Using ODIN for a PharmGKB revalidation experiment

The need for efficient text-mining tools that support curation of the biomedical literature is ever increasing. In this article, we describe an experiment aimed at verifying whether a text-mining tool capable of extracting meaningful relationships among domain entities can be successfully integrated into the curation workflow of a major biological database. We evaluate in particular (i) the usability of the system's interface, as perceived by users, and (ii) the correlation of the ranking of interactions, as provided by the text-mining system, with the choices of the curators

Testing of a Tool for Prostate Cancer Screening Discussions in Primary Care

BackgroundAs prostate cancer (PCa) screening decisions often occur in outpatient primary care, a brief tool to help the PCa screening conversation in busy clinic settings is needed.MethodsA previously created 9-item tool to aid PCa screening discussions was tested in five diverse primary care clinics. Fifteen providers were recruited to use the tool for 4 weeks, and the tool was revised based upon feedback. The providers then used the tool with a convenience sample of patients during routine clinic visits. Pre- and post-visit surveys were administered to assess patients’ knowledge of the option to be screened for PCa and of specific factors to consider in the decision. McNemar’s and Stuart–Maxwell tests were used to compare pre-and post-survey responses.Results14 of 15 providers completed feedback surveys and had positive responses to the tool. All 15 providers then tested the tool on 95 men aged 40–69 at the five clinics with 2–10 patients each. The proportion of patients who strongly agreed that they had the option to choose to screen for PCa increased from 57 to 72% (p = 0.018) from the pre- to post-survey, that there are factors in the personal or family history that may affect PCa risk from 34 to 47% (p = 0.012), and that their opinions about possible side effects of treatment for PCa should be considered in the decision from 47 to 61% (p = 0.009).ConclusionA brief conversation tool for the PCa screening discussion was well received in busy primary-care settings and improved patients’ knowledge about the screening decision

Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

<p>Abstract</p> <p>Background</p> <p>Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development.</p> <p>Methods</p> <p>A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death.</p> <p>Results</p> <p>The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90).</p> <p>Conclusions</p> <p>This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.</p

Macrophages Inhibit Neovascularization in a Murine Model of Age-Related Macular Degeneration

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 y of age in at least three continents. Choroidal neovascularization (CNV) is the process by which abnormal blood vessels develop underneath the retina. CNV develops in 10% of patients with AMD but accounts for up to 90% of the blindness from AMD. Although the precise etiology of CNV in AMD remains unknown, the macrophage component of the inflammatory response, which has been shown to promote tumor growth and support atherosclerotic plaque formation, is thought to stimulate aberrant angiogenesis in blinding eye diseases. The current theory is that macrophage infiltration promotes the development of neovascularization in CNV. METHODS AND FINDINGS: We examined the role of macrophages in a mouse model of CNV. IL-10 (−/−) mice, which have increased inflammation in response to diverse stimuli, have significantly reduced CNV with increased macrophage infiltrates compared to wild type. Prevention of macrophage entry into the eye promoted neovascularization while direct injection of macrophages significantly inhibited CNV. Inhibition by macrophages was mediated by the TNF family death molecule Fas ligand (CD95-ligand). CONCLUSIONS: Immune vascular interactions can be highly complex. Normal macrophage function is critical in controlling pathologic neovascularization in the eye. IL-10 regulates macrophage activity in the eye and is an attractive therapeutic target in order to suppress or inhibit CNV in AMD that can otherwise lead to blindness

The pharmacogenetics and pharmacogenomics knowledge base: accentuating the knowledge

PharmGKB is a knowledge base that captures the relationships between drugs, diseases/phenotypes and genes involved in pharmacokinetics (PK) and pharmacodynamics (PD). This information includes literature annotations, primary data sets, PK and PD pathways, and expert-generated summaries of PK/PD relationships between drugs, diseases/phenotypes and genes. PharmGKB's website is designed to effectively disseminate knowledge to meet the needs of our users. PharmGKB currently has literature annotations documenting the relationship of over 500 drugs, 450 diseases and 600 variant genes. In order to meet the needs of whole genome studies, PharmGKB has added new functionalities, including browsing the variant display by chromosome and cytogenetic locations, allowing the user to view variants not located within a gene. We have developed new infrastructure for handling whole genome data, including increased methods for quality control and tools for comparison across other data sources, such as dbSNP, JSNP and HapMap data. PharmGKB has also added functionality to accept, store, display and query high throughput SNP array data. These changes allow us to capture more structured information on phenotypes for better cataloging and comparison of data. PharmGKB is available at www.pharmgkb.or

Global distribution of the decay timescale of mixed layer inertial motions observed by satellite-tracked drifters

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 114 (2009): C11010, doi:10.1029/2008JC005216.The decay timescale of mixed layer inertial amplitudes has been estimated from satellite tracked drifter trajectories from 1990 to 2004 as the e-folding timescale of the temporal correlation functions. The decay timescales increase with latitude in all basins except the North Atlantic. A beta dispersion model shows that dephasing leads to meridional variations of the decay timescale in the North Pacific and the Southern Ocean, but meridional variations of the buoyancy structure in the North Atlantic act to compensate the beta effect, leading to a lack of meridional variation of the decay timescale in that ocean.Jong Jin Park was supported by a WHOI postdoctoral scholarship. Ray Schmitt acknowledges NSF grant OCE 84794900. This study was partly supported by ‘‘A Study on the Monitoring of the Global Ocean Variability with ARGO Program’’ in Meteorological Research Institute/KMA

Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. METHODS AND FINDINGS: A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures. CONCLUSIONS: The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means

Functional Characterization of Rare RAB12 Variants and Their Role in Musician's and Other Dystonias

Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician's dystonia (MD) and writer's dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A> G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson's disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias

Age dependent plasticity in endocannabinoid modulation of pain processing through postnatal development

Significant age and experience-dependent remodelling of spinal and supraspinal neural networks occur resulting in altered pain responses in early life. In adults endogenous opioid peptide and endocannabinoid (ECs) pain control systems exist which modify pain responses but the role they play in acute responses to pain and postnatal neurodevelopment is unknown. Here we have studied the changing role of the ECs in brainstem nuclei essential for the control of nociception from birth to adulthood in both rat and human. Using in vivo electrophysiology we show that substantial functional changes occur in the effect of microinjection of ECs receptor agonists and antagonists in the periaqueductal grey (PAG) and rostroventral medulla (RVM), both of which play central roles in the supraspinal control of pain and the maintenance of chronic pain states in adulthood. We show that in immature PAG and RVM the orphan receptor GPR55 is able to mediate profound analgesia which is absent in adults. We show that tissue levels of endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol within the PAG and RVM are developmentally regulated (using mass spectrometry). The expression patterns and levels of ECs enzymes and receptors were assessed using quantitative PCR and immunohistochemistry. In human brainstem we show age-related alterations in the expression of key enzymes and receptors in involved in ECs function using PCR and in situ hybridisation. These data reveal significant changes on ECs that to this point have been unknown and which shed new light into the complex neurochemical changes that permit normal, mature responses to pain