Defining a Registry of Candidate Regulatory Elements to Interpret Disease Associated Genetic Variation

Over the last decade there has been a great effort to annotate noncoding regions of the genome, particularly those that regulate gene expression. These regulatory elements contain binding sites for transcription factors (TF), which interact with one another and transcriptional machinery to initiate, enhance, or repress gene expression. The Encyclopedia of DNA Elements (ENCODE) consortium has generated thousands of epigenomic datasets, such as DNase-seq and ChIP-seq experiments, with the goal of defining such regions. By integrating these assays, we developed the Registry of candidate Regulatory Elements (cREs), a collection of putative regulatory regions across human and mouse. In total, we identified over 1.3M human and 400k mouse cREs each annotated with cell-type specific signatures (e.g. promoter-like, enhancer-like) in over 400 human and 100 mouse biosamples. We then demonstrated the biological utility of these regions by analyzing cell type enrichments for genetic variants reported by genome wide association studies (GWAS). To search and visualize these cREs, we developed the online database SCREEN (search candidate regulatory elements by ENCODE). After defining cREs, we next sought to determine their potential gene targets. To compare target gene prediction methods, we developed a comprehensive benchmark of enhancer-gene links by curating ChIA-PET, Hi-C and eQTL datasets. We then used this benchmark to evaluate unsupervised linking approaches such as the correlation of epigenomic signal. We determined that these methods have low overall performance and do not outperform simply selecting the closest gene. We then developed a supervised Random Forest model which had notably better performance than unsupervised methods. We demonstrated that this model can be applied across cell types and can be used to predict target genes for GWAS associated variants. Finally, we used the registry of cREs to annotate variants associated with psychiatric disorders. We found that these psych SNPs are enriched in cREs active in brain tissue and likely target genes involved in neural development pathways. We also demonstrated that psych SNPs overlap binding sites for TFs involved in neural and immune pathways. Finally, by identifying psych SNPs with allele imbalance in chromatin accessibility, we highlighted specific cases of psych SNPs altering TF binding motifs resulting in the disruption of TF binding. Overall, we demonstrated our collection of putative regulatory regions, the Registry of cREs, can be used to understand the potential biological function of noncoding variation and develop hypotheses for future testing

Everyday

In our everyday lives we are bombarded with thousands, even millions, of images. Suffering information overload, we filter out the vast majority of these impressions – the person we pass on the street or sitting in the car next to us at a stop light. We only ‘see’ those people, places and things that ‘matter’, all else becomes ‘noise’; filtered into the background of consciousness – vaguely familiar, yet simultaneously foreign, creating a ‘manageable paradigm’ or construct of the world we inhabit. I take photographic portraits every day. Not of the ‘important’ in my life, but the nondescript, often overlooked and unknown individuals we each encounter daily. These portraits may not be newsworthy, but are tributes to those steering their lives through the everyday, the ignored moments, and the places they pass. What I present invites the viewer to take an interest, to notice, and ultimately to acknowledge the people depicted. Photography has afforded me a reason and the luxury to approach complete strangers which I find interesting and ask if they would allow me to take their portraits, and while doing so, tell me a little about their lives. Most of these encounters last for a relatively short time, the memories, however, surpass what is caught on film

Research to support the development of teacher training and guidance.

This report in conjunction with a new quality framework for delivering career guidance in schools, will be the foundation of a new web-based resource which will help teachers in schools across Europe to develop their provision in response to these issues. Throughout the report, the chapters are cross-referenced to the framework to allow a consistent read across and to inform the development of training and development programmes.This report is one of the products of an Erasmus + funded project. This project has received the financial support of the European Commissio

Effect of Rectal Hygiene on Sexually Transmitted Infections Among HIV-Negative Men Who Have Sex with Men (MSM)

Abstract Background Rectal gonorrhea (NG) and chlamydia (Connecticut) infections are common among men who have sex with men (MSM). Rectal douching/enema (RDE) is a common practice among MSM that can affect the rectal microbiome. It is unclear if this practice is associated with acquiring rectal infections (RI) with either NG or CT. Methods From 2013–2015, 398 adult HIV-negative MSM and transwomen were enrolled in a randomized controlled study on text messaging for adherence to pre-exposure prophylaxis (PrEP). Participants were surveyed on sexual behavior, frequency of RDE, drug use, and nutritional habits in conjunction with routine sexually transmitted infection testing. Pearson’s χ 2 and two sample t-tests were used to measure significance of RDE and other risk factors with RI. Multivariable logistic regression model was used to control for confounding and assess the association of RDE with RIs. Confounders (i.e., age, number anal receptive sex, number sex partners) were selected a priori for inclusion in the final model based on a causal model and statistical significance. Results Of 397 participants, 262 (67%) performed RDE and 132 (33%) had at least one NG or CT rectal infection over 48 weeks. Number of condomless anal receptive sex acts (mean = 19, P < 0.001), condom use for anal receptive sex (P = 0.017), number of male sex partners in past 3 months (mean = 14, P = 0.001), and the use of poppers (P < 0.001) were associated with RI. There was no significant association between nutritional habits, probiotic foods or supplements and RI, with the exception of energy bars (P = 0.029). Controlling for confounders, RI was associated with RDE less than weekly with OR = 1.02 (95% CI 0.52–1.99) while RDE weekly or more had OR = 2.08 (95% CI 1.03–4.17). Stratified by number of partners, MSMs with more than the median (>6) number of partners had OR = 4.96 (95% CI 1.29–19.03) if performing RDE less than weekly, and OR = 6.03 (95% CI 1.55–23.49) if weekly or more. Conclusion Rectal hygiene with douching/enemas is a common practice among MSMs on PrEP, which increases the odds of acquiring rectal NG and/or CT. This finding is suggestive for the use of rectal hygiene products/practices as potential targets for sexually transmitted infection prevention. Disclosures All authors: No reported disclosures

Frame me if you must: PrEP framing and the impact on adherence to HIV Pre-exposure Prophylaxis

Abstract Background “PrEP whore” has been used both as a pejorative by PrEP opponents in the gay community and, reactively, by PrEP advocates as a method to reclaim the label from stigmatization and “slut-shaming.” The actual prevalence and impact of such PrEP-directed stigma on adherence have been insufficiently studied. Methods CCTG 595 was a randomized controlled PrEP demonstration project in 398 HIV-uninfected MSM and transwomen. Intracellular tenofovir-diphosphate (TFV-DP) levels at weeks 12 and 48 were used as a continuous measure of adherence. At study visits, participants were asked to describe how they perceived others’ reactions to them being on PrEP. These perceptions were categorized a priori as either “positively framed,” “negatively framed,” or both. We used Wilcoxon rank-sum to determine the association between positive and negative framing and TFV-DP levels at weeks 12 and 48. Results By week 4, 29% of participants reported perceiving positive reactions from members of their social groups, 5% negative, and 6% both. Reporting decreased over 48 weeks, but positive reactions were consistently reported more than negative. At week 12, no differences in mean TFV-DP levels were observed in participants with positively-framed reactions compared with those reporting no outcome or only negatively-framed (1338 [IQR, 1036-1609] vs. 1281 [946-1489] fmol/punch, P = 0.17). Additionally, no differences were observed in those with negative reactions vs. those without (1209 [977–1427] vs. 1303 [964–1545], P = 0.58). At week 48, mean TFV-DP levels trended toward being higher among those that report any reaction, regardless if positive (1335 [909–1665] vs. 1179 [841–1455], P = 0.09) or negative (1377 [1054–1603] vs. 1192 [838–1486], P = 0.10) than those reporting no reaction. At week 48, 46% of participants reported experiencing some form of PrEP-directed judgment, 23% reported being called “PrEP whore,” and 21% avoiding disclosing PrEP use. Conclusion Over 48 weeks, nearly half of participants reported some form of judgment or stigmatization as a consequence of PrEP use. However, individuals more frequently perceived positively framed reactions to being on PrEP than negative. Importantly, long-term PrEP adherence does not appear to suffer as a result of negative PrEP framing. Disclosures All authors: No reported disclosures

Beating around the bush : How obfuscation and attractiveness interact in customer perceptions of service providers [abstract]

Abstract only availableFaculty Mentor: S. Ratneshwar, MarketingPrior research has found that both knowledgeability and attractiveness enhance customer perceptions of service providers (Ahearne, Gruen, and Jarvis 1999). In many service situations, however, a service provider may not know the answer to a question posed by a customer. In such cases, the service provider could (a) be honest and admit not knowing the answer, (b) obfuscate, i.e., provide a confusing, roundabout answer that does not really answer the question, or (c) lie outright. The purpose of this research is to investigate whether the attractiveness of a service provider alters the effects of obfuscation vs. an honest "don't know" answer on customer perceptions. The study design involves a 3 X 2 experiment. The honesty variable will have three conditions, namely, (1) service provider provides the correct answer, (2) service provider obfuscates, (3) service provider gives an honest "don't know" answer. The attractiveness variable will have two conditions, namely, (1) highly attractive looks and (2) highly unattractive looks. Subjects will be provided service encounter scenarios in which they will read dialog from the perspective of a restaurant patron. The dialog will portray the purported interaction between a server and a group of patrons at a bar & grille. The dialog will include a key question from the patron for which the server's answer will be manipulated between subjects to reflect one of the above three answer conditions. The materials provided to subjects will also include a picture (headshot) of the server that will be manipulated between subjects in accord with the attractiveness variable. After participants read over the interaction dialog, they will fill out a short questionnaire. The questions will assess their perceptions of the service provider, their satisfaction with the service rendered, and their likely tip amount. We expect to find that when a server is attractive, he or she is more likely to get away with obfuscation than a server that is not as attractive. We also expect that an honest "don't know" will be more damaging when a server is unattractive (vs. highly attractive).Life Sciences Undergraduate Research Opportunity Progra

CIRCLING THE WAGONS AND SHOOTING INWARD”: UNDERSTANDING HOW NURSING ADMINISTRATORS APPROACH THE POLICY PROCESS

The purpose of this qualitative study was to develop an understanding of factors that nursing education executives in higher education believe are essential to influencing and implementing sound policy decisions. This study sought to answer the following: (a) what characteristics and skills do nurse administrators in higher education believe are essential to positively influencing the policy-making process, and (b) what organizational features do these nurse executives believe impede or facilitate their ability to influence policy processes? This study utilized an exploratory qualitative design representing a collective case study. The sample selection was purposive and included in-depth interviews with nurse educators who had at least two years’ experience as nursing education executives. Themes emerging from the narrative data were that a collaboration leadership style, effective communication, and political awareness were considered essential skills for successfully navigating the policy process. The theme of complexity created by institutions and stakeholders involved in policy was observed. Implications of the study included (a) the complexity of higher education institutions regarding the need to interface with multiple internal and external stakeholders acts as a barrier to policy process, (b) lack of formal preparation to manage policy can be a barrier for nurse leaders who typically lack such preparation, and (c) collaboration is at the center of how these nurse leaders drive and implement policy in their educational institutions. Recommendations made for future research include, (a) complexity and nursing education, (b) preparation of nurse education for policy-making, and (c) understanding policy experiences of a more diverse group of nurse educators

Recent HIV Risk Behavior and Partnership Type Predict PrEP Adherence in Men Who Have Sex with Men

Abstract Background Individuals engaging in higher risk behavior are often more adherent to PrEP but it is unclear if partnership type itself affects PrEP adherence. We examined the effect of recent HIV risk behaviors and partnership type on PrEP adherence in men who have sex with men (MSM) taking PrEP. Methods CCTG 595 is a 48-week PrEP demonstration study of 398 HIV− at-risk MSM. At baseline and week 48, HIV risk score was estimated as the probability of seroconversion over the next year based on number of condomless anal sex acts with HIV+/unknown partners in the last month and any STI diagnosed at study visit. HIV risk score was categorized as low (<0.12), moderate (0.12−0.59) and high (>0.59) risk based on population seroconversion probabilities. Partnership type was assigned as no/single HIV− partner, single HIV+ partner, or multiple partners of any serostatus in the past 3 months. PrEP adherence was estimated by intracellular tenofovir-diphosphate (TFV-DP) levels as a continuous variable at week 48. Statistical methods included McNemar’s test, Wilcoxon rank-sum test, and linear regression model where appropriate. Results Of 313 MSM who completed week 48, there was no significant change in HIV risk category from baseline to week 48 (low: 44 to 42%; moderate: 27 to 24%; high: 28 to 34%; P = 0.25). There was a significant change in partnership type, with the proportion of those with no or single HIV− partnerships increasing (1 to 9%, P < 0.001). In univariate analysis, moderate and high-risk groups had higher TFV-DP levels than the low-risk group at week 48 (P = 0.018). Participants with no/single HIV− partner had significantly lower TFV-DP levels than those with one HIV+ partner or multiple partners (P = 0.007). In a multivariable linear regression model, only low-risk partnerships remained significant where no/single HIV− partnerships were associated with lower TFV-DP levels (mean difference = −344fmol/punch [−617, −71], P = 0.014). Conclusion Although there was a shift in partnership type towards lower risk partnerships, objective HIV risk behavior remained stable over time. Individuals with higher HIV risk behaviors and risk partnerships had higher TFV-DP levels suggesting maintained strong motivation for PrEP adherence. Thus, recent sexual risk behavior and partnership type may be important predictors of PrEP adherence in MSM. Disclosures All authors: No reported disclosures