Silencing CD28 attenuated chest blast exposure-induced traumatic brain injury through the PI3K/AKT/NF-κB signaling pathway in male mice.

In modern war or daily life, blast-induced traumatic brain injury (bTBI) is a growing health concern. Our previous studies demonstrated that inflammation was one of the main features of bTBI, and CD28-activated T cells play a central role in inflammation. However, the mechanism of CD28 in bTBI remains to be elucidated. In this study, traumatic brain injury model induced by chest blast exposure in male mice was established, and the mechanism of CD28 in bTBI was studied by elisa, immunofluorescence staining, flow cytometry analysis and western blot. After exposure to chest shock wave, the inflammatory factors IL-4, IL-6 and HMGB1 in serum were increased, and CD3+ T cells, CD4+ and CD8+ T cell subsets in the lung were activated. In addition, chest blast exposure resulted in impaired spatial learning and memory ability, disruption of the blood-brain barrier (BBB), and the expression of Tau, p-tau, S100ß and choline acetyltransferase were increased. The results indicated that genetic knockdown of CD28 could inhibit inflammatory cell infiltration, as well as the activation of CD3+ T cells, CD4+ and CD8+ T cell subsets in the lung, improve spatial learning and memory ability, and ameliorate BBB disruption and hippocampal neuron damage. Moreover, genetic knockdown of CD28 could reduce the expression of p-PI3K, p-AKT and NF-κB. In conclusion, chest blast exposure could lead to bTBI, and attenuate bTBI via the PI3K/AKT/NF-κB signaling pathway in male mice. This study provides new targets for the prevention and treatment of veterans with bTBI.

Macroscopic changes in aquaporin-4 underlie blast traumatic brain injury-related impairment in glymphatic function.

Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown. We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28 days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction. These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration.

Blast injury: Impact to the cornea.

Visual disorders are common even after mild traumatic brain injury (mTBI) or blast exposure. The cost of blast-induced vision loss in civilians, military personnel, and veterans is significant. The visual consequences of blasts associated with TBI are elusive. Active military personnel and veterans report various ocular pathologies including corneal disorders post-combat blasts. The wars and conflicts in Afghanistan, Iraq, Syria, and Ukraine have significantly increased the number of corneal and other ocular disorders among military personnel and veterans. Binocular vision, visual fields, and other visual functions could be impaired following blast-mediated TBI. Blast-associated injuries can cause visual disturbances, binocular system problems, and visual loss. About 25% of veterans exposed to blasts report corneal injury. Blast exposure induces corneal edema, corneal opacity, increased corneal thickness, damage of corneal epithelium, corneal abrasions, and stromal and endothelial abnormality including altered endothelial density, immune cell infiltration, corneal neovascularization, Descemet membrane rupture, and increased pain mediators in animal models and the blast-exposed military personnel including veterans. Immune response exacerbates blast-induced ocular injury. TBI is associated with dry eyes and pain in veterans. Subjects exposed to blasts that cause TBI should undergo immediate clinical visual and ocular examinations. Delayed visual care may lead to progressive vision loss, lengthening/impairing rehabilitation and ultimately may lead to permanent vision problems and blindness. Open-field blast exposure could induce corneal injuries and immune responses in the cornea. Further studies are warranted to understand corneal pathology after blast exposure. A review of current advancements in blast-induced corneal injury will help elucidate novel targets for potential therapeutic options. This review discusses the impact of blast exposure-associated corneal disorders.

Methemoglobinemia screening and treatment in tank warfare survivors.

INTRODUCTION: Methemoglobinemia, characterized by the conversion of functional hemoglobin to methemoglobin, can significantly impede tissue oxygenation. Prompt diagnosis and treatment of methemoglobinemia are critical to optimizing clinical outcomes. Although the underlying etiology of methemoglobinemia is often attributed to a medication reaction or chemical exposure, its association with battlefield trauma remains underexplored. This case series explores the presence of methemoglobinemia in nine soldiers evacuated from tanks targeted by explosives, shedding new light on screening needs and treatment strategies. CASES DESCRIPTION: Nine combat trauma patients with methemoglobinemia were admitted to Soroka Medical Center over a two-month period. Detailed case descriptions illustrate the diverse presentations and treatment responses. Notably, the administration of methylene blue resulted in rapid methemoglobin reductions and an improvement in oxygenation without any observed side effects. DISCUSSION: This series highlights an unexpected consequence of an explosion within an armored fighting vehicle and the challenges related to standard pulse oximetry interpretation and accuracy in the presence of methemoglobinemia, emphasizing the need for vigilant monitoring and co-oximetry utilization. Additionally, the coexistence of carboxyhemoglobin further warrants attention due to its synergistic and deleterious effects on oxygen delivery. Collaborative efforts with military authorities should aim to explore the underlying mechanisms associated with trauma and methemoglobinemia and optimize battlefield care. CONCLUSION: This case series underscores the significance of methemoglobinemia screening in combat trauma patients, and advocates for systematic co-oximetry utilization and methylene blue availability in combat zones. Early detection and intervention of methemoglobinemia in combat soldiers are often difficult in the context of battlefield injuries but are necessary to mitigate the potentially fatal consequences of this condition.

Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Association of Blast Exposure in Military Breaching with Intestinal Permeability Blood Biomarkers Associated with Leaky Gut.

Injuries and subclinical effects from exposure to blasts are of significant concern in military operational settings, including tactical training, and are associated with self-reported concussion-like symptomology and physiological changes such as increased intestinal permeability (IP), which was investigated in this study. Time-series gene expression and IP biomarker data were generated from "breachers" exposed to controlled, low-level explosive blast during training. Samples from 30 male participants at pre-, post-, and follow-up blast exposure the next day were assayed via RNA-seq and ELISA. A battery of symptom data was also collected at each of these time points that acutely showed elevated symptom reporting related to headache, concentration, dizziness, and taking longer to think, dissipating ~16 h following blast exposure. Evidence for bacterial translocation into circulation following blast exposure was detected by significant stepwise increase in microbial diversity (measured via alpha-diversity p = 0.049). Alterations in levels of IP protein biomarkers (i.e., Zonulin, LBP, Claudin-3, I-FABP) assessed in a subset of these participants (n = 23) further evidenced blast exposure associates with IP. The observed symptom profile was consistent with mild traumatic brain injury and was further associated with changes in bacterial translocation and intestinal permeability, suggesting that IP may be linked to a decrease in cognitive functioning. These preliminary findings show for the first time within real-world military operational settings that exposures to blast can contribute to IP.

Study protocol: Identifying transcriptional regulatory alterations of chronic effects of blast and disturbed sleep in United States Veterans.

Injury related to blast exposure dramatically rose during post-911 era military conflicts in Iraq and Afghanistan. Mild traumatic brain injury (mTBI) is among the most common injuries following blast, an exposure that may not result in a definitive physiologic marker (e.g., loss of consciousness). Recent research suggests that exposure to low level blasts and, more specifically repetitive blast exposure (RBE), which may be subconcussive in nature, may also impact long term physiologic and psychological outcomes, though findings have been mixed. For military personnel, blast-related injuries often occur in chaotic settings (e.g., combat), which create challenges in the immediate assessment of related-injuries, as well as acute and post-acute sequelae. As such, alternate means of identifying blast-related injuries are needed. Results from previous work suggest that epigenetic markers, such as DNA methylation, may provide a potential stable biomarker of cumulative blast exposure that can persist over time. However, more research regarding blast exposure and associations with short- and long-term sequelae is needed. Here we present the protocol for an observational study that will be completed in two phases: Phase 1 will address blast exposure among Active Duty Personnel and Phase 2 will focus on long term sequelae and biological signatures among Veterans who served in the recent conflicts and were exposed to repeated blast events as part of their military occupation. Phase 2 will be the focus of this paper. We hypothesize that Veterans will exhibit similar differentially methylated regions (DMRs) associated with changes in sleep and other psychological and physical metrics, as observed with Active Duty Personnel. Additional analyses will be conducted to compare DMRs between Phase 1 and 2 cohorts, as well as self-reported psychological and physical symptoms. This comparison between Service Members and Veterans will allow for exploration regarding the natural history of blast exposure in a quasi-longitudinal manner. Findings from this study are expected to provide additional evidence for repetitive blast-related physiologic changes associated with long-term neurobehavioral symptoms. It is expected that findings will provide foundational data for the development of effective interventions following RBE that could lead to improved long-term physical and psychological health.

Investigating neuropathological changes and underlying neurobiological mechanisms in the early stages of primary blast-induced traumatic brain injury: Insights from a rat model.

The utilization of explosives and chemicals has resulted in a rise in blast-induced traumatic brain injury (bTBI) in recent times. However, there is a dearth of diagnostic biomarkers and therapeutic targets for bTBI due to a limited understanding of biological mechanisms, particularly in the early stages. The objective of this study was to examine the early neuropathological characteristics and underlying biological mechanisms of primary bTBI. A total of 83 Sprague Dawley rats were employed, with their heads subjected to a blast shockwave of peak overpressure ranging from 172 to 421 kPa in the GI, GII, and GIII groups within a closed shock tube, while the body was shielded. Neuromotor dysfunctions, morphological changes, and neuropathological alterations were detected through modified neurologic severity scores, brain water content analysis, MRI scans, histological, TUNEL, and caspase-3 immunohistochemical staining. In addition, label-free quantitative (LFQ)-proteomics was utilized to investigate the biological mechanisms associated with the observed neuropathology. Notably, no evident damage was discernible in the GII and GI groups, whereas mild brain injury was observed in the GIII group. Neuropathological features of bTBI were characterized by morphologic changes, including neuronal injury and apoptosis, cerebral edema, and cerebrovascular injury in the shockwave's path. Subsequently, 3153 proteins were identified and quantified in the GIII group, with subsequent enriched neurological responses consistent with pathological findings. Further analysis revealed that signaling pathways such as relaxin signaling, hippo signaling, gap junction, chemokine signaling, and sphingolipid signaling, as well as hub proteins including Prkacb, Adcy5, and various G-protein subunits (Gnai2, Gnai3, Gnao1, Gnb1, Gnb2, Gnb4, and Gnb5), were closely associated with the observed neuropathology. The expression of hub proteins was confirmed via Western blotting. Accordingly, this study proposes signaling pathways and key proteins that exhibit sensitivity to brain injury and are correlated with the early pathologies of bTBI. Furthermore, it highlights the significance of G-protein subunits in bTBI pathophysiology, thereby establishing a theoretical foundation for early diagnosis and treatment strategies for primary bTBI.

Cutaneous burn injury represents a major risk factor for the development of traumatic ectopic bone formation following blast-related extremity injury.

Blast-related traumatic heterotopic ossification (tHO) impacts clinical outcomes in combat-injured patients, leading to delayed wound healing, inflammatory complications, and reduced quality of life. Blast injured patients often have significant burns. This study investigated whether a partial thickness thermal burn injury exacerbates blast-related tHO in a clinically relevant polytrauma animal model. Adult male Sprague Dawley rats were subjected to an established model involving a whole-body blast overpressure exposure (BOP), complex extremity trauma followed by hind limb amputation (CET) followed by the addition of a 10 % total body surface area (TBSA) second degree thermal burn (BU). Micro-CT scans on post-operative day 56 showed a significant increase in HO volume in the CET + BU as compared to the CET alone injury group (p < .0001; 22.83 ± 3.41 mm3 vs 4.84 ± 5.77 mm3). Additionally, CET + BU concomitant with BOP significantly increased HO (p < .0001; 34.95 ± 7.71 mm3) as compared to CET + BU alone, confirming BOP has a further synergistic effect. No HO was detectable in rats in the absence of CET. Serum analysis revealed similar significant elevated (p < .0001) levels of pro-inflammatory markers (Cxcl1 and Il6) at 6 h post-injury (hpi) in the CET + BU and BOP + CET + BU injury groups as compared to naïve baseline values. Real-time qPCR demonstrated similar levels of chondrogenic and osteogenic gene expression in muscle tissue at the site of injury at 168 hpi in both the CET + BU and BOP+CET + BU injury groups. These results support the hypothesis that a 10 % TBSA thermal burn markedly enhances tHO following acute musculoskeletal extremity injury in the presence and absence of blast overpressure. Furthermore, the influence of BOP on tHO cannot be accounted for either in regards to systemic inflammation induced from remote injury or inflammatory-osteo-chondrogenic expression changes local to the musculoskeletal trauma, suggesting that another mechanism beyond BOP and BU synergistic effects are at play. Therefore, these findings warrant future investigations to explore other mechanisms by which blast and burn influence tHO, and testing prophylactic measures to mitigate the local and systemic inflammatory effects of these injuries on development of HO.

MCC950 Attenuates Microglial NLRP3-Mediated Chronic Neuroinflammation and Memory Impairment in a Rat Model of Repeated Low-Level Blast Exposure.

Blast-induced traumatic brain injury is typically regarded as a signature medical concern for military personnel who are exposed to explosive devices in active combat zones. However, soldiers as well as law enforcement personnel may be repeatedly exposed to low-level blasts during training sessions with heavy weaponries as part of combat readiness. Service personnel who sustain neurotrauma from repeated low-level blast (rLLB) exposure do not display overt pathological symptoms immediately but rather develop mild symptoms including cognitive impairments, attention deficits, mood changes, irritability, and sleep disturbances over time. Recently, we developed a rat model of rLLB by applying controlled low-level blast pressures (≤ 70 kPa) repeated five times successively to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also investigated the role of the NLRP3 inflammasome, a complex involved in chronic microglial activation and pro-inflammatory cytokine interleukin (IL)-1ß release, in rLLB-induced neuroinflammation. NLRP3 and caspase-1 protein expression, microglial activation, and IL-1ß release were examined as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic short-term memory impairments and chronic anxiety-like symptoms accompanied by increased microglial activation, NLRP3 expression, and IL-1ß release. Treatment with MCC950, an NLRP3 inflammasome complex inhibitor, suppressed microglial activation, reduced NLRP3 expression and IL-1ß release, and improved short-term memory deficits after rLLB exposure. Collectively, this study demonstrates that rLLB induces chronic neurobehavioral and neuropathological changes by increasing NLRP3 inflammasome protein expression followed by cytokine IL-1ß release.

Repeated Mild Concussive Events Heighten the Vulnerability of Brain to Blast Exposure.

Mild concussive events without loss of consciousness are typically left untreated and can result in neurological abnormalities at later stages of life. No systematic studies have been carried out to determine the effect of concussion or repeated mild concussive episodes on brain vulnerability towards blast exposure. We have evaluated the effect of repeated mild concussive events on the vulnerability of brain to blast exposure using neurobehavioral functional assessments. Rats were subjected to either repeated mild concussive impacts (two impacts 1 week apart using a modified Marmarou weight drop model), a single blast exposure (19 psi using an advanced blast simulator), or a single blast exposure one day after the second mild concussive impact. Neurobehavioral changes were monitored using rotating pole test, open field exploration test, and novel object recognition test. Rotating pole test results indicated that vestibulomotor function was unaffected by blast or repeated mild concussive impacts, but significant impairment was observed in the blast exposed animals who had prior repeated mild concussive impacts. Novel object recognition test revealed short-term memory loss at 1 month post-blast only in rats subjected to both repeated mild concussive impacts and blast. Horizontal activity count, ambulatory activity count, center time and margin time legacies in the open field exploratory activity test indicated that only those rats exposed to both repeated mild concussive impacts and blast develop anxiety-like behaviors at both acute and sub-acute time-points. The results indicate that a history of repeated mild concussive episodes heightens brain vulnerability to blast exposure.

Combat Deployed Service Members by Blast TBI and Service Separation Status 5-years Post-deployment: Comparison of Cognitive, Neurobehavioral, and Psychological Profiles of Those Who Left vs. Those Still Serving.

INTRODUCTION: Longitudinal research regarding the pre- and post-separation experience has been relatively limited, despite its potential as a major life transition. Separating from the military and re-integration to civilian life is noted to be a period of increased risk of significant adjustment challenges, which impacts a service member in a multitude of areas. Active duty service members with combat-related physical or mental health or pre-existing adjustment conditions may be more likely to separate from service and more at risk for post-military service adjustment problems. MATERIALS AND METHODS: This is a secondary data analysis from a prospective, observational, longitudinal, multicohort study involving deployed service members originally enrolled between 2008 and 2013 in combat or following medical evacuation to Landstuhl, Germany. Two combat-deployed cohorts were examined: non-head-injured control without blast exposure (n = 109) and combat-related concussion arising from blast (n = 165). Comprehensive clinical evaluations performed at 1 year and 5 year follow-up included identical assessment batteries for neurobehavioral, psychiatric, and cognitive outcomes. In addition to demographics collected at each study visit, the current analysis leveraged the Glasgow Outcome Scale Extended (GOS-E), a measure of overall global disability. For neurobehavioral impairment, the Neurobehavioral Rating Scale-Revised (NRS) was used as well as the Headache Impact Test (HIT-6) to assess headache burden. To compare psychiatric symptom burden between those separated to those still serving, the Clinician-Administered PTSD Scale for DSM-IV (CAPS) and Montgomery-Asberg Depression Rating Scale (MADRS) for depression were used as well as the Michigan Alcohol Screening Test (MAST) to be able to compare alcohol misuse across groups. Overall cognitive function/performance was defined for each service member by aggregating the 19 neuropsychological measures. RESULTS: Overall comparisons following adjustment by linear regression and correction for multiple comparisons by separation status subgroup for non-blast control or blast traumatic brain injury (TBI) identified significant differences at 5 years post-enrollment in measures of global disability, neurobehavioral impairment, and psychiatric symptom burden. Those who separated had worse global disability, worse neurobehavioral symptoms, worse Post-Traumatic Stress Disorder symptoms, and worse depression symptoms than active duty service members. While service members who sustain a mild blast TBI during combat are more likely to separate from service within 5 years, there is a proportion of those non-injured who also leave during this time frame. Clinical profiles of both groups suggest service members who separated have elevated psychiatric and neurobehavioral symptoms but not cognitive dysfunction. Interestingly, the symptom load in these same domains is lower for those without blast TBI who separated during this time frame. CONCLUSIONS: These results appear to support previous research depicting that, for some service members, transitioning out of the military and re-integrating into civilian life can be a challenging adjustment. Many factors, including personal and social circumstances, prior mental or emotional difficulties, availability of social or community support or resources, can influence the adjustment outcomes of veterans. Service members with prior adjustment difficulties and/or those with blast TBI history (and ongoing neurobehavioral symptoms) may find the transition from military to civilian life even more challenging, given the potential substantial changes in lifestyle, structure, identity, and support.

Metabotropic Glutamate Receptor 2 Expression Is Chronically Elevated in Male Rats With Post-Traumatic Stress Disorder Related Behavioral Traits Following Repetitive Low-Level Blast Exposure.

Many military veterans who experienced blast-related traumatic brain injuries in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems that include depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast develop cognitive and PTSD-related behavioral traits that are present for more than 1 year after exposure. We previously reported that a group II metabotropic receptor (mGluR2/3) antagonist reversed blast-induced behavioral traits. In this report, we explored mGluR2/3 expression following blast exposure in male rats. Western blotting revealed that mGluR2 protein (but not mGluR3) was increased in all brain regions studied (anterior cortex, hippocampus, and amygdala) at 43 or 52 weeks after blast exposure but not at 2 weeks or 6 weeks. mGluR2 RNA was elevated at 52 weeks while mGluR3 was not. Immunohistochemical staining revealed no changes in the principally presynaptic localization of mGluR2 by blast exposure. Administering the mGluR2/3 antagonist LY341495 after behavioral traits had emerged rapidly reversed blast-induced effects on novel object recognition and cued fear responses 10 months following blast exposure. These studies support alterations in mGluR2 receptors as a key pathophysiological event following blast exposure and provide further support for group II metabotropic receptors as therapeutic targets in the neurobehavioral effects that follow blast injury.

Model matters: Differential outcomes in traumatic optic neuropathy pathophysiology between blunt and blast-wave mediated head injuries.

Over 3 million people in the United States live with long-term disability because of a traumatic brain injury (TBI). The purpose of this study was to characterize and compare two different animal models of TBI (blunt head trauma and blast TBI) to determine common and divergent characteristics of these models. With recent literature reviews noting the prevalence of visual system injury in animal models of TBI, coupled with clinical estimates of 50-75% of all TBI cases, we decided to assess commonalities, if they existed, through visual system injury. A unilateral (left directed) blast and repeat blast model injury with coup-contra-coup injury patterns were compared to a midline blunt injury. Injuries were induced in adult male mice to observe and quantify visual deficits. Retinal ganglion cell loss and axonal degeneration in the optic tract, superior colliculus, and lateral geniculate nuclei were examined to trace injury outcomes throughout major vision-associated areas. Optokinetic response, immunohistochemistry, and western blots were analyzed. Where a single blunt injury produces significant visual deficits a single blast injury appears to have less severe visual consequences. Visual deficits after repeat blasts are similar to a single blast. Single blast injury induces contralateral damage to the right optic chiasm and tract whereas bilateral injury follows a single blunt TBI. Repeat blast injuries are required to see degeneration patterns in downstream regions similar to the damage seen in a single blunt injury. This finding is further supported by amyloid precursor protein (APP) staining in injured cohorts. Blunt injured groups present with staining 1.2 mm ahead of the optic nerve, indicating axonal breakage closer to the optic chiasm. In blast groups, APP was identifiable in a bilateral pattern only in the geniculate nucleus. Evidence for unilateral neuronal degeneration in brain tissue with bilateral axonal ruptures are pivotal discoveries in this model differentiation. Analysis of the two injury models suggests that there is a significant difference in the histological outcomes dependent on injury type, though visual system injury is likely present in more cases than are currently diagnosed clinically.

Neurological Effects of Repeated Blast Exposure in Special Operations Personnel.

Exposure to blast overpressure has been a pervasive feature of combat-related injuries. Studies exploring the neurological correlates of repeated low-level blast exposure in career "breachers" demonstrated higher levels of tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 and decreases in IL-10 within brain-derived extracellular vesicles (BDEVs). The current pilot study was initiated in partnership with the U.S. Special Operations Command (USSOCOM) to explore whether neuroinflammation is seen within special operators with prior blast exposure. Data were analyzed from 18 service members (SMs), inclusive of 9 blast-exposed special operators with an extensive career history of repeated blast exposures and 9 controls matched by age and duration of service. Neuroinflammation was assessed utilizing positron emission tomography (PET) imaging with [18F]DPA-714. Serum was acquired to assess inflammatory biomarkers within whole serum and BDEVs. The Blast Exposure Threshold Survey (BETS) was acquired to determine blast history. Both self-report and neurocognitive measures were acquired to assess cognition. Similarity-driven Multi-view Linear Reconstruction (SiMLR) was used for joint analysis of acquired data. Analysis of BDEVs indicated significant positive associations with a generalized blast exposure value (GBEV) derived from the BETS. SiMLR-based analyses of neuroimaging demonstrated exposure-related relationships between GBEV, PET-neuroinflammation, cortical thickness, and volume loss within special operators. Affected brain networks included regions associated with memory retrieval and executive functioning, as well as visual and heteromodal processing. Post hoc assessments of cognitive measures failed to demonstrate significant associations with GBEV. This emerging evidence suggests neuroinflammation may be a key feature of the brain response to blast exposure over a career in operational personnel. The common thread of neuroinflammation observed in blast-exposed populations requires further study.

Local Firework Restrictions and Ocular Trauma.

Importance: Fireworks can cause vision-threatening injuries, but the association of local legislation with the mitigation of these injuries is unclear. Objective: To evaluate the odds of firework-related ocular trauma among residents of areas where fireworks are permitted vs banned. Design, Setting, and Participants: This case-control study was conducted at a level 1 trauma center in Seattle, Washington, among 230 patients presenting with ocular trauma in the 2 weeks surrounding the Independence Day holiday, spanning June 28 to July 11, over an 8-year period (2016-2022). Exposures: Firework ban status of patient residence. Main Outcomes and Measures: Odds of firework-related injuries among residents of areas where fireworks are legal vs where they are banned, calculated as odds ratios (ORs) and 95% CIs. Results: Of 230 consultations for ocular trauma during the study period, 94 patients (mean [SD] age, 25 [14] years; 86 male patients [92%]) sustained firework-related injuries, and 136 (mean [SD] age, 43 [23] years; 104 male patients [77%]) sustained non-firework-related injuries. The odds of firework-related ocular trauma were higher among those living in an area where fireworks were legal compared with those living in an area where fireworks were banned (OR, 2.0 [95% CI, 1.2-3.5]; P = .01). In addition, the odds of firework injuries were higher for patients younger than 18 years (OR, 3.1 [95% CI, 1.7-5.8]; P < .001) and for male patients (OR, 3.3 [95% CI, 1.5-7.1]; P = .004). Firework injuries were more likely to be vision threatening (54 of 94 [57%]) compared with non-firework-related injuries (54 of 136 [40%]; OR, 2.1 [95% CI, 1.2-3.5]; P = .01). Conclusions and Relevance: This case-control study suggests that the odds of firework-related ocular trauma were slightly higher among residents of areas where fireworks were legal compared with residents of areas where fireworks were banned. Although these results suggest that local firework bans may be associated with a small reduction in the odds of firework-related ocular trauma, additional studies are warranted to assess what actions might lead to greater reductions.

Proteomic Changes in the Hippocampus after Repeated Explosive-Driven Blasts.

Repeated blast-traumatic brain injury (blast-TBI) has been hypothesized to cause persistent and unusual neurological and psychiatric symptoms in service members returning from war zones. Blast-wave primary effects have been supposed to induce damage and molecular alterations in the brain. However, the mechanisms through which the primary effect of an explosive-driven blast wave generate brain lesions and induce brain consequences are incompletely known. Prior findings from rat brains exposed to two consecutive explosive-driven blasts showed molecular changes (hyperphosphorylated-Tau, AQP4, S100ß, PDGF, and DNA-polymerase-ß) that varied in magnitude and direction across different brain regions. We aimed to compare, in an unbiased manner, the proteomic profile in the hippocampus of double blast vs sham rats using mass spectrometry (MS). Data showed differences in up- and down-regulation for protein abundances in the hippocampus of double blast vs sham rats. Tandem mass tag (TMT)-MS results showed 136 up-regulated and 94 down-regulated proteins between the two groups (10.25345/C52B8VP0X). These TMT-MS findings revealed changes never described before in blast studies, such as increases in MAGI3, a scaffolding protein at cell-cell junctions, which were confirmed by Western blotting analyses. Due to the absence of behavioral and obvious histopathological changes as described in our previous publications, these proteomic data further support the existence of an asymptomatic blast-induced molecular altered status (ABIMAS) associated with specific protein changes in the hippocampus of rats repeatedly expsosed to blast waves generated by explosive-driven detonations.

High Lifetime Blast Exposure Using the Blast Exposure Threshold Survey Is Associated With Worse Warfighter Brain Health Following Mild Traumatic Brain Injury.

The purpose of this study was to extend previous research by examining the relationship between lifetime blast exposure and neurobehavioral functioning after mild TBI (MTBI) by (a) using a comprehensive measure of lifetime blast exposure, and (b) controlling for the influence of post-traumatic stress disorder (PTSD). Participants were 103 United States service members and veterans (SMVs) with a medically documented diagnosis of MTBI, recruited from three military treatment facilities (74.8%) and community-based recruitment initiatives (25.2%, e.g., social media, flyers). Participants completed a battery of neurobehavioral measures 12 or more months post-injury (Neurobehavioral Symptom Inventory, PTSD-Checklist PCLC, TBI-Quality of Life), including the Blast Exposure Threshold Survey (BETS). The sample was classified into two lifetime blast exposure (LBE) groups: High (n = 57) and Low (n = 46) LBE. In addition, the sample was classified into four LBE/PTSD subgroups: High PTSD/High LBE (n = 38); High PTSD/Low LBE (n = 19); Low PTSD/High LBE (n = 19); and Low PTSD/Low LBE (n = 27). The High LBE group had consistently worse scores on all neurobehavioral measures compared with the Low LBE group. When controlling for the influence of PTSD (using ANCOVA), however, only a handful of group differences remained. When comparing measures across the four LBE/PTSD subgroups, in the absence of clinically meaningful PTSD symptoms (i.e., Low PTSD), participants with High LBE had worse scores on the majority of neurobehavioral measures (e.g., post-concussion symptoms, sleep, fatigue). When examining the total number of clinically elevated measures, the High LBE subgroup consistently had a greater number of clinically elevated scores compared with the Low LBE subgroup for the majority of comparisons (i.e., four to 15 or more elevated symptoms). In contrast, in the presence of clinically meaningful PTSD symptoms (i.e., High PTSD), there were no differences between High versus Low LBE subgroups for all measures. When examining the total number of clinically elevated measures, however, there were meaningful differences between High versus Low LBE subgroups for those comparisons that included a high number of clinically elevated scores (i.e., six to 10 or more), but not for a low number of clinically elevated scores (i.e., one to five or more). High LBE, as quantified using a more comprehensive measure than utilized in past research (i.e., BETS), was associated with worse overall neurobehavioral functioning after MTBI. This study extends existing literature showing that lifetime blast exposure, that is largely subconcussive, may negatively impact warfighter brain health and readiness beyond diagnosable brain injury.