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Traumatic brain injury (TBI) and opioid use disorder (OUD) comprise twin plagues causing considerable morbidity and mortality worldwide. As interactions between TBI and OUD are to our knowledge uncharted, we review the possible mechanisms by which TBI may stimulate the development of OUD and discuss the interaction or crosstalk between these two processes. Central nervous system damage due to TBI appears to drive adverse effects of subsequent OUD and opioid use/misuse affecting several molecular pathways. Pain, a neurological consequence of TBI, is a risk factor that increases the likelihood of opioid use/misuse after TBI. Other comorbidities including depression, anxiety, posttraumatic stress disorder, and sleep disturbances are also associated with deleterious outcomes. We examine the hypothesis that a TBI "first hit" induces a neuroinflammatory process involving microglial priming, which, on a second hit related to opioid exposure, exacerbates neuroinflammation, modifies synaptic plasticity, and spreads tau aggregates to promote neurodegeneration. As TBI also impairs myelin repair by oligodendrocytes, it may reduce or degrade white matter integrity in the reward circuit resulting in behavioral changes. Along with approaches focused on specific patient symptoms, understanding the CNS effects following TBI offers a promise of improved management for individuals with OUD., (Copyright © 2023 Society of Biological Psychiatry. All rights reserved.)

Mild traumatic brain injury (mTBI) induced by low-intensity blast (LIB) is a serious health problem affecting military service members and veterans. Our previous reports using a single open-field LIB mouse model showed the absence of gross microscopic damage or necrosis in the brain, while transmission electron microscopy (TEM) identified ultrastructural abnormalities of myelin sheaths, mitochondria, and synapses. The neurovascular unit (NVU), an anatomical and functional system with multiple components, is vital for the regulation of cerebral blood flow and cellular interactions. In this study, we delineated ultrastructural abnormalities affecting the NVU in mice with LIB exposure quantitatively and qualitatively. Luminal constrictive irregularities were identified at 7 days post-injury (DPI) followed by dilation at 30 DPI along with degeneration of pericytes. Quantitative proteomic analysis identified significantly altered vasomotor-related proteins at 24 h post-injury. Endothelial cell, basement membrane and astrocyte end-foot swellings, as well as vacuole formations, occurred in LIB-exposed mice, indicating cellular edema. Structural abnormalities of tight junctions and astrocyte end-foot detachment from basement membranes were also noted. These ultrastructural findings demonstrate that LIB induces multiple-component NVU damage. Prevention of NVU damage may aid in identifying therapeutic targets to mitigate the effects of primary brain blast injury., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Neurocognitive consequences of blast-induced traumatic brain injury (bTBI) pose significant concerns for military service members and veterans with the majority of "invisible injury." However, the underlying mechanism of such mild bTBI by low-intensity blast (LIB) exposure for long-term cognitive and mental deficits remains elusive. Our previous studies have shown that mice exposed to LIB result in nanoscale ultrastructural abnormalities in the absence of gross or apparent cellular damage in the brain. Here we tested the hypothesis that glutamatergic hyperexcitability may contribute to long-term learning deficits. Using brain slice electrophysiological recordings, we found an increase in averaged frequencies with a burst pattern of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 neurons in LIB-exposed mice at 1- and 7-days post injury, which was blocked by a specific NMDA receptor antagonist AP5. In addition, cognitive function assessed at 3-months post LIB exposure by automated home-cage monitoring showed deficits in dynamic patterns of discrimination learning and cognitive flexibility in LIB-exposed mice. Collected hippocampal tissue was further processed for quantitative global-proteomic analysis. Advanced data-independent acquisition for quantitative tandem mass spectrometry analysis identified altered expression of proteins involved in synaptic plasticity and serine protease inhibitors in LIB-exposed mice. Some were correlated with the ability of discrimination learning and cognitive flexibility. These findings show that acute glutamatergic hyperexcitability in the hippocampus induced by LIB may contribute to long-term cognitive dysfunction and protein alterations. Studies using this military-relevant mouse model of mild bTBI provide valuable insights into developing a potential therapeutic strategy to ameliorate hyperexcitability-modulated LIB injuries., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Most traumatic brain injuries (TBIs) during military deployment or training are clinically "mild" and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Siedhoff, Chen, Song, Cui, Cernak, Cifu, DePalma and Gu.)

Mild traumatic brain injury induced by low-intensity blast (LIB) exposure poses concerns in military personnel. Using an open-field, non-inertial blast model and assessments by conventional behavioral tests, our previous studies revealed early-phase anxiety-like behaviors in LIB-exposed mice. However, the impact of LIB upon long-term anxiety-like behaviors requires clarification. This study applied a highly sensitive automated home-cage monitoring (HCM) system, which minimized human intervention and environmental changes, to assess anxiety-like responses in mice 3 months after LIB exposure. Initial assessment of 72-h spontaneous activities in a natural cage condition over multiple light and dark phases showed altered sheltering behaviors. LIB-exposed mice exhibited a subtle, but significantly decreased, duration of short shelter visits as compared to sham controls. Other measured responses between LIB-exposed mice and sham controls were insignificant. When behavioral assessments were performed in a challenged condition using an aversive spotlight, LIB-exposed mice demonstrated a significantly higher frequency of movements of shorter distance and duration per movement. Taken together, these findings demonstrated the presence of chronic anxiety-like behaviors assessed by the HCM system under both natural and challenged conditions in mice occurring post-LIB exposure. This model thus provides a platform to test for screening and interventions on anxiety disorders occurring after LIB non-inertial brain injury., Competing Interests: No competing financial interests exist., (© Heather R. Siedhoff et al., 2021; Published by Mary Ann Liebert, Inc.)

This report provides perspectives concerning dual roles of serum ferritin as a measure of both iron status and inflammation. We suggest benefits of a lower range of serum ferritin as has occurred for total serum cholesterol and fasting blood glucose levels. Observations during a prospective randomized study using phlebotomy in patients with peripheral arterial disease offered unique insights into dual roles of serum ferritin both as an iron status marker and acute phase reactant. Robust positive associations between serum ferritin, interleukin 6 [IL-6], tissue necrosis factor-alpha, and high sensitivity C-reactive protein were discovered. Elevated serum ferritin and IL-6 levels associated with increased mortality and with reduced mortality at ferritin levels <100 ng mL-1. Epidemiologic studies demonstrate similar outcomes. Extremely elevated ferritin and IL-6 levels also occur in individuals with high mortality due to SARS-CoV-2 infection. Disordered iron metabolism reflected by a high range of serum ferritin level signals disease severity and outcomes. Based upon experimental and epidemiologic data, we suggest testing the hypotheses that optimal ferritin levels for cardiovascular mortality reduction range from 20 to 100 ng mL-1 with % transferrin levels from 20 to 50%, to ensure adequate iron status and that ferritin levels above 194 ng mL-1 associate with all-cause mortality in population cohorts., (Published by Oxford University Press 2021.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Hajj, Dhaini, Mondello, Kaafarani, Kobeissy and DePalma.)

Introduction: Blast overpressure exposure, an important cause of traumatic brain injury (TBI), may occur during combat or military training. TBI, most commonly mild TBI, is considered a signature injury of recent combat in Iraq and Afghanistan. Low intensity primary blast-induced TBI (bTBI), caused by exposure to an explosive shock wave, commonly leaves no obvious physical external signs. Numerous studies have been conducted to understand its biological effects; however, the role of shock wave energy as related to bTBI remains poorly understood. This report combines shock wave analysis with established biological effects on the mouse brain to provide insights into the effects of shock wave physics as related to low intensity bTBI outcomes from both open-air and shock tube environments., Methods: Shock wave peak pressure, rise time, positive phase duration, impulse, shock velocity, and particle velocity were measured using the Missouri open-air blast model from 16 blast experiments totaling 122 mice to quantify physical shock wave properties. Open-air shock waves were generated by detonating 350-g 1-m suspended Composition C-4 charges with targets on 1-m elevated stands at 2.15, 3, 4, and 7 m from the source., Results: All mice sustained brain injury with no observable head movement, because of mice experiencing lower dynamic pressures than calculated in shock tubes. Impulse, pressure loading over time, was found to be directly related to bTBI severity and is a primary shock physics variable that relates to bTBI., Discussion: The physical blast properties including shock wave peak pressure, rise time, positive phase duration, impulse, shock velocity, and particle velocity were examined using the Missouri open-air blast model in mice with associated neurobehavioral deficits. The blast-exposed mice sustained ultrastructural abnormalities in mitochondria, myelinated axons, and synapses, implicating that primary low intensity blast leads to nanoscale brain damage by providing the link to its pathogenesis. The velocity of the shock wave reflected back from the target stand was calculated from high-speed video and compared with that of the incident shock wave velocity. Peak incident pressure measured from high sample rate sensors was found to be within 1% of the velocity recorded by the high-speed camera, concluding that using sensors in or close to an animal brain can provide useful information regarding shock velocity within the brain, leading to more advanced knowledge between shock wave physics and tissue damage that leads to bTBIs., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pulsed microwaves above specific energy thresholds have been reported to cause brain injury in animal models. The actual physical mechanism causing brain damage is unexplained while the clinical reality of these injuries remains controversial. Here we propose mechanisms by which pulsed microwaves may injure brain tissue by transduction of microwave energy into damaging acoustic phonons in brain water. We have shown that low intensity explosive blast waves likely initiate phonon excitations in brain tissues. Brain injury in this instance occurs at nanoscale subcellular levels as predicted by physical consideration of phonon interactions in brain water content. The phonon mechanism may also explain similarities between primary non-impact blast-induced mild Traumatic Brain Injury (mTBI) and recent clinical and imaging findings of unexplained brain injuries observed in US embassy personnel possibly due to directed radiofrequency radiation. We describe experiments to elucidate mechanisms, RF frequencies and power levels by which pulsed microwaves potentially injure brain tissue. Pathological documentation of nanoscale brain blast injury has been supported experimentally using transmission electron microscopy (TEM) demonstrating nanoscale cellular damage in the absence of gross or light microscopic findings. Similar studies are required to better define pulsed microwave brain injury. Based upon existing findings, clinical diagnosis of both low intensity blast and microwave-induced brain injury likely will require diffusion tensor imaging (DTI), a specialized water based magnetic resonance imaging (MRI) technique., (Copyright © 2020 At least a portion of this work is authored by Stuart W. Hoffman, Tim D. Andreadis, and Ralph G. DePalma on behalf of the U.S. Government and, as regards Dr. Hoffman, Dr. Andreadis, and Dr. DePalma and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

Service members during military actions or combat training are exposed frequently to primary blast generated by explosive weaponry. The majority of military-related neurotrauma are classified as mild and designated as "invisible injuries" that are prevalent during current conflicts. While the previous experimental blast injury studies using moderate- to high-intensity exposures focused mainly on gross and microscopic neuropathology, our previous studies have shown that low-intensity blast (LIB) exposures resulted in nanoscale subcellular myelin and mitochondrial damages and subsequent behavioral disorders in the absence of gross or detectable cellular damage. In this study, we used transmission electron microscopy to delineate the LIB effects at the ultrastructural level specifically focusing on the neuron perikaryon, axons, and synapses in the cortex and hippocampus of mice at seven and 30 days post-injury (DPI). We found dysmorphic dark neuronal perikaryon and "cytoplasmic aeration" of dendritic processes, as well as increased microtubular fragmentation of the myelinated axons along with biochemically measured elevated tau/phosphorylated tau/Aβ levels. The number of cortical excitatory synapses decreased along with a compensatory increase of the post-synaptic density (PSD) thickness both at seven and 30 DPI, while the amount of hippocampal CA1 synapses increased with the reduced PSD thickness. In addition, we observed a significant increase in protein levels of PSD95 and synaptophysin mainly at seven DPI indicating potential synaptic reorganization. These results demonstrated that a single LIB exposure can lead to ultrastructural brain injury with accompanying multi-focal neuronal organelle alterations. This pre-clinical study provides key insights into disease pathogenesis related to primary blast exposure.

Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures >100 kPa, whereas understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with a peak overpressure at 46.6 kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. In this study, we used tandem mass tagged (TMT) quantitative proteomics and bioinformatics analysis to seek insights into the molecular mechanisms underlying ultrastructural pathology. Changes in global- and phospho-proteomes were determined at 3 and 24 h and at 7 and 30 days post injury (DPI), in order to investigate the biochemical and molecular correlates of mitochondrial dysfunction. Results showed striking dynamic changes in a total of 2216 proteins and 459 phosphorylated proteins at vary time points after blast. Disruption of key canonical pathways included evidence of mitochondrial dysfunction, oxidative stress, axonal/cytoskeletal/synaptic dysregulation, and neurodegeneration. Bioinformatic analysis identified blast-induced trends in networks related to cellular growth/development/movement/assembly and cell-to-cell signaling interactions. With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration-relevant enzyme activities. Insights on the early pathogenesis of primary LIB-induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers, and targets for intervention.

Blast-induced mild traumatic brain injury (mTBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat. The impact of primary low-intensity blast mediated pathophysiology upon later neurobehavioral disorders has been controversial. Developing a military preclinical blast model to simulate the pathophysiology of human blast injury is an important first step. This article provides an overview of primary blast effects and perspectives of our recent studies demonstrating ultrastructural changes in the brain and behavioral disorders resulting from open-field blast exposures up to 46.6 kPa using a murine model. The model is scalable and permits exposure to varying magnitudes of primary blast injuries by placing animals at different distances from the blast center or by changing the amount of C4 charge. We here review the implications and future applications and directions of using this animal model to uncover the underlying mechanisms related to primary blast injury. Overall, these studies offer the prospect of enhanced understanding of the pathogenesis of primary low-intensity blast-induced TBI and insights for prevention, diagnosis and treatment of blast induced TBI, particularly mTBI/concussion related to current combat exposures., Competing Interests: None declared

Explosive blast-induced mild traumatic brain injury (mTBI), a "signature wound" of recent military conflicts, commonly affects service members. While past blast injury studies have provided insights into TBI with moderate- to high-intensity explosions, the impact of primary low-intensity blast (LIB)-mediated pathobiology on neurological deficits requires further investigation. Our prior considerations of blast physics predicted ultrastructural injuries at nanoscale levels. Here, we provide quantitative data using a primary LIB injury murine model exposed to open field detonation of 350 g of high-energy explosive C4. We quantified ultrastructural and behavioral changes up to 30 days post blast injury (DPI). The use of an open-field experimental blast generated a primary blast wave with a peak overpressure of 6.76 PSI (46.6 kPa) at a 3-m distance from the center of the explosion, a positive phase duration of approximate 3.0 milliseconds (ms), a maximal impulse of 8.7 PSI × ms and a sharp rising time of 9 × 10 -3  ms, with no apparent impact/acceleration in exposed animals. Neuropathologically, myelinated axonal damage was observed in blast-exposed groups at 7 DPI. Using transmission electron microscopy, we observed and quantified myelin sheath defects and mitochondrial abnormalities at 7 and 30 DPI. Inverse correlations between blast intensities and neurobehavioral outcomes including motor activities, anxiety levels, nesting behavior, spatial learning and memory occurred. These observations uncover unique ultrastructural brain abnormalities and associated behavioral changes due to primary blast injury and provide key insights into its pathogenesis and potential treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Blast exposures are associated with traumatic brain injury (TBI) and blast-induced TBIs are common injuries affecting military personnel. Department of Defense and Veterans Administration (DoD/VA) reports for TBI indicated that the vast majority (82.3%) has been mild TBI (mTBI)/concussion. mTBI and associated posttraumatic stress disorders (PTSD) have been called "the invisible injury" of the current conflicts in Iraq and Afghanistan. These injuries induce varying degrees of neuropathological alterations and, in some cases, chronic cognitive, behavioral and neurological disorders. Appropriate animal models of blast-induced TBI will not only assist the understanding of physical characteristics of the blast, but also help to address the potential mechanisms. This report provides a brief overview of physical principles of blast, injury mechanisms related to blast exposure, current blast animal models, and the neurological behavioral and neuropathological findings related to blast injury in experimental settings. We describe relationships between blast peak pressures and the observed injuries. We also report preliminary use of a highly reproducible and intensity-graded blast murine model carried out in open-field with explosives, and describe physical and pathological findings in this experimental model. Our results indicate close relationships between blast intensities and neuropathology and behavioral deficits, particularly at low level blast intensities relevant to mTBI., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Between April 2007 and December 2015, the Veterans Health Administration (VHA) screened one million combat veterans for traumatic brain injury (TBI), among 2.6 million deployed during operations Enduring Freedom, Iraqi Freedom and New Dawn (OEF/OIF/OND). Since 2007, among those reporting, screened and referred for definitive evaluation, approximately 8.4% of these Veterans received a diagnosis of TBI, the majority characterized as mTBI/Concussion (mTBI) and, in great proportion, related to blast exposures. Mild Traumatic brain injury called "a signature injury" is also known as 'the invisible injury' of these conflicts. Identifying and assessing neuropathological, cellular and resulting cognitive, emotional, behavioral and neurological consequences of mTBI comprise vast clinical and research challenges. We provide a brief overview of current history, injury mechanisms related to blast exposure, coordinated research support, and the need to understand specific cellular and neurological changes occurring with blast injury, particularly mTBI., (Published by Elsevier B.V.)

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Introduction: Type 2 diabetes (T2D) and cardiovascular disease (CVD) risk associate with ferritin and percent transferrin saturation (%TS) levels. However, increased risk has been observed at levels considered within the "normal range" for these markers., Objective: To define normative ferritin and %TS levels associated with T2D and CVD risk., Methods: Six-monthly ferritin, %TS and hemoglobin levels from 1,277 iron reduction clinical trial participants with CVD (peripheral arterial disease, 37% diabetic) permitted pair-wise analysis using Loess Locally Weighted Smoothing plots. Curves showed continuous quantitative ferritin, hemoglobin (reflecting physiologic iron requirements), and %TS (reflecting iron transport and sequestration) levels over a wide range of values. Inflection points in the curves were compared to ferritin and %TS levels indicating increased T2D and CVD risk in epidemiologic and intervention studies., Results: Increasing ferritin up to about 80 ng/mL and %TS up to about 25% TS corresponded to increasing hemoglobin levels, and minimal T2D and CVD risk. Displaced Loess trajectories reflected lower hemoglobin levels in diabetics compared to non-diabetics. Ferritin levels up to about 100 ng/mL paralleled proportionately increasing %TS levels up to about 55%TS corresponding to further limitation of T2D and CVD risk. Ferritin levels over 100 ng/mL did not associate with hemoglobin levels and coincided with increased T2D and CVD risk., Conclusions: Recognition of modified normal ranges for ferritin from about 15 ng/mL up to about 80- 100 ng/mL and %TS from about 15% up to about 25-55% may improve the value of iron biomarkers to assess and possibly lower T2D and CVD risk., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.

Oxidative stress from excess iron may contribute to racial health disparities. Previously we reported improved clinical outcomes with lower ferritin and higher percent transferrin saturation (%TS) levels in White but not Black participants with peripheral arterial disease entered to a clinical trial. This report demonstrates racially variant interactions between hemoglobin, ferritin, and %TS levels. Lower hemoglobin and %TS levels, and higher ferritin levels were documented in Black compared with White participants within cardiovascular disease risk categories. Ferritin levels near 80 ng/mL related to higher hemoglobin levels in White but not Black participants. Higher %TS levels with ferritin levels above 80 ng/mL in White participants were blunted in Black participants. Ferritin/%TS ratios were significantly higher in Black than White participants. Iron incorporation into hemoglobin and scavenging by transferrin may buffer iron toxicity more effectively in White than in Black individuals. Metabolic vulnerability to iron excess may explain, in part, racial health disparities.

Elevated body iron (ferritin) levels may contribute to adverse health outcomes. Racial differences in iron measures and clinical outcomes were observed during an iron reduction trial in peripheral arterial disease. At entry, Black compared with White participants had higher ferritin and lower red cell measures, as well as differing ferritin and percent transferrin saturation (%TS) responses, and HDL/LDL ratios associated with statin use. Lower hematocrit levels during follow-up resulted in fewer phlebotomies, less iron unloading (ferritin reduction, p=.035) and 32% less iron removed in Black compared with White participants randomized to iron reduction. Improved primary (all-cause mortality) and secondary (death plus non-fatal myocardial infarction and stroke) outcomes among White participants correlated with lower ferritin levels (p=.005 and p=.053, respectively) and higher %TS levels (p&lt;.001 and p=.001 respectively), associations not observed in Black participants. Variant iron homeostasis contributory to racial health disparities warrants personalized intervention strategies and race-specific clinical trial design.

A prospective randomized trial suggested that iron (ferritin) reduction improved outcomes in smokers. The present study reanalyzed the trial results in smokers compared with non-smokers. Randomization of 1262 men with peripheral arterial disease (540 smokers and 722 non-smokers) to iron reduction (phlebotomy) or control groups permitted analysis of the effects of iron reduction and smoking on primary (all-cause mortality) and secondary (death plus non-fatal myocardial infarction or stroke) endpoints. Iron reduction resulted in significant improvement in the primary (hazard ratio [HR] 0.661, 95% confidence interval [CI] 0.45, 0.97; P = 0.036) and secondary (HR 0.64, 95% CI 0.46, 0.88; P = 0.006) endpoints compared with controls in smokers but not in non-smokers. Smokers required removal of a greater volume of blood to attain targeted ferritin reduction as compared with non-smokers (P = 0.003) and also exhibited differing characteristics from non-smokers, including significantly less statin use. Phlebotomy-related outcomes favored smokers over non-smokers. Biological linkages responsible for this unique effect offer promising lines for future iron reduction studies (ClinicalTrial.Gov Identifier: NCT00032357).

Objectives: We postulated the existence of a statin-iron nexus by which statins improve cardiovascular disease outcomes at least partially by countering proinflammatory effects of excess iron stores., Methods: Using data from a clinical trial of iron (ferritin) reduction in advanced peripheral arterial disease, the Iron and Atherosclerosis Study, we compared effects of ferritin levels versus high-density lipoprotein to low-density lipoprotein ratios (both were randomization variables) on clinical outcomes in participants receiving and not receiving statins., Results: Statins increased high-density lipoprotein to low-density lipoprotein ratios and reduced ferritin levels by noninteracting mechanisms. Improved clinical outcomes were associated with lower ferritin levels but not with improved lipid status., Conclusions: There are commonalities between the clinical benefits of statins and the maintenance of physiologic iron levels. Iron reduction may be a safe and low-cost alternative to statins.

Current health care trends include movements toward general health care reform and rapidly evolving changes affecting treatment of vascular disease. Government-sponsored programs and private coalitions increasingly influence practice management and patient care. Emerging organizational influences derive from public perceptions, policies, laws, and regulations intended to make health care safe, effective, patient centered, timely, efficient, and equitable. These trends energized methods of quality assessment, cost containment, and practice protocols over individual judgments and seek to exert increasing direction over clinical practice. Some evolving measures are good, some controversial, and some, without deliberate intent, may be harmful. This review considers evolving initiatives in the context of ethics of practice and practicalities of managing patients with vascular disease. Key issues include compliance with purely process-based measures, pay for performance, and assessment of quality outcomes. Strengths, weaknesses, opportunities, and potential threats to vascular practice are outlined., (Copyright © 2011. Published by Mosby, Inc.)

As health-care reforms progress, quality and risk assessment in the health-care system of the USA surface as critical issues. This review considers past, present and possible future changes in quality assessment along with formal programs of complication reduction and pay for performance (PFP) as related to surgery and vascular interventions. Strategies for quality improvement include aggregate and risk-adjusted outcome measurement, process compliance with the Surgical Complication Improvement Program, oversight and PFP, now policies of the Centers for Medicare and Medicaid Services (CMS). Advantages, disadvantages and unintended consequences of these policies are discussed. While ongoing system changes will influence vascular surgical practice, unique opportunities and obligations exist for vascular surgeons to contribute to quality assessment of their interventions, to evaluate long-term outcomes and to devise strategies for comprehensive cost-effective care for the conditions affecting patients with vascular disease.

Background: Laparoscopic cholecystectomy (LC) accounts for more than 85% of cholecystectomies. Factors prompting open cholecystectomy (OC) or conversion from LC to OC (CONV) are not completely understood., Methods: Prospectively collected data from the National Surgical Quality Improvement Program (NSQIP) were combined with administrative data to identify patients undergoing cholecystectomy from October 2005 to October 2008. Three cohorts were defined: LC, OC, and CONV. Using logistic hierarchical modeling, we identified predictors of the choice of OC and the decision to CONV., Results: A total of 11,669 patients underwent cholecystectomy at 117 VA hospitals, including 9,530 LC (81.7%). While the rate of conversion from LC to OC remained stable over the study period (9.0% overall), the percentage of OC decreased from 11.5% in 2006 to 10.1% in 2007 and 8.9% in 2008 (P = .0002). Compared with LC, the OC cohort had more comorbidities (35 of 41 preoperative characteristics, all P <.05), a higher 30-day morbidity rate (18.7% vs 4.8%. P <.0001), and a higher 30-day mortality rate (2.4% vs .4%, P <.0001). American Society of Anesthesiologist (ASA) class, patient comorbidities (eg, ascites, bleeding disorders, pneumonia) and functional status predicted a choice of OC. Age, preoperative albumin, previous abdominal surgery and emergency status predicted OC and CONV (all P <.05). A higher hospital conversion rate was independently predictive of OC (odds ratio [1% rate increase]: 1.05 [1.02-1.07]; P = .0004)., Conclusion: In the last 3 years, there has been a trend towards performing fewer OCs in VA hospitals. More patient comorbidities and higher hospital-level conversion rates are predictive of the choice to perform or convert to OC., (Published by Elsevier Inc.)

Background: This study delineated correlations between ferritin, inflammatory biomarkers, and mortality in a cohort of 100 cancer-free patients with peripheral arterial disease (PAD) participating in the Veterans Affairs (VA) Cooperative Study #410, the Iron (Fe) and Atherosclerosis Study (FeAST). FeAST, a prospective, randomized, single-blind clinical trial, tested the hypothesis that reduction of iron stores using phlebotomy would influence clinical outcomes in 1227 PAD patients randomized to iron reduction or control groups. The effects of statin administration were also examined in the Sierra Nevada Health Care (SNHC) cohort by measuring serum ferritin levels at entry and during the 6-year study period. No difference was documented between treatment groups in all-cause mortality and secondary outcomes of death plus nonfatal myocardial infarction and stroke. Iron reduction in the main study caused a significant age-related improvement in cardiovascular disease outcomes, new cancer diagnoses, and cancer-specific death., Methods: Tumor necrosis factor (TNF)-alpha, TNF-alpha receptors 1 and 2, interleukin (IL)-2, IL-6, IL-10, and high-sensitivity C reactive protein (hs-CRP) were measured at entry and at 6-month intervals for 6 years. Average levels of ferritin and lipids at entry and at the end of the study were compared. The clinical course and ferritin levels of 23 participants who died during the study were reviewed., Results: At entry, mean age of entry was 67 +/- 9 years for the SNHCS cohort, comparable to FeAST and clinical and laboratory parameters were equivalent in substudy participants randomized to iron reduction (n = 51) or control (n = 49). At baseline, 53 participants on statins had slightly lower mean entry-level ferritin values (114.06 ng/mL; 95% confidence interval [CI] 93.43-134.69) vs the 47 off statins (127.62 ng/mL; 95% CI, 103.21-152.02). Longitudinal analysis of follow-up data, after adjusting for the phlebotomy treatment effect, showed that statin use was associated with significantly lower ferritin levels (-29.78 ng/mL; Cohen effect size, -0.47 [t(df, 134) = 2.33, P = .02]). Mean follow-up average ferritin levels were higher in 23 participants who died (132.5 ng/mL; 95% CI, 79.36-185.66) vs 77 survivors (83.6 ng/mL; 95% CI, 70.34-96.90; Wilcoxon P = .05). Mean follow-up IL-6 levels were higher in dead participants (21.68 ng/mL; 95% CI, 13.71-29.66) vs survivors (12.61 ng/mL; 95% CI, 10.72-14.50; Wilcoxon P = .018). Ferritin levels correlated (Pearson) with average IL-6 levels (r = 0.1845; P = .002) and hsCRP levels (r = .1175; P = .04) during the study., Conclusion: These data demonstrate statistical correlations between levels of ferritin, inflammatory biomarkers, and mortality in this subset of patients with PAD., (Published by Mosby, Inc.)

Objective: To describe incorrect surgical procedures reported from Veterans Health Administration (VHA) Medical Centers from 2001 to mid-2006 and provide proposed solutions for preventing such events., Design: Descriptive study., Setting: Veterans Health Administration Medical Centers., Participants: Veterans of the US Armed Forces., Interventions: The VHA instituted an initial directive, "Ensuring Correct Surgery and Invasive Procedures," in January 2003. The directive was updated in 2004 to include non-operating room (OR) invasive procedures and incorporated requirements of The Joint Commission Universal Protocol for preventing wrong-site operations., Main Outcome Measures: The categories included 5 incorrect event types (wrong patient, side, site, procedure, or implant), major or minor surgical procedures, location in or out of the OR, therapeutic or diagnostic events, adverse event or close call, inpatient or ambulatory events, specialty department, body segment, and severity and probability of harm., Results: We reviewed 342 reported events (212 adverse events and 130 close calls). Of these, 108 adverse events (50.9%) occurred in an OR, and 104 (49.1%) occurred elsewhere. When examining adverse events only, ophthalmology and invasive radiology were the specialties associated with the most reports (45 [21.2%] each), whereas orthopedics was second to ophthalmology for number of reported adverse events occurring in the OR. Pulmonary medicine cases (such as wrong-side thoracentesis) and wrong-site cases (such as wrong spinal level) were associated with the most harm. The most common root cause of events was communication (21.0%)., Conclusions: Incorrect ophthalmic and orthopedic surgical procedures appear to be overrepresented among adverse events occurring in ORs. Outside the OR, adverse events by invasive radiology were most frequently reported. Incorrect surgical procedures are not only an OR challenge but also a challenge for events occurring outside of the OR. We support earlier communication based on crew resource management to prevent surgical adverse events.

This report describes outcomes of care for abdominal aortic aneurysms (AAAs), along with methods used by the Veterans Affairs (VA) National Surgical Quality Improvement Program (NSQIP) in tracking, monitoring, and improving surgical results in VA facilities. Since the inception of NSQIP in 1994, a continual drop in overall surgical mortality, along with decreased morbidity, has occurred. A parallel improvement in results of vascular surgery and AAA repair was also observed. Soon after introduction of endovascular aneurysm repair (EVAR), with Food and Drug Administration device approval in 1999, robust electronic NSQIP records immediately began to capture individual facility performances and outcomes for both types of AAA repair. The NSQIP data center provided actual and risk-adjusted analyses for both procedures semiannually. These analyses have been used by its executive board to provide recommendations, often based on site visits, to improve outcomes. Requirements for reporting of facility-specific data and feedback, paper audits, and site visits appear to relate directly to improved AAA care. Veterans Health Administration (VHA) outcomes of AAA repair are comparable to those reported nationally and internationally and have continued to improve in recent years. National VHA initiatives, based on data feedback and active oversight, relate to some of the lowest AAA mortality rates available. This review describes past, present, and possible future NSQIP strategies to improve outcomes for AAA repair with general comments about recent alternative proposals.

Secondary chronic venous disorders (CVD) usually follow an episode of acute deep venous thrombosis (DVT). Most occluded venous segments recanalize over the first 6 to 12 months after an episode of acute DVT, leading to chronic luminal changes and a combination of partial obstruction and reflux. Such morphological changes produce venous hypertension with the highest levels of ambulatory venous pressure occurring in patients with combined outflow obstruction and distal reflux. The clinical manifestations of secondary CVD, including pain, venous claudication, edema, skin changes, and ulceration are commonly referred to as the post-thrombotic syndrome. Such sequelae are best avoided by early and aggressive treatment of proximal DVT. The diagnostic evaluation of secondary CVD is similar to primary CVD and is based upon duplex ultrasound. However, the definition of hemodynamically significant venous stenosis remains obscure and there are no reliable tests to confirm the presence of such lesions. Diagnosis depends more on anatomic rather than hemodynamic criteria, and IVUS is superior to venography in estimating the morphological degree and extent of iliac vein stenosis. The fundamental role of compression in the treatment of CVD is well recognized. Compliance with compression is essential to heal ulcers and minimize recurrence. The efficacy of various adjuncts to ulcer treatment, including complex wound dressings and medications have been variable. Although superficial venous surgery has not been demonstrated to improve ulcer healing rates, it does decrease ulcer recurrence. Deep venous valve reconstruction is performed in only a few specialized centers, and the results are better for primary than for secondary CVD. Treatment of incompetent perforating veins remains controversial. Although artificial venous valves are promising, most early experimental models have failed. With respect to venous obstruction, iliocaval angioplasty and stenting has emerged as the primary treatment for proximal iliofemoral venous obstruction with surgical bypass assuming a secondary role.

Background: The episode of care for colorectal surgery in 8 outlier Veterans Affairs Hospitals with high mortality and the volume outcome relationship in 118 Hospitals are examined., Methods: A total of 103 deaths were reviewed. Mean age was 74 with 63% of the patients undergoing emergency surgery; 54% of the patients had malignant disease and 21% had metastatic disease., Results: Nineteen percent of the patients had a delay in diagnosis, 22% had delay in surgery and 14% should have received a different surgery usually less radical. In addition, system related issues were identified in 19% of the cases and practitioner related issues in 20% of the cases. The Spearman rank correlation between colorectal surgery volume and unadjusted mortality was 0.114 (P = 0.22)., Conclusion: Colorectal surgery death is prevalent in elderly patients undergoing emergency surgery for malignancy or metastatic disease and is not related to hospital volume. Timely diagnosis, less radical surgery while optimizing system based pathways might improve outcome.

Background: The increase in obesity coupled with greater acceptance of the field of bariatric surgery has resulted in a substantial rise in the number of weight-loss operations. Because obese individuals are at high risk for surgical complications, concern about the safety of bariatric procedures exists. Earlier investigations of the clinical features associated with surgical complications have produced conflicting results. We sought to identify risk factors for surgical complications in a large, nationally representative population of US veterans., Study Design: We analyzed data on bariatric procedures performed at 12 Veterans' Affairs medical centers approved to perform weight-loss operations between 1998 and 2004. Detailed pre-, intra-, and postoperative information and longterm mortality data were prospectively collected using the National Surgical Quality Improvement Program methodology. We used multivariable logistic regression to identify clinical features associated with postoperative complications., Results: Among 575 bariatric patients assessed between 1998 and 2004, 74% were men with a mean age of 51 years. Thirty-day mortality was 1.4%. Overall complication rate was 19.7%. Of those with complications, one-half were of considerable clinical importance, as they were associated with prolonged length of stay. Clinical features that were predictive of adverse events in our multivariable analyses were superobesity, weight>350 pounds, and smoking. A more than 20 pack-year history of smoking was also associated with difficulty in weaning from a ventilator postoperatively., Conclusions: We identified smoking and superobesity as preoperative risk factors associated with postoperative complications. Future studies should examine the effect of preoperative weight loss and smoking cessation on bariatric procedure outcomes.

This review describes the development, implementation, and current status of programs that promote and maintain surgical quality performance within the Department of Veterans Affairs, Veterans Health Administration (VHA). It also considers evolving initiatives to improve surgical outcomes and enhance patient safety. The VHA is a nationwide health care system operated and funded by the federal government. It consists of 154 federal hospitals and 875 clinics staffed by 16,000 nurses, 33,000 other health care professionals, 15,000 doctors, and 25,000 university-affiliated faculty physicians. The VHA trains 90,000 health care professionals, and additionally its activities are supported by 140,000 dedicated volunteers. More than 1000 surgeons in all specialties serve in its facilities. Since these programs began more than 19 years ago, there has been a steady decrease in both risk-adjusted and actual mortality rates tracked annually.

This exploratory substudy of The Iron (Fe) and Atherosclerosis Study (FeAST) compared baseline inflammatory markers, including cytokines, C-reactive protein (CRP), and ferritin, in subjects with peripheral arterial disease (PAD) taking statins with subjects with PAD who were not taking statins. Inflammatory markers in the serum of 47 subjects with PAD not taking statins and a healthy cohort of 21 medication-free men were compared with 53 PAD subjects taking statins at entry to the FeAST. Healthy subjects demonstrated lower levels of tumor necrosis factor (TNF)-R1, interleukin-6 (IL-6), and CRP. TNF-alpha R1 averaged 2.28 ng/mL versus 3.52 ng/mL, p = .0025; IL-6 averaged 4.24 pg/mL versus 16.61 pg/mL, p = .0008; and CRP averaged 0.58 mg/dL versus 0.92 mg/dL, p = .0192. A higher level of IL-6 was observed in PAD statin takers versus PAD subjects not taking statins: 19.47 pg/mL versus 13.24 pg/mL, p = .0455. As expected, total cholesterol and low-density lipoprotein levels were lower in the statin-treated group, p = .0006 and p = .0001, respectively. No significant differences in inflammatory cytokines were detected for varying doses of simvastatin. Additionally, no significant differences in inflammatory biomedical markers were found in subjects with PAD alone compared with those with concomitant coronary artery disease (CAD). Unexpectedly, serum inflammatory cytokine IL-6 levels were significantly higher in PAD subjects receiving statins. There was no difference in measured inflammatory markers in PAD subjects with concomitant CAD.

Background: There has been concern that a reduced level of surgical resident supervision in the operating room (OR) is correlated with worse patient outcomes. Until September 2004, Veterans' Affairs (VA) hospitals entered in the surgical record level 3 supervision on every surgical case when the attending physician was available but not physically present in the OR or the OR suite. In this study, we assessed the impact of level 3 on risk-adjusted morbidity and mortality in the VA system., Methods: Surgical cases entered into the National Surgical Quality Improvement Program database between 1998 and 2004, from 99 VA teaching facilities, were included in a logistic regression analysis for each year. Level 3 versus all other levels of supervision were forced into the model, and patient characteristics then were selected stepwise to arrive at a final model. Confidence limits for the odds ratios were calculated by profile likelihood., Results: A total of 610,660 cases were available for analysis. Thirty-day mortality and morbidity rates were reported in 14,441 (2.36%) and 63,079 (10.33%) cases, respectively. Level 3 supervision decreased from 8.72% in 1998 to 2.69% in 2004. In the logistic regression analysis, the odds ratios for mortality for level 3 ranged from .72 to 1.03. Only in the year 2000 were the odds ratio for mortality statistically significant at the .05 level (odds ratio, .72; 95% confidence interval, .594-.858). For morbidity, the odds ratios for level 3 supervision ranged from .66 to 1.01, and all odds ratios except for the year 2004 were statistically significant., Conclusions: Between 1998 and 2004, the level of resident supervision in the OR did not affect clinical outcomes adversely for surgical patients in the VA teaching hospitals.

Objective: The objective of this study was to identify the determinants of 30-day postoperative mortality and long-term survival after major surgery as exemplified by 8 common operations., Summary Background Data: The National Surgical Quality Improvement Program (NSQIP) database contains pre-, intra-, and 30-day postoperative data, prospectively collected in a standardized fashion by a dedicated nurse reviewer, on major surgery in the Veterans Administration (VA). The Beneficiary Identification and Records Locator Subsystem (BIRLS) is a VA file that depicts the vital status of U.S. veterans with 87% to 95% accuracy., Methods: NSQIP data were merged with BIRLS to determine the vital status of 105,951 patients who underwent 8 types of operations performed between 1991 and 1999, providing an average follow up of 8 years. Logistic and Cox regression analyses were performed to identify the predictors of 30-day mortality and long-term survival, respectively., Results: The most important determinant of decreased postoperative survival was the occurrence, within 30 days postoperatively, of any one of 22 types of complications collected in the NSQIP. Independent of preoperative patient risk, the occurrence of a 30-day complication in the total patient group reduced median patient survival by 69%. The adverse effect of a complication on patient survival was also influenced by the operation type and was sustained even when patients who did not survive for 30 days were excluded from the analyses., Conclusions: The occurrence of a 30-day postoperative complication is more important than preoperative patient risk and intraoperative factors in determining the survival after major surgery in the VA. Quality and process improvement in surgery should be directed toward the prevention of postoperative complications.

Background: Iron accumulation and inflammation may affect atherosclerosis. This study intended to define a cytokine signature in atherosclerotic claudicants and to determine whether reduction in serum ferritin by phlebotomy influenced this pattern., Methods: Ninety-one subjects with peripheral vascular disease (PVD; mean age, 67 years) were recruited from the VA Cooperative Iron and Atherosclerosis Study (FeAST) testing the hypothesis that ferritin reduction to 25 ng/ml may ameliorate atherosclerosis. Cytokines TNF-a, IL-2, IL-6, and IL-10 were analyzed by enzyme amplified sensitivity assay (EASIA). Fasting iron and cholesterol panels, complete blood count, C-reactive protein (CRP), uric acid, fibrinogen, glucose, and hemoglobin A1c levels were also quantified. Values were compared with "healthy" controls (n = 21; mean age, 56 years). After randomization of PVD to phlebotomy (intervention group [IG], n = 44) or control (nonintervention group [NG], n = 47), analyses were compared at 6 and 12 months using t test, Wilcoxon rank sum test, chi-square, and robust MM regression., Findings: Age, glucose, and hemoglobin A1c were higher in PVD compared with healthy controls (P < 0.01), whereas serum iron (P < 0.01) and percentage of transferrin saturation (P < 0.05) were lower. Tumor necrosis factor-alpha (TNF-alpha; P < 0.05), IL-6 (P < 0.01), and CRP (P < 0.05) levels were higher in the PVD group, whereas IL-10 was lower (P < 0.01). At 6 months post phlebotomy, ferritin levels were reduced (P < 0.01), although ferritin levels were reduced less in smokers. IL-6 and fibrinogen, CRP and ferritin levels correlated positively. At 6 and 12 months, subjects with TNF-alpha (n= 15) and IL-6 (n = 10) levels in the upper 25th percentile were reduced by phlebotomy., Interpretation: An inflammatory cytokine signature exists in atherosclerosis. Elevated levels of TNF-alpha and IL-6, reportedly associated with recurrent and future myocardial infarction, were reduced by phlebotomy. The utility of the iron/inflammatory hypotheses will ultimately relate to clinical outcomes obtained prospectively by the FeAST trial.