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Sara Montemerani,1 Cosimo Fabrizi,1 Cecilia Sacchi,2 Antoine Belperio,3 Lorenzo Moriani,3 Samuele Pacchi,3 Cinzia Garofalo,4 Giovanni Sbrana,5 Duccio Venezia,6 Maurizio Zanobetti,1 Simone Nocentini3 1UOC Medicina d’Emergenza Urgenza e Pronto Soccorso Ospedale San Donato, Dipartimento Emergenza Urgenza, Azienda USL Toscana Sud Est, Arezzo, Italia; 2Scuola di specializzazione in Medicina d’Emergenza Urgenza, Università degli Studi di Siena, Siena, Italia; 3COES Arezzo, Dipartimento Emergenza Territoriale, Azienda USL Toscana Sud Est, Arezzo, Italia; 4UOC Direzione Infermieristica Emergenza e Urgenza Area provinciale Arezzo, Siena e Grosseto, Azienda USL Toscana Sud Est, Arezzo, Italia; 5UOC Elisoccorso ed Emergenza Territoriale 118 area provinciale grossetana, Dipartimento Emergenza Territoriale, Azienda USL Toscana Sud Est Grosseto, Arezzo, Italia; 6UOC Radiologia Ospedale San Donato, Azienda USL Toscana Sud Est, Arezzo, ItaliaCorrespondence: Sara Montemerani, UOC Medicina d’Emergenza Urgenza e Pronto Soccorso Ospedale San Donato, Dipartimento Emergenza Urgenza, Azienda USL Toscana Sud Est, Via Curtatone, Arezzo, 52100, Italia, Email sara.montemerani@uslsudest.toscana.itPurpose: Mild Traumatic brain injury is classified based on Glasgow Coma Scale (GCS 13– 15), it also involves transient alteration of brain function, which may lead to severe short- and long-term sequelae. When treating a patient with a mild head injury outside the hospital, it is of crucial importance to decide whether to transport him to a center without neurosurgery or to a center equipped with neurosurgery (primary centralization). Recent decades have seen exploration of portable, non-invasive devices for intracranial injury and stroke detection, with microwave frequency electromagnetic field technology showing promising clinical outcomes. This clinical investigation aims to assess the diagnostic accuracy of the TES HT100 medical device, utilizing electromagnetic fields for endocranial lesion screening.Patients and Methods: Patients with mild traumatic brain injury were randomly enrolled according to inclusion criteria. Twenty-three patients recruited from the Intensive Short-Term Observation (ISTO) unit at San Donato Hospital in Arezzo. The sensitivity and specificity of the TES HT were evaluated statistically against cranial computed tomography (CT), the gold standard.Results: A preliminary analysis shows a sensitivity of 100% and a specificity of 100%. Based on these results, there is maximum concordance between the two examinations, and the AUC is 1. No adverse events related to the use of TES HT100 or the examination.Conclusion: The device’s ability to differentiate patients with intracranial lesions from those without can streamline the diagnostic and therapeutic process, potentially leading to improved patient outcomes. If Temnography will maintain high standards of sensitivity and specificity with the expansion of the enrolled population, it could be considered as a stable screening tool in the Emergency Room (ER). We could think to apply this technology to reduce the length of stay that patients with mTBI have to spend in ER for observation. Temnography could also be useful in special categories of patients such as pregnant women or the pediatric population. Moreover, another front of future development of this technology could be extending the study to include Territorial Emergency. In this context, Temnography could aid centralized decision-making in patient care.Keywords: temnography, mild traumatic brain injury, mTBI, traumatic brain injury, TBI, emergency medicine, pre-hospital

Aims. Mild Traumatic Brain Injury (mTBI) is the most common type of craniocerebral injury. Proper management appears to be a key factor in preventing post-concussion syndrome. The aim of this prospective study was to evaluate the effect and safety of selected training protocol in patients after mTBI. Methods. This was a prospective study that included 25 patients with mTBI and 25 matched healthy controls. Assessments were performed in two sessions and included a post-concussion symptoms questionnaire, battery of neurocognitive tests, and magnetic resonance with tractography. Participants were divided into two groups: a passive subgroup with no specific recommendations and an active subgroup with simple physical and cognitive training. Results. The training program with slightly higher initial physical and cognitive loads was well tolerated and was harmless according to the noninferiority test. The tractography showed overall temporal posttraumatic changes in the brain. The predictive model was able to distinguish between patients and controls in the first (AUC=0.807) and second (AUC=0.652) sessions. In general, tractography had an overall predictive dominance of measures. Conclusion. The results from our study objectively point to the safety of our chosen training protocol, simultaneously with the signs of slight benefits in specific cognitive domains. The study also showed the capability of machine learning and predictive models in mTBI patient recognition.

Purpose: To determine the psychological and neuropsychological status of patients with both blast-related ocular injury and mild traumatic brain injury (TBI) late after the traumatic event. Material and Methods: Thirty patients with blast-related ocular injury, reduced visual function and comorbid mild TBI were included in the study. The following methods of psychological and neuropsychological assessment were used: formalized interview; Suicidality, Post-traumatic Stress Disorder (PTSD), Alcohol Dependence, and Drug Dependence scales of the Mini-International Neuropsychiatric Interview (MINI); Raven’s Progressive Matrix scale; Personal and Social Performance (PSP) scale; PROMIS® Pain-Interference scale; Hospital Anxiety and Depression Scale (HADS); Mazes subtest of the Neuropsychological Assessment Battery (NAB); and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results: The following significant correlations were found: PSP functioning and support from the family (r = 0.533, p = 0.002); total RBANS score and Mazes subtest score (r = 0.466, p = 0.009); total RBANS score and self-reported stress score (negative correlation, r = -0.492, p = 0.006); HADS depression and self-reported stress score (r = 0.646, p = 0.000114); PROMIS pain scale and PTSD scale (r = 0.482, p = 0.007). No association was found between the number of mild TBI events experienced and neuropsychological and psychological measurements. Conclusion: Blast-related mild TBI concomitant with ocular injury has a substantial and long-term impact on casualty’s cognitive and psychological functions. In such patients, the most prominent cognitive deficits occur in the domain of executive function (including cognitive control and planning and problem-solving skills). In the presence of reduced visual function, these deficits have a substantial impact on total cognitive scores, scores of other psychic functions (namely, attention and memory) and significantly affect the patient’s capacity for independent functioning.

Abstract Introduction Mild traumatic brain injury (mTBI) represents a major public health concern and affects millions of people worldwide every year. Diagnosis mainly relies on clinical criteria and computed tomography (CT) scans. GFAP (glial fibrillary acidic protein) and UCH-L1 (ubiquitin carboxyl-terminal hydrolase-L1) have been recently studied as potential biomarkers of mTBI. This study retrospectively evaluated the possible use of these combined biomarkers as negative predictors for excluding brain injuries in patients with suspected mTBI in the emergency department. Methods Adult patients (n = 130) enrolled at Tor Vergata University Hospital (Rome, Italy), consecutively registered at the triage of the emergency department between October 2022 and January 2023, with non-penetrating TBI and Glasgow Coma Scale (GCS) score of 13–15, were considered. All eligible patients underwent intracranial CT scans and blood tests, within 12 h after trauma, for GFAP and UCH-L1 serum concentrations. Results Intracranial CT detected injuries in only seven patients (5%); GFAP and UCH-L1 tested positive in 96 patients and negative in 34 patients (74% vs. 26%). Combined biomarkers had a sensitivity equal to 1.00 (95% CI 0.64-1.00) and a negative predictive value (NPV) of 1.00 (0.99-1.00) in mTBI diagnosis with a negative CT. Conclusions Combined laboratory tests for GFAP and UCH-L1 biomarkers might play a potential clinical role in avoiding unnecessary head CT scans after mTBI in emergency departments.

Abstract Background Mild traumatic brain injury (mTBI), i.e. a TBI with an admission Glasgow Coma Scale (GCS) of 13–15, is a common cause of emergency department visits. Only a small fraction of these patients will develop a traumatic intracranial hemorrhage (tICH) with an even smaller subgroup suffering from severe outcomes. Limitations in existing management guidelines lead to overuse of computed tomography (CT) for emergency department (ED) diagnosis of tICH which may result in patient harm and higher healthcare costs. Objective To perform a systematic review and meta-analysis to characterize known and potential novel risk factors that impact the risk of tICH in patients with mTBI to provide a foundation for improving existing ED guidelines. Methods The literature was searched using MEDLINE, EMBASE and Web of Science databases. Reference lists of major literature was cross-checked. The outcome variable was tICH on CT. Odds ratios (OR) were pooled for independent risk factors. Results After completion of screening, 17 papers were selected for inclusion, with a pooled patient population of 26,040 where 2,054 cases of tICH were verified through CT (7.9%). Signs of a skull base fracture (OR 11.71, 95% CI 5.51–24.86), GCS

The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water. Repeated mild traumatic brain injury mice developed cold nociceptive hypersensitivity and negative affective states, as well as increased locomotor activity and risk-taking behavior. Minocycline reversed negative affect and pain hypersensitivities in male but not female mice. Repeated mild traumatic brain injury also produced an increase in microglial and brain-derived neurotropic factor mRNA transcripts in limbic structures known to be involved in nociception and affect, but many of these changes were sex dependent. Finally, we show that the antiepileptic drug, gabapentin, produced negative reinforcement in male rmTBI mice that was prevented by minocycline treatment, whereas rmTBI female mice showed a place aversion to gabapentin. Collectively, pain hypersensitivity, increased tonic-aversive pain components, and negative affective states were evident in both male and female rmTBI mice, but suppression of microglial reactivity was only sufficient to reverse behavioral changes in male mice. Neuroinflammation in limbic structures seems to be a contributing factor in behavioral changes resulting from rmTBI.

The gray matter/white matter (GM/WM) boundary of the brain is vulnerable to shear strain associated with mild traumatic brain injury (mTBI). It is, however, unknown whether GM/WM microstructure is associated with long-term outcomes following mTBI. The diffusion and structural MRI data of 278 participants between 18 and 65 years of age with and without military background from the Department of Defense INTRuST study were analyzed. Fractional anisotropy (FA) was extracted at the GM/WM boundary across the brain and for each lobe. Additionally, two conventional analytic approaches were used: whole-brain deep WM FA (TBSS) and whole-brain cortical thickness (FreeSurfer). ANCOVAs were applied to assess differences between the mTBI cohort (n = 147) and the comparison cohort (n = 131). Associations between imaging features and post-concussive symptom severity, and functional and cognitive impairment were investigated using partial correlations while controlling for mental health comorbidities that are particularly common among military cohorts and were present in both the mTBI and comparison group. Findings revealed significantly lower whole-brain and lobe-specific GM/WM boundary FA (p < 0.011), and deep WM FA (p = 0.001) in the mTBI cohort. Whole-brain and lobe-specific GM/WM boundary FA was significantly negatively correlated with post-concussive symptoms (p < 0.039), functional (p < 0.016), and cognitive impairment (p < 0.049). Deep WM FA was associated with functional impairment (p = 0.002). Finally, no significant difference was observed in cortical thickness, nor between cortical thickness and outcome (p > 0.05). Findings from this study suggest that microstructural alterations at the GM/WM boundary may be sensitive markers of adverse long-term outcomes following mTBI.

Summary: Background: Following mild traumatic brain injury (mTBI), elevated concentrations of brain-specific blood proteins glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) may be indicative of intracranial lesions normally detected by head CT scans. We sought to validate the performance of this combination of biomarkers at predetermined cutoff values with an automated immunoassay to predict which patients did not have intracranial lesions. Methods: This prospective, observational study was conducted in France and Spain at 16 emergency departments. Adult patients with mTBI were eligible if they had a head CT scan and gave a 10-ml blood sample within 12 h of injury. GFAP and UCH-L1 serum concentrations were measured and analysed, in less than an hour time, according to predefined cutoff values of 22 pg/ml and 327 pg/ml, respectively. Serum concentrations of S100B protein were concomitantly determined in a subset of patients. The primary outcome measures were the sensitivity and negative predictive value (NPV) of the combined GFAP–UCH-L1 test to rule out intracranial lesions on head CT scans. ClinicalTrials.gov (NCT04032509). Findings: Between August 2019 and June 2021, 1508 patients were recruited, and 1438 were included in the main analysis. Median age was 69 years (IQR 44–83). Most patients (74%) presented 3 h after trauma. 179 (12.4%) patients were positive for intracranial lesions by CT. The sensitivity of the combined test was 98.3% (95% CI 95.0–99.7) and the specificity 24.9 (95% CI 22.6–27.4), with a NPV of 99.1% (95% CI 97.1–99.8). Three patients with a positive CT scan had negative biomarker test results. S100B had a sensitivity of 83.0% (95% CI 76.2–88.2) and a NPV of 94.2% (95% CI 91.6–96.0). Patients with higher biomarker values more frequently had poorer recovery at 3 months after injury. Interpretation: Testing for GFAP and UCH-L1, using validated cutoffs obtained with a new, fast automated immunoassay platform, accurately predicted the absence of intracranial lesions on head CT following mTBI. Funding: This study is co-funded by the European Institute of Innovation and Technology (EIT) Health, a body of the European Union (Grant nº19474). Biomarkers tests were funded by bioMérieux.