Examining the Cascade of Participant Attrition in a Genomic Medicine Research Study: Barriers and Facilitators to Achieving Diversity

Background/Aims: Recent genomic medicine initiatives underscore the importance of including diverse participants in research. Considerable literature has identified barriers to and facilitators of increasing diversity, yet disparities in recruiting and retaining adequate numbers of participants from diverse groups continue to limit the generalizability of clinical genomic research. Methods: The North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing study employed evidence-based strategies to enhance the participation of under-represented minority patients. In this study, we evaluate the impact of our efforts by systematically analyzing the "cascade" of attrition of participants throughout study interactions. Results: Although successful in recruiting a cohort that included ~30% non-Caucasian patients overall, the study still enrolled and retained a lower proportion of minorities compared to the pool of eligible patients who were nominated. We evaluated sociodemographic characteristics and related variables as potential factors associated with attrition throughout these phases of the study. Conclusions: These results suggest that varied approaches will be needed to increase participation in genomic medicine research. Our findings highlight factors to consider when developing strategies to address this critical need. Failing to include a broad range of populations in research studies will exacerbate existing disparities in the translation of genomic sequencing to medical care

Transcriptional Responses of Cultured Rat Sympathetic Neurons during BMP-7-Induced Dendritic Growth

Dendrites are the primary site of synapse formation in the vertebrate nervous system; however, relatively little is known about the molecular mechanisms that regulate the initial formation of primary dendrites. Embryonic rat sympathetic neurons cultured under defined conditions extend a single functional axon, but fail to form dendrites. Addition of bone morphogenetic proteins (BMPs) triggers these neurons to extend multiple dendrites without altering axonal growth or cell survival. We used this culture system to examine differential gene expression patterns in naïve vs. BMP-treated sympathetic neurons in order to identify candidate genes involved in regulation of primary dendritogenesis.To determine the critical transcriptional window during BMP-induced dendritic growth, morphometric analysis of microtubule-associated protein (MAP-2)-immunopositive processes was used to quantify dendritic growth in cultures exposed to the transcription inhibitor actinomycin-D added at varying times after addition of BMP-7. BMP-7-induced dendritic growth was blocked when transcription was inhibited within the first 24 hr after adding exogenous BMP-7. Thus, total RNA was isolated from sympathetic neurons exposed to three different experimental conditions: (1) no BMP-7 treatment; (2) treatment with BMP-7 for 6 hr; and (3) treatment with BMP-7 for 24 hr. Affymetrix oligonucleotide microarrays were used to identify differential gene expression under these three culture conditions. BMP-7 significantly regulated 56 unique genes at 6 hr and 185 unique genes at 24 hr. Bioinformatic analyses implicate both established and novel genes and signaling pathways in primary dendritogenesis.This study provides a unique dataset that will be useful in generating testable hypotheses regarding transcriptional control of the initial stages of dendritic growth. Since BMPs selectively promote dendritic growth in central neurons as well, these findings may be generally applicable to dendritic growth in other neuronal cell types

Outcome measurement in female sexual dysfunction clinical trials: review and recommendations

Defining and measuring Female Sexual Dysfunction (FSD) is a complex and challenging task. Several factors have confounded the theory and measurement of FSD including: the use of an inappropriate male paradigm; difficulty in capturing the complexity of women's sexual response; an evolving but presently untested nosology; and the relative independence between subjective and objective aspects of women's sexual response. Each of these factors have contributed to the difficulty in developing meaningful and valid endpoints for clinical trials.\ud \ud The Food and Drug Administration's (FDA) 2000 draft guidance document for female sexual dysfunction clinical trials recommended the use of daily diary measures as primary and self-administered questionnaires (SAQs) as secondary endpoints. Event logs or diary measures may be adequate for assessing aspects of male sexual performance (e.g., erectile function), or in other therapeutic areas with discrete and readily observable endpoints (e.g., incontinence). However, psychometric theory suggests that for female sexual dysfunction clinical trials, SAQ instruments may provide more sensitive and reliable measures of outcome. We offer an alternative set of recommendations in the hope that the FDA will reconsider its position and to serve as potential guidelines for non-industry sponsored research on female sexuality as well. First, we propose that SAQs be elevated from their current status as secondary endpoints to be considered as potential primary endpoints in clinical trials of FSD. Second, we recommend that depending on the trial design and intervention under study, either an SAQ or diary measure (typically one or the other, and not both), might serve as a primary endpoint in a clinical trial. Third, SAQs and diaries should be employed, analyzed and interpreted in their particular areas of strength. Diaries are most useful for enumerating events and/or counting frequencies. SAQs are superior at gathering subjective data related to women's sexual function. Fourth, we believe there is a theoretical basis for considering SAQs to be superior measurement tools compared to diaries in assessing sexual dysfunction in women. At present, however there is insufficient objective data to fully support this opinion. Conversely, we do not anticipate either theoretical or objective evidence to support the alternative hypothesis (that diaries are superior to SAQs). If this proves to be correct in the future, diary measures may no longer be considered as primary endpoints for FSD clinical trials. Finally, we recommend that the FDA and/or other regulatory agencies reconsider the emphasis given to the number of successful or satisfactory sexual events over time as primary endpoints because they do not definitively demonstrate whether there has or has not been any improvement in the FSD endpoint under study (e.g., sexual desire). Successful and satisfactory encounters represent an amalgam of subjective assessments that are too far removed from the essential FSD component

Effect of Nucleation Cavities on Enhanced Boiling Heat Transfer in Microchannels

Boiling instabilities, high temperatures of the onset of boiling (ONB), and early transition to dryout are some of the insufficiently resolved issues of flow boiling in microchannels. This article addresses the flow boiling challenges with the incorporation of flow restrictors to reduce the boiling instabilities and hinder vapor backflows. In addition, the temperature of the ONB was lowered and the heat transfer coefficient was increased during boiling with the fabrication of potential nucleation cavities in the microchannel walls and bottom. Experiments were conducted with degassed double-distilled water in arrays of microchannels with the hydraulic diameter ranging from 25 to 80 µm, whereas the nucleation cavities characteristic sizes varied from 2 to 12 µm. The temperatures of the ONB were up to 35 K lower in the microchannel array with properly sized nucleation cavities compared to arrays of microchannels, in which the etched nucleation cavities were less suitable. The combined effect of fabricated nucleation cavities and interconnected microchannels increased the heat transfer coefficient from three to 10 times depending on the size of the etched nucleation cavities and the transferred heat flux in the microchannel arrays