Audio Personalisation for Accessible Augmented Reality Narratives

Augmented Reality (AR) is rapidly growing across a diverse range of uses. Along with other Extended Reality (XR) technologies, it has the potential to not only make the world more accessible but to provide new and unique opportunities for impaired users. This will not happen accidentally but requires greater thought and development with impaired users central to decision making. This work explores whether creative and personalisable audio practices can be used to develop mobile-based AR content which is accessible to Visually Impaired (VI) users and includes them in enjoyable, immersive ways. It begins by assessing the accessibility of current AR applications (apps). Despite developments in the use of AR to make the world more accessible, most mobile AR content does not take access needs into account. 37 AR apps were tested against a rubric of features with few found to be accessible. In Study 1, 8 VI participants validated these results by evaluating a subset of these apps. This work then tests the efficacy of accessibility strategies centred upon two concepts. First, using well-designed audio creatively to include and immerse users in meaningful and enjoyable ways. Second, allowing users to personalise experiences to suit their needs. To this end, a bespoke narrative AR app was developed, with accessibility features initially equivalent to those in Study 1. In Study 2, 6 VI participants and 5 content creators displayed positivity towards the strategies and suggested ideas for their implementation. Based on this, the app was updated to include enhanced audio accessibility features. These were evaluated in Study 3 by 12 VI participants and 3 content creators. The results demonstrate positivity towards the strategies’ potential to provide an enjoyable, immersive experience. However, they underline how difficult AR is for VI users, highlighting fundamental challenges which need addressing before such strategies can be applied

Patients Reasons for Choosing Office-based Buprenorphine: Preference for Patient-Centered Care

Objectives - To explore HIV-infected patients\u27 attitudes about buprenorphine treatment in office-based and opioid treatment program (OTP) settings. Methods - We conducted in-depth qualitative interviews with 29 patients with co-existing HIV infection and opioid dependence seeking buprenorphine maintenance therapy in office-based and OTP settings. We used thematic analysis of transcribed audiorecorded interviews to identify themes. Results - Patients voiced a strong preference for office-based treatment. Four themes emerged to explain this preference. First, patients perceived the greater convenience of office-based treatment as improving their ability to address HIV and other healthcare issues. Second, they perceived a strong patient-focused orientation in patient-provider relationships underpinning their preference for office-based care. This was manifest as increased trust, listening, empathy, and respect from office-based staff and providers. Third, they perceived shared power and responsibility in officebased settings. Finally, patients viewed office-based treatment as a more supportive environment for sobriety and relapse prevention. This was partly due to strong therapeutic alliances with office-based staff and providers who prioritized a harm reduction approach, but also due to the perception that the office-based settings were safer for sobriety, compared with increased opportunities for purchasing and using illicit opiates in OTP settings. Conclusions - HIV-infected patients with opioid dependence preferred office-based buprenorphine because they perceived it as offering a more patient-centered approach to care compared with OTP referral. Office-based buprenorphine may facilitate engagement in care for patients with co-existing opioid dependence and HIV infection

Manipulating Replisome Dynamics to Enhance Lambda Red-Mediated Multiplex Genome Engineering

Disrupting the interaction between primase and helicase in Escherichia coli increases Okazaki fragment (OF) length due to less frequent primer synthesis. We exploited this feature to increase the amount of ssDNA at the lagging strand of the replication fork that is available for λ Red-mediated Multiplex Automatable Genome Engineering (MAGE). Supporting this concept, we demonstrate that MAGE enhancements correlate with OF length. Compared with a standard recombineering strain (EcNR2), the strain with the longest OFs displays on average 62% more alleles converted per clone, 239% more clones with 5 or more allele conversions and 38% fewer clones with 0 allele conversions in 1 cycle of co-selection MAGE (CoS-MAGE) with 10 synthetic oligonucleotides. Additionally, we demonstrate that both synthetic oligonucleotides and accessible ssDNA targets on the lagging strand of the replication fork are limiting factors for MAGE. Given this new insight, we generated a strain with reduced oligonucleotide degradation and increased genomic ssDNA availability, which displayed 111% more alleles converted per clone, 527% more clones with 5 or more allele conversions and 71% fewer clones with 0 allele conversions in 1 cycle of 10-plex CoS-MAGE. These improvements will facilitate ambitious genome engineering projects by minimizing dependence on time-consuming clonal isolation and screening

Improving Lambda Red Genome Engineering in Escherichia coli via Rational Removal of Endogenous Nucleases

Lambda Red recombineering is a powerful technique for making targeted genetic changes in bacteria. However, many applications are limited by the frequency of recombination. Previous studies have suggested that endogenous nucleases may hinder recombination by degrading the exogenous DNA used for recombineering. In this work, we identify ExoVII as a nuclease which degrades the ends of single-stranded DNA (ssDNA) oligonucleotides and double-stranded DNA (dsDNA) cassettes. Removing this nuclease improves both recombination frequency and the inheritance of mutations at the 3′ ends of ssDNA and dsDNA. Extending this approach, we show that removing a set of five exonucleases (RecJ, ExoI, ExoVII, ExoX, and Lambda Exo) substantially improves the performance of co-selection multiplex automatable genome engineering (CoS-MAGE). In a given round of CoS-MAGE with ten ssDNA oligonucleotides, the five nuclease knockout strain has on average 46% more alleles converted per clone, 200% more clones with five or more allele conversions, and 35% fewer clones without any allele conversions. Finally, we use these nuclease knockout strains to investigate and clarify the effects of oligonucleotide phosphorothioation on recombination frequency. The results described in this work provide further mechanistic insight into recombineering, and substantially improve recombineering performance

Predicting Emergency Department “Bouncebacks”: A Retrospective Cohort Analysis

Introduction: The short-term return visit rate among patients discharged from emergency departments (ED) is a quality metric and target for interventions. The ability to accurately identify which patients are more likely to revisit the ED could allow EDs and health systems to develop more focused interventions, but efforts to reduce revisits have not yet found success. Whether patients with a high number of ED visits are at increased risk of a return visit remains underexplored.Methods: This was a population-based, retrospective, cohort study using administrative data from a large physician partnership. We included patients discharged from EDs from 80 hospitals in seven states from July 2014 – June 2016. We performed multivariable logistic regression of short-term return visits on patient, visit, hospital, and community characteristics. The primary outcome was the proportion of patients who had a return visit within 14 days of an index ED visit.Results: Among 6,699,717 index visits, the overall risk of 14-day revisit was 12.6%. Frequent visitors accounted for 18.7% of all visits and 40.2% of all 14-day revisits. Frequent visitor status was associated with the highest odds of a revisit (odds ratio [OR] 3.06; 95% confidence interval [CI], 3.041 – 3.073). Other predictors of revisits were cellulitis (OR 2.131; 95% CI, 2.106 – 2.156), alcohol-related disorders (OR 1.579; 95%CI, 1.548 – 1.610), congestive heart failure (OR 1.175; 95% CI, 1.126 – 1.226), and public insurance (Medicaid OR 1.514; 95% CI, 1.501 – 1.528; Medicare OR 1.601; 95% CI, 1.583 – 1.620).Conclusion: Previous ED use – even a single previous visit – was a stronger predictor of a return visit than any other patient, hospital, or community characteristic. Clinicians should consider previous ED use when considering treatment decisions and risk of return visit, as should stakeholders targeting patients at risk of a return visit

The FIRST-Optical-VLA Survey for Lensed Radio Lobes

We present results from a survey for gravitationally lensed radio lobes. Lensed lobes are a potentially richer source of information about galaxy mass distributions than lensed point sources, which have been the exclusive focus of other recent surveys. Our approach is to identify radio lobes in the FIRST catalog and then search optical catalogs for coincident foreground galaxies, which are candidate lensing galaxies. We then obtain higher-resolution images of these targets at both optical and radio wavelengths, and obtain optical spectra for the most promising candidates. We present maps of several radio lobes that are nearly coincident with galaxies. We have not found any new and unambiguous cases of gravitational lensing. One radio lobe in particular, FOV J0743+1553, has two hot spots that could be multiple images produced by a z=0.19 spiral galaxy, but the lensing interpretation is problematic.Comment: 38 pages, 18 figures, aastex, accepted to A

Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study

Background: The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product’s actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication. Methods: We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials. Results: Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01–2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15–0.16). Conclusions: Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers

SDSS J115517.35+634622.0: A Newly Discovered Gravitationally Lensed Quasar

We report the discovery of SDSSJ115517.35+634622.0, a previously unknown gravitationally lensed quasar. The lens system exhibits two images of a $z = 2.89$ quasar, with an image separation of 1{\farcs}832 \pm 0.007 . Near-IR imaging of the system reveals the presence of the lensing galaxy between the two quasar images. Based on absorption features seen in the Sloan Digital Sky Survey (SDSS) spectrum, we determine a lens galaxy redshift of $z = 0.1756$. The lens is rather unusual in that one of the quasar images is only 0{\farcs}22\pm0{\farcs}07 ($\sim 0.1 R_{\rm eff}$) from the center of the lens galaxy and photometric modeling indicates that this image is significantly brighter than predicted by a SIS model. This system was discovered in the course of an ongoing search for strongly lensed quasars in the dataset from the SDSS.Comment: 18 pages, 6 figures. Accepted for publication in A

Rational optimization of tolC as a powerful dual selectable marker for genome engineering

Selection has been invaluable for genetic manipulation, although counter-selection has historically exhibited limited robustness and convenience. TolC, an outer membrane pore involved in transmembrane transport in E. coli, has been implemented as a selectable/counter-selectable marker, but counter-selection escape frequency using colicin E1 precludes using tolC for inefficient genetic manipulations and/or with large libraries. Here, we leveraged unbiased deep sequencing of 96 independent lineages exhibiting counter-selection escape to identify loss-of-function mutations, which offered mechanistic insight and guided strain engineering to reduce counter-selection escape frequency by ∼40-fold. We fundamentally improved the tolC counter-selection by supplementing a second agent, vancomycin, which reduces counter-selection escape by 425-fold, compared colicin E1 alone. Combining these improvements in a mismatch repair proficient strain reduced counter-selection escape frequency by 1.3E6-fold in total, making tolC counter-selection as effective as most selectable markers, and adding a valuable tool to the genome editing toolbox. These improvements permitted us to perform stable and continuous rounds of selection/counter-selection using tolC, enabling replacement of 10 alleles without requiring genotypic screening for the first time. Finally, we combined these advances to create an optimized E. coli strain for genome engineering that is ∼10-fold more efficient at achieving allelic diversity than previous best practices