The potential utility of blood-derived biochemical markers as indicators of early clinical trends following severe traumatic brain injury.

OBJECTIVE: Severe traumatic brain injury (TBI) is a dynamic neuropathologic process in which a substantial proportion of patients die within the first 48-hours. The assessment of injury severity and prognosis are of primary concern in the initial management of severe TBI. Supplemental testing that aids in the stratification of patients at high risk for deterioration may significantly improve posttraumatic management in the acute setting. METHODS: This retrospective study assessed the utility of both single-marker and multimarker models as predictive indicators of acute clinical status after severe TBI. Forty-four patients who sustained severe TBI (admission Glasgow Coma Scale [GCS] score ≤ 8) were divided into two cohorts according to a dichotomized clinical outcome at 72 hours after admission: Poor status (death or GCS score ≤ 8) and improved status (GCS score improved to >8). Threshold values for clinical status prediction were calculated for serum S-100B, matrix metalloproteinase-9, and plasma D-dimer, upon admission and at 24 hours after TBI by the use of receiver operating characteristic analysis. Performance characteristics of these single-marker predictors were compared with those derived from a multimarker logistic regression analysis. RESULTS: Biomarkers with the greatest predictive value for poor status at 72 hours included serum S-100B on admission, as well as plasma D-dimer and serum S-100B at 24 hours, for which, associations were strongly significant. Multimarker analysis indicated no substantial improvement in prediction accuracy over the best single predictors during this time frame. CONCLUSION: In conjunction with other clinical, physical, and radiologic evidence, blood-derived biochemical markers may serve to enhance prediction of early clinical trends after severe TBI.

Recombinant activated factor VII use in critically ill patients: clinical outcomes and thromboembolic events.

BACKGROUND: Hemorrhage and coagulopathy are associated with morbidity and mortality in critically ill patients. Recombinant activated factor VII (rFVIIa) is frequently used in these situations to control bleeding; however, few controlled clinical trials have demonstrated clinical benefit and prolonged survival. OBJECTIVE: To compare clinical outcomes and thromboembolic events in intensive care unit (ICU) patients who received rFVIIa versus ICU patients who did not between 2000 and 2005. METHODS: A total of 2918 nonhemophiliac adult ICU patients, which included 1459 who received at least 1 dose of rFVIIa and 1459 matched controls who did not, were included in a retrospective database study. Data were extracted from the Solucient ACTracker database, which included 550 hospitals across the US. Measures included patient demographics, rFVIIa prescribing, death, thromboembolic events, discharge disposition, length of stay, and transfusion data. RESULTS: The most common primary diagnoses for patients receiving rFVIIa included traumatic brain injury, cirrhosis, and nontraumatic intracranial hemorrhage. Patients receiving rFVIIa were more likely to have comorbidities, including mechanical ventilation, acute kidney injury, sepsis, hemodialysis, and gastrointestinal bleeding (p < 0.0001). The average rFVIIa dose was 4.8 mg and 82% of patients received 1 dose. Compared to controls, patients receiving rFVIIa had greater odds of death (OR 2.1, 95% CI 1.8-2.6, p < 0.0001), transfusion (OR 2.1, 95% CI 1.8-2.5, p < 0.0001), and longer length of stay (p < 0.001). There was no significant difference in thromboembolic events between groups. CONCLUSIONS: While we cannot show direct causality between rFVIIa and the poor clinical outcomes documented in ICU patients, they provide important insight for critical care clinicians.

Análisis intra: sesión de la extinción del condicionamiento pavloviano de miedo usando regresión robusta / . Within-session analysis of the extinction of pavlovian fear-conditioning using robust regression

El análisis de datos de extinción en experimentos de miedo condicionado ha involucrado, tradicionalmente, el uso de modelos lineales estándar, primordialmente ANOVA de diferencias entre grupos de sujetos sometidos a diferentes protocolos de extinción, manipulaciones farmacológicas o algún otro tratamiento. Aún cuando algunos estudios reportan diferencias individuales en indicadores como tasas de supresión o porcentajes de congelamiento, esas diferencias no son incluidas en el análisis estadístico. Los patrones de respuesta intra-sujeto son entonces promediados usando ventanas temporales de baja resolución, las cuales pueden ignorar esta dinámica del desempeño individual. Este trabajo ilustra un procedimiento analítico alternativo que consta de 2 pasos: estimación de la tendencia para los datos intra-sesión y el análisis de las diferencias entre-grupo usando la tendencia como variable de respuesta. Este procedimiento se pone a prueba usando datos reales de extinción de miedo condicionado, comparando estimaciones de tendencia robusta vía Mínimos Cuadrados Medianos con Mínimos Cuadrados Ordinarios, y comparando las diferencias de grupo usando la pendiente robusta versus la mediana del porcentaje de congelamiento como variable dependiente.

Traditionally , the analysis of extinction data in fear conditioning experimentshas involved the use of standard linear models, mostly ANOVA of between-group differences of subjects that have undergone different extinction protocols, pharmacological manipulations or some other treatment. Although some studies reportindividual differences in quantities such as suppression rates or freezing percentages, these differences are not included in the statistical modeling. Withinsubject response patterns are then averaged using coarse-grain time windows which can overlook these individual performance dynamics. Here we illustrate an alternative analytical procedure consisting of 2 steps: the estimation of a trend for within-session data and analysis of group differences in trend as main outcome. This procedure is tested on real fear-conditioning extinction data, comparing trend estimates via Ordinary Least Squares (OLS) and robust Least Median of Squares (LMS) regression estimates, as well as comparing between-group differences and analyzing mean freezing percentage versus LMS slopes as outcomes.

Análisis cuantitativo de la dinámica individual de trabajos de grado de Psicología / Quantitative analysis of the individual dynamics of Psychology theses

El presente trabajo analiza longitudinalmente tres cohortes de trabajos (n = 57) realizados por estudiantes de último año de pregrado en psicología, de la Universidad Católica Andrés Bello, usando cinco medidas de progreso. Se prueba un modelo aditivo generalizado para predecir el tiempo de culminación de los trabajos de grado, medido en dos niveles: temprano y demorado. Las medidas de magnitud de efecto favorecen un modelo de indicadores en múltiples dimensiones, por encima de uno de progreso global. La trayectoria de los indicadores a lo largo de las cinco medidas facilita diferenciar la culminación temprana de la demorada. Las probabilidades de culminación estimadas a partir del modelo basado en dimensiones permiten establecer niveles de oscilación diferenciales para los distintos tiempos de culminación. Los indicadores de progreso inicial habilitan predecir la culminación temprana con un 71% de acierto, mientras que la medición final tiene un acierto de 89%. Los resultados apoyan la efectividad del sistema de supervisión y el análisis de la dinámica de la progresión de los trabajos de grado desde un modelo de demora de tarea, centrado en la relación entre el monto de tarea completada y las metas temporales.

Three cohorts of undergraduate psychology theses (n = 57) performed by last year undergraduate psychology students from Universidad Católica Andrés Bello, were monitored using 5 longitudinal measurements of progression. A Generalized Additive Model, to predict the completion time of the theses, is tested against two completion times: early and delayed. Effect size measures favor a multiple dimension model over a global progress model. The trajectory of the indicators through the 5 measurements allows the differentiation between early and delayed completion. The completion probabilities estimated by the dimensional model allow the identification of differential oscillation levels for the distinct completion times. The initial progression indicators allow the prediction of early completion with a 71% success rate, while the final measurement shows a success rate of 89%. The results support the effectiveness of the supervisory system and the analysis of the progression dynamics of the theses from a task-delay model, focused on the relationship between the amount oftask completion and the deadlines.

Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial.

Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg/kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg/kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.

Effect of sampling frequency on automatically-generated activity and freezing scores in a Pavlovian fear-conditioning preparation / Efecto de la frecuencia de muestreo sobre los índices automáticos de actividad y congelamiento en un procedimiento de condicionamiento pavloviano del miedo

Conditioned freezing has long held conceptual importance in behavior analysis, being pivotal in the explanation of anxiety-like behavior. Although initially measured indirectly, through its disruptive effect on operant behavior (conditioned suppression), and later by direct observation, automated techniques of measuring movement have recently become available, which also enable theme asurement of conditioned freezing. These video processing techniques allow for the direct and virtually continuous measurement of activity, as compared to the traditional interval sampling approach of direct observation. We examined whether automatically generated freezing and movement scores were equally sensitive to traditional Pavlovian conditioning manipulations, and how this sensitivity was affected by the sampling frequency of the data. Extinction data for 42 mice were collected at a rate of 30 Hz, transformed via re-sampling and analyzed by a generalized linear model to determine the effect size for the presence of the conditioned stimulus for each individual time series under four conditions: high and low resolution raw activity scores and high and low resolution dichotomous freezing scores. The resolution of the data proved to be the most important dimension in estimating local changes in the level of the individual time-series, with activity and freezings cores presenting comparable effect sizes. In contrast with the above, only high-resolution activity measurements proved to be effective in detecting local changes in trends.

La respuesta condicionada de congelamiento tiene importancia conceptual de larga data para el Análisis Conductual, siendo clave en la explicación de las conductasde ansiedad. Aún cuando inicialmente fue medida deforma indirecta, mediante sus efectos sobre la conducta operante (como en el arreglo de supresión condicionada) y más tarde mediante la observación directa, recientemente se han hecho disponibles alternativas para la medición automática del movimiento que permiten también la medición del congelamiento condicionado. Estas nuevas técnicas de video permiten la medición directa y virtualmente constante de la actividad del organismo, por contraposición a las técnicas tradicionales de muestreo de tiempo características del registro observacional. En el presente artículo se compara el efecto de manipulaciones pavlovianas tradicionales sobre la sensibilidad de los delos índices automatizados de congelamiento y actividad, así como el posible efecto de la densidad de muestreo sobre dicha sensibilidad. Para ello se analizan datos provenientes de sesiones de extinción pavloviana de 42 ratones, recogidos con una frecuencia 30 Hz y transformados mediante una técnica de remuestreo, para luego ser analizado mediante un modelo lineal generalizado, a fin de determinar la magnitud del efecto de la presencia del estímulo condicionado en cada una de cuatro condiciones: puntajes brutos de actividad de alta y baja resolución y puntajes dicotómicos de congelamiento de alta y baja resolución. La resolución de los datos mostró ser la dimensión más relevante para la estimación de cambios locales de nivel en las series temporales individuales, siendo dichos cambios igualmente fáciles de detectar en los índices de congelamiento y de actividad. A diferencia de lo anterior, sólo las medidas de actividad de alta resolución permitieron la detección de cambios locales de tendencia.

The effect of daily bathing with chlorhexidine on the acquisition of methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental multicenter trial.

OBJECTIVE: Spread of multidrug-resistant organisms within the intensive care unit (ICU) results in substantial morbidity and mortality. Novel strategies are needed to reduce transmission. This study sought to determine if the use of daily chlorhexidine bathing would decrease the incidence of colonization and bloodstream infections (BSI) because of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) among ICU patients. DESIGN, SETTING, AND PATIENTS: Six ICUs at four academic centers measured the incidence of MRSA and VRE colonization and BSI during a period of bathing with routine soap for 6 months and then compared results with a 6-month period where all admitted patients received daily bathing with a chlorhexidine solution. Changes in incidence were evaluated by Poisson and segmented regression modeling. INTERVENTIONS: Daily bathing with a chlorhexidine-containing solution. MEASUREMENTS AND MAIN RESULTS: Acquisition of MRSA decreased 32% (5.04 vs. 3.44 cases/1000 patient days, p = 0.046) and acquisition of VREdecreased 50% (4.35 vs. 2.19 cases/1000 patient days, p = 0.008) following the introduction of daily chlorhexidine bathing. Segmented regression analysis demonstrated significant reductions in VRE bacteremia (p = 0.02) following the introduction of chlorhexidine bathing. VRE-colonized patients bathed with chlorhexidine had a lower risk of developing VRE bacteremia (relative risk 3.35; 95% confidence interval 1.13-9.87; p = 0.035), suggesting that reductions in the level of colonization led to the observed reductions in BSI. CONCLUSION: We conclude that daily chlorhexidine bathing among ICU patients may reduce the acquisition of MRSA and VRE. The approach is simple to implement and inexpensive and may be an important adjunctive intervention to barrier precautions to reduce acquisition of VRE and MRSA and the subsequent development of healthcare-associated BSI.

Comparison of two drug-burden computational procedures applied to anticholinergic drugs.

Two computational procedures for estimating continuous drug-burden scores are compared, using a simulation study based on a sample of patients exposed to anticholinergic medications. Both procedures seek to quantify the medication burden to overcome the limitations of a binary classification of exposure. An artificial neural network procedure renders better statistical properties than a linear weighted score, even when both scores are correlated and are viable alternatives to binary classification.

Analysis of the genotype and virulence of Staphylococcus epidermidis isolates from patients with infective endocarditis.

Staphylococcus epidermidis is one of the most common causes of infections of prosthetic heart valves (prosthetic valve endocarditis [PVE]) and an increasingly common cause of infections of native heart valves (native valve endocarditis [NVE]). While S. epidermidis typically causes indolent infections of prosthetic devices, including prosthetic valves and intravascular catheters, S. epidermidis NVE is a virulent infection associated with valve destruction and high mortality. In order to see if the differences in the course of infection were due to characteristics of the infecting organisms, we examined 31 S. epidermidis NVE and 65 PVE isolates, as well as 21 isolates from blood cultures (representing bloodstream infections [BSI]) and 28 isolates from nasal specimens or cultures considered to indicate skin carriage. Multilocus sequence typing showed both NVE and PVE isolates to have more unique sequence types (types not shared by the other groups; 74 and 71%, respectively) than either BSI isolates (10%) or skin isolates (42%). Thirty NVE, 16 PVE, and a total of 9 of the nasal, skin, and BSI isolates were tested for virulence in Caenorhabditis elegans. Twenty-one (70%) of the 30 NVE isolates killed at least 50% of the worms by day 5, compared to 1 (6%) of 16 PVE isolates and 1 (11%) of 9 nasal, skin, or BSI isolates. In addition, the C. elegans survival rate as assessed by log rank analyses of Kaplan-Meier survival curves was significantly lower for NVE isolates than for each other group of isolates (P < 0.0001). There was no correlation between the production of poly-beta(1-6)-N-acetylglucosamine exopolysaccharide and virulence in worms. This study is the first analysis suggesting that S. epidermidis isolates from patients with NVE constitute a more virulent subset within this species.

Sensitivity to initial conditions in the route-finder model.

A model of stimulus generalization [Staddon, J.E.R., Reid, A.K., 1990. On the dynamics of generalization. Psychol. Rev. 97, 576-578] was extended by Reid and Staddon [Reid, A.K., Staddon, J.E.R., 1998. A dynamic route finder for the cognitive map. Psychol. Rev. 105, 585-601] to account for the route-finder issue in the Tolman-Guthrie discussion about cognitive maps. This deterministic model has been described as sensitive to initial conditions in terms of the parameters of a diffusion equation [Reid, A.K., Staddon, J.E.R., 1998. A dynamic route finder for the cognitive map. Psychol. Rev. 105, 585-601]. A simulation study was carried out to test this assertion, evaluating whether the pattern of variation in the model output resembled a chaotic pattern. Results indicate that the model is sensitive to initial conditions, suggesting that the spatial navigation task addressed by this model involves non-linear relationships and complexity beyond the apparent simplicity of the stimulus generalization process.

A cautionary note on the use of simulation procedures for analyzing contingency tables containing small expected cell frequencies.

A comparison of a simple simulation procedure and exact tests for tables used in psychiatric genetic studies is performed, with focus on tables with small expected cell counts. The study shows that naive simulation procedures using uniform random numbers, could lead to conservative results, as compared with Fisher exact test for contingency tables, thus discarding as non-significant tables that are significant according to the exact test. Exact tests are recommended as an alternative to naive simulation for evaluating the statistical significance of contingency tables with small expected cell counts.

Factor structure and external validity of the PANSS revisited.

Considerable controversy exists concerning the positive and negative syndrome scale (PANSS), one of the most widely used instruments in schizophrenia research. In this article we revisited the factor structure and external validity of the PANSS in a sample of 500 participants with DSM IV diagnoses of schizophrenia. We found that a model with six latent factors provided a relatively good fit, considered adequate by two rules of thumb. Five factors corresponded closely to those typically derived in other studies: Negative, Positive, Excited/Activation, Anxious-Depressed/Dysphoric, and Disorganized/Autistic preoccupation. The sixth factor seemed to have face validity and was labeled Withdrawn. With the exception of Anxious-Depressed/Dysphoric, Cronbach's Alpha ranged from 0.70 to 0.85 suggesting an acceptable internal consistency. External validity was studied through correlations with socio-demographic variables, DSM IV (subtype) diagnoses, clinical characteristics, and drug use. The many significant correlations suggested that the six PANSS scales measure meaningful aspects of schizophrenia. Furthermore, the pattern of correlations varied, providing evidence that the scales assessed partly different aspects of the disease. Our analyses also suggested that some of the controversy about the PANSS can possibly be attributed to methodological factors where the substantial cross-loadings of some PANSS items may play an important role.

lga972: a cross-platform application for optimizing LD studies using a genetic algorithm.

lga972 is a user-friendly cross-platform application with a graphical interface for determining the design features of two-stage genetic linkage disequilibrium studies that minimize the genotyping burden.