphorylated Akt (p-Akt), and its effect on NSC neurogenesis was shown to be dependent on the PI3K/Akt pathway. In summary, our findings elucidate for the first time the role of 2-acetylacteoside in enhancing neurological recovery, primarily by promoting neurogenesis via Akt activation following ischemic brain injury, which offers a novel strategy for long-term cerebrological recovery in ischemic stroke.

Daidzein ameliorates experimental traumatic brain injury-induced neurological symptoms by suppressing oxidative stress and apoptosis.

Traumatic brain injury (TBI) causes deficits in neurological function, induces pathological changes, and increases oxidative stress. The current investigation aimed to determine Daidzein's neuroprotective potential in experimental TBI. Initially, the HT-22 cell line exposed to H2O2 underwent in vitro examination, and the results showed that Daidzein had a neuroprotective effect evident from enhanced cell viability and decreased NO generation. Using three different Daidzein doses-1 mg/kg, 5 mg/kg, and 10 mg/kg-in the in vivo experiment, the potential of Daidzein was evaluated against TBI. The neurological severity score (NSS), kondziela's screen test, and elevated plus maze showed improvements after treatment with Daidzein manifested by decreased score, enhanced motor coordination, and anti-anxiety effects. Additionally, Daidzein improved mechanical allodynia and restored the breakdown of the blood-brain barrier. The FTIR spectral analysis showed restoration of the biochemical compositional changes. Furthermore, H & E and Toluidine blue staining revealed an improvement in the histopathological alterations. The RT-qPCR revealed an increase in mRNA expression level of Nrf2, HO-1, and Bcl-2 and the downregulation of Keap-1, Bax and Cleaved caspase-3 expressions. Thus, exhibiting its antioxidant and antiapoptotic potential. The RT-qPCR also manifested a decrease in mRNA expression of GFAP and Iba-1. Further immunohistochemistry results indicated Daidzein's antioxidant and antiapoptotic properties by upregulating Nrf2 and downregulating cleaved caspase-3. Daidzein also lowered the apoptosis index and improved neuronal survival evidenced by flow cytometric analysis. In addition to this, Daidzein notably increased the antioxidant enzyme levels and decreased the oxidative stress markers. The current study's findings point to the neuroprotective potential of the phytoestrogen Daidzein as it lessened neurological abnormalities, decreased oxidative stress, and lowered proapoptotic protein expression.

Helmets with lattice liners can mitigate traumatic brain injury from impacts

This study explores the effectiveness of architected lattice structures, specifically made of PA12 material, as potential helmet liners to mitigate traumatic brain injuries (TBI), with a focus on rotational acceleration. Evaluating three lattice unit cell topologies (simple cubic, dode-medium, and rhombic dodecahedron), the research builds upon prior investigations indicating that PA12 lattice liners may outperform conventional EPS liners. Employing a high-fidelity finite element male head model and utilizing direct and oblique impact scenarios, mechanical quantities, such as maximum principal strain (MPS) and shear strain, cumulative strain damage measure and intracranial pressure were measured at the tissue level in different brain regions, Results indicate that lattice liners, especially with dode-medium topology, exhibit promising reductions in brain tissue strains. On average, during oblique impacts, less than 1 % of the brain volume experienced an MPS level of 0.4 when the lattice liners were adopted, whereas that percentage was above 70 % with the expandable polystyrene (EPS) foam liners. Pressure-based assessments suggest that lattice liners may outperform EPS liners in oblique impacts, showcasing the limitations of EPS for effective TBI mitigation. Despite certain model limitations, this study emphasizes the need for advancements in helmet technology, particularly in the development of commercial lattice liners using additive manufacturing, to address the limitations of existing EPS liners in preventing rotational consequences of impacts and reducing TBI.

Microrna Biomarkers on Day of Injury Among Patients with Post Concussive Symptoms at 28-Days: A Prospective Cohort Study.

After mild traumatic brain injury (mTBI), some patients experience symptoms that persist for weeks to months. Recovery from mTBI is primarily assessed using selfreported symptom questionnaires. Blood biomarkers, including microRNA species, have shown promise to assist diagnosis of mTBI, however, little is known about how blood microRNA measures might predict symptom recovery. The aim of this study was to investigate the variances in plasma microRNAs on the day of injury between individuals with mTBI who report post-concussive symptoms at the 28- day mark and those who do not. Patients who presented to an adult, tertiary referral hospital emergency department on the day of the injury and were diagnosed with isolated mTBI (n=35) were followed up for 28 days. Venous blood samples were collected and symptom severity was assessed using the Rivermead Post-Concussion Symptom Questionnaire (RPQ) on the day of injury and at 28 days. Patients who reported ongoing symptoms of total RPQ score ≥10 or at least one symptom severity ≥2, were compared to those with lesser symptom severity or symptom resolution. There were 9 (25.7%; 95%CI: 12.5-43.3) patients who reported persistent symptoms. Day of injury plasma miR-223-3p levels were significantly higher in individuals with ongoing symptoms compared to those without, however, no such differences were observed for miRs 142- 3p, 423-3p, 32-5p, 144-3p, and let-7f-5p. Acute plasma miR-223-3p levels appear to detect patients who later have persistent symptoms after mTBI. The results demonstrate the potential utility for such biomarkers to assist in decisions towards early referral for therapy after mTBI.

The association of gene polymorphisms of adenosine and dopamine receptors with the response to caffeine citrate treatment in infants with apnea of prematurity: a prospective nested case-control study

BackgroundTo investigate the potential influence of adenosine and dopamine receptor genes polymorphisms in combination with clinical factors on the response of preterm infants to caffeine citrate treatment in apnea of prematurity (AOP).MethodsA prospective nested case-control study enrolled 221 preterm infants with gestational age < 34 weeks. These infants were divided into the response (n = 160) and the non-response groups (n = 61). 22 single-nucleotide polymorphisms in adenosine and dopamine receptor genes were genotyped. The basic characteristics and clinical outcomes of the two groups were compared. Univariate logistic regression analysis was performed to evaluate the differences in genotype distribution between the groups. Multivariable logistic regression analysis was performed to identify independent risk and protective factors and develop a nomogram to predict caffeine citrate response in preterm infants.ResultsPreterm infants in the non-response group had lower gestational age, lower birth weight, longer periods of oxygen supplementation and caffeine citrate use, and higher incidence of patent ductus arteriosus (PDA), bronchopulmonary dysplasia (BPD), neonatal respiratory distress syndrome (NRDS), retinopathy of prematurity (ROP), and brain injury (P < 0.05 for all). The ADORA1 rs10920573, ADORA2B rs2015353, ADORA3 rs10776728, DRD3 rs7625282, and DRD3 rs6280 gene polymorphisms were associated with caffeine citrate response in preterm infants (PFDR < 0.05 for all). The ADORA1 rs10920573 CC (aOR, 3.51; 95% CI, 1.34–9.25) and DRD3 rs6280 CT genotypes (aOR, 3.19; 95% CI, 1.53–6.65) were independent risk factors for non-response, whereas greater gestational age (aOR, 0.631; 95% CI, 0.53–0.75) was an independent protective factor for response. The concordance index of the nomogram was 0.764 (95% CI, 0.687–0.842), and the calibration and decision curve analysis indicated the nomogram had excellent predict performance.ConclusionsAdenosine receptor gene and dopamine receptor gene polymorphisms influence caffeine citrate treatment response in AOP. By combining genetic and clinical variables, it is possible to predict the response to caffeine citrate treatment in preterm infants.

Functional outcomes in children and adolescents with neurodisability accessing music therapy: A scoping review.

To determine the evidence for functional outcomes experienced by a population with paediatric neurodisability (such as acquired brain injury, cerebral palsy, spinal cord injury, and other neurological disorders), who access music therapy through neurorehabilitation services across the rehabilitation spectrum. Using scoping review methodology of the JBI and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), a systematic search was conducted across eight databases and expert knowledge users were consulted. Articles were screened by title and abstract, and data from eligible studies were categorized using the International Classification of Functioning, Disability and Health: Children and Youth version (ICF-CY). From 1726 records identified, 53 eligible primary sources were included in the synthesis. Most literature (n = 30) related to children and adolescents with an acquired or traumatic brain injury. Physical functionwas the most frequently reported outcome across sources(n = 27), followed by communication (n = 25), social (n = 22), cognitive (n = 17), emotional (n = 13), psychological (n = 13), behavioural (n = 8), and sensory (n = 5). Evidence for functional outcomes experienced by children and adolescents accessing music therapy as part of their neurorehabilitation is limited. More than half of the included sources were clinical descriptions with small samples. High-quality studies involving children, adolescents, families, and interprofessional teams are needed to identify the most effective music therapy methods and techniques for functional outcomes in paediatric neurodisability.

BRIVA-ONE study: 12-month outcomes of brivaracetam monotherapy in clinical practice.

This study investigated the effectiveness and tolerability of brivaracetam (BRV) monotherapy in a large series of patients with epilepsy. This was a multicenter, retrospective, observational, non-interventional study in 24 hospitals across Spain. Patients aged ≥18 years who started on BRV monotherapy, either as first-line or following conversion, at least 1 year before database closure were included. Patients were evaluated at baseline and at 3, 6 and 12 months after initiation of BRV monotherapy, in accordance with usual clinical practice at these centers. Data were collected retrospectively from patients' individual charts by participating physicians. The primary effectiveness and safety endpoints were the percentage of seizure-free patients 1 year after initiation of BRV monotherapy and the proportion of patients reporting adverse events (AEs) over the complete follow-up period. Retention rates and subpopulation analysis (levetiracetam switchers, elderly and different etiologies) were also investigated. A total of 276 patients were included (48 with BRV as first-line monotherapy and 228 who converted to BRV monotherapy). The overall retention rate in monotherapy at 12 months was 89.9% (87.5% for first-line monotherapy group; 90.4% for conversion-to-monotherapy group). Seizure-freedom rates at 12 months were 77.8% (75% for first-line monotherapy group; 78.4% for conversion-to-monotherapy group). AEs occurred in 39.5% of patients at 12 months (35.4% for first-line monotherapy group; 40.4% for conversion-to-monotherapy group). Most AEs were mild-to-moderate. The most frequent AEs were irritability (12.3%) and dizziness (10.1%). The most frequent AEs leading to BRV withdrawal were dizziness (1.8%) and memory problems (1.4%). Similar outcomes in terms of effectiveness and tolerability of BRV monotherapy were observed in patients switching from levetiracetam, those with different epilepsy etiologies, and elderly patients. BRV was effective and well tolerated both as first-line monotherapy and following conversion to monotherapy in a real-world setting of patients with epilepsy. The goal of the medical treatment of epilepsy is to ensure best possible patient quality of life, by maximizing seizure control and minimizing medication toxicity. Brivaracetam (BRV) is a new-generation epilepsy treatment that is well tolerated by patients. In our study, monotherapy with BRV reduced seizures in patients who had not received other treatments and in patients who switched from a previous treatment to BRV monotherapy. BRV was well tolerated and also effective in sensitive patients (i.e., the elderly and those who had epilepsy caused by a brain tumor or a brain injury).

Goal-Oriented Attentional Self-Regulation Training in Chronic Mild Traumatic Brain Injury is Linked to Microstructural Plasticity in Prefrontal White Matter.

Impaired attention is one of the most common, debilitating, and persistent consequences of traumatic brain injury (TBI), which impacts overall cognitive and executive functions in these patients. Previous neuroimaging studies, trying to understand the neural mechanism underlying attention impairment post TBI, have highlighted the role of prefrontal white matter tracts in attentional functioning in mild TBI (mTBI). Goal-Oriented Attentional Self-Regulation (GOALS) is a cognitive rehabilitation training program that targets executive control functions in participants by applying mindfulness-based attention regulation and goal management strategies. GOALS training has been demonstrated to improve attention and executive functioning in patients with chronic TBI. However, its impact on microstructural integrity of attention-associated prefrontal white matter tracts is still unclear. Here, using diffusion magnetic resonance imaging in a pilot randomized controlled trial, we investigated the effect of GOALS training on prefrontal white matter microstructure in 19 U.S. military veterans with chronic mTBI, compared with a matched control group of 14 veterans with chronic mTBI who received standard of care brain health education. We also tested for an association between microstructural white matter changes and sustained attention ability in these patients pre- and post-GOALS training. Our results show significantly better white matter microstructural integrity in left and right anterior corona radiata (ACR) in the GOALS group compared with the control group post-training. Moreover, we found a significant correlation between sustained attention ability of GOALS training participants and white matter integrity of their right ACR pre- and post-training. Finally, our findings indicated that the improved white matter integrity of the ACR in GOALS training participants was the result of increased neurite density and decreased fiber orientation dispersion within this tract.

Immune Response in Traumatic Brain Injury.

This review aims to comprehensively examine the immune response following traumatic brain injury (TBI) and how its disruption can impact healing and recovery. The immune response is now considered a key element in the pathophysiology of TBI, with consequences far beyond the acute phase after injury. A delicate equilibrium is crucial for a healthy recovery. When this equilibrium is disrupted, chronic inflammation and immune imbalance can lead to detrimental effects on survival and disability. Globally, traumatic brain injury (TBI) imposes a substantial burden in terms of both years of life lost and years lived with disability. Although its epidemiology exhibits dynamic trends over time and across regions, TBI disproportionally affects the younger populations, posing psychosocial and financial challenge for communities and families. Following the initial trauma, the primary injury is succeeded by an inflammatory response, primarily orchestrated by the innate immune system. The inflammasome plays a pivotal role during this stage, catalyzing both programmed cell death pathways and the up-regulation of inflammatory cytokines and transcription factors. These events trigger the activation and differentiation of microglia, thereby intensifying the inflammatory response to a systemic level and facilitating the migration of immune cells and edema. This inflammatory response, initially originated in the brain, is monitored by our autonomic nervous system. Through the vagus nerve and adrenergic and cholinergic receptors in various peripheral lymphoid organs and immune cells, bidirectional communication and regulation between the immune and nervous systems is established.

Outcomes after Traumatic Brain Injury with and Without Computed Tomography.

Our recent improved understanding of traumatic brain injury (TBI) comes largely from cohort studies of TBI patients with indication for computed tomography (CT). Using CT head as an inclusion criterion may overestimate poor outcomes after TBI with Glasgow Coma Scale (GCS) 13-15. We aimed to compare outcomes after TBI in adults who had a head CT scan (with negative findings) versus those who had no CT when presenting to an emergency department. This was a secondary analysis of a trial that recruited adults with GCS = 13-15 after TBI in Vancouver, Canada. We included 493 participants (18-69 years, 54% female), after removing n = 19 with traumatic abnormalities on CT (intracranial and/or skull fracture). Outcomes were Glasgow Outcome Scale Extended (GOSE), Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Patient Health Questionnaire (PHQ)-9, and generalized anxiety disorder (GAD)-7 at 6 months post-injury. Over half (55%) of participants received a CT. At 6 months, 55% of participants with CT and 49% without CT had functional limitations on GOSE; 32% with CT and 33% without CT reported severe post-concussion symptoms (RPQ ≥16); 26% (with CT) and 28% (without CT) screened positive for depression (PHQ-9 ≥ 10), and 25% (with CT) and 28% (without CT) screened positive for anxiety (GAD-7 ≥ 8). In regression adjusted for personal variables, participants with CT had somewhat higher odds of worse functioning (ordinal GOSE; 1.4, 95% CI 1.0-2.0) but similar odds of severe post-concussion symptoms (1.1, 95% CI: 0.7-1.7), and depression (1.1, 95% CI: 0.7-1.7) and anxiety (1.0, 95% CI: 0.6-1.5) symptoms. Adults with and without head CT have mostly comparable outcomes from TBI with GCS = 13-15. Requiring CT by clinical indication for study entry may not create problematic selection bias for outcome research.

Low-Value Clinical Practices in Pediatric Trauma Care.

Reducing low-value care has the potential to improve patient experiences and outcomes and decrease the unnecessary use of health care resources. Research suggests that low-value practices (ie, the potential for harm exceeds the potential for benefit) in adult trauma care are frequent and subject to interhospital variation; evidence on low-value practices in pediatric trauma care is lacking. To estimate the incidence of low-value practices in pediatric trauma care and evaluate interhospital practice variation. A retrospective multicenter cohort study in a Canadian provincial trauma system was conducted. Children younger than 16 years admitted to any of the 59 provincial trauma centers from April 1, 2016, to March 31, 2022, were included. Low-value practices were identified from systematic reviews of clinical practice guidelines on pediatric trauma. The frequencies of low-value practices were evaluated by estimating incidence proportions and cases per 1000 admissions (low if ≤10% and ≤10 cases, moderate if >10% or >10 cases, and high if >10% and >10 cases) were identified. Interhospital variation with intraclass correlation coefficients (ICCs) were assessed (low if <5%, moderate if 5%-20%, and high if >20%). A total of 10 711 children were included (mean [SD] age, 7.4 [4.9] years; 6645 [62%] boys). Nineteen low-value practices on imaging, fluid resuscitation, hospital/intensive care unit admission, specialist consultation, deep vein thrombosis prophylaxis, and surgical management of solid organ injuries were identified. Of these, 14 (74%) could be evaluated using trauma registry data. Five practices had moderate to high frequencies and interhospital variation: head computed tomography in low-risk children (7.1%; 33 per 1000 admissions; ICC, 8.6%), pretransfer computed tomography in children with a clear indication for transfer (67.6%; 4 per 1000 admissions; ICC, 5.7%), neurosurgical consultation in children without clinically important intracranial lesions (11.6%; 13 per 1000 admissions; ICC, 15.8%), hospital admission in isolated mild traumatic brain injury (38.8%; 98 per 1000 admissions; ICC, 12.4%), and hospital admission in isolated minor blunt abdominal trauma (10%; 5 per 1000 admissions; ICC, 31%). In this cohort study, low-value practices appeared to be frequent and subject to interhospital variation. These practices may represent priority targets for deimplementation interventions, particularly as they can be measured using routinely collected data.

The role of TRAP1 in regulating mitochondrial dynamics during acute hypoxia-induced brain injury

Brain damage caused by acute hypoxia is associated with the physiological activities of mitochondria. Although mitochondria being dynamically regulated, our comprehensive understanding of the response of specific brain cell types to acute hypoxia remains ambiguous. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial-based molecular chaperone, plays a role in controlling mitochondrial movements. Herein, we demonstrated that acute hypoxia significantly alters mitochondria morphology and functionality in both in vivo and in vitro brain injury experiments. Summary-data-based Mendelian Randomization (SMR) analyses revealed possible causative links between mitochondria-related genes and hypoxia injury. Advancing the protein-protein interaction network and molecular docking further elucidated the associations between TRAP1 and mitochondrial dynamics. Furthermore, it was shown that TRAP1 knockdown levels variably affected the expression of key mitochondrial dynamics proteins (DRP1, FIS1, and MFN1/2) in primary hippocampal neurons, astrocytes, and BV-2 cell, leading to changes in mitochondrial structure and function. Understanding the function of TRAP1 in altering mitochondrial physiological activity during hypoxia-induced acute brain injury could help serve as a potential therapeutic target to mitigate neurological damage.

A Combination of Low Doses of Lithium and Valproate Improves Cognitive Outcomes after Mild Traumatic Brain Injury.

The prevalence of mild traumatic brain injury (mTBI) is high compared with moderate and severe TBI, comprising almost 80% of all brain injuries. mTBI activates a complex cascade of biochemical, molecular, structural, and pathological changes that can result in neurological and cognitive impairments. These impairments can manifest even in the absence of overt brain damage. Given the complexity of changes triggered by mTBI, a combination of drugs that target multiple TBI-activated cascades may be required to improve mTBI outcomes. It has been previously demonstrated that cotreatment with the U.S. Food and Drug Administration (FDA)-approved drugs lithium plus valproate (Li + VPA) for 3 weeks after a moderate-to-severe controlled cortical impact injury reduced cortical tissue loss and improved motor function. Since both lithium and valproate can exhibit toxicity at high doses, it would be beneficial to determine if this combination treatment is effective when administered at low doses and for a shorter duration, and if it can improve cognitive function, after a mild diffuse TBI. In the present study, we tested if the combination of low doses of lithium (1 mEq/kg or 0.5 mEq/kg) plus valproate (20 mg/kg) administered for 3 days after a mild fluid percussion injury can improve hippocampal-dependent learning and memory. Our data show that the combination of low-dose Li + VPA improved spatial learning and memory, effects not seen when either drug was administered alone. In addition, postinjury Li + VPA treatment improved recognition memory and sociability and reduced fear generalization. Postinjury Li + VPA also reduced the number of anti-ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia counted using a convolutional neural network, indicating a reduction in neuroinflammation. These findings indicate that low-dose Li + VPA administered acutely after mTBI may have translational utility to reduce pathology and improve cognitive function.

Unraveling Neurotoxicity Discrepancies: Comparative In vitro and In vivo Analysis of Colistin and Polymyxin B and the Underlying Mechanisms.

Polymyxins, including colistin and polymyxin B, are the final resort against Gram-negative bacterial infections. However, its clinical application is restricted due to concerns related to neurotoxicity. Despite the similar antibacterial spectrum and mode of action shared between colistin and polymyxin B, there is still a lack of definitive evidence to support the idea that their neurotoxicity profiles are identical. To comprehensively compare the neurotoxicity between colistin and polymyxin B both in vivo and in vitro and establish a theoretical foundation to guide the rational use of polymyxins within clinical settings. in vitro experiments simulated nerve damage by exposing N2a and RSC96 cells to colistin and polymyxin B. The evaluation of nerve injury included assessments of cell viability and apoptosis. To discern the variance in the mechanisms of nerve injury between colistin and polymyxin B, oxidative stress levels were examined, such as SOD, CAT, GSH, and malondialdehyde (MDA). In in vivo experiments, a rat nerve injury model was created by intraventricular injections of colistin and polymyxin B, respectively. The impact of these drugs on brain injury in rats, particularly within the hippocampus and medulla oblongata, was measured using HE and Nissl staining. The potential influence of polymyxins on the ferroptosis pathway was evaluated by assessing LPO and Fe2+ levels and the degree of mitochondrial impairment. At equivalent doses, colistin demonstrated a reduced level of neurotoxicity compared to polymyxin B, both in vitro and in vivo. in vitro experiments revealed greater cell viability and a lower apoptosis rate after colistin treatment than after polymyxin B treatment. This variance in outcomes could be attributed to the comparatively lower levels of oxidative stress associated with colistin administration.In a rat model, nerve injury resulted in observable damage to both the hippocampus and the medulla oblongata. A comprehensive assessment of the extent of damage in the CA1 to CA4 regions of the hippocampus, and the solitary tract nucleus of the medulla oblongata underscored that the neurotoxic effects of colistin remained milder compared to those elicited by polymyxin B. Even when evaluated at equivalent multiples of clinically recommended doses, colistin exhibited lower neurotoxicity in vivo than polymyxin B. For the first time, this study demonstrated the role of ferroptosis in polymyxin B-induced nerve damage. The activation levels observed within the ferroptosis pathway due to polymyxin B exceeded those triggered by colistin. Colistin exhibited a marked reduction in neurotoxicity compared to polymyxin B, evident in both the equivalent and clinically recommended doses. These findings suggest that, from the perspective of neurotoxicity, colistin presents a more favorable option for clinical use.

A comparative analysis of national dementia plans: preventive strategies in five European countries

Abstract Background About 8.5% of people aged +65 live with dementia in Europe. Preventive measures can avert up to 40% of cases. The aim of the study is to analyse National Dementia Plans (NDP) in Europe, to elicit how much dementia prevention is considered a priority and whether policies are evidence-based. Methods A qualitative comparative analysis was performed between NDPs of countries with the best healthy life expectancy in the elderly in Europe. The NDPs of France, Ireland, Italy, Spain, and Sweden were included. The consensus on actions and elements of prevention policies was evaluated, according to the WHO recommendations and to Cheung’s framework designed for evaluating chronic diseases policies. Results All the NDPs prioritised early diagnosis, public awareness, and community engagement for dementia risk reduction. They fostered the development of information system for data collection and established committees for progress monitoring. However, not all NDPs defined timelines for policy implementation and most of them expired years ago. NDPs included prevention research agenda, but their preventive actions did not address alcohol consumption, traumatic brain injury, and air pollution, representing 3 well-known risk factors attributable for the 15% of preventable cases. Neither integration of dementia with other chronic disease preventive strategies was present and a clear allocation of funds for NDPs always missed. Conclusions NDPs partially address risk factors of preventable cases. All countries need to update their NDPs, integrating new scientific evidence and allocating clear financial funds. This can potentially prevent millions of new cases, decreasing the burden of disease and improving the sustainability of health systems. Key messages • NDPs do not target adequately dementia in Europe. • New evidence-based preventive policies, including most recent identified risk factors, would have a clear impact on burden of disease and health systems’ sustainability.