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The objective of this work was to evaluate the efficacy of an induced normothermia protocol by comparing patient mortality and outcomes in patients treated at Boston Medical Center (BMC) before and after the implementation of the protocol. The controls (regular fever management) and the cases (induced normothermia) were demographically similar, except there were more whites (p = 0.01) in the control group and more of the patients in the control group were transferred to BMC from outside hospitals (p = 0.006), although there was not a higher incidence of death among patients who were transferred from outside hospitals (p = 0.55). The patients in the case group were kept normothermic throughout the first 7 days of their hospital stay more effectively than those in the control group (p = 0.0001). Average intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were not different between the two groups, although mean arterial pressure (MAP) was (p = 0.84; p = 0.08; p = 0.02, respectively). Mortality was lower in the case group by hospital discharge (p = 0.007) and patients in the case group were more likely to achieve a positive functional outcome (p = 0.03). In light of these findings, there is a need for high-quality prospective trials to assess the efficacy of induced normothermia compared to regular fever management.

Working is a form of societal participation highly valued in American culture. The state-federal vocational rehabilitation system helps people with disabilities obtain and maintain employment in their communities. Although some people with traumatic brain injury return to work with minor adjustments, high proportions do not return to former employment or find work after their injuries. Analyzing vocational rehabilitation services, and other variables that impact competitive employment outcomes for this population, is important. This study examined the association of types and degree of limitations to functional capacities, and competitive employment outcomes; and selected VR services, and competitive employment, after controlling for demographic variables. The sample for this study consisted of 340 consumers of Illinois state-federal VR system whose cases were closed in fiscal years 2006 and 2007. Eligible individuals with TBI who did not receive services were also described (N=120). The present study also provided information on the types and reasons for case closure, length of rehabilitation, case expenditure, types and number of services received, and weekly earnings at case closure. Contrary to expectations, the degree of limitation across all areas of functional capacity, used by VR counselors to determine severity of disability, and priority for services, were not found to be significantly related to competitive employment among customers with TBI. Results also found that, when relevant demographic characteristics are controlled, the odds of achieving competitive employment increased significantly for VR clients with TBI in Illinois who received job placement and on-the-job supports. For clients who were of minority background, received SSI/SSDI at application, or had lower socioeconomic status (based on income, education and pre-service work status), these odds significantly decreased. Service variables were stronger predictors of competitive employment than demographic variables. Implications, future directions, and limitations of this study are also discussed.

Cognitive impairment is the most frequent cause of disability in humans following traumatic brain injury (TBI), yet the behavioral tasks used to assess cognitive behavior in rodent models of brain injury are underrepresented in the field. Additionally, few of these tasks have been used to assess behavior across degrees of injury severity. The goal of the present study was to compare four behavioral tasks commonly used in the field in frontally-injured rats with both mild and moderate-to-severe brain injuries. At the start of the study, rats were assigned to two of the following behavioral tasks: Dig scent discrimination (Dig) task, novel object recognition (NOR) task, Morris water maze (MWM), and passive avoidance (PA) task. Four days prior to injury, Dig rats were trained to dig in unscented sand and MWM rats were trained to locate a hidden platform positioned in the northeast quadrant of the MWM. Following training, bilateral controlled cortical impact injuries were induced (mild bilateral frontal TBI, moderate-to-severe bilateral frontal TBI, or non-injured, sham). Following a seven day recovery period, rats were tested on the two assigned behavioral tasks. Following testing, linear mixed effects modeling was performed assessing performance differences on the four tasks as a function of injury (injured vs. non-injured), injury severity (mild TBI vs. moderate-to-severe TBI), and task interaction. The results indicated that, while all four behavioral tasks were effective at assessing injury, some of the tasks were more effective at differentiating between injury severities than others. Specifically, the Dig task and MWM were effective at differentiating between rats with mild TBIs and rats with moderate-to-severe TBIs. Interactions between tasks also occurred such that Dig rats also assigned to the NOR task had significantly higher learning curves on the scent discriminations. The results from the current study indicate that all four behavioral tasks have the potential to assess cognitive impairment after TBI. However, these results are only a beginning. More work is needed before we can fully understand the efficacy of each of these tasks as behavioral assessment measures for cognitive functioning after TBI.

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Every year 2.8 million Americans suffer a traumatic brain injury (TBI). Despite the prevalence and debilitating consequences of TBI, effective treatment options are scarce due to the limited understanding of the neurobiological effects of injury, especially in acute phases when the cellular processes leading to neuropathology are first initiated. To identify changes in neural function and cerebral blood flow (CBF) that might account for TBI-induced cognitive and sensory deficits, we took a multidisciplinary approach, examining synaptic function, cortical activity patterns, and microvascular hemodynamics. we used a weight drop model in mice to induce mild TBI, the most common form in humans, and focused on responses within the first hours of injury where existing data are particularly limited. For synaptic function, we measured excitatory and inhibitory input onto pyramidal cells in the piriform cortex with whole-cell recordings in acute brain slices. Increased excitation appeared at one hour but excitatory-inhibitory balance was reestablished by 48 hours, highlighting the importance of studying rapid-onset injury responses. We also compared neural activity before and after TBI using in vivo two-photon calcium imaging of pyramidal cells in visual cortex. While neural activity substantially decreased in most cells one hour after injury, a minority of cells showed hyperactivation or prolonged increases in intracellular calcium, again indicating major physiological disturbances during immediate post-injury phases. Finally, we measured in vivo changes in CBF throughout the cortical microvasculature with laser speckle contrast imaging and optical coherence tomography, tracking injury effects up to three weeks after TBI. CBF and capillary flow were dramatically reduced within minutes and remained suppressed for over one hour. As neurons’ high energetic needs require a constant supply of glucose and oxygen from local vasculature, decreased CBF likely contributes to altered neural activity and loss of ion homeostasis and thus potentially cognitive and sensory deficits after TBI. Our results reveal that even mild injury creates rapid, pronounced, and heterogeneous alterations in neural activity and capillary flow. The transient nature of these effects suggests that the first two hours after injury may be a key window for delivering interventions, and that restoring CBF may reduce damage due to metabolic stress.

Yes / Background: Depression is a common psychiatric problem following traumatic brain injury (TBI) with reported prevalence rates of 30-77% in the first year post-TBI. Given the negative influence of post-TBI depression on cognition, interpersonal, social, physical and occupational functioning; early initiation of pharmacotherapy to prevent post-TBI depression has been considered. This systematic review will synthesize the available evidence from published studies on the effectiveness and harms of pharmacotherapy for the secondary prevention of post-TBI depression. Method: Studies published before November 2017 were reviewed. Six databases were searched, with additional searching of key additional documents. Studies meeting inclusion criteria were evaluated for methodological quality. Results: Six articles addressing five studies met inclusion criteria. Study designs included three randomised controlled trials (RCT), two retrospective cohorts and one case-control. Prophylactic pharmacotherapy included antidepressants, beta-blockers and statins. In one RCT, the number-needed-to-treat with sertraline to prevent one case of depression post-TBI at 24 weeks was 5.9 (95%CI: 3.1-71.1). Prescribing beta-blockers prior to TBI reduced the depression risk regardless of the specific brain trauma. TBI patients with pre-existing hyperlipidemia not treated with statins had an increased depression risk compared to those without hyperlipidemia. Conclusion: Early initiation of sertraline prophylaxis in nondepressed TBI patients shows promise to reduce the odds of post-TBI depression developing. However, in the absence of rigorous study of tolerability, existing data are insufficient to recommend sertraline prophylaxis. Optimal timing and treatment duration with identification of patients most likely to benefit from prophylaxis require further consideration. Dedicated prospective studies assessing the effects of beta-blockers and statins on post-TBI depression are required. / The Transport Accident Commission (TAC), through the Institute for Safety, Compensation and Recovery Research (ISCRR) at Monash University, provided funding for this review.

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Keratins are fibrous structural proteins found in human hair that have been used to develop bioactive and biocompatible constructs for a wide variety of tissue engineering and healthcare applications. Their ubiquity, capacity for self-assembly, ease of use and versatility in blended materials, and ability to modulate cell behavior and promote tissue ingrowth have made keratins well-suited for the development of regenerative therapies. In particular, keratins have demonstrated bioactivity in both in-vivo and in-vitro studies, by altering immune and stem cell phenotype and function and promoting an anti-inflammatory/wound healing environment. This work seeks to build on previous research by investigating the ability of low and high molecular weight keratins to augment anti-inflammatory primary macrophage phenotypes and examining the influence of keratin biomaterials on cellular and inflammatory mechanisms in two models of injury and disease. Rodent models of blast induced neurotrauma (BINT) and severe osteoporosis were used to inform the development of 2D and 3D in-vitro models of macrophage/endothelial cell injury and osteogenic differentiation respectively. Keratin biomaterials exhibited some potential to alter macrophage and endothelial cell dynamics following blast, specifically by promoting anti-inflammatory (M2c-like) macrophage polarization and diminishing endothelial cell injury responses (i.e. endothelial glycocalyx shedding). A more clinically relevant model of osteoporosis found that stem cells harvested from older, osteoporotic animals demonstrated limited proliferative and bone differentiation potential compared to healthy cells. However, 3D constructs (especially keratin-based materials) were able to enhance calcification and osteogenic gene expression of diseased cells. These results highlight the complexity of macrophage phenotypic switching and cellular dynamics in these systems. However, keratin-based therapeutics may prove useful for facilitating tissue regeneration and limiting detrimental inflammatory and cellular responses in various models of injury and disease. / Ph. D.