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ObjectiveTo appraise the currency, completeness and quality of evidence from systematic reviews (SRs) of acute management of moderate to severe traumatic brain injury (TBI).MethodsWe conducted comprehensive searches to March 2016 for published, English-language SRs and RCTs of acute management of moderate to severe TBI. Systematic reviews and RCTs were grouped under 12 broad intervention categories. For each review, we mapped the included and non-included RCTs, noting the reasons why RCTs were omitted. An SR was judged as 'current' when it included the most recently published RCT we found on their topic, and 'complete' when it included every RCT we found that met its inclusion criteria, taking account of when the review was conducted. Quality was assessed using the AMSTAR checklist (trichotomised into low, moderate and high quality).FindingsWe included 85 SRs and 213 RCTs examining the effectiveness of treatments for acute management of moderate to severe TBI. The most frequently reviewed interventions were hypothermia (n = 17, 14.2%), hypertonic saline and/or mannitol (n = 9, 7.5%) and surgery (n = 8, 6.7%). Of the 80 single-intervention SRs, approximately half (n = 44, 55%) were judged as current and two-thirds (n = 52, 65.0%) as complete. When considering only the most recently published review on each intervention (n = 25), currency increased to 72.0% (n = 18). Less than half of the 85 SRs were judged as high quality (n = 38, 44.7%), and nearly 20% were low quality (n = 16, 18.8%). Only 16 (20.0%) of the single-intervention reviews (and none of the five multi-intervention reviews) were judged as current, complete and high-quality. These included reviews of red blood cell transfusion, hypothermia, management guided by intracranial pressure, pharmacological agents (various) and prehospital intubation. Over three-quarters (n = 167, 78.4%) of the 213 RCTs were included in one or more SR. Of the remainder, 17 (8.0%) RCTs post-dated or were out of scope of existing SRs, and 29 (13.6%) were on interventions that have not been assessed in SRs.ConclusionA substantial number of SRs in acute management of moderate to severe TBI lack currency, completeness and quality. We have identified both potential evidence gaps and also substantial research waste. Novel review methods, such as Living Systematic Reviews, may ameliorate these shortcomings and enhance utility and reliability of the evidence underpinning clinical care.

This systematic literature review aimed to provide an overview of the characteristics and methods used in studies applying the Disability-Adjusted Life Years (DALY) concept for infectious diseases within European Union (EU)/European Economic Area (EEA)/European Free Trade Association (EFTA) countries and the United Kingdom. Electronic databases and grey literature were searched for articles reporting the assessment of DALY and its components. We considered studies in which researchers performed DALY calculations using primary epidemiological data input sources. We screened 3,053 studies of which 2,948 were excluded and 105 studies met our inclusion criteria. Of these studies, 22 were multi-country and 83 were single-country studies, of which 46 were from the Netherlands. Food- and water-borne diseases were the most frequently studied infectious diseases. Between 2015 and 2022, the number of burden of infectious disease studies was 1.6 times higher compared to that published between 2000 and 2014. Almost all studies (97%) estimated DALYs based on the incidence- and pathogen-based approach and without social weighting functions; however, there was less methodological consensus with regards to the disability weights and life tables that were applied. The number of burden of infectious disease studies undertaken across Europe has increased over time. Development and use of guidelines will promote performing burden of infectious disease studies and facilitate comparability of the results., peer-reviewed

The power Doppler is a useful tool in the evaluation of pediatric acute scrotal pain. Nonetheless, it may have some inherent limitations in scrotal vascularization analysis, potentially causing unnecessary surgery. The microvascular imaging ultrasound (MicroV) is an innovative Doppler technique able to improve the detection of very low flow. This retrospective study aims to compare both power Doppler and MicroV in the evaluation of a pediatric population with early-stage scrotal pain onset, first in testis vascularization analysis, and second in their diagnostic performances. 69 patients met the following inclusion criteria, age

Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud’s phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E2) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E2 stimulates the expression of vascular alpha 2C-adrenoceptors (α2C-AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E2, namely E2:BSA, mimics E2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E2-induced α2C-AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen’s effect on the expression of vascular α2C-AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women.

Glycosylation is one of the most significant and abundant posttranslational modifications in mammalian cells. It mediates a wide range of biofunctions, including cell adhesion, cell communication, immune cell trafficking, and protein stability. Also, aberrant glycosylation has been associated with various diseases such as diabetes, Alzheimer’s disease, inflammation, immune deficiencies, congenital disorders, and cancers. The alterations in the distributions of glycan and glycopeptide isomers are involved in the development and progression of several human diseases. However, the microheterogeneity of glycosylation brings a great challenge to glycomic and glycoproteomic analysis, including the characterization of isomers. Over several decades, different methods and approaches have been developed to facilitate the characterization of glycan and glycopeptide isomers. Mass spectrometry (MS) has been a powerful tool utilized for glycomic and glycoproteomic isomeric analysis due to its high sensitivity and rich structural information using different fragmentation techniques. However, a comprehensive characterization of glycan and glycopeptide isomers remains a challenge when utilizing MS alone. Therefore, various separation methods, including liquid chromatography, capillary electrophoresis, and ion mobility, were developed to resolve glycan and glycopeptide isomers before MS. These separation techniques were coupled to MS for a better identification and quantitation of glycan and glycopeptide isomers. Additionally, bioinformatic tools are essential for the automated processing of glycan and glycopeptide isomeric data to facilitate isomeric studies in biological cohorts. Here in this review, we discuss commonly employed MS-based techniques, separation hyphenated MS methods, and software, facilitating the separation, identification, and quantitation of glycan and glycopeptide isomers.

SARS-CoV-2 infection may be associated with uncommon complications such as intracerebral hemorrhage (ICH), with a high mortality rate. We compared a series of hospitalized ICH cases infected with SARS-CoV-2 with a non-SARS-CoV-2 infected control group and evaluated if the SARS-CoV-2 infection is a predictor of mortality in ICH patients.In a multinational retrospective study, 63 cases of ICH in SARS-CoV-2 infected patients admitted to 13 tertiary centers from the beginning of the pandemic were collected. We compared the clinical and radiological characteristics and in-hospital mortality of these patients with a control group of non-SARS-CoV-2 infected ICH patients of a previous cohort from the country where the majority of cases were recruited.Among 63 ICH patients with SARS-CoV-2 infection, 23 (36.5%) were women. Compared to the non-SARS-CoV-2 infected control group, in SARS-CoV-2 infected patients, ICH occurred at a younger age (61.4 ± 18.1 years versus 66.8 ± 16.2 years, P = 0.044). These patients had higher median ICH scores ([3 (IQR 2-4)] versus [2 (IQR 1-3)], P = 0.025), a more frequent history of diabetes (34% versus 16%, P = 0.007), and lower platelet counts (177.8 ± 77.8 × 10Infection with SARS-CoV-2 may be associated with increased odds of in-hospital mortality in ICH patients.

The effect of high arterial oxygen levels and supplemental oxygen administration on outcomes in traumatic brain injury (TBI) is debated, and data from large cohorts of TBI patients are limited. We investigated whether exposure to high blood oxygen levels and high oxygen supplementation is independently associated with outcomes in TBI patients admitted to the intensive care unit (ICU) and undergoing mechanical ventilation.This is a secondary analysis of two multicenter, prospective, observational, cohort studies performed in Europe and Australia. In TBI patients admitted to ICU, we describe the arterial partial pressure of oxygen (PaOThe analysis included 1084 patients (11,577 measurements) in the CENTER-TBI cohort, of whom 55% had an unfavorable outcome, and 26% died at a 6-month follow-up. Median PaOIn two large prospective multicenter cohorts of critically ill patients with TBI, levels of PaO

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) in which activated immune cells attack the CNS and cause inflammation and demyelination. While the etiology of MS is still largely unknown, the interaction between hormones and the immune system plays a role in disease progression, but the mechanisms by which this occurs are incompletely understood. Several in vitro and in vivo experimental, but also clinical studies, have addressed the possible role of the endocrine system in susceptibility and severity of autoimmune diseases. Although there are several demyelinating models, experimental autoimmune encephalomyelitis (EAE) is the oldest and most commonly used model for MS in laboratory animals which enables researchers to translate their findings from EAE into human. Evidences imply that there is great heterogeneity in the susceptibility to the induction, the method of induction, and the response to various immunological or pharmacological interventions, which led to conflicting results on the role of specific hormones in the EAE model. In this review, we address the role of endocrine system in EAE model to provide a comprehensive view and a better understanding of the interactions between the endocrine and the immune systems in various models of EAE, to open up a ground for further detailed studies in this field by considering and comparing the results and models used in previous studies.

Degenerative cervical spondylotic myelopathy (DCM) is the commonest form of spinal cord injury in adults. However, a limited number of clinical reports have assessed the role of biomarkers in DCM.We evaluated cerebrospinal fluid (CSF) biomarkers in patients scheduled for DCM surgery and hypothesized that CSF biomarkers levels (1) would reflect the severity of preoperative neurological status; and (2) correlate with radiological appearance; and (3) correlate with clinical outcome.Prospective clinical and laboratory study.Twenty-three DCM patients, aged 66.4±12.8 years and seven controls aged 45.4±5.3 years were included.The American Spinal Injury Association Impairment Scale, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire and EuroQol 5-dimensions were assessed preoperatively and at 3 months post-surgery.We measured preoperative biomarkers (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], phosphorylated neurofilament-H [pNF-H] and Ubiquitin C-terminal hydrolase L1) in CSF samples collected from patients with progressive clinical DCM who underwent surgical treatment. Biomarker concentrations in DCM patients were compared with those of cervical radiculopathy controls.The median symptom duration was 10 (interquartile range 6) months. The levels of GFAP, NFL, pNF-H, Ubiquitin C-terminal hydrolase L1 were significantly higher in the DCM group compared to controls (p=.044, p=.002, p=.016, and p=.006, respectively). Higher pNF-H levels were found in patients with low signal on T1 Magnetic Resonance Imaging sequence compared to those without (p=.022, area under the receiver operating characteristic curve [AUC] 0.780, 95% Confidence Interval: 0.59-0.98). Clinical improvement following surgery correlated mainly with NFL and GFAP levels (p.05).Our results suggest that CSF biomarkers of white matter injury and astrogliosis may be a useful tool to assess myelopathy severity and predict outcome after surgery, while providing valuable information on the underlying pathophysiology.

Serum biomarkers are promising tools for evaluating patients following traumatic brain injury (TBI). However, their relationship with diffuse histopathology remains unclear. Additionally, translatability is a focus of neurotrauma research, however, studies using translational animal models are limited. Here, we evaluated associations between circulating biomarkers and acute thalamic histopathology in a translational micro pig model of mTBI. Serum samples were collected pre-injury, and 1 min-6 h following mTBI. Markers of neuronal injury (Ubiquitin Carboxy-terminal Hydrolase L1 [UCH-L1]), microglial/macrophage activation (Ionized calcium binding adaptor molecule-1 [Iba-1]) and interleukin-6 [IL-6]) and astrogliosis/astrocyte damage (glial fibrillary acidic protein [GFAP]) were measured. Axonal injury and histological features of neurons and glia were also investigated using immunofluorescent labeling and correlated to serum levels of the associated biomarkers. Consistent with prior experimental and human studies, GFAP, was highest at 6 h post-injury, while no substantial changes were observed in UCH-L1, Iba-1 or IL-6 over 6 h. This study also found promising associations between thalamic glial histological signatures and ensuing release of Iba-1 and GFAP into the circulation. Our findings suggest that in diffuse injury, monitoring serum Iba-1 and GFAP levels can provide clinically relevant insight into the underlying acute pathophysiology and biomarker release kinetics following mTBI, providing previously underappreciated diagnostic capability.

Background Years after a traumatic spinal cord injury (SCI), a subset of patients may develop progressive clinical deterioration due to intradural scar formation and spinal cord tethering, with or without an associated syringomyelia. Meningitis, intradural hemorrhages, or intradural tumor surgery may also trigger glial scar formation and spinal cord tethering, leading to neurological worsening. Surgery is the treatment of choice in these chronic SCI patients. Objective We hypothesized that cerebrospinal fluid (CSF) and plasma biomarkers could track ongoing neuronal loss and scar formation in patients with spinal cord tethering and are associated with clinical symptoms. Methods We prospectively enrolled 12 patients with spinal cord tethering and measured glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and phosphorylated Neurofilament-heavy (pNF-H) in CSF and blood. Seven patients with benign lumbar intradural tumors and 7 patients with cervical radiculopathy without spinal cord involvement served as controls. Results All evaluated biomarker levels were markedly higher in CSF than in plasma, without any correlation between the two compartments. When compared with radiculopathy controls, CSF GFAP and pNF-H levels were higher in patients with spinal cord tethering (p ≤ 0.05). In contrast, CSF UCH-L1 levels were not altered in chronic SCI patients when compared with either control groups. Conclusions The present findings suggest that in patients with spinal cord tethering, CSF GFAP and pNF-H levels might reflect ongoing scar formation and neuronal injury potentially responsible for progressive neurological deterioration.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sleep and neurological sensorimotor disorder. The prevalence of RLS is at ∼5-15% in the general population. RLS could severely impact the daytime work productivity and the life quality of patients. However, the current diagnostic methods fail to provide an accurate and timely diagnosis, and the pathophysiology of RLS is not fully understood. Glycomics can help to unravel the underlying biochemical mechanisms of RLS, to identify specific glycome changes, and to develop powerful biomarkers for early detection and guiding interventions. Herein, we undertook a shotgun glycomics approach to determine and characterize the potential glycan biomarker candidates in the blood serum of RLS patients. Glycan profiles and isomeric quantitations were assessed by liquid chromatography-mass spectrometry analysis and compared with healthy controls. 24

Becker muscular dystrophy (BMD) is a severe X-linked muscle disease. Age of onset, clinical variability, speed of progression and affected tissues display wide variability, making a clinical trial design for drug development very complex. The histopathological changes in skeletal muscle tissue are central to the pathogenesis, but they have not been thoroughly elucidated yet. Here we analysed muscle biopsies from a large cohort of BMD patients, focusing our attention on the histopathological muscle parameters, as fibrosis, fatty replacement, fibre cross sectional area, necrosis, regenerating fibres, splitting fibres, internalized nuclei and dystrophy evaluation. We correlated histological parameters with both demographic features and clinical functional evaluations. The most interesting results of our study are the accurate quantification of fibroadipose tissue replacement and the identification of some histopathological aspects that well correlate with clinical performances. Through correlation analysis, we divided our patients into three clusters with well-defined histological and clinical features. In conclusion, this is the first study that analyses in detail the histological characteristics of muscle biopsies in a large cohort of BMD patients, correlating them to a functional impairment. The collection of these data help to better understand the histopathological progression of the disease and can be useful to validate any pharmacological trial in which the modification of muscle biopsy is utilized as outcome measure.

The proteome represents all the proteins expressed by a genome, a cell, a tissue, or an organism at any given time under defined physiological or pathological circumstances. Proteomic analysis has provided unparalleled opportunities for the discovery of expression patterns of proteins in a biological system, yielding precise and inclusive data about the system. Advances in the proteomics field opened the door to wider knowledge of the mechanisms underlying various post-translational modifications (PTMs) of proteins, including glycosylation. As of yet, the role of most of these PTMs remains unidentified. In this state-of-the-art review, we present a synopsis of glycosylation processes and the pathophysiological conditions that might ensue secondary to glycosylation shortcomings. The dynamics of protein glycosylation, a crucial mechanism that allows gene and pathway regulation, is described. We also explain how—at a biomolecular level—mutations in glycosylation-related genes may lead to neuropsychiatric manifestations and neurodegenerative disorders. We then analyze the shortcomings of glycoproteomic studies, putting into perspective their downfalls and the different advanced enrichment techniques that emanated to overcome some of these challenges. Furthermore, we summarize studies tackling the association between glycosylation and neuropsychiatric disorders and explore glycoproteomic changes in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington disease, multiple sclerosis, and amyotrophic lateral sclerosis. We finally conclude with the role of glycomics in the area of traumatic brain injury (TBI) and provide perspectives on the clinical application of glycoproteomics as potential diagnostic tools and their application in personalized medicine.

Alzheimer’s disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies including AD not only for their use as biomarkers but also for their implications in the therapeutic field. In this study, miRNA and protein profiles were obtained from brain tissues of different stage (Braak III-IV and Braak V-VI) of AD patients and compared to matched controls. The aim of the study was to identify in the late stage of AD, the key dysregulated pathways that may contribute to pathogenesis and then to evaluate whether any of these pathways could be detected in the early phase of AD, opening new opportunity for early treatment that could stop or delay the pathology. Six common pathways were found regulated by miRNAs and proteins in the late stage of AD, with one of them (Rap1 signalling) activated since the early phase. MiRNAs and proteins were also compared to explore an inverse trend of expression which could lead to the identification of new therapeutic targets. These results suggest that specific miRNA changes could represent molecular fingerprint of neurodegenerative processes and potential therapeutic targets for early intervention.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, and poses a substantial public health burden. TBI is increasingly documented not only as an acute condition but also as a chronic disease with long-term consequences, including an increased risk of late-onset neurodegeneration. The first Lancet Neurology Commission on TBI, published in 2017, called for a concerted effort to tackle the global health problem posed by TBI. Since then, funding agencies have supported research both in high-income countries (HICs) and in low-income and middle-income countries (LMICs). In November 2020, the World Health Assembly, the decision-making body of WHO, passed resolution WHA73.10 for global actions on epilepsy and other neurological disorders, and WHO launched the Decade for Action on Road Safety plan in 2021. New knowledge has been generated by large observational studies, including those conducted under the umbrella of the International Traumatic Brain Injury Research (InTBIR) initiative, established as a collaboration of funding agencies in 2011. InTBIR has also provided a huge stimulus to collaborative research in TBI and has facilitated participation of global partners. The return on investment has been high, but many needs of patients with TBI remain unaddressed. This update to the 2017 Commission presents advances and discusses persisting and new challenges in prevention, clinical care, and research.

Background Several studies have reported an association between serum biomarker values and functional outcome following traumatic brain injury. We aimed to examine the incremental (added) prognostic value of serum biomarkers over demographic, clinical, and radiological characteristics and over established prognostic models, such as IMPACT and CRASH, for prediction of functional outcome. Methods We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core study. We included patients aged 14 years or older who had blood sampling within 24 h of injury, results from a CT scan, and outcome assessment according to the Glasgow Outcome Scale-Extended (GOSE) at 6 months. Amounts in serum of six biomarkers (S100 calcium-binding protein B, neuron-specific enolase, glial fibrillary acidic protein, ubiquitin C-terminal hydrolase L1 [UCH-L1], neurofilament protein-light, and total tau) were measured. The incremental prognostic value of these biomarkers was determined separately and in combination. The primary outcome was the GOSE 6 months after injury. Incremental prognostic value, using proportional odds and a dichotomised analysis, was assessed by delta C-statistic and delta R-2 between models with and without serum biomarkers, corrected for optimism with a bootstrapping procedure. Findings Serum biomarker values and 6-month GOSE were available for 2283 of 4509 patients. Higher biomarker levels were associated with worse outcome. Adding biomarkers improved the C-statistic by 0 center dot 014 (95% CI 0 center dot 009-0 center dot 020) and R-2 by 4 center dot 9% (3 center dot 6-6 center dot 5) for predicting GOSE compared with demographic, clinical, and radiological characteristics. UCH-L1 had the greatest incremental prognostic value. Adding biomarkers to established prognostic models resulted in a relative increase in R-2 of 48-65% for IMPACT and 30-34% for CRASH prognostic models. Interpretation Serum biomarkers have incremental prognostic value for functional outcome after traumatic brain injury. Our findings support integration of biomarkers-particularly UCH-L1-in established prognostic models.

Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities in rapid eye movement. To date, no cure has been established for this life-threatening condition. Misdiagnosis of NT1 is also quite common, although it is not exceedingly rare. Therefore, successfully identifying candidate serum biomarkers for NT1 would be a head start for accurate diagnosis and development of therapeutics for this disorder. This study aims to identify such potential serum biomarkers. A depletion protocol was employed for 27 human serum samples (16 NT1 and 11 healthy controls), followed by applying LC-MS/MS bottom-up proteomics analysis, then LC-PRM-MS for validation. The comparison of the proteome profiles of the low-abundant proteins in the samples was then investigated based on age, sex, sample groups, and the presence of the Human Leukocyte Antigen (HLA) DQB1*0602 allele. The results were tracked to gene expression studies as well as system biology to identify key proteins and understand their relationship in the pathogenesis of NT1. Our results revealed 36 proteins significantly and differentially expressed. Among the impaired pathways and bioprocesses, the complement activation pathway is impaired by six of the differentially expressed proteins (DEPs). They are coded by the genes C2, CFB, C5, C1R, C1S, and MASP1, while 11 DEPs are involved in Acute Phase Response Signaling (APRS), which are coded by the genes FN1, AMBP, APOH, CFB, CP, ITIH2, C5, C2, F2, C1, and ITIH4. The combined AUCs of the downregulated and upregulated DEPs are 0.95 and 0.76, respectively. Overall, this study reveals potential serum-protein biomarkers of NT1 and explains the possible correlation between the biomarkers and pathophysiological effects, as well as important biochemical pathways involved in NT1.

IntroductionOwing to their inherent vulnerabilities, the burden of COVID-19 and particularly of its control measures on migrants has been magnified. A thorough assessment of the value of the interventions for COVID-19 tailored to migrants is essential for improving their health outcomes as well as promoting an effective control of the pandemic. In this study, based on evidence from primary biomedical research, we aimed to systematically identify health interventions for COVID-19 targeting migrants and to assess and compare their effectiveness. The review will be conducted within a programme aimed at defining and implementing interventions to control the COVID-19 pandemic in Italy, funded by the Italian Ministry of Health and conducted by a consortium of Italian regional health authorities.Methods and analysesData sources will include the bibliographic databases MEDLINE, Embase, LOVE Platform COVID-19 Evidence, and Cochrane Central Register of Controlled Trials. Eligible studies must evaluate health interventions for COVID-19 in migrants. Two independent reviewers will screen articles for inclusion using predefined eligibility criteria, extract data of retained articles and assess methodological quality by applying the Cochrane Risk of Bias tool. Disagreements will be resolved through consensus or arbitrated by a third reviewer if necessary. In synthesising the evidence, we will structure results by interventions, outcomes and quality. Where studies are sufficiently homogenous, trial data will be pooled and meta-analyses will be performed. Data will be reported according to methodological guidelines for systematic review provided by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Ethics and disseminationThis is a review of existing literature, and ethics approval is not required. We will submit results for peer-review publication and present at relevant conferences. The review findings will be included in future efforts to develop evidence-informed recommendations, policies or programmatic actions at the national and regional levels and address future high-quality research in public health.

Glycans play essential functional roles in the nervous system and their pathobiological relevance has become increasingly recognized in numerous brain disorders, but not fully explored in traumatic brain injury (TBI). We investigated longitudinal glycome patterns in patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) to characterize glyco-biomarker signatures and their relation to clinical features and long-term outcome.This prospective single-center observational study included 51 adult patients with TBI (GCS ≤12) admitted to the neurosurgical unit of the University Hospital of Pecs, Pecs, Hungary, between June 2018 and April 2019. We used a high-throughput liquid chromatography-tandem mass spectrometry platform to assess serum levels of N-glycans up to 3 days after injury. Outcome was assessed using the Glasgow Outcome Scale-Extended (GOS-E) at 12 months post-injury. Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, were used to analyze glycomics data and define highly influential structures driving class distinction. Receiver operating characteristic analyses were used to determine prognostic accuracy.We identified 94 N-glycans encompassing all typical structural types, including oligomannose, hybrid, and complex-type entities. Levels of high mannose, hybrid and sialylated structures were temporally altered (p0·05). Four influential glycans were identified. Two brain-specific structures, HexNAc5Hex3DeoxyHex0NeuAc0 and HexNAc5Hex4DeoxyHex0NeuAc1, were substantially increased early after injury in patients with unfavorable outcome (GOS-E≤4) (area under the curve [AUC]=0·75 [95%CI 0·59-0·90] and AUC=0·71 [0·52-0·89], respectively). Serum levels of HexNAc7Hex7DeoxyHex1NeuAc2 and HexNAc8Hex6DeoxyHex0NeuAc0 were persistently increased in patients with favorable outcome, but undetectable in those with unfavorable outcome. Levels of HexNAc5Hex4DeoxyHex0NeuAc1 were acutely elevated in patients with mass lesions and in those requiring decompressive craniectomy.In spite of the exploratory nature of the study and the relatively small number of patients, our results provide to the best of our knowledge initial evidence supporting the utility of glycomics approaches for biomarker discovery and patient phenotyping in TBI. Further larger multicenter studies will be required to validate our findings and to determine their pathobiological value and potential applications in practice.This work was funded by the Italian Ministry of Health (grant number GR-2013-02354960), and also partially supported by a NIH grant (1R01GM112490-08).

INTRODUCTION Traumatic brain injury (TBI) is a major global health issue, resulting in debilitating consequences to families, communities, and health-care systems. Prior research has found that biomarkers aid in the pathophysiological characterization and diagnosis of TBI. Significantly, the FDA has recently cleared both a bench-top assay and a rapid point-of-care assays of tandem biomarker (UCH-L1/GFAP)-based blood test to aid in the diagnosis mTBI patients. With the global necessity of TBI biomarkers research, several major consortium multicenter observational studies with biosample collection and biomarker analysis have been created in the USA, Europe, and Canada. As each geographical region regulates its data and findings, the International Initiative for Traumatic Brain Injury Research (InTBIR) was formed to facilitate data integration and dissemination across these consortia. AREAS COVERED This paper covers heavily investigated TBI biomarkers and emerging non-protein markers. Finally, we analyze the regulatory pathways for converting promising TBI biomarkers into approved in-vitro diagnostic tests in the United States, European Union, and Canada. EXPERT OPINION TBI biomarker research has significantly advanced in the last decade. The recent approval of an iSTAT point of care test to detect mild TBI has paved the way for future biomarker clearance and appropriate clinical use across the globe.

Traumatic Brain Injury (TBI) is one of the leading causes of death and disability worldwide. Aspirin (ASA) and clopidogrel (CLOP) are antiplatelet agents that inhibit platelet aggregation. They are implicated in worsening the intracerebral haemorrhage (ICH) risk post-TBI. However, antiplatelet drugs may also exert a neuroprotective effect post-injury. We determined the impact of ASA and CLOP treatment, alone or in combination, on ICH and brain damage in an experimental rat TBI model. We assessed changes in platelet aggregation and measured serum thromboxane by enzyme immune assay. We also explored a panel of brain damage and apoptosis biomarkers by immunoblotting. Rats were treated with ASA and/or CLOP for 48 h prior to TBI and sacrificed 48 h post-injury. In rats treated with antiplatelet agents prior to TBI, platelet aggregation was completely inhibited, and serum thromboxane was significantly decreased, compared to the TBI group without treatment. TBI increases UCHL-1 and GFAP, but decreases hexokinase expression compared to the non-injured controls. All groups treated with antiplatelet drugs prior to TBI had decreased UCH-L1 and GFAP serum levels compared to the TBI untreated group. Furthermore, the ASA and CLOP single treatments increased the hexokinase serum levels. We confirmed that αII-spectrin cleavage increased post-TBI, with the highest cleavage detected in CLOP-treated rats. Aspirin and/or CLOP treatment prior to TBI is a double-edged sword that exerts a dual effect post-injury. On one hand, ASA and CLOP single treatments increase the post-TBI ICH risk, with a further detrimental effect from the ASA + CLOP treatment. On the other hand, ASA and/or CLOP treatments are neuroprotective and result in a favourable profile of TBI injury markers. The ICH risk and the neuroprotection benefits from antiplatelet therapy should be weighed against each other to ameliorate the management of TBI patients.

Background: Neurological conditions are highly prevalent and disabling, in particular in the elderly. The Italian population has witnessed sharp ageing and we can thus expect a rising trend in the incidence, prevalence and disability of these conditions. Methods: We relied on the Global Burden of Disease 2019 study to extract Italian data on incidence, prevalence and years lived with a disability (YLDs) referred to a broad set of neurological disorders including, brain and nervous system cancers, stroke, encephalitis, meningitis, tetanus, traumatic brain injury, and spinal cord injury. We assessed changes between 1990 and 2019 in counts and age-standardized rates. Results: The most prevalent conditions were tension-type headache, migraine, and dementias, whereas the most disabling were migraine, dementias and traumatic brain injury. YLDs associated with neurological conditions increased by 22.5%, but decreased by 2.3% in age-standardized rates. The overall increase in prevalence and YLDs counts was stronger for non-communicable diseases with onset in old age compared to young to adult-age onset ones. The same trends were in the opposite direction when age-standardized rates were taken into account. Conclusions: The increase in YLDs associated with neurological conditions is mostly due to population ageing and growth: nevertheless, lived disability and, as a consequence, impact on health systems has increased. Actions are needed to improve outcome and mitigate disability associated with neurological conditions, spanning among diagnosis, treatment, care pathways and workplace interventions.

This study evaluated the association between the H1299R factor V (FV) variant (rs1800595) and recurrent pregnancy loss (RPL). Pubmed (MEDLINE) and Embase (OVID) bibliographic databases were searched from the inception to 31 May 2022 to identify suitable articles according to PRISMA and MOOSE guidelines. We included observational studies, case-control studies, cross-sectional studies, and cohort studies reporting a numerical and well-distinguished Het or Hom status of the H1299R variant obtained through PCR or other biochemical techniques and comparing RPL patients with a healthy control group. The review protocol was registered at PROSPERO (CRD42022330077). Two authors independently screened studies, extracted data, and carried out the risk of bias assessment using the Newcastle Ottawa scale (NOS). A meta-analysis was performed with RevMan software Version 5.4 using an odds ratio (OR) with an M-H, random effect, and 95% CI. We included 13 clinical studies for a total of 1669 RPL patients and 1466 healthy women as a control group. H1299R variant was slightly associated with RPL albeit without significance (OR 1.18, 95% CI: 0.78–1.80, p = 0.44). Subgroup analyses considering H1299R in heterozygosity (OR 1.13, 95% CI: 0.76–1.67, p = 0.56) and in homozygosity (OR: 2.11, 95% CI: 0.74–6.01, p = 0.16) revealed a similar trend. Lastly, we evaluated the association between H1299R and RPL based on the number of previous miscarriages (≥2 or ≥3). This comprehensive systematic review and meta-analysis sheds light on the specific influence of the H1299R variant in the F5 gene on RPL, constituting valid support for medical care during pregnancy and genetic counseling.

The power Doppler is a useful tool in the evaluation of pediatric acute scrotal pain. Nonetheless, it may have some inherent limitations in scrotal vascularization analysis, potentially causing unnecessary surgery. The microvascular imaging ultrasound (MicroV) is an innovative Doppler technique able to improve the detection of very low flow. This retrospective study aims to compare both power Doppler and MicroV in the evaluation of a pediatric population with early-stage scrotal pain onset, first in testis vascularization analysis, and second in their diagnostic performances.69 patients met the following inclusion criteria, age 18-year-old, a clinical diagnosis of acute scrotal disease, pain onset ≤ 6 h, ultrasound examination (including B-mode, power Doppler, and MicroV), 3-months follow-up. For both power Doppler and MicroV, through a defined vascularization scale, it was evaluated the agreement in vascularization detection, and the sensitivity and specificity in US diagnostic abilities.Retrospective diagnoses were of 8 testicular torsion, 15 orchi-epididymitis, and 46 children with other scrotal conditions. Power Doppler provided inconclusive US evaluation in 37.68% of the cases, while MicroV only in the 1.45% (p 0.0001). Testicular torsion and orchi-epididymitis were identified, respectively, with MicroV in 100% (sensitivity, specificity, PPV, NPV, and accuracy of 100%) and 80% of patients (80% sensitivity, 100% specificity and PPV, 94.73% NPV, 95.65% accuracy); with power Doppler the identification was, respectively, of 87.5% (87.5% sensitivity, 100% specificity and PPV, 98.38% NPV and accuracy) and of 73.3% (73.33% sensitivity, 98.14% specificity, 91.66% PPV, 92.98% NPV, 92.75% accuracy).Our findings indicate that MicroV is a reliable technique in vascularization detection of pediatric testes, being able also to detect vascularization in healthy testicles with no-flow at power Doppler examination. Moreover, MicroV could be a valuable ally in the US diagnostic of children with early-stage scrotal pain onset.

IntroductionSport-related repetitive subconcussive head impacts (RSHIs) are increasingly thought to be associated with adverse long-term outcomes. However, owing to potentially subtle effects, accurate assessment of harm to the brain as a consequence of RSHI is a major challenge and an unmet need. Several studies suggest that biofluid markers can be valuable objective tools to aid the diagnosis and injury characterisation and help in medical decision-making. Still, by and large, the results have been limited, heterogeneous and inconsistent. The main aims of this scoping review are therefore (1) to systematically examine the extent, nature and quality of available evidence from studies investigating effects of RSHI on fluid biomarkers and (2) to formulate guidelines and identify gaps with the aim to inform future clinical studies and the development of research priorities.Methods and analysesWe will use a comprehensive search strategy to retrieve all available and relevant articles in the literature. The following electronic databases will be systematically searched: MEDLINE (EBSCO host; from 1809 to 2020); Scopus (from 1788 to 2020); SPORTDiscus (from 1892 to 2020); CINAHL Complete (from 1937 to 2020); PsycINFO (from 1887 to 2020); Cochrane Library (to 2020); OpenGrey (to 2020); ClinicalTrials.gov (to 2020) and WHO International Clinical Trials Registry Platform (to 2020). We will consider primarily biomedical studies evaluating the biofluid markers following RSHI. Two independent reviewers will screen articles for inclusion using predefined eligibility criteria and extract data of retained articles. Disagreements will be resolved through consensus or arbitrated by a third reviewer if necessary. Data will be reported qualitatively given the heterogeneity of the included studies. In synthesising the evidence, we will structure results by markers, sample types, outcomes, sport and timepoints.Ethics and disseminationEthics approval is not required. We will submit results for peer-review publication, and present at relevant conferences.

Traumatic brain injury (TBI) has been recognized as one of the major public health issues that leads to devastating neurological disability. As a consequence of primary and secondary injury phases, neuronal loss following brain trauma leads to pathophysiological alterations on the molecular and cellular levels that severely impact the neuropsycho-behavioral and motor outcomes. Thus, to mitigate the neuropathological sequelae post-TBI such as cerebral edema, inflammation and neural degeneration, several neurotherapeutic options have been investigated including drug intervention, stem cell use and combinational therapies. These treatments aim to ameliorate cellular degeneration, motor decline, cognitive and behavioral deficits. Recently, the use of neural stem cells (NSCs) coupled with selective drug therapy has emerged as an alternative treatment option for neural regeneration and behavioral rehabilitation post-neural injury. Given their neuroprotective abilities, NSC-based neurotherapy has been widely investigated and well-reported in numerous disease models, notably in trauma studies. In this review, we will elaborate on current updates in cell replacement therapy in the area of neurotrauma. In addition, we will discuss novel combination drug therapy treatments that have been investigated in conjunction with stem cells to overcome the limitations associated with stem cell transplantation. Understanding the regenerative capacities of stem cell and drug combination therapy will help improve functional recovery and brain repair post-TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies, affecting approximately 1 to 3% of women worldwide. Scientific data highlight a possible correlation between thrombophilic genetic variants and RPL. H1299R variant in the factor V gene would lead to an increased thrombotic risk associated with frequent miscarriages. However, the data are often conflicting, making this an interesting question for further investigations by evaluating genotype-phenotype correlations to improve the clinical management and genetic counseling of couples. A systematic review and meta-analysis will follow the preferred reporting elements for systematic review and meta-analysis protocols (PRISMA-P). The Pubmed (MEDLINE) and Embase (OVID) databases will be explored to identify suitable articles based on inclusion and exclusion criteria. Inclusion criteria are: (a) H1299R genotyping with clear data reported, referred to as Heterozygous (Het) and/or Homozygous (Hom); (b) articles written in English; (c) analyses of only RPL female patients having at least two or more previous pregnancy losses and compared with a control group. This analysis will present selected scientific evidence, addressing the questions concerning the association between the H1299R variant and RPL, hoping to clarify this still unresolved issue. PROSPERO registration number: CRD42022330077.

Background: Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods: We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings: We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4-65·1) million cases globally in 2019 to 152·8 (130·8-175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [-7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64-1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52-1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41-67]) and western Europe (74% [58-90]), and the largest in north Africa and the Middle East (367% [329-403]) and eastern sub-Saharan Africa (357% [323-395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation: Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia. F Carvalho and E F Fernandes acknowledge support from the University of Porto (UID/MULTI/04378/2019 and UID/QUI/50006/2019 with funding from FCT/MCTES through national funds). L F S Castro-de-Araujo acknowledges support from the Medical Research Council (London; grant number MC_PC_MR/T03355X/1). V M Costa acknowledges her grant (SFRH/BHD/110001/2015), received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória (DL57/2016/CP1334/CT0006). A Douiri acknowledges support from the NIHR Applied Research Collaboration (ARC) South London at King’s College Hospital NHS Foundation Trust and the Royal College of Physicians, as well as the support from the NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. N Ghith acknowledges her salary as a postdoc is covered by a grant to her research group provided by Novo Nordisk Foundation. V K Gupta and V B Gupta acknowledge funding support from National Health and Medical Research Council (NHMRC), Australia. S Haque acknowledges support from Jazan University, Saudi Arabia, for providing access to the Saudi Digital Library for this study. C Herteliu is partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation (CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084). Y J Kim was supported by the Research Management Centre, Xiamen University, Malaysia (No. XMUMRF/2020-C6/ITCM/0004). M Kivimäki was supported by the MRC (S011676) and the Wellcome Trust (221854/Z/20/Z). M Kumar acknowledges support from Fogarty International Center (K43 TW010716-04). S Lorkowski acknowledges institutional support from the Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig (Germany; German Federal Ministry of Education and Research, grant agreement number 01EA1808A). S Mondello was supported by the Italian Ministry of Health (GR-2013-02354960). A Raggi acknowledges support from a grant from the Italian Ministry of Health (Ricerca Corrente, Fondazione Istituto Neurologico C. Besta, Linea – Outcome Research: dagli Indicatori alle Raccomandazioni Cliniche). D A S Silva acknowledges support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES; Finance Code 001 / CAPES-PRINT). J P Silva acknowledges support from the Applied Molecular Biosciences Unit (UCIBIO; grant number UIDB/04378/2020), supported through Portuguese national funds via FCT/MCTES. Sí

Traumatic brain injury (TBI) is a major cause of disability and death. Mild TBI (mTBI) constitutes ~75% of all TBI cases. Repeated exposure to mTBI (rmTBI), leads to the exacerbation of the symptoms compared to single mTBI. To date, there is no FDA-approved drug for TBI or rmTBI. This research aims to investigate possible rmTBI neurotherapy by targeting TBI pathology-related mechanisms. Oxidative stress is partly responsible for TBI/rmTBI neuropathologic outcomes. Thus, targeting oxidative stress may ameliorate TBI/rmTBI consequences. In this study, we hypothesized that mitoquinone (MitoQ), a mitochondria-targeted antioxidant, would ameliorate TBI/rmTBI associated pathologic features by mitigating rmTBI-induced oxidative stress. To model rmTBI, C57BL/6 mice were subjected to three concussive head injuries. MitoQ (5 mg/kg) was administered intraperitoneally to rmTBI+MitoQ mice twice per week over one month. Behavioral and cognitive outcomes were assessed, 30 days following the first head injury, using a battery of behavioral tests. Immunofluorescence was used to assess neuroinflammation and neuronal integrity. Also, qRT-PCR was used to evaluate the expression levels of antioxidant enzymes. Our findings indicated that MitoQ alleviated fine motor function and learning impairments caused by rmTBI. Mechanistically, MitoQ reduced astrocytosis, microgliosis, dendritic and axonal shearing, and increased the expression of antioxidant enzymes. MitoQ administration following rmTBI may represent an efficient approach to ameliorate rmTBI neurological and cellular outcomes with no observable side effects.

Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7-15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.

Stressful life events, are differently handled by women and men. This study evaluates gender differences in perceived stress and health status among a sample of subjects going through a transition period from unemployment to work. This cross-sectional study enrolled 395 participants, 245 men (62%) and 150 (38%) women, between 19 and 67 years, that were going to be hired for a 6-month contract. Before being employed, all participants underwent a mandatory protocol consisting in a general medical check. Stress assessment was performed by using the Perceived Stress Scale (PSS). Most of the participants (68%) showed normal to low perceived stress level. But dividing the sample by gender, out of the remaining 32% with medium to high stress level, 11% male subjects and 22.7% females reported high perceived stress values. We found mean PSS values that are overlapping with those in the general population of developed countries. This study does not suggest an association between perceived stress and health or social parameters. However, our results highlight that the female gender is associated with higher stress level, pointing out the relevance of specific and designed interventions in the context of health promotion programs, especially in order to mitigate stress in more susceptible subjects.

The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients. Data Source: This multicenter, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand). Main Outcomes and Measures: The outcome was the risk of subsequent stroke (ischemic stroke, intracranial hemorrhage, cerebral venous/sinus thrombosis). The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined study protocol. Data Extraction and Synthesis: Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test. The risk of subsequent stroke was estimated through meta-analyses with random effect models. Binary logistic regression was used to determine the associated factors with the outcome measure. The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines. Results: We received data from 18,311 hospitalized SARS-CoV-2 patients from 77 tertiary centers in 46 regions of 11 countries until May 1 st , 2020. A total of 17,799 patients were included in meta-analyses. Among them, 156(0.9%) patients had a stroke—123(79%) ischemic stroke, 27(17%) intracerebral/subarachnoid hemorrhage, and 6(4%) cerebral sinus thrombosis. Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5% among all centers in all countries, and 0.7% among countries with higher health expenditures. The need for mechanical ventilation (OR: 1.9, 95% CI:1.1-3.5, p = 0.03) and the presence of ischemic heart disease (OR: 2.5, 95% CI:1.4-4.7, p =0·006) were predictive of stroke. Conclusion and Relevance: The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5% (pooled risk: 0.9%). The need for mechanical ventilation and the history of ischemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients.

Objective and Design: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. Main Outcome Measures: We investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11[5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p Conclusions and Relevance: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. The stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.

A massive chemical detonation occurred on August 4, 2020 in the Port of Beirut, Lebanon. An uncontrolled fire in an adjacent warehouse ignited ~2,750 tons of Ammonium Nitrate (AN), producing one of the most devastating blasts in recent history. The blast supersonic pressure and heat wave claimed the lives of 220 people and injured more than 6,500 instantaneously, with severe damage to the nearby dense residential and commercial areas. This review represents one of the in-depth reports to provide a detailed analysis of the Beirut blast and its health and environmental implications. It further reviews prior AN incidents and suggests actionable recommendations and strategies to optimize chemical safety measures, improve emergency preparedness, and mitigate the delayed clinical effects of blast and toxic gas exposures. These recommended actionable steps offer a starting point for government officials and policymakers to build frameworks, adopt regulations, and implement chemical safety protocols to ensure safe storage of hazardous materials as well as reorganizing healthcare system disaster preparedness to improve emergency preparedness in response to similar large-scale disasters and promote population safety. Future clinical efforts should involve detailed assessment of physical injuries sustained by blast victims, with systemic mitigation and possible treatment of late blast effects involving individuals, communities and the region at large.

SARS-CoV-2 infects cells through angiotensin-converting enzyme 2 (ACE2), a ubiquitous receptor that interacts with the virus’ surface S glycoprotein. Recent reports show that the virus affects the central nervous system (CNS) with symptoms and complications that include dizziness, altered consciousness, encephalitis, and even stroke. These can immerge as indirect immune effects due to increased cytokine production or via direct viral entry into brain tissue. The latter is possible through neuronal access via the olfactory bulb, hematogenous access through immune cells or directly across the blood-brain barrier (BBB), and through the brain’s circumventricular organs characterized by their extensive and highly permeable capillaries. Last, the COVID-19 pandemic increases stress, depression, and anxiety within infected individuals, those in isolation, and high-risk populations like children, the elderly, and health workers. This review surveys the recent updates of CNS manifestations post SARS-CoV-2 infection along with possible mechanisms that lead to them.

Objectives: Traumatic brain injury (TBI) represents a major health concern worldwide with a large impact in the Middle East and North Africa (MENA) region as a consequence of protracted wars and conflicts that adversely affect the general population. Currently, systematic TBI studies in the MENA region are lacking, nonetheless they are immensely needed to enhance trauma management and increase survival rates among TBI patients. This systematic review aims to characterize TBI in the MENA region to guide future policy choices and research efforts and inform tailored guidelines capable of improving TBI management and patient treatment and outcome. Furthermore, it will serve as a road map to evaluate and assess knowledge of trauma impact on regional health systems that can be adopted by health-care providers to raise awareness and improve trauma care. Methods: We conducted a comprehensive search strategy of several databases including MEDLINE/Ovid, PubMed, Embase, Scopus, CINAHL, Google Scholar, and the grey literature in accordance with the PROSPERO systematic review protocol CRD42017058952. Abstracts were screened, and selected eligible studies were reviewed independently by 2 reviewers. We collected demographics information along with TBI characteristics, mortality rates, and regional distribution. Data were extracted using REDCap and checked for accuracy. Results: The search strategy yielded 23,385 citations; 147 studies met the eligibility criteria and were included in this review. Motor vehicle accident (MVA) was the leading cause of TBI (41%) in the MENA region, followed by the military- (15.6%) and fall- (8.8%) related TBI. Males predominantly suffer from TBI-related injuries (85%), with a high prevalence of MVA- and military-related TBI injuries. The TBI mortality rate was 12.9%. The leading causes of mortality were MVA (68%), military (20.5%), and assault (2.9%). The vast majority of reported TBI severity was mild (63.1%) compared to moderate (10.7%) and severe TBI (20.2%). Patients mainly underwent a Glasgow Coma Scale assessment (22.1%), followed by computed tomography scan (8.9%) and surgery (4.1%). Conclusions: Despite its clinical, social, and economic burden, the evidence of TBI research in the MENA region is scarce. Further research and high-quality epidemiological studies are urgently needed to gain a deep understanding of the TBI burden in the region, facilitate the allocation of adequate resources, implement effective preventive and intervention strategies and advise on the TBI patient management as reflective on the TBI patterns and modes.

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.

Background and Purpose: Stroke is reported as a consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in several reports. However, data are sparse regarding the details of these patients in a multinational and large scale. Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke, intracranial hemorrhage, and cerebral venous or sinus thrombosis among SARS-CoV-2–infected patients. We further investigated the risk of large vessel occlusion, stroke severity as measured by the National Institutes of Health Stroke Scale, and stroke subtype as measured by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria among patients with acute ischemic stroke. In addition, we explored the neuroimaging findings, features of patients who were asymptomatic for SARS-CoV-2 infection at stroke onset, and the impact of geographic regions and countries’ health expenditure on outcomes. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least 1 eligible stroke patient. Of 432 patients included, 323 (74.8%) had acute ischemic stroke, 91 (21.1%) intracranial hemorrhage, and 18 (4.2%) cerebral venous or sinus thrombosis. A total of 183 (42.4%) patients were women, 104 (24.1%) patients were P =0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; P Conclusions: We observed a considerably higher rate of large vessel occlusions, a much lower rate of small vessel occlusion and lacunar infarction, and a considerable number of young stroke when compared with the population studies before the pandemic. The rate of mechanical thrombectomy was significantly lower in countries with lower health expenditures.

Contains fulltext : 238746.pdf (Publisher’s version ) (Closed access) Recent biomarker innovations hold potential for transforming diagnosis, prognostic modeling, and precision therapeutic targeting of traumatic brain injury (TBI). However, many biomarkers, including brain imaging, genomics, and proteomics, involve vast quantities of high-throughput and high-content data. Management, curation, analysis, and evidence synthesis of these data are not trivial tasks. In this review, we discuss data management concepts and statistical and data sharing strategies when dealing with biomarker data in the context of TBI research. We propose that application of biomarkers involves three distinct steps-discovery, evaluation, and evidence synthesis. First, complex/big data has to be reduced to useful data elements at the stage of biomarker discovery. Second, inferential statistical approaches must be applied to these biomarker data elements for assessment of biomarker clinical utility and validity. Last, synthesis of relevant research is required to support practice guidelines and enable health decisions informed by the highest quality, up-to-date evidence available. We focus our discussion around recent experiences from the International Traumatic Brain Injury Research (InTBIR) initiative, with a specific focus on four major clinical projects (Transforming Research and Clinical Knowledge in TBI, Collaborative European NeuroTrauma Effectiveness Research in TBI, Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe, and Approaches and Decisions in Acute Pediatric TBI Trial), which are currently enrolling subjects in North America and Europe. We discuss common data elements, data collection efforts, data-sharing opportunities, and challenges, as well as examine the statistical techniques required to realize successful adoption and use of biomarkers in the clinic as a foundation for precision medicine in TBI.

Accurate diagnosis of traumatic brain injury (TBI) is critical to effective management and intervention, but can be challenging in patients with mild TBI. A substantial number of studies have reported the use of circulating biomarkers as signatures for TBI, capable of improving diagnostic accuracy and clinical decision making beyond current practice standards. We performed a systematic review and meta-analysis to comprehensively and critically evaluate the existing body of evidence for the use of blood protein biomarkers (S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], neuron specific enolase [NSE], ubiquitin C-terminal hydrolase-L1 [UCH-L1]. tau, and neurofilament proteins) for diagnosis of intracranial lesions on CT following mild TBI. Effects of potential confounding factors and differential diagnostic performance of the included markers were explored. Further, appropriateness of study design, analysis, quality, and demonstration of clinical utility were assessed. Studies published up to October 2016 were identified through searches of MEDLINE®, Embase, EBM Reviews, the Cochrane Library, World Health Organization (WHO), International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov. Following screening of the identified articles, 26 were selected as relevant. We found that measurement of S100B can help informed decision making in the emergency department, possibly reducing resource use; however, there is insufficient evidence that any of the other markers is ready for clinical application. Our work pointed out serious problems in the design, analysis, and reporting of many of the studies, and identified substantial heterogeneity and research gaps. These findings emphasize the importance of methodologically rigorous studies focused on a biomarker's intended use, and defining standardized, validated, and reproducible approaches. The living nature of this systematic review, which will summarize key updated information as it becomes available, can inform and guide future implementation of biomarkers in the clinical arena.

Traumatic brain injury (TBI) is an important cause of death and disability at all ages in the world. Complete functional recovery is not always complete, and, often, persistent symptoms may last for a long time. Sleep disorders and sleep-wake alterations are among the most common complications both in the acute and chronic phases after the trauma, and they may have a negative impact on daily activities and on quality of life of these patients. Sleep and sleep-wake cycle are not always carefully assessed in patients after TBI, they are overlooked, and often patients have a persistent excessive daytime sleepiness, even for years after the TBI, without receiving a proper diagnosis and treatment. Moreover, scientific evidence has been provided for the role of sleep in neuroprotection and recovery after brain injury; hence, promoting an optimal sleep function and early diagnosing and treating sleep disorders may be helpful for rehabilitation and functional recovery of patients after TBI.

As a result of armed conflict, head trauma from exposure to blasts is an increasing critical health issue, particularly among military service members. Whilst numerous studies examined the burden of blast-related brain injuries on service members', few systematic reviews have been published. This work provides a comprehensive summary of the evidence on blast-related mild traumatic brain injury (mTBI) burden in active U.S. military service members and inactive Veterans, describing characteristics and outcomes. Records published up to April 2017 were identified through a search of PubMed, Web of Science, Scopus, Ovid MEDLINE, and Cochrane Library. Records-based and original research reporting on U.S. military service members and Veterans with mild blast TBI were included. Data on subject characteristics, exposure, diagnostic criterion, and outcomes were extracted from included studies using a standardized extraction form and were presented narratively. Of the 2,290 references identified by the search, 106 studies with a total of 37,515 participants met inclusion criteria for blast-related mTBI. All but nine studies were based out of military or Veteran medical facilities. Unsurprisingly, men were over-represented (75–100%). The criteria used to define blast-related mTBI were consistent; however, the methodology used to ascertain whether individuals met those criteria for diagnosis were inconsistent. The diagnosis, most prevalent among the Army, heavily relied on self-reported histories. Commonly reported adverse outcomes included hearing disturbances and headaches. The most frequently associated comorbidities were post-traumatic stress disorder, depression, anxiety, sleep disorders, attention disorders, and cognitive disorders. The primary objective of this review was to provide a summary of descriptive data on blast-related mTBI in a U.S. military population. Low standardization of the methods for reaching diagnosis and problems in the study reporting emphasize the importance to collect high-quality data to fill knowledge gaps pertaining to blast-related mTBI.

Traumatic brain injury (TBI) remains a significant leading cause of death and disability among adults and children globally. To date, there are no Food and Drug Administration–approved drugs that can substantially attenuate the sequelae of TBI. The innumerable challenges faced by the conventional de novo discovery of new pharmacological agents led to the emergence of alternative paradigm, which is drug repurposing. Repurposing of existing drugs with well-characterized mechanisms of action and human safety profiles is believed to be a promising strategy for novel drug use. Compared to the conventional discovery pathways, drug repurposing is less costly, relatively rapid, and poses minimal risk of the adverse outcomes to study on participants. In recent years, drug repurposing has covered a wide range of neurodegenerative diseases and neurological disorders including brain injury. This review highlights the advances in drug repurposing and presents some of the promising candidate drugs for potential TBI treatment along with their possible mechanisms of neuroprotection. Edaravone, glyburide, ceftriaxone, levetiracetam, and progesterone have been selected due to their potential role as putative TBI neurotherapeutic agents. These drugs are Food and Drug Administration–approved for purposes other than brain injuries; however, preclinical and clinical studies have shown their efficacy in ameliorating the various detrimental outcomes of TBI.

Background: In light of the increasing trend in the global number of individuals affected by dementia and the lack of any available disease-modifying therapies, it is necessary to fully understand and quantify the global burden of dementia. This work aimed to estimate the proportion of dementia due to Down syndrome, Parkinson’s disease, clinical stroke, and traumatic brain injury (TBI), globally and by world region, in order to better understand the contribution of clinical diseases to dementia prevalence. Methods: Through literature review, we obtained data on the relative risk of dementia with each condition and estimated relative risks by age using a Bayesian meta-regression tool. We then calculated population attributable fractions (PAFs), or the proportion of dementia attributable to each condition, using the estimates of relative risk and prevalence estimates for each condition from the Global Burden of Disease Study 2019. Finally, we multiplied these estimates by dementia prevalence to calculate the number of dementia cases attributable to each condition. Findings: For each clinical condition, the relative risk of dementia decreased with age. Relative risks were highest for Down syndrome, followed by Parkinson’s disease, stroke, and TBI. However, due to the high prevalence of stroke, the PAF for dementia due to stroke was highest. Together, Down syndrome, Parkinson’s disease, stroke, and TBI explained 10.0% (95% UI: 6.0–16.5) of the global prevalence of dementia. Interpretation: Ten percent of dementia prevalence globally could be explained by Down syndrome, Parkinson’s disease, stroke, and TBI. The quantification of the proportion of dementia attributable to these 4 conditions constitutes a small contribution to our overall understanding of what causes dementia. However, epidemiological research into modifiable risk factors as well as basic science research focused on elucidating intervention approaches to prevent or delay the neuropathological changes that commonly characterize dementia will be critically important in future efforts to prevent and treat disease.

Traumatic brain injury (TBI) is a major health concern worldwide and is classified based on severity into mild, moderate, and severe. The mechanical injury in TBI leads to a metabolic and ionic imbalance, which eventually leads to excessive production of reactive oxygen species (ROS) and a state of oxidative stress. To date, no drug has been approved by the food and drug administration (FDA) for the treatment of TBI. Nevertheless, it is thought that targeting the pathology mechanisms would alleviate the consequences of TBI. For that purpose, antioxidants have been considered as treatment options in TBI and were shown to have a neuroprotective effect. In this review, we will discuss oxidative stress in TBI, the history of antioxidant utilization in the treatment of TBI, and we will focus on two novel antioxidants, mitoquinone (MitoQ) and edaravone. MitoQ can cross the blood brain barrier and cellular membranes to accumulate in the mitochondria and is thought to activate the Nrf2/ARE pathway leading to an increase in the expression of antioxidant enzymes. Edaravone is a free radical scavenger that leads to the mitigation of damage resulting from oxidative stress with a possible association to the activation of the Nrf2/ARE pathway as well.

Mondello, Stefania/0000-0002-8587-3614; Alizada, Orkhan/0000-0003-0942-9906; Ghorbani, Mohammad/0000-0002-7709-3095; Abedi, Vida/0000-0001-7689-933X WOS:000575454600010 PubMed ID: 32818804 Background: There is an increased attention to stroke following SARS-CoV-2. The goal of this study was to better depict the short-term risk of stroke and its associated factors among SARS-CoV-2 hospitalized patients. Methods: This multicentre, multinational observational study includes hospitalized SARS-CoV-2 patients from North and South America (United States, Canada, and Brazil), Europe (Greece, Italy, Finland, and Turkey), Asia (Lebanon, Iran, and India), and Oceania (New Zealand). The outcome was the risk of subsequent stroke. Centres were included by non-probability sampling. The counts and clinical characteristics including laboratory findings and imaging of the patients with and without a subsequent stroke were recorded according to a predefined protocol. Quality, risk of bias, and heterogeneity assessments were conducted according to ROBINS-E and Cochrane Q-test. The risk of subsequent stroke was estimated through meta-analyses with random effect models. Bivariate logistic regression was used to determine the parameters with predictive outcome value. The study was reported according to the STROBE, MOOSE, and EQUATOR guidelines. Findings: We received data from 26,175 hospitalized SARS-CoV-2 patients from 99 tertiary centres in 65 regions of 11 countries until May 1st, 2020. A total of 17,799 patients were included in meta-analyses. Among them, 156(0.9%) patients had a stroke-123(79%) ischaemic stroke, 27(17%) intracerebral/subarachnoid hemorrhage, and 6(4%) cerebral sinus thrombosis. Subsequent stroke risks calculated with meta-analyses, under low to moderate heterogeneity, were 0.5% among all centres in all countries, and 0.7% among countries with higher health expenditures. The need for mechanical ventilation (OR: 1.9, 95% CI:1.1-3.5, p = 0.03) and the presence of ischaemic heart disease (OR: 2.5, 95% CI:1.4-4.7, p = 0.006) were predictive of stroke. Interpretation: The results of this multi-national study on hospitalized patients with SARS-CoV-2 infection indicated an overall stroke risk of 0.5%(pooled risk: 0.9%). The need for mechanical ventilation and the history of ischaemic heart disease are the independent predictors of stroke among SARS-CoV-2 patients. (C) 2020 The Authors. Published by Elsevier B.V.