Showing papers by "Vanderbilt University published in 2006"

Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer

Abstract: bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P = 0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. Conclusions The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non–small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.)

Regression Modeling Strategies

Abstract: Regression models are frequently used to develop diagnostic, prognostic, and health resource utilization models in clinical, health services, outcomes, pharmacoeconomic, and epidemiologic research, and in a multitude of non-health-related areas. Regression models are also used to adjust for patient heterogeneity in randomized clinical trials, to obtain tests that are more powerful and valid than unadjusted treatment comparisons.

Developments in the Measurement of Subjective Well-Being

Abstract: For good reasons, economists have had a long-standing preference for studying peoples' revealed preferences; that is, looking at individuals' actual choices and decisions rather than their stated intentions or subjective reports of likes and dislikes. Yet people often make choices that bear a mixed relationship to their own happiness. A large literature from behavioral economics and psychology finds that people often make inconsistent choices, fail to learn from experience, exhibit reluctance to trade, base their own satisfaction on how their situation compares with the satisfaction of others and depart from the standard model of the rational economic agent in other ways. If people display bounded rationality when it comes to maximizing utility, then their choices do not necessarily reflect their "true" preferences, and an exclusive reliance on choices to infer what people desire loses some of its appeal. Direct reports of subjective well-being may have a useful role in the measure

The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements

Abstract: Over the last decade, the introduction of microarray technology has had a profound impact on gene expression research. The publication of studies with dissimilar or altogether contradictory results, obtained using different microarray platforms to analyze identical RNA samples, has raised concerns about the reliability of this technology. The MicroArray Quality Control (MAQC) project was initiated to address these concerns, as well as other performance and data analysis issues. Expression data on four titration pools from two distinct reference RNA samples were generated at multiple test sites using a variety of microarray-based and alternative technology platforms. Here we describe the experimental design and probe mapping efforts behind the MAQC project. We show intraplatform consistency across test sites as well as a high level of interplatform concordance in terms of genes identified as differentially expressed. This study provides a resource that represents an important first step toward establishing a framework for the use of microarrays in clinical and regulatory settings.

Guest Editor's Introduction: Model-Driven Engineering

Abstract: Model-driven engineering technologies offer a promising approach to address the inability of third-generation languages to alleviate the complexity of platforms and express domain concepts effectively.

The max-min hill-climbing Bayesian network structure learning algorithm

Abstract: We present a new algorithm for Bayesian network structure learning, called Max-Min Hill-Climbing (MMHC). The algorithm combines ideas from local learning, constraint-based, and search-and-score techniques in a principled and effective way. It first reconstructs the skeleton of a Bayesian network and then performs a Bayesian-scoring greedy hill-climbing search to orient the edges. In our extensive empirical evaluation MMHC outperforms on average and in terms of various metrics several prototypical and state-of-the-art algorithms, namely the PC, Sparse Candidate, Three Phase Dependency Analysis, Optimal Reinsertion, Greedy Equivalence Search, and Greedy Search. These are the first empirical results simultaneously comparing most of the major Bayesian network algorithms against each other. MMHC offers certain theoretical advantages, specifically over the Sparse Candidate algorithm, corroborated by our experiments. MMHC and detailed results of our study are publicly available at http://www.dsl-lab.org/supplements/mmhc_paper/mmhc_index.html.

Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression.

Abstract: Antidepressant medication is considered the current standard for severe depression, and cognitive therapy is the most widely investigated psychosocial treatment for depression. However, not all patients want to take medication, and cognitive therapy has not demonstrated consistent efficacy across trials. Moreover, dismantling designs have suggested that behavioral components may account for the efficacy of cognitive therapy. The present study tested the efficacy of behavioral activation by comparing it with cognitive therapy and antidepressant medication in a randomized placebo-controlled design in adults with major depressive disorder (N = 241). In addition, it examined the importance of initial severity as a moderator of treatment outcome. Among more severely depressed patients, behavioral activation was comparable to antidepressant medication, and both significantly outperformed cognitive therapy. The implications of these findings for the evaluation of current treatment guidelines and dissemination are discussed.

Introduction to Response to Intervention: What, Why, and How Valid Is It?.

Abstract: On December 3, 2004, President Bush signed into law the Individuals with Disabilities Education Improvement Act (IDEA, 2004). The revised law is different from the previous version in at least one important respect. Whereas practitioners were previously encouraged to use IQ–achievement discrepancy to identify children with learning disabilities (LD), they now may use “Response to Intervention,” or RTI, a new, alternative method. It is also a means of providing early intervention to all children at risk for school failure. IDEA 2004 permits districts to use as much as 15% of their special education monies to fund early intervention activities. All this has implications for the number and type of children identified, the kinds of educational services provided, and who delivers them. RTI may be especially important to Reading Research Quarterly readers because roughly 80% of those with an LD label have been described as reading disabled (Lyon, 1995). With RTI, there may be a larger role for reading specialists, which in turn might affect preand inservice professional development activities conducted by universities and school districts. Yet much still needs to be understood to ensure that RTI implementation will promote effective early intervention and represents a valid means of LD identification. In this article, we explain important features of RTI, why it has been promoted as a substitute for IQ–achievement discrepancy, and what remains to be understood before it may be seen as a valid means of LD identification. What is RTI?

Finding Common Ground: The Importance of Place Attachment to Community Participation and Planning

Abstract: This article draws connections between the environmental and community psychology literature on place attachment and meaning with the theory, research, and practice of community participation and p...

Asthma Control Test: Reliability, validity, and responsiveness in patients not previously followed by asthma specialists

Abstract: Background The development of the Asthma Control Test (ACT), a short, simple, patient-based tool for identifying patients with poorly controlled asthma, was recently described in patients under the routine care of an asthma specialist. Objectives We sought to evaluate the reliability and validity of the ACT in a longitudinal study of asthmatic patients new to the care of an asthma specialist. Methods Patients (n = 313) completed the ACT and the Asthma Control Questionnaire (ACQ) at 2 physician visits (4-12 weeks apart). Pulmonary function was measured, and asthma specialists rated asthma control. Results Internal consistency reliability of the ACT was 0.85 (baseline) and 0.79 (follow-up). Test-retest reliability was 0.77. Criterion validity was demonstrated by significant correlations between baseline ACT scores and baseline specialists' ratings of asthma control ( r = 0.52, P r = −0.89, P P r = 0.44, P r = −0.69, P 1 values ( r = 0.29, P Conclusions The ACT is reliable, valid, and responsive to changes in asthma control over time in patients new to the care of asthma specialists. A cutoff score of 19 or less identifies patients with poorly controlled asthma. Clinical implications In a clinical setting the ACT should be a useful tool to help physicians identify patients with uncontrolled asthma and facilitate their ability to follow patients' progress with treatment.

Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors

Abstract: Background Use of angiotensin-converting–enzyme (ACE) inhibitors during the second and third trimesters of pregnancy is contraindicated because of their association with an increased risk of fetopathy. In contrast, first-trimester use of ACE inhibitors has not been linked to adverse fetal outcomes. We conducted a study to assess the association between exposure to ACE inhibitors during the first trimester of pregnancy only and the risk of congenital malformations. Methods We studied a cohort of 29,507 infants enrolled in Tennessee Medicaid and born between 1985 and 2000 for whom there was no evidence of maternal diabetes. We identified 209 infants with exposure to ACE inhibitors in the first trimester alone, 202 infants with exposure to other antihypertensive medications in the first trimester alone, and 29,096 infants with no exposure to antihypertensive drugs at any time during gestation. Major congenital malformations were identified from linked vital records and hospitalization claims during the first year of life and confirmed by review of medical records. Results

Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients.

Abstract: Background:Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain but may contribute to patients’ transitioning into delirium.Methods:In this cohort study, the authors d

Understanding and Preventing Noncontact Anterior Cruciate Ligament Injuries A Review of the Hunt Valley II Meeting, January 2005

Abstract: The incidence of noncontact anterior cruciate ligament injuries in young to middle-aged athletes remains high. Despite early diagnosis and appropriate operative and nonoperative treatments, posttraumatic degenerative arthritis may develop. In a meeting in Atlanta, Georgia (January 2005), sponsored by the American Orthopaedic Society for Sports Medicine, a group of physicians, physical therapists, athletic trainers, biomechanists, epidemiologists, and other scientists interested in this area of research met to review current knowledge on risk factors associated with noncontact anterior cruciate ligament injuries, anterior cruciate ligament injury biomechanics, and existing anterior cruciate ligament prevention programs. This article reports on the presentations, discussions, and recommendations of this group.

Energy Shocks and Financial Markets

Abstract: This study analyzes the information transmission mechanism linking oil futures with stock prices, where we examine the lead and lag cross-correlations of returns in one market with the others We investigate the dynamic interactions between oil futures prices traded on the New York Mercantile Exchange (NYMEX) and US stock prices, which allows us to examine the effects of energy shocks on financial markets In particular, we examine the extent to which these markets are contemporaneously correlated, with particular attention paid to the association of oil price indexes with the SP 12 major industry stock price indices and 3 individual oil company stock price series We also examine the extent to which price changes or returns in one market dynamically lead returns in the others and whether volatility spillover effects exist across these markets Using VAR model estimates for various time series of returns we find that petroleum industry stock index and our three oil company stocks are the only series where we can reject the null hypothesis that oil futures do not lead Treasury Bill rates and stock returns, while we can reject the hypothesis that oil futures lag these other two series Finally, the return volatility evidence for oil futures leading individual oil company stocks is much weaker than is the evidence for returns themselves

Long γ-ray bursts and core-collapse supernovae have different environments

Abstract: When massive stars exhaust their fuel, they collapse and often produce the extraordinarily bright explosions known as core-collapse supernovae. On occasion, this stellar collapse also powers an even more brilliant relativistic explosion known as a long-duration γ-ray burst. One would then expect that these long γ-ray bursts and core-collapse supernovae should be found in similar galactic environments. Here we show that this expectation is wrong. We find that the γ-ray bursts are far more concentrated in the very brightest regions of their host galaxies than are the core-collapse supernovae. Furthermore, the host galaxies of the long γ-ray bursts are significantly fainter and more irregular than the hosts of the core-collapse supernovae. Together these results suggest that long-duration γ-ray bursts are associated with the most extremely massive stars and may be restricted to galaxies of limited chemical evolution. Our results directly imply that long γ-ray bursts are relatively rare in galaxies such as our own Milky Way.

Effect of Introduction of the Pneumococcal Conjugate Vaccine on Drug-Resistant Streptococcus pneumoniae

Abstract: BACKGROUND Five of seven serotypes in the pneumococcal conjugate vaccine, introduced for infants in the United States in 2000, are responsible for most penicillin-resistant infections. We examined the effect of this vaccine on invasive disease caused by resistant strains. METHODS We used laboratory-based data from Active Bacterial Core surveillance to measure disease caused by antibiotic-nonsusceptible pneumococci from 1996 through 2004. Cases of invasive disease, defined as disease caused by pneumococci isolated from a normally sterile site, were identified in eight surveillance areas. Isolates underwent serotyping and susceptibility testing. RESULTS Rates of invasive disease caused by penicillin-nonsusceptible strains and strains not susceptible to multiple antibiotics peaked in 1999 and decreased by 2004, from 6.3 to 2.7 cases per 100,000 (a decline of 57 percent; 95 percent confidence interval, 55 to 58 percent) and from 4.1 to 1.7 cases per 100,000 (a decline of 59 percent; 95 percent confidence interval, 58 to 60 percent), respectively. Among children under two years of age, disease caused by penicillin-nonsusceptible strains decreased from 70.3 to 13.1 cases per 100,000 (a decline of 81 percent; 95 percent confidence interval, 80 to 82 percent). Among persons 65 years of age or older, disease caused by penicillin-nonsusceptible strains decreased from 16.4 to 8.4 cases per 100,000 (a decline of 49 percent). Rates of resistant disease caused by vaccine serotypes fell 87 percent. An increase was seen in disease caused by serotype 19A, a serotype not included in the vaccine (from 2.0 to 8.3 per 100,000 among children under two years of age). CONCLUSIONS The rate of antibiotic-resistant invasive pneumococcal infections decreased in young children and older persons after the introduction of the conjugate vaccine. There was an increase in infections caused by serotypes not included in the vaccine.

Prostaglandins and cancer

Abstract: Chemoprevention has been considered as a possible approach for cancer prevention. A significant effort has been made in the development of novel drugs for both cancer prevention and treatment over the past decade. Recent epidemiological studies and clinical trials indicate that long term use of aspirin and similar agents, also called non-steroidal anti-inflammatory drugs (NSAIDs), can decrease the incidence of certain malignancies, including colorectal, oesophageal, breast, lung, and bladder cancers. The best known targets of NSAIDs are cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandins (PGs) and thromboxane. COX-2 derived prostaglandin E(2)(PGE(2)) can promote tumour growth by binding its receptors and activating signalling pathways which control cell proliferation, migration, apoptosis, and/or angiogenesis. However, the prolonged use of high dosages of COX-2 selective inhibitors (COXIBs) is associated with unacceptable cardiovascular side effects. Thus it is crucial to develop more effective chemopreventive agents with minimal toxicity. Recent efforts to identify the molecular mechanisms by which PGE(2) promotes tumour growth and metastasis may provide opportunities for the development of safer strategies for cancer prevention and treatment.

The prevention of depressive symptoms in children and adolescents: A meta-analytic review.

Abstract: Research on the prevention of depressive symptoms in children and adolescents was reviewed and synthesized with meta-analysis. When all 30 studies were included, selective prevention programs were found to be more effective than universal programs immediately following intervention. Both selective and indicated prevention programs were more effective than universal programs at follow-up, even when the 2 studies with college students were excluded. Effect sizes for selective and indicated prevention programs tended to be small to moderate, both immediately postintervention and at an average follow-up of 6 months. Most effective interventions are more accurately described as treatment rather than prevention. Suggestions for future research include testing potential moderators (e.g., age, gender, anxiety, parental depression) and mechanisms, designing programs that are developmentally appropriate and gender and culturally sensitive, including longer follow-ups, and using multiple measures and methods to assess both symptoms and diagnoses.

Sensory Experiences Questionnaire: Discriminating Sensory Features in Young Children with Autism, Developmental Delays, and Typical Development.

Abstract: Background: This study describes a new caregiver-report assessment, the Sensory Experiences Questionnaire (SEQ), and explicates the nature of sensory patterns of hyper- and hyporesponsiveness, their prevalence, and developmental correlates in autism relative to comparison groups. Method: Caregivers of 258 children in five diagnostic groups (Autism, PDD, DD/MR, Other DD, Typical) ages 5–80 months completed the SEQ. Results: The SEQ's internal consistency was α′ = .80. Prevalence of overall sensory symptoms for the Autism group was 69%. Sensory symptoms were inversely related to mental age. The Autism group had significantly higher symptoms than either the Typical or DD groups and presented with a unique pattern of response to sensory stimuli –hyporesponsiveness in both social and nonsocial contexts. A pattern of hyperresponsiveness was similar in the Autism and DD groups, but significantly greater in both clinical groups than in the Typical group. Conclusion: The SEQ was able to characterize sensory features in young children with autism, and differentiate their sensory patterns from comparison groups. These unique sensory patterns have etiological implications, as well as relevance for assessment and intervention practices.

Newborn Screening: Toward a Uniform Screening Panel and System—Executive Summary

Abstract: The Maternal and Child Health Bureau commissioned the American College of Medical Genetics to outline a process of standardization of outcomes and guidelines for state newborn screening programs and to define responsibilities for collecting and evaluating outcome data, including a recommended uniform panel of conditions to include in state newborn screening programs. The expert panel identified 29 conditions for which screening should be mandated. An additional 25 conditions were identified because they are part of the differential diagnosis of a condition in the core panel, they are clinically significant and revealed with screening technology but lack an efficacious treatment, or they represent incidental findings for which there is potential clinical significance. The process of identification is described, and recommendations are provided.

Procedure Guideline for Tumor Imaging with 18F-FDG PET/CT 1.0

Abstract: The purpose of these guidelines is to assist physicians in recommending, performing, interpreting, and reporting the results of 18F-FDG PET/CT for oncologic imaging of adult and pediatric patients. PET is a tomographic scintigraphic technique in which a computer-generated image of local radioactive

Corneal avascularity is due to soluble VEGF receptor-1

Abstract: Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

Remissions in maternal depression and child psychopathology: A STAR*D-child report

Abstract: ContextChildren of depressed parents have high rates of anxiety, disruptive, and depressive disorders that begin early, often continue into adulthood, and are impairing.ObjectiveTo determine whether effective treatment with medication of women with major depression is associated with reduction of symptoms and diagnoses in their children.DesignAssessments of children whose depressed mothers were being treated with medication as part of the multicenter Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial conducted (between December 16, 2001 and April 24, 2004) in broadly representative primary and psychiatric outpatient practices. Children were assessed by a team of evaluators not involved in maternal treatment and unaware of maternal outcomes. Study is ongoing with cases followed at 3-month intervals.Setting and PatientsOne hundred fifty-one mother-child pairs in 8 primary care and 11 psychiatric outpatient clinics across 7 regional centers in the United States. Children were aged 7 to 17 years.Main Outcome MeasuresChild diagnoses based on the Kiddie Schedule for Affective Disorders and Schizophrenia; child symptoms based on the Child Behavior Checklist; child functioning based on the Child Global Assessment Scale in mothers whose depression with treatment remitted with a score of 7 or lower or whose depression did not remit with a score higher than 7 on the Hamilton Rating Scale for Depression.ResultsRemission of maternal depression after 3 months of medication treatment was significantly associated with reductions in the children's diagnoses and symptoms. There was an overall 11% decrease in rates of diagnoses in children of mothers whose depression remitted compared with an approximate 8% increase in rates of diagnoses in children of mothers whose depression did not. This rate difference remained statistically significant after controlling for the child's age and sex, and possible confounding factors (P = .01). Of the children with a diagnosis at baseline, remission was reported in 33% of those whose mothers' depression remitted compared with only a 12% remission rate among children of mothers whose depression did not remit. All children of mothers whose depression remitted after treatment and who themselves had no baseline diagnosis for depression remained free of psychiatric diagnoses at 3 months, whereas 17% of the children whose mothers remained depressed acquired a diagnosis. Findings were similar using child symptoms as an outcome. Greater level of maternal response was associated with fewer current diagnoses and symptoms in the children, and a maternal response of at least 50% was required to detect an improvement in the child.ConclusionsRemission of maternal depression has a positive effect on both mothers and their children, whereas mothers who remain depressed may increase the rates of their children's disorders. These findings support the importance of vigorous treatment for depressed mothers in primary care or psychiatric clinics and suggest the utility of evaluating the children, especially children whose mothers continue to be depressed.

Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas.

Abstract: Purpose High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC. Patients and Methods EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points. Results Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were...

Cytochrome P450s and other enzymes in drug metabolism and toxicity.

Abstract: The cytochrome P450 (P450) enzymes are the major catalysts involved in the metabolism of drugs. bioavailability and toxicity are 2 of the most common barriers in drug development today, and P450 and the conjugation enzymes can influence these effects. The toxicity of drugs can be considered in 5 contexts: on-target toxicity, hypersensitivity and immunological reactions, off-target pharmacology, bioactivation to reactive intermediates, and idiosyncratic drug reactions. the chemistry of bioactivation is reasonably well understood, but the mechanisms underlying biological responses are not. In the article we consider what fraction of drug toxicity actually involves metabolism, and we examine how species and human interindividual variations affect pharmacokinetics and toxicity.

A dynamic model for replication protein A (RPA) function in DNA processing pathways

Abstract: Processing of DNA in replication, repair and recombination pathways in cells of all organisms requires the participation of at least one major single-stranded DNA (ssDNA)-binding protein This protein protects ssDNA from nucleolytic damage, prevents hairpin formation and blocks DNA reannealing until the processing pathway is successfully completed Many ssDNA-binding proteins interact physically and functionally with a variety of other DNA processing proteins These interactions are thought to temporally order and guide the parade of proteins that 'trade places' on the ssDNA, a model known as 'hand-off', as the processing pathway progresses How this hand-off mechanism works remains poorly understood Recent studies of the conserved eukaryotic ssDNA-binding protein replication protein A (RPA) suggest a novel mechanism by which proteins may trade places on ssDNA by binding to RPA and mediating conformation changes that alter the ssDNA-binding properties of RPA This article reviews the structure and function of RPA, summarizes recent studies of RPA in DNA replication and other DNA processing pathways, and proposes a general model for the role of RPA in protein-mediated hand-off