Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment

Abstract Background Pharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study. Methods Women planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication. Results A total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P < 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6. Conclusions CYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact

Rapid planetesimal formation in turbulent circumstellar discs

The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.Comment: To appear in Nature (30 August 2007 issue). 18 pages (in referee mode), 3 figures. Supplementary Information can be found at 0708.389

The implementation of a translational study involving a primary care based behavioral program to improve blood pressure control: The HTN-IMPROVE study protocol (01295)

<p>Abstract</p> <p>Background</p> <p>Despite the impact of hypertension and widely accepted target values for blood pressure (BP), interventions to improve BP control have had limited success.</p> <p>Objectives</p> <p>We describe the design of a 'translational' study that examines the implementation, impact, sustainability, and cost of an evidence-based nurse-delivered tailored behavioral self-management intervention to improve BP control as it moves from a research context to healthcare delivery. The study addresses four specific aims: assess the implementation of an evidence-based behavioral self-management intervention to improve BP levels; evaluate the clinical impact of the intervention as it is implemented; assess organizational factors associated with the sustainability of the intervention; and assess the cost of implementing and sustaining the intervention.</p> <p>Methods</p> <p>The project involves three geographically diverse VA intervention facilities and nine control sites. We first conduct an evaluation of barriers and facilitators for implementing the intervention at intervention sites. We examine the impact of the intervention by comparing 12-month pre/post changes in BP control between patients in intervention sites versus patients in the matched control sites. Next, we examine the sustainability of the intervention and organizational factors facilitating or hindering the sustained implementation. Finally, we examine the costs of intervention implementation. Key outcomes are acceptability and costs of the program, as well as changes in BP. Outcomes will be assessed using mixed methods (<it>e.g</it>., qualitative analyses--pattern matching; quantitative methods--linear mixed models).</p> <p>Discussion</p> <p>The study results will provide information about the challenges and costs to implement and sustain the intervention, and what clinical impact can be expected.</p

A three-year longitudinal evaluation of the forearm bone density of users of etonogestrel- and levonorgestrel-releasing contraceptive implants

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to evaluate bone mineral density (BMD) at baseline and at 18 and 36 months of use of etonogestrel (ENG)-and levonorgestrel (LNG)-releasing contraceptive implants. This is a continuation of a previous study in which BMD was evaluated at baseline and at 18 months of use.</p> <p>Methods</p> <p>A total of 111 women, 19–43 years of age, wererandomly allocated to use one of the two implants. At 36 months of follow-up, only 36 and 39 women were still using the ENG- and LNG-releasing implants, respectively. BMD was evaluated at the distal and at the ultra-distal radius of the non-dominant forearm using dual-energy X-ray absorptiometry.</p> <p>Results</p> <p>There was no difference in the BMD of users of either implant at 18 and at 36 months. BMD was significantly lower at 18 and at 36 months at the distal radius in both groups of users compared to pre-insertion values; however, no difference was found at the ultra-distal radius.</p> <p>Conclusion</p> <p>Women 19–43 years of age using either one of these two contraceptive implants for 36 months had lower BMD values at the distal radius compared to pre-insertion values; however, no difference was found at the ultra-distal radius.</p

Statistical Methods for Linking Health, Exposure, and Hazards

The Environmental Public Health Tracking Network (EPHTN) proposes to link environmental hazards and exposures to health outcomes. Statistical methods used in case–control and cohort studies to link health outcomes to individual exposure estimates are well developed. However, reliable exposure estimates for many contaminants are not available at the individual level. In these cases, exposure/hazard data are often aggregated over a geographic area, and ecologic models are used to relate health outcome and exposure/hazard. Ecologic models are not without limitations in interpretation. EPHTN data are characteristic of much information currently being collected—they are multivariate, with many predictors and response variables, often aggregated over geographic regions (small and large) and correlated in space and/or time. The methods to model trends in space and time, handle correlation structures in the data, estimate effects, test hypotheses, and predict future outcomes are relatively new and without extensive application in environmental public health. In this article we outline a tiered approach to data analysis for EPHTN and review the use of standard methods for relating exposure/hazards, disease mapping and clustering techniques, Bayesian approaches, Markov chain Monte Carlo methods for estimation of posterior parameters, and geostatistical methods. The advantages and limitations of these methods are discussed

Timing of birth for women with a twin pregnancy at term: a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time.</p> <p>The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications.</p> <p>Methods/Design</p> <p>Design: Multicentred randomised trial.</p> <p>Inclusion Criteria: women with a twin pregnancy at 36⁶weeks or more without contraindication to continuation of pregnancy.</p> <p>Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36⁺⁶weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care.</p> <p>Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible).</p> <p>Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity.</p> <p>Sample Size: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power).</p> <p>Discussion</p> <p>This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.</p> <p>Clinical Trial Registration</p> <p>Current Controlled Trials ISRCTN15761056</p

Obesity and Gastroesophageal Reflux: Quantifying the Association Between Body Mass Index, Esophageal Acid Exposure, and Lower Esophageal Sphincter Status in a Large Series of Patients with Reflux Symptoms

Obesity and gastroesophageal reflux disease (GERD) are increasingly important health problems. Previous studies of the relationship between obesity and GERD focus on indirect manifestations of GERD. Little is known about the association between obesity and objectively measured esophageal acid exposure. The aim of this study is to quantify the relationship between body mass index (BMI) and 24-h esophageal pH measurements and the status of the lower esophageal sphincter (LES) in patients with reflux symptoms. Data of 1,659 patients (50% male, mean age 51 ± 14) referred for assessment of GERD symptoms between 1998 and 2008 were analyzed. These subjects underwent 24-h pH monitoring off medication and esophageal manometry. The relationship of BMI to 24-h esophageal pH measurements and LES status was studied using linear regression and multiple regression analysis. The difference of each acid exposure component was also assessed among four BMI subgroups (underweight, normal weight, overweight, and obese) using analysis of variance and covariance. Increasing BMI was positively correlated with increasing esophageal acid exposure (adjusted R 2 = 0.13 for the composite pH score). The prevalence of a defective LES was higher in patients with higher BMI (p &lt; 0.0001). Compared to patients with normal weight, obese patients are more than twice as likely to have a mechanically defective LES [OR = 2.12(1.63–2.75)]. An increase in body mass index is associated with an increase in esophageal acid exposure, whether BMI was examined as a continuous or as a categorical variable; 13% of the variation in esophageal acid exposure may be attributable to variation in BMI

A prospective registry of emergency department patients admitted with infection

<p>Abstract</p> <p>Background</p> <p>Patients with infections account for a significant proportion of Emergency Department (ED) workload, with many hospital patients admitted with severe sepsis initially investigated and resuscitated in the ED. The aim of this registry is to systematically collect quality observational clinical and microbiological data regarding emergency patients admitted with infection, in order to explore in detail the microbiological profile of these patients, and to provide the foundation for a significant programme of prospective observational studies and further clinical research.</p> <p>Methods/design</p> <p>ED patients admitted with infection will be identified through daily review of the computerised database of ED admissions, and clinical information such as site of infection, physiological status in the ED, and components of management abstracted from patients' charts. This information will be supplemented by further data regarding results of investigations, microbiological isolates, and length of stay (LOS) from hospital electronic databases. Outcome measures will be hospital and intensive care unit (ICU) LOS, and mortality endpoints derived from a national death registry.</p> <p>Discussion</p> <p>This database will provide substantial insights into the characteristics, microbiological profile, and outcomes of emergency patients admitted with infections. It will become the nidus for a programme of research into compliance with evidence-based guidelines, optimisation of empiric antimicrobial regimens, validation of clinical decision rules and identification of outcome determinants. The detailed observational data obtained will provide a solid baseline to inform the design of further controlled trials planned to optimise treatment and outcomes for emergency patients admitted with infections.</p

Integrated information increases with fitness in the evolution of animats

One of the hallmarks of biological organisms is their ability to integrate disparate information sources to optimize their behavior in complex environments. How this capability can be quantified and related to the functional complexity of an organism remains a challenging problem, in particular since organismal functional complexity is not well-defined. We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent ("animat") evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its "fit" to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better measure when the task requires memory. A correlation of measures of information integration (but also information processing) and fitness strongly suggests that these measures reflect the functional complexity of the animat, and that such measures can be used to quantify functional complexity even in the absence of fitness data.Comment: 27 pages, 8 figures, one supplementary figure. Three supplementary video files available on request. Version commensurate with published text in PLoS Comput. Bio

The Genomic Signature of Crop-Wild Introgression in Maize

The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana, (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes were particularly resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly informing our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies