Joseph A. Rosenthal

National High School Athlete Concussion Rates From 2005-2006 to 2011-2012

Background: High school athletes are at risk for concussions. Although a previously published study showed an increase in concussion rates for a single school district, it remains unknown if the rate of concussions among high school athletes is increasing nationally. Purpose: To investigate national high school athlete concussion rates over time. Study Design: Descriptive epidemiologic study. Methods: The rate of concussions per 1000 athlete-exposures was calculated for academic years 2005-2006 through 2011-2012 using the High School Reporting Information Online sports injury surveillance system. Results: During the 7-year period of this study, High School Reporting Information Online captured 4024 concussions with overall concussion diagnosis rates increasing significantly from 0.23 to 0.51 (P = .004). Concussion diagnosis rates increased for each of the 9 sports studied, with 5 sports having statistically significant increases over this 7-year period. Conclusion: The study analysis indicates that national concussion diagnosis rates for high school sports have increased significantly over time.

Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies

Significance Conjugate vaccines have proven to be an effective and safe strategy for reducing the incidence of disease caused by bacterial pathogens. However, the manufacture of these vaccines is technically demanding, inefficient, and expensive, thereby limiting their widespread use. Here, we describe an alternative methodology for generating glycoconjugate vaccines whereby recombinant polysaccharide biosynthesis is coordinated with vesicle formation in nonpathogenic Escherichia coli, resulting in glycosylated outer membrane vesicles (glycOMVs) that can effectively deliver pathogen-mimetic glycotopes to the immune system. An attractive feature of our approach is the fact that different plasmid-encoded polysaccharide biosynthetic pathways can be readily transformed into E. coli, enabling a “plug-and-play” platform for the on-demand creation of glycOMV vaccine candidates that carry heterologous glycotopes from numerous pathogenic bacteria. The O-antigen polysaccharide (O-PS) component of lipopolysaccharides on the surface of gram-negative bacteria is both a virulence factor and a B-cell antigen. Antibodies elicited by O-PS often confer protection against infection; therefore, O-PS glycoconjugate vaccines have proven useful against a number of different pathogenic bacteria. However, conventional methods for natural extraction or chemical synthesis of O-PS are technically demanding, inefficient, and expensive. Here, we describe an alternative methodology for producing glycoconjugate vaccines whereby recombinant O-PS biosynthesis is coordinated with vesiculation in laboratory strains of Escherichia coli to yield glycosylated outer membrane vesicles (glycOMVs) decorated with pathogen-mimetic glycotopes. Using this approach, glycOMVs corresponding to eight different pathogenic bacteria were generated. For example, expression of a 17-kb O-PS gene cluster from the highly virulent Francisella tularensis subsp. tularensis (type A) strain Schu S4 in hypervesiculating E. coli cells yielded glycOMVs that displayed F. tularensis O-PS. Immunization of BALB/c mice with glycOMVs elicited significant titers of O-PS–specific serum IgG antibodies as well as vaginal and bronchoalveolar IgA antibodies. Importantly, glycOMVs significantly prolonged survival upon subsequent challenge with F. tularensis Schu S4 and provided complete protection against challenge with two different F. tularensis subsp. holarctica (type B) live vaccine strains, thereby demonstrating the vaccine potential of glycOMVs. Given the ease with which recombinant glycotopes can be expressed on OMVs, the strategy described here could be readily adapted for developing vaccines against many other bacterial pathogens.

Mechanistic insight into the TH1-biased immune response to recombinant subunit vaccines delivered by probiotic bacteria-derived outer membrane vesicles.

Recombinant subunit vaccine engineering increasingly focuses on the development of more effective delivery platforms. However, current recombinant vaccines fail to sufficiently stimulate protective adaptive immunity against a wide range of pathogens while remaining a cost effective solution to global health challenges. Taking an unorthodox approach to this fundamental immunological challenge, we isolated the TLR-targeting capability of the probiotic E. coli Nissle 1917 bacteria (EcN) by engineering bionanoparticlate antigen carriers derived from EcN outer membrane vesicles (OMVs). Exogenous model antigens expressed by these modified bacteria as protein fusions with the bacterial enterotoxin ClyA resulted in their display on the surface of the carrier OMVs. Vaccination with the engineered EcN OMVs in a BALB/c mouse model, and subsequent mechanism of action analysis, established the EcN OMV’s ability to induce self-adjuvanted robust and protective humoral and TH1-biased cellular immunity to model antigens. This finding appears to be strain-dependent, as OMV antigen carriers similarly engineered from a standard K12 E. coli strain derivative failed to generate a comparably robust antigen-specific TH1 bias. The results demonstrate that unlike traditional subunit vaccines, these biomolecularly engineered “pathogen-like particles” derived from traditionally overlooked, naturally potent immunomodulators have the potential to effectively couple recombinant antigens with meaningful immunity in a broadly applicable fashion.

Systematic review of interventions for fatigue after traumatic brain injury: a NIDRR traumatic brain injury model systems study.

Objective:To conduct a systematic review of the evidence on interventions for posttraumatic brain injury fatigue (PTBIF). Methods:Systematic searches of multiple databases for peer-reviewed studies published in English on interventions targeting PTBIF as a primary or secondary outcome through January 22, 2014. Reference sections were also reviewed to identify additional articles. Articles were rated using the 2011 American Academy of Neurology Classification of Evidence Scheme for therapeutic studies. Results:The searches yielded 1526 articles. Nineteen articles met all inclusion criteria: 4 class I, 1 class II/III, 10 class III, and 4 class IV. Only 5 articles examined fatigue as a primary outcome. Interventions were pharmacological and psychological or involved physical activity, bright blue light, electroencephalographic biofeedback, or electrical stimulation. Only 2 interventions (modafinil and cognitive behavioral therapy with fatigue management) were evaluated in more than 1 study. Conclusions:Despite areas of promise, there is insufficient evidence to recommend or contraindicate any treatments of PTBIF. Modafinil is not likely to be effective for PTBIF. Piracetam may reduce it, as may bright blue light. Cognitive behavioral therapy deserves additional study. High-quality research incorporating appropriate definition and measurement of fatigue is required to explore the potential benefits of promising interventions, evaluate fatigue treatments shown to be effective in other populations, and develop new interventions for PTBIF.

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study

Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate‐to‐severe TBI requiring rehabilitation and surviving at least 5 years.

Predictors of agitated behavior during inpatient rehabilitation for traumatic brain injury

OBJECTIVE To identify predictors of the severity of agitated behavior during inpatient traumatic brain injury (TBI) rehabilitation. DESIGN Prospective, longitudinal observational study. SETTING Inpatient rehabilitation centers. PARTICIPANTS Consecutive patients enrolled between 2008 and 2011, admitted for inpatient rehabilitation after index TBI, who exhibited agitation during their stay (n=555, N=2130). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE Daytime Agitated Behavior Scale scores. RESULTS Infection and lower FIM cognitive scores predicted more severe agitation. The medication classes associated with more severe agitation included sodium channel antagonist anticonvulsants, second-generation antipsychotics, and gamma-aminobutyric acid-A anxiolytics/hypnotics. Medication classes associated with less severe agitation included antiasthmatics, statins, and norepinephrine-dopamine-5 hydroxytryptamine (serotonin) agonist stimulants. CONCLUSIONS Further support is provided for the importance of careful serial monitoring of both agitation and cognition to provide early indicators of possible beneficial or adverse effects of pharmacologic interventions used for any purpose and for giving careful consideration to the effects of any intervention on underlying cognition when attempting to control agitation. Cognitive functioning was found to predict agitation, medications that have been found in previous studies to enhance cognition were associated with less agitation, and medications that can potentially suppress cognition were associated with more agitation. There could be factors other than the interventions that account for these relations. In addition, the study provides support for treatment of underlying disorders as a possible first step in management of agitation. Although the results of this study cannot be used to draw causal inferences, the associations that were found can be used to generate hypotheses about the most viable interventions that should be tested in future controlled trials.

Prognostic models for predicting posttraumatic seizures during acute hospitalization, and at 1 and 2 years following traumatic brain injury.

Posttraumatic seizures (PTS) are well‐recognized acute and chronic complications of traumatic brain injury (TBI). Risk factors have been identified, but considerable variability in who develops PTS remains. Existing PTS prognostic models are not widely adopted for clinical use and do not reflect current trends in injury, diagnosis, or care. We aimed to develop and internally validate preliminary prognostic regression models to predict PTS during acute care hospitalization, and at year 1 and year 2 postinjury.

Prevalence, Risk Factors, and Correlates of Anxiety at 1 Year After Moderate to Severe Traumatic Brain Injury

OBJECTIVE To determine at 1 year after moderate to severe traumatic brain injury the (1) rate of clinically significant anxiety; (2) rates of specific symptoms of anxiety; (3) risk factors for anxiety; and (4) associations of anxiety with other 1-year outcomes, including participation and quality of life. DESIGN Prospective longitudinal observational study. SETTING Inpatient rehabilitation centers, with data capture at injury and 1-year follow-up. PARTICIPANTS Persons with moderate to severe traumatic brain injury who were enrolled in the Traumatic Brain Injury Model Systems database (N=1838). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES The 7-item Generalized Anxiety Disorder Scale, Patient Health Questionnaire (9-item screen for depression), FIM, Participation Assessment with Recombined Tools-Objective, and Satisfaction with Life Scale. RESULTS Clinically significant anxiety was reported by 21% of the participants. Of these, >80% reported interference with daily activities, with the most common symptoms being excessive worry and irritability. A common pattern was comorbid anxiety and depression, with smaller proportions reporting either disorder alone. Anxiety had large effect sizes with respect to life satisfaction and cognitive disability and medium to small effect sizes relative to societal participation and self-care. Middle age, black race, lower socioeconomic status, preinjury mental health treatment, and at least 1 traumatic brain injury prior to the index injury were all risk factors for later anxiety. CONCLUSIONS Anxiety should be screened, fully evaluated, and treated after moderate to severe traumatic brain injury. Worry and irritability might be treated with pharmacologic agents or relatively simple behavioral interventions, which should be further researched in this population.

Head Trauma from Falling Increases Subsequent Emergency Department Visits More Than Other Fall-Related Injuries in Older Adults

To determine whether fall‐related injuries affect return to the ED after the initial visit.

Are triage questions sufficient to assign fall risk precautions in the ED

Objectives: The American College of Emergency Physicians Geriatric Emergency Department (ED) Guidelines and the Center for Disease Control recommend that older adults be assessed for risk of falls. The standard ED assessment is a verbal query of fall risk factors, which may be inadequate. We hypothesized that the addition of a functional balance test endorsed by the Center for Disease Control Stop Elderly Accidents, Deaths, and Injuries Falls Prevention Guidelines, the 4‐Stage Balance Test (4SBT), would improve the detection of patients at risk for falls. Methods: Prospective pilot study of a convenience sample of ambulatory adults 65 years and older in the ED. All participants received the standard nursing triage fall risk assessment. After patients were stabilized in their ED room, the 4SBT was administered. Results: The 58 participants had an average age of 74.1 years (range, 65‐94), 40.0% were women, and 98% were community dwelling. Five (8.6%) presented to the ED for a fall‐related chief complaint. The nursing triage screen identified 39.7% (n = 23) as at risk for falls, whereas the 4SBT identified 43% (n = 25). Combining triage questions with the 4SBT identified 60.3% (n = 35) as at high risk for falls, as compared with 39.7% (n = 23) with triage questions alone (P < .01). Ten (17%) of the patients at high risk by 4SBT and missed by triage questions were inpatients unaware that they were at risk for falls (new diagnoses). Conclusions: Incorporating a quick functional test of balance into the ED assessment for fall risk is feasible and significantly increases the detection of older adults at risk for falls.