Work Environment and Operational Failures Associated With Nurse Outcomes, Patient Safety, and Patient Satisfaction.

BACKGROUND: Operational failures, defined as the inability of the work system to reliably provide information, services, and supplies needed when, where, and to who, are a pervasive problem in U.S. hospitals that disrupt nurses' ability to provide safe and effective care. OBJECTIVES: We examined the relationship between operational failures, patient satisfaction, nurse-reported quality and safety, and nurse job outcomes (e.g., burnout and job satisfaction) and whether differences in hospital work environments explained the relationship. METHODS: We conducted a cross-sectional analysis using population-based survey data from 11,709 registered nurses in 415 hospitals who participated in the RN4CAST-US nurse survey (2015-2016) and the 2016 Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. The RN4CAST-US nurse survey focused on hospital quality and safety, job outcomes, and hospital work environments. The HCAHPS survey collected publicly reported patient data on their satisfaction with their care. Operational failures were evaluated using an eight-item composite measure that assessed missing supplies, orders, medication, missing/wrong patient diet, electronic documentation problems, insufficient staff, and time spent on workarounds and nonnursing tasks. Multilevel regression models were used to test the hypothesized relationships. RESULTS: Operational failures were associated with low patient satisfaction scores, poor quality and safety outcomes, and poor nurse job outcomes, and those associations were partly accounted for by hospital work environments. DISCUSSION: Operational failures prevent high-quality care and positive patient and nurse outcomes. Operational failures and the hospital work environment should be targeted simultaneously to maximize quality improvement efforts. Hospital leadership should work with frontline staff to identify and target the sources of operational failures in nursing units. Improvements to hospital work environments may reduce the occurrence of operational failures.

Practice environment, independence, and roles among DNP- and MSN-prepared primary care nurse practitioners.

BACKGROUND: Many nursing schools are adopting the Doctor of Nursing Practice (DNP) as the preferred model of nurse practitioner (NP) education and eliminating Master of Science in Nursing (MSN) programs. To date, no studies have explored the relationship between DNP preparation and NP practice environment, independence, and roles. PURPOSE: The purpos of this study is to compare practice environment, independence, and roles among DNP- and MSN-prepared primary care NPs. METHODS: This study used a cross-sectional design and observational regression analysis of survey data. FINDINGS: DNP-prepared NPs reported: 1) more favorable NP-Physician Relationships, 2) fewer clinical hours, and 3) more practice leadership. These differences were, however, small and not significant at 0.05 level. DISCUSSION: We found no major differences in practice environment, independence, and roles among DNP- and MSN-prepared primary care NPs. As more nursing schools establish DNP programs and more DNP-prepared NPs enter the field, it is especially important to continue to study the impact of DNP preparation on the NP workforce.

Methodology for a six-state survey of primary care nurse practitioners.

BACKGROUND: Primary care practices employing nurse practitioners (NPs) can play an important role in improving access to high quality health care services. However, most studies on the NP role in health care use administrative data, which have many limitations. PURPOSE: In this paper, we report the methods of the largest survey of primary care NPs to date. METHODS: To overcome the limitations of administrative data, we fielded a cross-sectional, mixed-mode (mail/online) survey of primary care NPs in six states to collect data directly from NPs on their clinical roles and practice environments. FINDINGS: While we were able to collect data from over 1,200 NPs, we encountered several challenges with our sampling frame, including provider turnover and challenges with identification of NP specialty. DISCUSSION: In future surveys, researchers can employ strategies to avoid the issues we encountered with the sampling frame and enhance large scale survey data collection from NPs.

Surveying Primary Care Nurse Practitioners: An Overview of National Sampling Frames.

Nurse practitioners (NPs) represent the fastest growing segment of the U.S. primary care workforce. Surveys of primary care NPs can help to better understand the care NPs deliver across different health care settings, the factors that impact NP job satisfaction and burnout, and the structural capabilities required to support their practice. The purpose of this article is to provide an overview of national sampling frames that can be used by researchers interested in surveying or studying the U.S. primary care NP workforce. We conducted an environmental scan and review of published literature on the NP workforce to identify data sources that can be used to sample primary care NPs. In this article, we (a) identify the data elements needed to develop an NP sampling frame and (b) describe national data sets that can be used to sample primary care NPs, including the strengths and weaknesses of each. This information is intended to facilitate research on the primary care NP workforce to inform practice and policy.

Novel TNF receptor-1 inhibitors identified as potential therapeutic candidates for traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) begins with the application of mechanical force to the head or brain, which initiates systemic and cellular processes that are hallmarks of the disease. The pathological cascade of secondary injury processes, including inflammation, can exacerbate brain injury-induced morbidities and thus represents a plausible target for pharmaceutical therapies. We have pioneered research on post-traumatic sleep, identifying that injury-induced sleep lasting for 6 h in brain-injured mice coincides with increased cortical levels of inflammatory cytokines, including tumor necrosis factor (TNF). Here, we apply post-traumatic sleep as a physiological bio-indicator of inflammation. We hypothesized the efficacy of novel TNF receptor (TNF-R) inhibitors could be screened using post-traumatic sleep and that these novel compounds would improve functional recovery following diffuse TBI in the mouse. METHODS: Three inhibitors of TNF-R activation were synthesized based on the structure of previously reported TNF CIAM inhibitor F002, which lodges into a defined TNFR1 cavity at the TNF-binding interface, and screened for in vitro efficacy of TNF pathway inhibition (IκB phosphorylation). Compounds were screened for in vivo efficacy in modulating post-traumatic sleep. Compounds were then tested for efficacy in improving functional recovery and verification of cellular mechanism. RESULTS: Brain-injured mice treated with Compound 7 (C7) or SGT11 slept significantly less than those treated with vehicle, suggesting a therapeutic potential to target neuroinflammation. SGT11 restored cognitive, sensorimotor, and neurological function. C7 and SGT11 significantly decreased cortical inflammatory cytokines 3 h post-TBI. CONCLUSIONS: Using sleep as a bio-indicator of TNF-R-dependent neuroinflammation, we identified C7 and SGT11 as potential therapeutic candidates for TBI.

Trends in Prescription Pain Medication Use by Race/Ethnicity Among US Adults With Noncancer Pain, 2000-2015.

OBJECTIVES: To examine national trends in the use of various pharmacological pain medication classes by race/ethnicity among the US pain population. METHODS: We used data from the Medical Expenditure Panel Survey to conduct a nationally representative, serial cross-sectional study of the noninstitutionalized US adult population from 2000 to 2015. We identified adults with moderate or severe self-reported pain and excluded individuals with cancer. We used complex survey design to provide national estimates of the percentage of adults with noncancer pain who received prescription pain medications among 4 groups: non-Hispanic White, non-Hispanic Black, Hispanic or Latino, and other. RESULTS: The age- and gender-adjusted percentage of prescription opioid use increased across all groups, with the greatest increase among non-Hispanic White individuals. By 2015, the percentage of non-Hispanic Black adults using opioids approximated that of non-Hispanic White adults-in 2015, approximately 23% of adults in these 2 groups used opioids. CONCLUSIONS: To our knowledge, this is the first evidence of a narrowing divide in opioid prescribing by race. However, in the context of the national epidemic of opioid-related addiction and mortality, opioid-related risks do not appear commensurate with the purported benefits.

Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury.

Clinically, traumatic brain injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head injury (mCHI), repetitive-mCHI and midline-fluid percussion injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood-brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/brain extraction. NP accumulation was analyzed using fluorescent microscopy in brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.

Symptoms, Nutrition, Pressure Ulcers, and Return to Community Among Older Women With Heart Failure at Skilled Nursing Facilities: A Pilot Study.

BACKGROUND: Mortality rate is high for older women with heart failure (HF) who are discharged to skilled nursing facilities (SNFs) after hospitalization, but little is known about their symptoms, nutritional factors, and pressure ulcer status and whether these variables predict the women's return to the community. OBJECTIVES: The aims of this study are to characterize symptoms (ie, dyspnea, cognitive dysfunction, depression, and pain) and nutritional and pressure ulcer status, evaluate relationships among symptoms, and examine predictors of return to the community among older women with HF admitted to SNFs. METHODS: In this pilot observational study, data were collected retrospectively from the electronic medical records and the Minimum Data Set 3.0. RESULTS: Data were obtained for 45 women with HF (mean age, 84.8 years). Frequency of symptoms was dyspnea 18%, cognitive dysfunction 20%, depression 5%, and pain 78%. Mean body mass index (BMI) was 29.8 kg/m. Frequency of pressure ulcer risk was 85% and 18% had pressure ulcers. The 4 symptoms were not significantly related. Younger age (odds ratio, 0.90; P = .023) and BMI of 25 kg/m or greater (odds ratio, 5.31; P = .017) predicted return to the community. CONCLUSIONS: The women in this study had frequent pain, moderately frequent cognitive dysfunction, and high pressure ulcer risk. Surprisingly, few women had dyspnea or depression. Women who were younger with higher BMI were more likely to return to the community. The study needs to be replicated in a larger more diverse group of older patients with HF.

Treatment-associated toxicities reported by patients with early-stage invasive breast cancer.

BACKGROUND: Patient-reported toxicities help to appraise the breast cancer treatment experience. Yet extant data come from clinical trials and health care claims, which may be biased. Using patient surveys, the authors sought to quantify the frequency, severity, and burden of treatment-associated toxicities. METHODS: Between 2013 and 2014, the iCanCare study surveyed a population-based sample of women residing in Los Angeles County and Georgia with early-stage, invasive breast cancer. The authors assessed the frequency and severity of toxicities; correlated toxicity severity with unscheduled health care use (clinic visits, emergency department visits/hospitalizations) and physical health; and examined patient, tumor, and treatment factors associated with reporting increased toxicity severity. RESULTS: The overall survey response rate was 71%. From the analyzed cohort of 1945 women, 866 (45%) reported at least 1 toxicity that was severe/very severe, 9% reported unscheduled clinic visits for toxicity management, and 5% visited an emergency department or hospital. Factors associated with reporting higher toxicity severity included receipt of chemotherapy (odds ratio [OR], 2.2; 95% confidence interval [95% CI], 2.0-2.5), receipt of both chemotherapy and radiotherapy (OR, 1.3; 95% CI, 1.0-1.7), and Latina ethnicity (OR vs whites: 1.3; 95% CI, 1.1-1.5). A nonsignificant increase in at least 1 severe/very severe toxicity report was observed for bilateral mastectomy recipients (OR, 1.2; 95% CI, 1.0-1.4). CONCLUSIONS: Women with early-stage invasive breast cancer report substantial treatment-associated toxicities and related burden. Clinicians should collect toxicity data routinely and offer early intervention. Toxicity differences observed by treatment modality may inform decision making. Cancer 2017;123:1925-1934. © 2017 American Cancer Society.

Functional status and quality of life among breast cancer survivors with heart failure: results of the Medicare Health Outcomes Survey.

PURPOSE: The purpose of this population-based study was to examine health-related quality of life (HRQOL) and functional status among breast cancer survivors with heart failure. METHODS: We examined Medicare Health Outcomes Survey data from women aged 65 and older diagnosed with breast cancer in the past 5 years. Surveys were linked to Surveillance, Epidemiology, and End Results cancer registries. Each woman identified with self-reported heart failure (n = 239) was matched to controls without heart failure (n = 685) using propensity scores. The Short Form-36/Veterans Rand-12 measured eight domains of HRQOL. Functional status impairment was measured by limitations in six activities of daily living (ADLs). Linear models estimated associations between heart failure status and HRQOL. Logistic regression models estimated odds ratios for associations between heart failure and ADL impairment. We examined associations for the total study population and subgroups stratified by cancer stage. RESULTS: Among all study participants, heart failure was associated with significant deficits in every HRQOL domain and impairment in all ADLs (p < 0.01, ORs ranged from 1.74 to 2.47). After stratification by cancer stage, heart failure was associated with physical HRQOL deficits across all cancer stages (physical function, vitality, general health) and mental HRQOL deficits only in women with stage I/II cancer (role-emotional, social function). Women with early stage cancer experienced the greatest HRQOL deficits associated with heart failure. CONCLUSIONS: Heart failure in breast cancer survivors is associated with substantial HRQOL deficits and functional status impairment, particularly in early stage cancer. Tailored interventions are needed to improve physical function and mental wellbeing in this high-risk population.

Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge.

BACKGROUND: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. RESULTS: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). CONCLUSIONS: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.

Aging with Traumatic Brain Injury: Effects of Age at Injury on Behavioral Outcome following Diffuse Brain Injury in Rats.

Development and aging are influenced by external factors with the potential to impact health throughout the life span. Traumatic brain injury (TBI) can initiate and sustain a lifetime of physical and mental health symptoms. Over 1.7 million TBIs occur annually in the USA alone, with epidemiology suggesting a higher incidence for young age groups. Additionally, increasing life spans mean more years to age with TBI. While there is ongoing research of experimental pediatric and adult TBI, few studies to date have incorporated animal models of pediatric, adolescent, and adult TBI to understand the role of age at injury across the life span. Here, we explore repeated behavioral performance between rats exposed to diffuse TBI at five different ages. Our aim was to follow neurological morbidities across the rodent life span with respect to age at injury. A single cohort of male Sprague-Dawley rats (n = 69) was received at postnatal day (PND) 10. Subgroups of this cohort (n = 11-12/group) were subjected to a single moderate midline fluid percussion injury at age PND 17, PND 35, 2 months, 4 months, or 6 months. A control group of naïve rats (n = 12) was assembled from this cohort. The entire cohort was assessed for motor function by beam walk at 1.5, 3, 5, and 7 months of age. Anxiety-like behavior was assessed with the open field test at 8 months of age. Cognitive performance was assessed using the novel object location task at 8, 9, and 10 months of age. Depression-like behavior was assessed using the forced swim test at 10 months of age. Age at injury and time since injury differentially influenced motor, cognitive, and affective behavioral outcomes. Motor and cognitive deficits occurred in rats injured at earlier developmental time points, but not in rats injured in adulthood. In contrast, rats injured during adulthood showed increased anxiety-like behavior compared to uninjured control rats. A single diffuse TBI did not result in chronic depression-like behaviors or changes in body weight among any groups. The interplay of age at injury and aging with an injury are translationally important factors that influence behavioral performance as a quality of life metric. More complete understanding of these factors can direct rehabilitative efforts and personalized medicine for TBI survivors.

Predictors of trajectories of epilepsy-specific quality of life among children newly diagnosed with epilepsy.

OBJECTIVE: The objective of this study was to identify two-year trajectories of epilepsy-specific health-related quality of life (HRQOL) among children newly diagnosed with epilepsy and to evaluate the predictive value of a comprehensive set of medical, psychosocial, and family factors. METHODS: Ninety-four children with epilepsy (8.14 ± 2.37 years of age and 63% male) and their caregivers participated in this study. Caregivers completed the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) and measures of psychological and family functioning at one month postdiagnosis. The QOLCE was also given at eight additional time points during the subsequent two years as a part of a large observational study in children with epilepsy. Adherence data were collected via MEMS TrackCaps, and medical information was collected through chart review. RESULTS: Unique trajectories were identified for the overall QOLCE scale, as well as the subscales. Most trajectory models for the QOLCE subscales contained at least one at-risk trajectory for children, indicating that there is a subgroup of children experiencing poor long-term HRQOL. Health-related quality-of-life trajectories remained predominantly stable during the two-year period following treatment initiation. The number of AEDs, internalizing problems, and externalizing problems emerged as the most consistent predictors across the HRQOL domains. SIGNIFICANCE: Medical and psychosocial interventions, such as cognitive-behavioral strategies, should target modifiable factors (e.g., internalizing symptoms, externalizing symptoms, number of AEDs trialed) shortly after diagnosis to improve HRQOL for children with epilepsy over the course of their disease.

Learning from non-representative instances: Children's sample and population predictions.

What do children learn from biased samples? Most samples people encounter are biased in some way, and responses to bias can distinguish among different theories of inductive inference. A sample of 67 4- to 8-year-old children learned to make conditional predictions about a set of sample items. They then made predictions about the properties of new instances or old instances from the training set. The experiment compared unbiased and biased sampling. Given unbiased samples, participants used what they learned to make predictions about population and sample instances. With biased samples, children were less accurate/confident about inferences about the population than about the sample. Children used information in a biased sample to make predictions about items in that sample, but they were less likely to generalize to new items than when samples were unbiased.

Experimental diffuse brain injury results in regional alteration of gross vascular morphology independent of neuropathology.

PRIMARY OBJECTIVE: A dynamic relationship exists between diffuse traumatic brain injury and changes to the neurovascular unit. The purpose of this study was to evaluate vascular changes during the first week following diffuse TBI. It was hypothesized that pathology is associated with modification of the vasculature. METHODS: Male Sprague-Dawley rats underwent either midline fluid percussion injury or sham-injury. Brain tissue was collected 1, 2 or 7 days post-injury or sham-injury (n = 3/time point). Tissue was collected and stained by de Olmos amino-cupric silver technique to visualize neuropathology or animals were perfused with AltaBlue casting resin before high-resolution vascular imaging. The average volume, surface area, radius, branching and tortuosity of the vessels were evaluated across three regions of interest. RESULTS: In M2, average vessel volume (p < 0.01) and surface area (p < 0.05) were significantly larger at 1 day relative to 2 days, 7 days and sham. In S1BF and VPM, no significant differences in the average vessel volume or surface area at any of the post-injury time points were observed. No significant changes in average radius, branching or tortuosity were observed. CONCLUSIONS: Preliminary findings suggest gross morphological changes within the vascular network likely represent an acute response to mechanical forces of injury, rather than delayed or chronic pathological processes.

Cardiotoxic heart failure in breast cancer survivors: a concept analysis.

AIM: To report an analysis of the concept of cardiotoxic heart failure in breast cancer survivors. BACKGROUND: Despite numerous studies describing cardiotoxic effects of breast cancer therapies, the literature lacks consistent terminology to describe cancer treatment-induced heart failure, defined by the authors as 'cardiotoxic heart failure'. Breast cancer survivors who develop heart failure may not fit existing conceptual models. A concept analysis of cardiotoxic heart failure in breast cancer survivors is needed to integrate previous research findings and establish the scientific foundation for future intervention research. DESIGN: Concept analysis. DATA SOURCES: An integrative review (1999-2014) was conducted to examine aetiologies and risk factors for heart failure in female breast cancer survivors. Databases searched were CINAHL, Cochrane Library, EmBase, Medline and Scopus. METHODS: Walker and Avant's method for concept analysis includes: select concept; determine purpose; identify uses; define attributes; identify model case; describe borderline, related and contrary cases; identify antecedents/consequences; define empirical referents. RESULTS: In the literature, substantial variation was noted in terminology for breast cancer treatment-induced cardiotoxicity. The authors define cardiotoxic heart failure in breast cancer survivors as chronic heart failure resulting from breast cancer treatment-induced cardiotoxicity among women without pre-existing heart failure diagnosis. No studies were found that described quality of life or tested interventions to preserve quality of life for this population. CONCLUSION: Prospective studies are needed to develop interventions for symptom management to improve quality of life in breast cancer survivors with heart failure. New conceptual paradigms may be needed to improve outcomes for this vulnerable population.

Refusal to participate in heart failure studies: do age and gender matter?

AIMS AND OBJECTIVES: The objective of this retrospective study was to evaluate reasons heart failure patients decline study participation, to inform interventions to improve enrollment. BACKGROUND: Failure to enrol older heart failure patients (age > 65) and women in studies may lead to sampling bias, threatening study validity. DESIGN: This study was a retrospective analysis of refusal data from four heart failure studies that enrolled 788 patients in four states. METHODS: Chi-Square and a pooled t-test were computed to analyse refusal data (n = 300) obtained from heart failure patients who were invited to participate in one of the four studies but declined. RESULTS: Refusal reasons from 300 patients (66% men, mean age 65·33) included: not interested (n = 163), too busy (n = 64), travel burden (n = 50), too sick (n = 38), family problems (n = 14), too much commitment (n = 13) and privacy concerns (n = 4). Chi-Square analyses showed no differences in frequency of reasons (p > 0·05) between men and women. Patients who refused were older, on average, than study participants. CONCLUSIONS: Some reasons were patient-dependent; others were study-dependent. With 'not interested' as the most common reason, cited by over 50% of patients who declined, recruitment measures should be targeted at stimulating patients' interest. Additional efforts may be needed to recruit older participants. However, reasons for refusal were consistent regardless of gender. RELEVANCE TO CLINICAL PRACTICE: Heart failure researchers should proactively approach a greater proportion of women and patients over age 65. With no gender differences in type of reasons for refusal, similar recruitment strategies can be used for men and women. However, enrolment of a representative proportion of women in heart failure studies has proven elusive and may require significant effort from researchers. Employing strategies to stimulate interest in studies is essential for recruiting heart failure patients, who overwhelmingly cited lack of interest as the top reason for refusal.

Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse.

Traumatic brain injury (TBI) is induced by mechanical forces which initiate a cascade of secondary injury processes, including inflammation. Therapies which resolve the inflammatory response may promote neural repair without exacerbating the primary injury. Specific derivatives of omega-3 fatty acids loosely grouped as specialized pro-resolving lipid mediators (SPMs) and termed resolvins promote the active resolution of inflammation. In the current study, we investigate the effect of two resolvin molecules, RvE1 and AT-RvD1, on post-traumatic sleep and functional outcome following diffuse TBI through modulation of the inflammatory response. Adult, male C57BL/6 mice were injured using a midline fluid percussion injury (mFPI) model (6-10min righting reflex time for brain-injured mice). Experimental groups included mFPI administered RvE1 (100ng daily), AT-RvD1 (100ng daily), or vehicle (sterile saline) and counterbalanced with uninjured sham mice. Resolvins or saline were administered daily for seven consecutive days beginning 3days prior to TBI to evaluate proof-of-principle to improve outcome. Immediately following diffuse TBI, post-traumatic sleep was recorded for 24h post-injury. For days 1-7 post-injury, motor outcome was assessed by rotarod. Cognitive function was measured at 6days post-injury using novel object recognition (NOR). At 7days post-injury, microglial activation was quantified using immunohistochemistry for Iba-1. In the diffuse brain-injured mouse, AT-RvD1 treatment, but not RvE1, mitigated motor and cognitive deficits. RvE1 treatment significantly increased post-traumatic sleep in brain-injured mice compared to all other groups. RvE1 treated mice displayed a higher proportion of ramified microglia and lower proportion of activated rod microglia in the cortex compared to saline or AT-RvD1 treated brain-injured mice. Thus, RvE1 treatment modulated post-traumatic sleep and the inflammatory response to TBI, albeit independently of improvement in motor and cognitive outcome as seen in AT-RvD1-treated mice. This suggests AT-RvD1 may impart functional benefit through mechanisms other than resolution of inflammation alone.

Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse.

Following mild traumatic brain injury (TBI), patients may self-treat symptoms of concussion, including post-traumatic headache, taking over-the-counter (OTC) analgesics. Administering one dose of OTC analgesics immediately following experimental brain injury mimics the at-home treated population of concussed patients and may accelerate the understanding of the relationship between brain injury and OTC pharmacological intervention. In the current study, we investigate the effect of acute administration of OTC analgesics on neurological function and cortical cytokine levels after experimental diffuse TBI in the mouse. Adult, male C57BL/6 mice were injured using a midline fluid percussion (mFPI) injury model of concussion (6-10 min righting reflex time for brain-injured mice). Experimental groups included mFPI paired with either ibuprofen (60 mg/kg, i.p.; n = 16), acetaminophen (40 mg/kg, i.p.; n = 9), or vehicle (15% ethanol (v/v) in 0.9% saline; n = 13) and sham injury paired OTC medicine or vehicle (n = 7-10 per group). At 24 h after injury, functional outcome was assessed using the rotarod task and a modified neurological severity score. Following behavior assessment, cortical cytokine levels were measured by multiplex ELISA at 24 h post-injury. To evaluate efficacy on acute inflammation, cortical cytokine levels were measured also at 6 h post-injury. In the diffuse brain-injured mouse, immediate pharmacological intervention did not attenuate or exacerbate TBI-induced functional deficits. Cortical cytokine levels were affected by injury, time, or their interaction. However, levels were not affected by treatment at 6 or 24 h post-injury. These data indicate that acute administration of OTC analgesics did not exacerbate or attenuate brain-injury deficits which may inform clinical recommendations for the at-home treated mildly concussed patient.