Variation in pediatric traumatic brain injury outcomes in the United States.

OBJECTIVE: To ascertain the degree of variation, by state of hospitalization, in outcomes associated with traumatic brain injury (TBI) in a pediatric population. DESIGN: A retrospective cohort study of pediatric patients admitted to a hospital with a TBI. SETTING: Hospitals from states in the United States that voluntarily participate in the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project. PARTICIPANTS: Pediatric (age ≤ 19 y) patients hospitalized for TBI (N=71,476) in the United States during 2001, 2004, 2007, and 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary outcome was proportion of patients discharged to rehabilitation after an acute care hospitalization among alive discharges. The secondary outcome was inpatient mortality. RESULTS: The relative risk of discharge to inpatient rehabilitation varied by as much as 3-fold among the states, and the relative risk of inpatient mortality varied by as much as nearly 2-fold. In the United States, approximately 1981 patients could be discharged to inpatient rehabilitation care if the observed variation in outcomes was eliminated. CONCLUSIONS: There was significant variation between states in both rehabilitation discharge and inpatient mortality after adjusting for variables known to affect each outcome. Future efforts should be focused on identifying the cause of this state-to-state variation, its relationship to patient outcome, and standardizing treatment across the United States.

Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic.

Cognitive impairment is common following traumatic brain injury (TBI), and neuroinflammatory mechanisms may predispose to the development of neurodegenerative disease. Apolipoprotein E (apoE) polymorphisms modify neuroinflammatory responses, and influence both outcome from acute brain injury and the risk of developing neurodegenerative disease. We demonstrate that TBI accelerates neurodegenerative pathology in double-transgenic animals expressing the common human apoE alleles and mutated amyloid precursor protein, and that pathology is exacerbated in the presence of the apoE4 allele. The administration of an apoE-mimetic peptide markedly reduced the development of neurodegenerative pathology in mice homozygous for apoE3 as well as apoE3/E4 heterozygotes. These results demonstrate that TBI accelerates the cardinal neuropathological features of neurodegenerative disease, and establishes the potential for apoE mimetic therapies in reducing pathology associated with neurodegeneration.

Child work and labour among orphaned and abandoned children in five low and middle income countries.

BACKGROUND: The care and protection of the estimated 143,000,000 orphaned and abandoned children (OAC) worldwide is of great importance to global policy makers and child service providers in low and middle income countries (LMICs), yet little is known about rates of child labour among OAC, what child and caregiver characteristics predict child engagement in work and labour, or when such work infers with schooling. This study examines rates and correlates of child labour among OAC and associations of child labour with schooling in a cohort of OAC in 5 LMICs. METHODS: The Positive Outcomes for Orphans (POFO) study employed a two-stage random sampling survey methodology to identify 1480 single and double orphans and children abandoned by both parents ages 6-12 living in family settings in five LMICs: Cambodia, Ethiopia, India, Kenya, and Tanzania. Regression models examined child and caregiver associations with: any work versus no work; and with working <21, 21-27, and 28+ hours during the past week, and child labour (UNICEF definition). RESULTS: The majority of OAC (60.7%) engaged in work during the past week, and of those who worked, 17.8% (10.5% of the total sample) worked 28 or more hours. More than one-fifth (21.9%; 13% of the total sample) met UNICEF's child labour definition. Female OAC and those in good health had increased odds of working. OAC living in rural areas, lower household wealth and caregivers not earning an income were associated with increased child labour. Child labour, but not working fewer than 28 hours per week, was associated with decreased school attendance. CONCLUSIONS: One in seven OAC in this study were reported to be engaged in child labour. Policy makers and social service providers need to pay close attention to the demands being placed on female OAC, particularly in rural areas and poor households with limited income sources. Programs to promote OAC school attendance may need to focus on the needs of families as well as the OAC.

Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury.

Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(2)AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because beta(2)ARs, unlike beta(1)ARs, couple to G(i) as well as G(s), we pretreated mice with the G(i) inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.

Multiple Response System: Evaluation of Policy Change in North Carolina's Child Welfare System.

Systemic challenges within child welfare have prompted many states to explore new strategies aimed at protecting children while meeting the needs of families, but doing so within the confines of shrinking budgets. Differential Response has emerged as a promising practice for low or moderate risk cases of child maltreatment. This mixed methods evaluation explored various aspects of North Carolina's differential response system, known as the Multiple Response System (MRS), including: child safety, timeliness of response and case decision, frontloading of services, case distribution, implementation of Child and Family Teams, collaboration with community-based service providers and Shared Parenting. Utilizing Child Protective Services (CPS) administrative data, researchers found that compared to matched control counties, MRS: had a positive impact on child safety evidenced by a decline in the rates of substantiations and re-assessments; temporarily disrupted timeliness of response in pilot counties but had no effect on time to case decision; and increased the number of upfront services provided to families during assessment. Qualitative data collected through focus groups with providers and phone interviews with families provided important information on key MRS strategies, highlighting aspects that families and social workers like as well as identifying areas for improvement. This information is useful for continuous quality improvement efforts, particularly related to the development of training and technical assistance programs at the state and local level.

Variation in Inpatient Rehabilitation Utilization After Hospitalization for Burn Injury in the United States.

Approximately 45,000 individuals are hospitalized annually for burn treatment. Rehabilitation after hospitalization can offer a significant improvement in functional outcomes. Very little is known nationally about rehabilitation for burns, and practices may vary substantially depending on the region based on observed Medicare post-hospitalization spending amounts. This study was designed to measure variation in rehabilitation utilization by state of hospitalization for patients hospitalized with burn injury. This retrospective cohort study used nationally collected data over a 10-year period (2001 to 2010), from the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SIDs). Patients hospitalized for burn injury (n = 57,968) were identified by ICD-9-CM codes and were examined to see specifically if they were discharged immediately to inpatient rehabilitation after hospitalization (primary endpoint). Both unadjusted and adjusted likelihoods were calculated for each state taking into account the effects of age, insurance status, hospitalization at a burn center, and extent of burn injury by TBSA. The relative risk of discharge to inpatient rehabilitation varied by as much as 6-fold among different states. Higher TBSA, having health insurance, higher age, and burn center hospitalization all increased the likelihood of discharge to inpatient rehabilitation following acute care hospitalization. There was significant variation between states in inpatient rehabilitation utilization after adjusting for variables known to affect each outcome. Future efforts should be focused on identifying the cause of this state-to-state variation, its relationship to patient outcome, and standardizing treatment across the United States.

Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish.

Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program.

Enhanced de novo alloantibody and antibody-mediated injury in rhesus macaques.

Chronic allograft rejection is a major impediment to long-term transplant success. Humoral immune responses to alloantigens are a growing clinical problem in transplantation, with mounting evidence associating alloantibodies with the development of chronic rejection. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing or eliminating, highlighting the need for a nonhuman primate model of antibody-mediated rejection. In this report, we demonstrate that depletion using anti-CD3 immunotoxin (IT) combined with maintenance immunosuppression that included tacrolimus with or without alefacept reliably prolonged renal allograft survival in rhesus monkeys. In these animals, a preferential skewing toward CD4 repopulation and proliferation was observed, particularly with the addition of alefacept. Furthermore, alefacept-treated animals demonstrated increased alloantibody production (100%) and morphologic features of antibody-mediated injury. In vitro, alefacept was found to enhance CD4 effector memory T cell proliferation. In conclusion, alefacept administration after depletion and with tacrolimus promotes a CD4+memory T cell and alloantibody response, with morphologic changes reflecting antibody-mediated allograft injury. Early and consistent de novo alloantibody production with associated histological changes makes this nonhuman primate model an attractive candidate for evaluating targeted therapeutics.

Validation of ICDPIC software injury severity scores using a large regional trauma registry.

BACKGROUND: Administrative or quality improvement registries may or may not contain the elements needed for investigations by trauma researchers. International Classification of Diseases Program for Injury Categorisation (ICDPIC), a statistical program available through Stata, is a powerful tool that can extract injury severity scores from ICD-9-CM codes. We conducted a validation study for use of the ICDPIC in trauma research. METHODS: We conducted a retrospective cohort validation study of 40,418 patients with injury using a large regional trauma registry. ICDPIC-generated AIS scores for each body region were compared with trauma registry AIS scores (gold standard) in adult and paediatric populations. A separate analysis was conducted among patients with traumatic brain injury (TBI) comparing the ICDPIC tool with ICD-9-CM embedded severity codes. Performance in characterising overall injury severity, by the ISS, was also assessed. RESULTS: The ICDPIC tool generated substantial correlations in thoracic and abdominal trauma (weighted κ 0.87-0.92), and in head and neck trauma (weighted κ 0.76-0.83). The ICDPIC tool captured TBI severity better than ICD-9-CM code embedded severity and offered the advantage of generating a severity value for every patient (rather than having missing data). Its ability to produce an accurate severity score was consistent within each body region as well as overall. CONCLUSIONS: The ICDPIC tool performs well in classifying injury severity and is superior to ICD-9-CM embedded severity for TBI. Use of ICDPIC demonstrates substantial efficiency and may be a preferred tool in determining injury severity for large trauma datasets, provided researchers understand its limitations and take caution when examining smaller trauma datasets.

Magnetic resonance imaging of graded skeletal muscle injury in live rats.

INTRODUCTION: Increasing number of stretch-shortening contractions (SSCs) results in increased muscle injury. METHODS: Fischer Hybrid rats were acutely exposed to an increasing number of SSCs in vivo using a custom-designed dynamometer. Magnetic resonance imaging (MRI) imaging was conducted 72 hours after exposure when rats were infused with Prohance and imaged using a 7T rodent MRI system (GE Epic 12.0). Images were acquired in the transverse plane with typically 60 total slices acquired covering the entire length of the hind legs. Rats were euthanized after MRI, the lower limbs removed, and tibialis anterior muscles were prepared for histology and quantified stereology. RESULTS: Stereological analyses showed myofiber degeneration, and cellular infiltrates significantly increased following 70 and 150 SSC exposure compared to controls. MRI images revealed that the percent affected area significantly increased with exposure in all SSC groups in a graded fashion. Signal intensity also significantly increased with increasing SSC repetitions. DISCUSSION: These results suggest that contrast-enhanced MRI has the sensitivity to differentiate specific degrees of skeletal muscle strain injury, and imaging data are specifically representative of cellular histopathology quantified via stereological analyses.

Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology.

The growing exposure to chemicals in our environment and the increasing concern over their impact on health have elevated the need for new methods for surveying the detrimental effects of these compounds. Today's gold standard for assessing the effects of toxicants on the brain is based on hematoxylin and eosin (H&E)-stained histology, sometimes accompanied by special stains or immunohistochemistry for neural processes and myelin. This approach is time-consuming and is usually limited to a fraction of the total brain volume. We demonstrate that magnetic resonance histology (MRH) can be used for quantitatively assessing the effects of central nervous system toxicants in rat models. We show that subtle and sparse changes to brain structure can be detected using magnetic resonance histology, and correspond to some of the locations in which lesions are found by traditional pathological examination. We report for the first time diffusion tensor image-based detection of changes in white matter regions, including fimbria and corpus callosum, in the brains of rats exposed to 8 mg/kg and 12 mg/kg trimethyltin. Besides detecting brain-wide changes, magnetic resonance histology provides a quantitative assessment of dose-dependent effects. These effects can be found in different magnetic resonance contrast mechanisms, providing multivariate biomarkers for the same spatial location. In this study, deformation-based morphometry detected areas where previous studies have detected cell loss, while voxel-wise analyses of diffusion tensor parameters revealed microstructural changes due to such things as cellular swelling, apoptosis, and inflammation. Magnetic resonance histology brings a valuable addition to pathology with the ability to generate brain-wide quantitative parametric maps for markers of toxic insults in the rodent brain.

Fractures in myelomeningocele.

BACKGROUND: In patients with myelomeningocele (MMC), a high number of fractures occur in the paralyzed extremities, affecting mobility and independence. The aims of this retrospective cross-sectional study are to determine the frequency of fractures in our patient cohort and to identify trends and risk factors relevant for such fractures. MATERIALS AND METHODS: Between March 1988 and June 2005, 862 patients with MMC were treated at our hospital. The medical records, surgery reports, and X-rays from these patients were evaluated. RESULTS: During the study period, 11% of the patients (n = 92) suffered one or more fractures. Risk analysis showed that patients with MMC and thoracic-level paralysis had a sixfold higher risk of fracture compared with those with sacral-level paralysis. Femoral-neck z-scores measured by dual-energy X-ray absorptiometry (DEXA) differed significantly according to the level of neurological impairment, with lower z-scores in children with a higher level of lesion. Furthermore, the rate of epiphyseal separation increased noticeably after cast immobilization. Mainly patients who could walk relatively well were affected. CONCLUSIONS: Patients with thoracic-level paralysis represent a group with high fracture risk. According to these results, fracture and epiphyseal injury in patients with MMC should be treated by plaster immobilization. The duration of immobilization should be kept to a minimum (<4 weeks) because of increased risk of secondary fractures. Alternatively, patients with refractures can be treated by surgery, when nonoperative treatment has failed.