Exome array analysis of pulmonary function in smokers with and without chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease characterized by airflow restriction and decreased lung function. It is the 3rd leading cause of death worldwide, accounting for approximately 3 million deaths in 2010. It is diagnosed using spirometric measurements, including the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). These measures reflect the severity of airway obstruction and predict population morbidity and mortality. The primary environmental cause of COPD is cigarette smoking, but genetics also play a role in individual susceptibility and disease progression. Genome-wide association studies (GWAS) have identified over 30 loci associated with lung, but together the identified variants can only explain a small proportion of the variation in spirometric measures and a small proportion of the estimated heritability. We hypothesized: 1) rare functional variation also affects lung function; and 2) genetic variation (both common and rare) affects longitudinal changes in lung function. This dissertation tests these hypotheses using data from the COPDgene study, a large multicenter study of current and former smokers

Lessons Learned During Turbulent Times to Weather and Thrive in the Storm of COVID-19

This article describes the lessons learned by our university during the global healthcare crisis of COVID-19. It highlights the agile solutions employed to continue learning under extraordinary circumstances. While we have captured the stories that allowed our students to power through this tumultuous period if they so desired, these lessons may also provide guidance to other higher education institutions not only for the current turbulent times, but also enhance their ability to pause and pivot by utilizing agile management to weather this and future storms

Strategies for Writing a Self-Study and Conducting a Site Review

This presentation will include a discussion of the principle components of a department self-study and provide examples from two departments (English and Fine and Performing Arts). The specific self-study structure we developed is especially beneficial for small university campuses that may need to justify programs or budgetary expenditures

Hybrid approaches to teaching: Re-imagining the teaching of a foundational science course during a global pandemic

Access to scientific knowledge, and teaching in the sciences, is believed to be about training because scientific knowledge is, generally, specialised. However, for students to gain full epistemological access in the sciences, they also need to be inducted as scientists and learners of science. We use Bernstein’s regulative and instructional discourse to engage with the notion of epistemological access and effectiveness of a foundational science course. We examine how the course can cultivate scientific identities amongst first year students at a recently established South African university. Our analysis assesses the impact of the forced shift from contact teaching to Emergency Remote Teaching due to the COVID-19 pandemic. We demonstrate that the course was able to begin to facilitate the cultivation of different kinds of knowers in science. However, several gaps remain. Thus, we argue that foundational science lecturers should focus on hybrid teaching approaches to promote enhanced learning amongst students

Smooth and sharp creation of a pointlike source for a (3+1)-dimensional quantum field

We analyze the smooth and sharp creation of a pointlike source for a quantized massless scalar field in (3+1)-dimensional Minkowski spacetime, as a model for the breakdown of correlations that has been proposed to occur at the horizon of an evaporating black hole. The creation is implemented by a time-dependent self-adjointness parameter at the excised spatial origin. In a smooth creation, the renormalized energy density is well defined away from the source, but it is unbounded both above and below: the outgoing pulse contains an infinite negative energy, while a cloud of infinite positive energy lingers near the fully-formed source. In the sharp creation limit, diverges everywhere in the timelike future of the creation event, and so does the response of an Unruh-DeWitt detector that operates in the timelike future of the creation event. The source creation is significantly more singular than the corresponding process in 1 + 1 dimensions, analyzed previously, and it may be sufficiently singular to break quantum correlations as proposed in a black hole spacetime

Jockeying for position: the construction of masculine identities

In this paper we examine the construction of masculine identities within a real-life social situation. Using data from an extensive series of interviews with small groups of sixth-form (17-18-year-old) students attending a UK-based, single-sex independent school, the analysis looks at the action orientation of different constructions of identity. More specifically, it focuses upon how the identity talk of one particular group of students were oriented towards managing their subordinate status within the school. In a number of instances the identity of the `new man' was adopted as a strategy of resistance. However, it was found that the more common strategy involved buying back into values embodied within a more traditional definition of masculinity

Identification of novel small molecule inhibitors of adenovirus gene transfer using a high throughput screening approach

Due to many favourable attributes adenoviruses (Ads) are the most extensively used vectors for clinical gene therapy applications. However, following intravascular administration, the safety and efficacy of Ad vectors are hampered by the strong hepatic tropism and induction of a potent immune response. Such effects are determined by a range of complex interactions including those with neutralising antibodies, blood cells and factors, as well as binding to native cellular receptors (coxsackie adenovirus receptor (CAR), integrins). Once in the bloodstream, coagulation factor X (FX) has a pivotal role in determining Ad liver transduction and viral immune recognition. Due to difficulties in generating a vector devoid of multiple receptor binding motifs, we hypothesised that a small molecule inhibitor would be of value. Here, a pharmacological approach was implemented to block adenovirus transduction pathways. We developed a high throughput screening (HTS) platform to identify the small molecule inhibitors of FX-mediated Ad5 gene transfer. Using an in vitro fluorescence and cell-based HTS, we evaluated 10,240 small molecules. Following sequential rounds of screening, three compounds, T5424837, T5550585 and T5660138 were identified that ablated FX-mediated Ad5 transduction with low micromolar potency. The candidate molecules possessed common structural features and formed part of the one pharmacophore model. Focused, mini-libraries were generated with structurally related molecules and in vitro screening revealed novel hits with similar or improved efficacy. The compounds did not interfere with Ad5:FX engagement but acted at a subsequent step by blocking efficient intracellular transport of the virus. In vivo, T5660138 and its closely related analogue T5660136 significantly reduced Ad5 liver transgene expression at 48 h post-intravenous administration of a high viral dose (1 × 10<sup>11</sup> vp/mouse). Therefore, this study identifies novel and potent small molecule inhibitors of the Ad5 transduction which may have applications in the Ad gene therapy setting

Whole home exercise intervention for depression in older care home residents (the OPERA study) : a process evaluation

Background: The ‘Older People’s Exercise intervention in Residential and nursing Accommodation’ (OPERA) cluster randomised trial evaluated the impact of training for care home staff together with twice-weekly, physiotherapist-led exercise classes on depressive symptoms in care home residents, but found no effect. We report a process evaluation exploring potential explanations for the lack of effect. Methods: The OPERA trial included over 1,000 residents in 78 care homes in the UK. We used a mixed methods approach including quantitative data collected from all homes. In eight case study homes, we carried out repeated periods of observation and interviews with residents, care staff and managers. At the end of the intervention, we held focus groups with OPERA research staff. We reported our first findings before the trial outcome was known. Results: Homes showed large variations in activity at baseline and throughout the trial. Overall attendance rate at the group exercise sessions was low (50%). We considered two issues that might explain the negative outcome: whether the intervention changed the culture of the homes, and whether the residents engaged with the intervention. We found low levels of staff training, few home champions for the intervention and a culture that prioritised protecting residents from harm over encouraging activity. The trial team delivered 3,191 exercise groups but only 36% of participants attended at least 1 group per week and depressed residents attended significantly fewer groups than those who were not depressed. Residents were very frail and therefore most groups only included seated exercises. Conclusions: The intervention did not change the culture of the homes and, in the case study homes, activity levels did not change outside the exercise groups. Residents did not engage in the exercise groups at a sufficient level, and this was particularly true for those with depressive symptoms at baseline. The physical and mental frailty of care home residents may make it impossible to deliver a sufficiently intense exercise intervention to impact on depressive symptoms