Neuroinflammation Profiling of Brain Cytokines Following Repeated Blast Exposure.

Due to use of explosive devices and heavy weapons systems in modern conflicts, the effect of BW on the brain and body is of increasing concern. These exposures have been commonly linked with neurodegenerative diseases and psychiatric disorders in veteran populations. A likely neurobiological link between exposure to blasts and the development of neurobehavioral disorders, such as depression and PTSD, could be neuroinflammation triggered by the blast wave. In this study, we exposed rats to single or repeated BW (up to four exposures-one per day) at varied intensities (13, 16, and 19 psi) to mimic the types of blast exposures that service members may experience in training and combat. We then measured a panel of neuroinflammatory markers in the brain tissue with a multiplex cytokine/chemokine assay to understand the pathophysiological process(es) associated with single and repeated blast exposures. We found that single and repeated blast exposures promoted neuroinflammatory changes in the brain that are similar to those characterized in several neurological disorders; these effects were most robust after 13 and 16 psi single and repeated blast exposures, and they exceeded those recorded after 19 psi repeated blast exposures. Tumor necrosis factor-alpha and IL-10 were changed by 13 and 16 psi single and repeated blast exposures. In conclusion, based upon the growing prominence of negative psychological health outcomes in veterans and soldiers with a history of blast exposures, identifying the molecular etiology of these disorders, such as blast-induced neuroinflammation, is necessary for rationally establishing countermeasures and treatment regimens.

Semimechanistic Modeling of the Effects of Blast Overpressure Exposure on Cefazolin Pharmacokinetics in Mice.

Cefazolin is a first-line antibiotic to treat infection related to deployment-associated blast injuries. Prior literature demonstrated a 331% increase cefazolin liver area under the curve (AUC) in mice exposed to a survivable blast compared with controls. We repeated the experiment, validated the findings, and established a semimechanistic two-compartment pharmacokinetic (PK) model with effect compartments representing the liver and skin. We found that blast statistically significantly increased the pseudo-partition coefficient to the liver by 326% (95% confidence interval: 76-737%), which corresponds to the observed 331% increase in cefazolin liver AUC described previously. To a lesser extent, plasma AUC in blasted mice increased 14-45% compared with controls. Nevertheless, the effects of blast on cefazolin PK were transient, normalizing by 10 hours after the dose. It is unclear as to how this blast effect t emporally translates to humans; however, given the short-lived effect on PK, there is insufficient evidence to recommend cefazolin dosing changes based on blast overpressure injury alone. Clinicians should be aware that cefazolin may cause drug-induced liver injury with a single dose and the risk may be higher in patients with blast overpressure injury based on our findings. SIGNIFICANCE STATEMENT: Blast exposure significantly, but transiently, alters cefazolin pharmacokinetics in mice. The questions of whether other medications or potential long-term consequences in humans need further exploration.

Animal Orientation Affects Brain Biomechanical Responses to Blast-Wave Exposure.

In this study, we investigated how animal orientation within a shock tube influences the biomechanical responses of the brain and cerebral vasculature of a rat when exposed to a blast wave. Using three-dimensional finite element (FE) models, we computed the biomechanical responses when the rat was exposed to the same blast-wave overpressure (100 kPa) in a prone (P), vertical (V), or head-only (HO) orientation. We validated our model by comparing the model-predicted and the experimentally measured brain pressures at the lateral ventricle. For all three orientations, the maximum difference between the predicted and measured pressures was 11%. Animal orientation markedly influenced the predicted peak pressure at the anterior position along the midsagittal plane of the brain (P = 187 kPa; V = 119 kPa; and HO = 142 kPa). However, the relative differences in the predicted peak pressure between the orientations decreased at the medial (21%) and posterior (7%) positions. In contrast to the pressure, the peak strain in the prone orientation relative to the other orientations at the anterior, medial, and posterior positions was 40-88% lower. Similarly, at these positions, the cerebral vasculature strain in the prone orientation was lower than the strain in the other orientations. These results show that animal orientation in a shock tube influences the biomechanical responses of the brain and the cerebral vasculature of the rat, strongly suggesting that a direct comparison of changes in brain tissue observed from animals exposed at different orientations can lead to incorrect conclusions.

Editing the Sickle Cell Disease Mutation in Human Hematopoietic Stem Cells: Comparison of Endonucleases and Homologous Donor Templates.

Site-specific correction of a point mutation causing a monogenic disease in autologous hematopoietic stem and progenitor cells (HSPCs) can be used as a treatment of inherited disorders of the blood cells. Sickle cell disease (SCD) is an ideal model to investigate the potential use of gene editing to transvert a single point mutation at the ß-globin locus (HBB). We compared the activity of zinc-finger nucleases (ZFNs) and CRISPR/Cas9 for editing, and homologous donor templates delivered as single-stranded oligodeoxynucleotides (ssODNs), adeno-associated virus serotype 6 (AAV6), integrase-deficient lentiviral vectors (IDLVs), and adenovirus 5/35 serotype (Ad5/35) to transvert the base pair responsible for SCD in HBB in primary human CD34+ HSPCs. We found that the ZFNs and Cas9 directed similar frequencies of nuclease activity. In vitro, AAV6 led to the highest frequencies of homology-directed repair (HDR), but levels of base pair transversions were significantly reduced when analyzing cells in vivo in immunodeficient mouse xenografts, with similar frequencies achieved with either AAV6 or ssODNs. AAV6 also caused significant impairment of colony-forming progenitors and human cell engraftment. Gene correction in engrafting hematopoietic stem cells may be limited by the capacity of the cells to mediate HDR, suggesting additional manipulations may be needed for high-efficiency gene correction in HSPCs.

Medial patellofemoral ligament reconstruction with allograft versus autograft tissue results in similar recurrent dislocation risk and patient-reported outcomes.

PURPOSE: To determine the rate of recurrent dislocation and patellar instability following medial patellofemoral ligament (MPFL) reconstruction with allograft or autograft tissue and compare patient-reported outcomes for patients undergoing allograft and autograft MPFL reconstruction. METHODS: One hundred and fifteen MPFL reconstructions (78 allograft, 37 autograft) without concurrent bony procedures performed between 2008 and 2014 by four sports medicine fellowship-trained orthopedic surgeons at our center were identified. Patient demographics and surgical data were identified by chart review. Chart review and patient interviews were undertaken to identify recurrent patellar dislocations and as recurrent subjective patellofemoral instability. Recurrent dislocation and subjective instability risk were compared between the allograft and autograft groups. RESULTS: Eighty-seven patients (76%) with complete baseline data and minimum 1-year follow-up were contacted at a mean of 4.1 years following isolated MPFL reconstruction, including 57 patient with allograft reconstructions and 30 with autograft reconstructions. No significant differences in patient sex, age at reconstruction, body mass index, or time to follow-up were noted between groups. Recurrent dislocation occurred in 2 patients in the allograft group (3.5%) and 1 patient in the autograft group (3.3%), (n.s.). Recurrent subjective instability occurred in 17 patients in the allograft group (28.9%) and 11 patients in the autograft group (36.7%), (n.s.). No significant differences in patient-reported outcomes were noted between groups. CONCLUSION: The use of either allograft or autograft tissue for MPFL reconstruction results in low (< 3%) risk of recurrent patellar dislocation. Risk of recurrent subjective instability is higher but is similar for both graft types. Surgeons can utilize either graft choice at their discretion without anticipating a significant impact of graft choice on patient outcomes. LEVEL OF EVIDENCE: III.

Characterization of Gene Alterations following Editing of the ß-Globin Gene Locus in Hematopoietic Stem/Progenitor Cells.

The use of engineered nucleases combined with a homologous DNA donor template can result in targeted gene correction of the sickle cell disease mutation in hematopoietic stem and progenitor cells. However, because of the high homology between the adjacent human ß- and δ-globin genes, off-target cleavage is observed at δ-globin when using some endonucleases targeted to the sickle mutation in ß-globin. Introduction of multiple double-stranded breaks by endonucleases has the potential to induce intergenic alterations. Using a novel droplet digital PCR assay and high-throughput sequencing, we characterized the frequency of rearrangements between the ß- and δ-globin paralogs when delivering these nucleases. Pooled CD34+ cells and colony-forming units from sickle bone marrow were treated with nuclease only or including a donor template and then analyzed for potential gene rearrangements. It was observed that, in pooled CD34+ cells and colony-forming units, the intergenic ß-δ-globin deletion was the most frequent rearrangement, followed by inversion of the intergenic fragment, with the inter-chromosomal translocation as the least frequent. No rearrangements were observed when endonuclease activity was restricted to on-target ß-globin cleavage. These findings demonstrate the need to develop site-specific endonucleases with high specificity to avoid unwanted gene alterations.

Improving vision awareness in autism services: Evaluation of a dedicated education programme for support practitioners.

BACKGROUND: The research reported here sought to evaluate whether a dedicated education programme in vision awareness improved the knowledge and skills of autism support practitioners in identifying visual impairment in autistic people with intellectual disabilities and providing better support to those individuals identified as visually impaired. METHODS: Researchers undertook a mixed methods evaluation. A survey questionnaire was devised and administered before and after training and focus groups were undertaken in order to gain qualitative data relating how practitioners implemented their learning in practice. RESULTS: Knowledge confidence and practice confidence scores of participants were significantly improved by the programme, which maintained its impact one year on. Practitioners reported increased access to optometry, changes to support practice and improvements to service environments as a result of the training. CONCLUSION: Autism support practitioners' skills in identifying and supporting people with visual impairments were demonstrably enhanced through dedicated vision training.

CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ cells.

Targeted genome editing technology can correct the sickle cell disease mutation of the ß-globin gene in hematopoietic stem cells. This correction supports production of red blood cells that synthesize normal hemoglobin proteins. Here, we demonstrate that Transcription Activator-Like Effector Nucleases (TALENs) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease system can target DNA sequences around the sickle-cell mutation in the ß-globin gene for site-specific cleavage and facilitate precise correction when a homologous donor template is codelivered. Several pairs of TALENs and multiple CRISPR guide RNAs were evaluated for both on-target and off-target cleavage rates. Delivery of the CRISPR/Cas9 components to CD34+ cells led to over 18% gene modification in vitro. Additionally, we demonstrate the correction of the sickle cell disease mutation in bone marrow derived CD34+ hematopoietic stem and progenitor cells from sickle cell disease patients, leading to the production of wild-type hemoglobin. These results demonstrate correction of the sickle mutation in patient-derived CD34+ cells using CRISPR/Cas9 technology.

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.

'A certain magic' - autistic adults' experiences of interacting with other autistic people and its relation to Quality of Life: A systematic review and thematic meta-synthesis.

LAY ABSTRACT: Research has suggested that autistic people enjoy spending time with other autistic people and find them easier to talk to. We wanted to find out what autistic people say about spending time with other autistic people and whether this makes their life better. We found 52 papers which described this and reviewed what they found. We found that many autistic people had positive experiences of spending time with other autistic people and these experiences had positive impact on their lives in a range of different ways. The papers did not tell us whether this also happens for autistic people with a learning disability. More research is needed to find out more about why spending time with other autistic people helps some autistic people.

Blast Exposure Alters Synaptic Connectivity in the Mouse Auditory Cortex.

Blast exposure can cause auditory deficits that have a lasting, significant impact on patients. Although the effects of blast on auditory functions localized to the ear have been well documented, the impact of blast on central auditory processing is largely undefined. Understanding the structural and functional alterations in the central nervous system (CNS) associated with blast injuries is crucial for unraveling blast-induced pathophysiological pathways and advancing development of therapeutic interventions. In this study, we used electrophysiology in combination with optogenetics assay, proteomic analysis, and morphological evaluation to investigate the impairment of synaptic connectivity in the auditory cortex (AC) of mice following blast exposure. Our results show that the long-range functional connectivity between the medial geniculate nucleus (MGN) and AC was impaired in the acute phase of blast injury. We also identified impaired synaptic transmission and dendritic spine alterations within 7 days of blast exposure, which recovered at 28 days post-blast. Additionally, proteomic analysis identified a few differentially expressed proteins in the cortex that are involved in synaptic signaling and plasticity. These findings collectively suggest that blast-induced alterations in the sound signaling network in the auditory cortex may underlie hearing deficits in the acute and sub-acute phases after exposure to shockwaves. This study may shed light on the perturbations underlying blast-induced auditory dysfunction and provide insights into the potential therapeutic windows for improving auditory outcomes in blast-exposed individuals.

Longitudinal Biochemical and Behavioral Alterations in a Gyrencephalic Model of Blast-Related Mild Traumatic Brain Injury.

Blast-related traumatic brain injury (bTBI) is a major cause of neurological disorders in the U.S. military that can adversely impact some civilian populations as well and can lead to lifelong deficits and diminished quality of life. Among these types of injuries, the long-term sequelae are poorly understood because of variability in intensity and number of the blast exposure, as well as the range of subsequent symptoms that can overlap with those resulting from other traumatic events (e.g., post-traumatic stress disorder). Despite the valuable insights that rodent models have provided, there is a growing interest in using injury models using species with neuroanatomical features that more closely resemble the human brain. With this purpose, we established a gyrencephalic model of blast injury in ferrets, which underwent blast exposure applying conditions that closely mimic those associated with primary blast injuries to warfighters. In this study, we evaluated brain biochemical, microstructural, and behavioral profiles after blast exposure using in vivo longitudinal magnetic resonance imaging, histology, and behavioral assessments. In ferrets subjected to blast, the following alterations were found: 1) heightened impulsivity in decision making associated with pre-frontal cortex/amygdalar axis dysfunction; 2) transiently increased glutamate levels that are consistent with earlier findings during subacute stages post-TBI and may be involved in concomitant behavioral deficits; 3) abnormally high brain N-acetylaspartate levels that potentially reveal disrupted lipid synthesis and/or energy metabolism; and 4) dysfunction of pre-frontal cortex/auditory cortex signaling cascades that may reflect similar perturbations underlying secondary psychiatric disorders observed in warfighters after blast exposure.

Long-term consequences of single and multiple mild blast exposure on select physiological parameters and blood-based biomarkers.

Mild traumatic brain injury (mTBI), especially when it is repeated (rmTBI), can lead to progressive degenerative diseases and lasting neuropsychiatric abnormalities. To better understand the long-term pathobiological changes in mTBI and rmTBI, we exposed rats to single or repeated (5 total; administered on consecutive days) mild blast overpressure, monitored changes in physiological parameters, and determined the plasma levels of select biomarkers at 42 days post injury by proteomics. We unexpectedly found comparable changes in arterial oxygen saturation levels and heart rates of single-injured (SI) and multiple-injured (MI) rats throughout the observation period. Our analyses indicated lasting oxidative stress, vascular abnormalities, and neuronal and glial cell loss in both injured groups. However, MI rats exhibited a relatively more pronounced increase in the plasma levels of most of the tested markers-particularly those associated with inflammation-albeit the differences between the two injured groups were not statistically significant. Our findings indicate that the frequency of blast exposures is an important determinant of the resulting cumulative damage in rmTBI.

Effect of hyperoxia on resuscitation of experimental combined traumatic brain injury and hemorrhagic shock in mice.

BACKGROUND: Hypotension and hypoxemia worsen traumatic brain injury outcomes. Hyperoxic resuscitation is controversial. The authors proposed that hyperoxia would improve hemodynamics and neuronal survival by augmenting oxygen delivery despite increased oxidative stress and neuroinflammation in experimental combined controlled cortical impact plus hemorrhagic shock in mice. METHODS: Adult C57BL6 mice received controlled cortical impact followed by 35 min of hemorrhagic shock (mean arterial pressure, 25-27 mmHg). The resuscitation phase consisted of lactated Ringer's boluses titrated to mean arterial pressure greater than 70 mmHg. Definitive care included returning shed blood. Either oxygen or room air was administered during the resuscitation phases. Brain tissue levels of oxidative stress and inflammatory markers were measured at 24 h and hippocampal neuronal survival was quantified at 7 days. RESULTS: Hyperoxia markedly increased brain tissue oxygen tension approximately four- to fivefold (n = 8) and reduced resuscitation fluid requirements approximately 15% (n = 53; both P < 0.05). Systemic and cerebral physiologic variables were not significantly affected by hyperoxia. Hippocampal neuron survival was approximately 40% greater with oxygen versus room air (n = 18, P = 0.03). However, ascorbate depletion doubled with oxygen versus room air (n = 11, P < 0.05). Brain tissue cytokines and chemokines were increased approximately 2- to 20-fold (n = 10) after combined controlled cortical impact injury plus hemorrhagic shock, whereas hyperoxia shifted cytokines toward a proinflammatory profile. CONCLUSIONS: Hyperoxic resuscitation of cortical impact plus hemorrhagic shock reduced fluid requirements and increased brain tissue oxygen tension and hippocampal neuronal survival but exacerbated ascorbate depletion and neuroinflammation. The benefits of enhanced oxygen delivery during resuscitation of traumatic brain injury may outweigh detrimental increases in oxidative stress and neuroinflammation.

Cerebrospinal Fluid Levels of Lysophosphatidic Acids Can Provide Suitable Biomarkers of Blast-Induced Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) has been identified as the signature injury of Operation Iraqi Freedom and Operation Enduring Freedom. Although the incidence of bTBI increased significantly after the introduction of improvised explosive devices, the mechanism of the injury is still uncertain, which is negatively impacting the development of suitable countermeasures. Identification of suitable biomarkers that could aid in the proper diagnosis of and prognosis for both acute and chronic bTBI is essential since bTBI frequently is occult and may not be associated with overtly detectable injuries to the head. Lysophosphatidic acid (LPA) is a bioactive phospholipid generated by activated platelets, astrocytes, choroidal plexus cells and microglia and is reported to play major roles in stimulating inflammatory processes. The levels of LPA in the cerebrospinal fluid (CSF) have been reported to increase acutely after non-blast related brain injuries. In the present study, we have evaluated the utility of LPA levels measured in the CSF and plasma of laboratory rats as an acute and chronic biomarker of brain injury resulting from single and tightly coupled repeated blast overpressure exposures. In the CSF, many LPA species increased at acute time-points, returned to normal levels at 1 month, and increased again at 6 months and 1 year post-blast overpressure exposures. In the plasma, several LPA species increased acutely, returned to normal levels by 24 h, and were significantly decreased at 1 year post-blast overpressure exposures. These decreases in LPA species in the plasma were associated with decreased levels of lysophosphatidyl choline, suggesting a defective upstream biosynthetic pathway of LPAs in the plasma. Notably, the changes in LPA levels in the CSF (but not plasma) negatively correlated with neurobehavioral functions in these rats, suggesting that CSF levels of LPAs may provide a suitable biomarker of bTBI that reflects severity of injury.

Comparison of Biomechanical Outcome Measures From Characteristically Different Blast Simulators and the Influence of Exposure Location.

INTRODUCTION: Simulation of blast exposure in the laboratory has been inconsistent across laboratories. This is primarily because of adoption of the shock wave-generation techniques that are used in aerodynamic tests as opposed to application of blast exposures that are relevant to combat and training environments of a Warfighter. Because of the differences in blast signatures, characteristically different pathological consequences are observed among the preclinical studies. This is also further confounded by the varied exposure positioning of the animal subject (e.g., inside the blast simulator vs. at the mouth of the simulator). In this study, we compare biomechanical responses to blast exposures created in an advanced blast simulator (ABS) that generates "free-field"-like blast exposure with those produced by a traditionally applied cylindrical blast simulator (CBS) that generates a characteristically different blast signature. In addition, we have tested soft-armor vest protective responses with the ABS and CBS to compare the biomechanical responses to this form of personal protective equipment in each setting in a rodent model. MATERIALS AND METHODS: Anesthetized male Sprague-Dawley rats (n = 6) were surgically probed with an intrathoracic pressure (ITP) transducer and an intracranial pressure (ICP) transducer directed into the lateral cerebral ventricle (Millar, Inc.). An ABS for short-duration blast or a CBS for long-duration blast was used to expose animals to an incident blast overpressure of 14.14 psi (impulse: 30.27 psi*msec) or 16.3 psi (impulse: 71.9 psi*msec) using a custom-made holder (n = 3-4/group). An external pitot probe located near the animal was used to measure the total pressure (tip) and static gauge (side-on) pressure. Data were recorded using a TMX-18 data acquisition system (AstroNova Inc.). MATLAB was used to analyze the recordings to identify the peak amplitudes and rise times of the pressure traces. Peak ICP, peak ITP, and their impulses were normalized by expressing them relative to the associated peak static pressure. RESULTS: Normalized impulse (ABS: 1.02 ± 0.03 [vest] vs. 1.02 ± 0.01 [no-vest]; CBS: 1.21 ± 0.07 [vest] vs. 1.01 ± 0.01 [no-vest]) and peak pressure for ICP (ABS: 1.03 ± 0.03 [vest] vs. 0.99 ± 0.04 [no-vest]; CBS: 1.06 ± 0.08 [vest] vs. 1.13 ± 0.06 [no-vest]) remained unaltered when comparisons are made between vest and no-vest groups, and the normalized peak ITP (ABS: 1.50 ± 0.02 [vest] vs. 1.24 ± 0.16 [no-vest]; CBS: 1.71 ± 0.20 [vest] vs. 1.37 ± 0.06 [no-vest]) showed a trend of an increase in the vest group compared to the no-vest group. However, impulses in short-duration ABS (0.94 ± 0.06 [vest] vs. 0.92 ± 0.13 [no-vest]) blast remained unaltered, whereas a significant increase of ITP impulse (1.21 ± 0.07 [vest] vs. 1.17 ± 0.01 [no-vest]) in CBS was observed. CONCLUSIONS: The differences in the biomechanical response between ABS and CBS could be potentially attributed to the higher dynamic pressures that are imparted from long-duration CBS blasts, which could lead to chest compression and rapid acceleration/deceleration. In addition, ICP and ITP responses occur independently of each other, with no evidence of thoracic surge.

Patient-Reported Outcomes Following Medial Patellofemoral Reconstruction With Peroneus Longus Allografts Demonstrate Good Results.

Purpose: To evaluate the recurrent dislocation risk and patient-reported outcomes of peroneus longus allograft tissue for medial patellofemoral ligament (MPFL) reconstruction. Methods: Patients who underwent MPFL reconstruction with peroneus longus allograft at an academic center between 2008 and 2016 were identified. Record review and patient contact were used to identify any cases of recurrent patellar dislocation and collect patient-reported outcomes scores (Knee injury and Osteoarthritis Outcome Score [KOOS], Norwich Patellar Instability score, Marx activity scale). Patients with 1-year minimum follow-up were included. Outcomes were quantified and the proportion of patients reaching a previously defined patient acceptable symptom state (PASS) for patellar instability was determined. Results: Sixty-one patients (42 female and 19 male) underwent MPFL reconstruction with peroneus longus allograft during the study period. Forty-six patients (76%) with 1-year minimum follow up were contacted at a mean of 3.5 years postoperative. The mean age at time of surgery was 22 ± 7.2 years. Patient-reported outcomes data were available in 34 patients. Mean KOOS subscale scores were as follows: Symptoms 83.2 ± 19.1, Pain 85.2 ± 17.6, Activities of Daily Living 89.9 ± 14.8, Sports 75 ± 26.2, and Quality of Life 72.6 ± 25.7. The mean Norwich Patellar Instability score was 14.9% ± 17.4%. The mean Marx activity score was 6.0 ± 5.2. No recurrent dislocations were noted during the study period. Sixty-three percent of patients who underwent isolated MPFL reconstruction met PASS thresholds in at least 4 of 5 KOOS subscales. Conclusions: The use of a peroneus longus allograft in MPFL reconstruction in conjunction with other indicated procedures results in a low re-dislocation risk and a high proportion of patients meeting PASS criteria for patient-reported outcome scores 3 to 4 years postoperatively. Level of Evidence: IV, case series.

Differential effects on TDP-43, piezo-2, tight-junction proteins in various brain regions following repetitive low-intensity blast overpressure.

Introduction: Mild traumatic brain injury (mTBI) caused by repetitive low-intensity blast overpressure (relBOP) in military personnel exposed to breaching and heavy weapons is often unrecognized and is understudied. Exposure to relBOP poses the risk of developing abnormal behavioral and psychological changes such as altered cognitive function, anxiety, and depression, all of which can severely compromise the quality of the life of the affected individual. Due to the structural and anatomical heterogeneity of the brain, understanding the potentially varied effects of relBOP in different regions of the brain could lend insights into the risks from exposures. Methods: In this study, using a rodent model of relBOP and western blotting for protein expression we showed the differential expression of various neuropathological proteins like TDP-43, tight junction proteins (claudin-5, occludin, and glial fibrillary acidic protein (GFAP)) and a mechanosensitive protein (piezo-2) in different regions of the brain at different intensities and frequency of blast. Results: Our key results include (i) significant increase in claudin-5 after 1x blast of 6.5 psi in all three regions and no definitive pattern with higher number of blasts, (ii) significant increase in piezo-2 at 1x followed by significant decrease after multiple blasts in the cortex, (iii) significant increase in piezo-2 with increasing number of blasts in frontal cortex and mixed pattern of expression in hippocampus and (iv) mixed pattern of TDP-3 and GFAP expression in all the regions of brain. Discussion: These results suggest that there are not definitive patterns of changes in these marker proteins with increase in intensity and/or frequency of blast exposure in any particular region; the changes in expression of these proteins are different among the regions. We also found that the orientation of blast exposure (e.g. front vs. side exposure) affects the altered expression of these proteins.

Soft-armor Vest Effectiveness and Intrathoracic Biomechanics in Rodents Exposed to Primary Blast.

The biomechanics and efficacy of personal protective equipment in mitigating injuries from blast overpressure remain unclear. The objectives of this study were to define intrathoracic pressures in response to blast wave (BW) exposure and biomechanically evaluate a soft-armor vest (SA) at diminishing these perturbations. Male Sprague-Dawley rats were instrumented with pressure sensors in the thorax and were exposed laterally to multiple exposures ranging from 33 to 108 kPa BW with SA and without SA. There were significant increases in rise time, peak negative pressure, and negative impulse in the thoracic cavity compared to the BW. Esophageal measurements were increased to a greater extent when compared to the carotid and the BW for all parameters (except positive impulse, which decreased). SA minimally altered the pressure parameters and energy content. This study establishes the relationship of external blast flow conditions and intra-body biomechanical responses in the thoracic cavity of rodents with and without SA.