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Background Obtaining informed consent is a cornerstone of biomedical research, yet participants comprehension of presented information is often low. The most effective interventions to improve understanding rates have not been identified. Purpose To systematically analyze the random controlled trials testing interventions to research informed consent process. The primary outcome of interest was quantitative rates of participant understanding; secondary outcomes were rates of information retention, satisfaction, and accrual. Interventional categories included multimedia, enhanced consent documents, extended discussions, test/feedback quizzes, and miscellaneous methods. Methods The search spanned from database inception through September 2010. It was run on Ovid MEDLINE, Ovid EMBASE, Ovid CINAHL, Ovid PsycInfo and Cochrane CENTRAL, ISI Web of Science and Scopus. Five reviewers working independently and in duplicate screened full abstract text to determine eligibility. We included only RCTs. 39 out of 1523 articles fulfilled review criteria (2.6%), with a total of 54 interventions. A data extraction form was created in Distiller, an online reference management system, through an iterative process. One author collected data on study design, population, demographics, intervention, and analytical technique. Results Meta-analysis was possible on 22 interventions: multimedia, enhanced form, and extended discussion categories; all 54 interventions were assessed by review. Meta-analysis of multimedia approaches was associated with a non-significant increase in understanding scores (SMD 0.30, 95% CI, -0.23 to 0.84); enhanced consent form, with significant increase (SMD 1.73, 95% CI, 0.99 to 2.47); and extended discussion, with significant increase (SMD 0.53, 95% CI, 0.21 to 0.84). By review, 31% of multimedia interventions showed significant improvement in understanding; 41% for enhanced consent form; 50% for extended discussion; 33% for test/feedback; and 29% for miscellaneous.Multiple sources of variation existed between included studies: control processes, the presence of a human proctor, real vs. simulated protocol, and assessment formats. Conclusions Enhanced consent forms and extended discussions were most effective in improving participant understanding. Interventions of all categories had no negative impact on participant satisfaction or study accrual. Identification of best practices for studies of informed consent interventions would aid future systematic comparisons.

Purpose: Electronic health records (EHRs) and their associated decision support tools are potentially important means of disseminating a patient’s pharmacogenomic profile to his or her health-care providers. We sought to create a proof-of-concept decision support alert system generated from pharmacogenomic incidental findings from exome sequencing. Methods: A pipeline for alerts from exome sequencing tests was created for patients in the New EXome Technology in (NEXT) Medicine study at the University of Washington. Decision support rules using discrete, machine-readable incidental finding results were programmed into a commercial EHR rules engine. An evaluation plan to monitor the alerts in real medical interactions was established. Results: Alerts were created for 48 actionable pharmacogenomic variants in 11 genes and were launched on 24 September 2014 for University of Washington inpatient care. Of the 94 participants enrolled in the NEXT Medicine study, 49 had one or more pharmacogenomic variants identified for return. Conclusion: Reflections on the process reveal that while incidental findings can be used to generate decision support alerts, substantial resources are required to ensure that each alert is consistent with rapidly evolving pharmacogenomic literature and is customized to fit in the clinical workflow unique to each incidental finding. Genet Med 17 11, 939–942.

To determine health care preferences expressed by patients in advance directives (ADs) and to identify characteristics of patients who completed them. A computer-generated random sample of 500 patients was selected from the 25,865 (margin of error, ±4.34%) unique patients who submitted ADs to Mayo Clinic Rochester between January 1, 2004, and July 1, 2005. After excluding 24 (4.8%) patients who had submitted documents related to financial and property matters instead of ADs, we analyzed the contents of the 476 ADs and the demographic features of the patients to whom the documents belonged. The median (range) age of the patients at the time they signed their respective ADs was 67 (19-97) years. Of the 476 study patients, 409 (91.3%) were high school graduates; 339 (71.2%) had submitted a combined AD, which has features of a living will and a health care power of attorney; 434 (91.2%) had designated a health care agent; and most had granted the agent powers to consent for procedures (340 [78.3%]), to access information (327 [75.3%]), and to withhold and withdraw life-sustaining treatments (337 [77.6%]). Most patients expressed a desire for pain control (308 [64.7%]). For the clinical situations of dying or permanent unconsciousness, most patients explicitly expressed a preference to avoid “general life support” (371 [77.9%]) but did not explicitly address common life-sustaining treatments, including cardiopulmonary resuscitation, mechanical ventilation, hemodialysis, blood transfusion, and artificial nutrition and hydration (if they did, nearly all expressed a preference to avoid the treatments). In ADs submitted to our institution, most patients designated a health care agent and granted the agent broad decision-making powers. Although most expressed a desire to avoid “general life support” if dying or permanently unconscious, few expressed preferences regarding specific life-sustaining treatments. Patients, clinicians, and others who use ADs, and investigators contemplating research involving ADs, might find these results informative.

Actionable pharmacogenomic (PGx) information is growing exponentially with lowering costs of sequencing technologies, yet the best means to disseminate such data to physicians remains unclear. One method involves alerts triggered when a physician prescribes a medication through a computerized physician order entry for a patient known to have a particular PGx variant. We sought to assess physician perspectives of a prototype alert built for patients with CYP2C19 variants being prescribed clopidogrel through a computer-based simulation and 15-item online questionnaire assessing their perceptions of the alert's design, placement in workflow, and PGx content. A random sample of 55 physicians participated in the study. 89% of participants would modify their prescription based on the alert; only 4% would override the alert. 92% of the sample found the alerts helpful in choosing an appropriate medication. 75% of the physicians were unfamiliar with the PGx interaction of clopidogrel and CYP2C19. In conclusion, this sample of physicians felt that the PGx alert was useful, though many were unfamiliar with the specific drug-gene interaction. Future work should assess the alerts in real settings and identify appropriate educational resources to supplement the alerts.

Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications. To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions. This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO₂), sulfur dioxide, particulate matter not greater than 10 μm in diameter, and particulate matter not greater than 2.5 μm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant. After adjustment for confounders, a 5-ppb increase in average NO₂ during the first year of life was associated with an odds ratio of 1.17 for physician-diagnosed asthma (95% confidence interval, 1.04-1.31). Early-life NO₂ exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma.

Animal chimeras are widely used for biomedical discoveries, from developmental biology to cancer research. However, the accurate quantitation of mixed cell types in chimeric and mosaic tissues is complicated by sample preparation bias, transgenic silencing, phenotypic similarity, and low-throughput analytical pipelines. Here, we have developed and characterized a droplet digital PCR single-nucleotide discrimination assay to detect chimerism among common albino and non-albino mouse strains. In addition, we validated that this assay is compatible with crude lysate from all solid organs, drastically streamlining sample preparation. This chimerism detection assay has many additional advantages over existing methods including its robust nature, minimal technical bias, and ability to report the total number of cells in a prepared sample. Moreover, the concepts discussed here are readily adapted to other genomic loci to accurately measure mixed cell populations in any tissue.

Introduction Clinical trials directed at mechanistic target of rapamycin (mTOR) inhibition have yielded disappointing results in glioblastoma (GBM). A major mechanism of resistance involves the activation of a salvage pathway stimulating internal ribosome entry site (IRES)-mediated protein synthesis. PRMT5 activity has been implicated in the enhancement of IRES activity. Methods We analyzed the expression and activity of PRMT5 in response to mTOR inhibition in GBM cell lines and short-term patient cultures. To determine whether PRMT5 conferred resistance we used genetic and pharmacological approaches to ablate PRMT5 activity and assessed the effects on in vitro and in vivo sensitivity. Mutational analyses of the requisite IRES- trans -acting factor (ITAF), hnRNP A1 determined whether PRMT5-mediated methylation was necessary for ITAF RNA binding and IRES activity. Results PRMT5 activity is stimulated in response to mTOR inhibitors. Knockdown or treatment with a PRMT5 inhibitor blocked IRES activity and sensitizes GBM cells. Ectopic expression of non-methylatable hnRNP A1 mutants demonstrated that methylation of either arginine residues 218 or 225 was sufficient to maintain IRES binding and hnRNP A1-dependent cyclin D1 or c-MYC IRES activity, however a double R218K/R225K mutant was unable to do so. The PRMT5 inhibitor EPZ015666 displayed synergistic anti-GBM effects in vitro and in a xenograft mouse model in combination with PP242. Conclusions These results demonstrate that PRMT5 activity is stimulated upon mTOR inhibition in GBM. Our data further support a signaling cascade in which PRMT5-mediated methylation of hnRNP A1 promotes IRES RNA binding and activation of IRES-mediated protein synthesis and resultant mTOR inhibitor resistance.