there is something here

26 pagesMy terminal creative project is concerned with spectatorship, freedom and control, the technologies of the grid and virtual reality, theatricality and performance. I investigate the tropes of the Western and the figure of the cowboy as an avatar of the ideology of freedom rooted in Manifest Destiny and widely distributed through culture. The final outcome is an installation including worn outdoor chairs, performance videos shown on a flat screen TV and a VR headset, a large-scale photo print, other smaller photographs, a metal wire mesh and a grid-like pattern on the floor made of holographic tape. The viewer becomes part of the choreography of the exhibition as a time-based event that brings different times and places together into a temporal togetherness

Assessing eligibility for lung cancer screening using parsimonious ensemble machine learning models: A development and validation study

BACKGROUND: Risk-based screening for lung cancer is currently being considered in several countries; however, the optimal approach to determine eligibility remains unclear. Ensemble machine learning could support the development of highly parsimonious prediction models that maintain the performance of more complex models while maximising simplicity and generalisability, supporting the widespread adoption of personalised screening. In this work, we aimed to develop and validate ensemble machine learning models to determine eligibility for risk-based lung cancer screening. METHODS AND FINDINGS: For model development, we used data from 216,714 ever-smokers recruited between 2006 and 2010 to the UK Biobank prospective cohort and 26,616 high-risk ever-smokers recruited between 2002 and 2004 to the control arm of the US National Lung Screening (NLST) randomised controlled trial. The NLST trial randomised high-risk smokers from 33 US centres with at least a 30 pack-year smoking history and fewer than 15 quit-years to annual CT or chest radiography screening for lung cancer. We externally validated our models among 49,593 participants in the chest radiography arm and all 80,659 ever-smoking participants in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. The PLCO trial, recruiting from 1993 to 2001, analysed the impact of chest radiography or no chest radiography for lung cancer screening. We primarily validated in the PLCO chest radiography arm such that we could benchmark against comparator models developed within the PLCO control arm. Models were developed to predict the risk of 2 outcomes within 5 years from baseline: diagnosis of lung cancer and death from lung cancer. We assessed model discrimination (area under the receiver operating curve, AUC), calibration (calibration curves and expected/observed ratio), overall performance (Brier scores), and net benefit with decision curve analysis. Models predicting lung cancer death (UCL-D) and incidence (UCL-I) using 3 variables-age, smoking duration, and pack-years-achieved or exceeded parity in discrimination, overall performance, and net benefit with comparators currently in use, despite requiring only one-quarter of the predictors. In external validation in the PLCO trial, UCL-D had an AUC of 0.803 (95% CI: 0.783, 0.824) and was well calibrated with an expected/observed (E/O) ratio of 1.05 (95% CI: 0.95, 1.19). UCL-I had an AUC of 0.787 (95% CI: 0.771, 0.802), an E/O ratio of 1.0 (95% CI: 0.92, 1.07). The sensitivity of UCL-D was 85.5% and UCL-I was 83.9%, at 5-year risk thresholds of 0.68% and 1.17%, respectively, 7.9% and 6.2% higher than the USPSTF-2021 criteria at the same specificity. The main limitation of this study is that the models have not been validated outside of UK and US cohorts. CONCLUSIONS: We present parsimonious ensemble machine learning models to predict the risk of lung cancer in ever-smokers, demonstrating a novel approach that could simplify the implementation of risk-based lung cancer screening in multiple settings

A review of the tolerability of the candidate TB vaccine, MVA85A compared with BCG and Yellow Fever vaccines, and correlation between MVA85A vaccine reactogenicity and cellular immunogenicity

© 2012 Elsevier Ltd. All rights reservedBackground: The development of a new, more effective vaccine against tuberculosis (TB) for use in healthy and HIV-infected adults, children and infants, remains a global health priority. MVA85A is a candidate tuberculosis vaccine designed to enhance immunity to the existing vaccine, Bacillus Calmette-Guerin (BCG). MVA85A entered clinical trials in 2002 and has now progressed to Phase IIb proof-of-concept efficacy trials in infants and HIV-infected adults in Africa. Methods: A detailed analysis was conducted of the cumulative safety data of intradermal delivery of MVA85A in 112 healthy adult subjects in a series of open label, single arm, non-controlled, Phase I safety and immunogenicity clinical trials in the UK. The trials differed with respect to previous mycobacterial exposure, vaccine regime and dose. Objective safety measures (local reaction size and body temperature) were evaluated for correlations with adaptive antigen-specific immune responses. Results: All subjects in the combined mid-dose group developed a local reaction, of which 92% were mild, 8% were moderate and no reactions were severe. Around 90% of subjects in each group reported at least one systemic adverse event, most commonly headache, myalgia, malaise, feeling feverish, fatigue and arthralgia. Of all systemic adverse events in the combined mid-dose group, 96% were mild, 3% were moderate and 1% were severe (but none of these were judged to be vaccine-related). Pre-vaccination mycobacterial exposure did not affect the adverse event profile. The size of local reaction and frequency of systemic adverse events increased with MVA85A vaccine dose. There were no documented fevers in the low-dose group, whilst 3% of subjects in the combined mid-dose group and 21% in the high-dose group had documented fevers. Peak local reactions were larger after a second poxvirus vaccination, but other local and systemic adverse events were comparable to a single MVA85A vaccination. No severe systemic AEs or serious adverse events in any group were judged to be vaccine-related. Local AEs compared favourably to BCG vaccine-induced local AE and systemic AEs after MVA85A vaccination were comparable to those after the live viral Yellow Fever vaccine in similar populations. There were no correlations found between local reaction size or body temperature and adaptive immune responses (measured by ex vivo interferon gamma Enzyme Linked Immunospot). Conclusions: The candidate TB vaccine, MVA85A has been safely administered to over 100 healthy adults in the UK. Intradermal vaccination with MVA85A induced a transient, superficial reaction local to the injection site and mild short-lived viral symptoms. The local and systemic AE profile of MVA85A vaccination was comparable to published data of other intradermal vaccines and live viral vaccines respectively. Local reaction sizes and body temperature measurements did not correlate with the adaptive cellular immune response to MVA85A.Funded by charitable grants from Europe Aid; TBVAC (EU 6th Framework Programme); The Oxford Biomedical Research Centre and the Wellcome Trus

Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

UO Art MFA 2022

36 pagesEach year the terminal creative projects from our MFA candidates elevate and activate discourse and pleasure in the Art Department and across the College of Design with an ethos of fearless possibility. Their creative research of new knowledge, or the rearrangement of old knowledge, brings with it the sense that new texts have been penned, and new discourses activated. The University of Oregon MFA Art 2022 Exhibition culminates three years of independent research and experimentation by a cohort of eight artists whose various practices engage a broad range of inquiry, from expressions of the personal and diaristic to the examination and fictionalization of history, gender, magical thinking, cinema tropes, and the natural world. Over the last three years these candidates have navigated generational complexities while trying to transform their experiences and transcend the moment. This year marks the 99th year of the University’s MFA degree, making it one of the oldest programs in the country. As the program’s centennial moment approaches, we watch The MFA Graduates of 2022 realize their creative perspectives while challenging their audiences to view the world through a new lens

Modified Vaccinia Virus Ankara-Based Vaccine Vectors Induce Apoptosis in Dendritic Cells Draining from the Skin via both the Extrinsic and Intrinsic Caspase Pathways, Preventing Efficient Antigen Presentation

Dendritic cells (DC) are potent antigen-presenting cells and central to the induction of immune responses following infection or vaccination. The collection of DC migrating from peripheral tissues by cannulation of the afferent lymphatic vessels provides DC which can be used directly ex vivo without extensive in vitro manipulations. We have previously used bovine migrating DC to show that recombinant human adenovirus 5 vectors efficiently transduce afferent lymph migrating DEC-205(+) CD11c(+) CD8(-) DC (ALDC). We have also shown that recombinant modified vaccinia virus Ankara (MVA) infects ALDC in vitro, causing downregulation of costimulatory molecules, apoptosis, and cell death. We now show that in the bovine system, modified vaccinia virus Ankara-induced apoptosis in DC draining from the skin occurs soon after virus binding via the caspase 8 pathway and is not associated with viral gene expression. We also show that after virus entry, the caspase 9 pathway cascade is initiated. The magnitude of T cell responses to mycobacterial antigen 85A (Ag85A) expressed by recombinant MVA-infected ALDC is increased by blocking caspase-induced apoptosis. Apoptotic bodies generated by recombinant MVA (rMVA)-Ag85A-infected ALDC and containing Ag85A were phagocytosed by noninfected migrating ALDC expressing SIRPα via actin-dependent phagocytosis, and these ALDC in turn presented antigen. However, the addition of fresh ALDC to MVA-infected cultures did not improve on the magnitude of the T cell responses; in contrast, these noninfected DC showed downregulation of major histocompatibility complex class II (MHC-II), CD40, CD80, and CD86. We also observed that MVA-infected ALDC promoted migration of DEC-205(+) SIRPα(+) CD21(+) DC as well as CD4(+) and CD8(+) T cells independently of caspase activation. These in vitro studies show that induction of apoptosis in DC by MVA vectors is detrimental to the subsequent induction of T cell responses

Balancing collective responsibility, individual opportunities and risks: a qualitative study on how police officers reason around volunteering in an HIV vaccine trial in Dar es Salaam, Tanzania

Results from HIV vaccine trials on potential volunteers will contribute to global efforts to develop an HIV vaccine. The purpose of this study among police officers in Dar es Salaam, Tanzania, was to explore the underlying reasons that induce people to enrol in an HIV vaccine trial.\ud We conducted discussions with eight focus groups, containing a total of 66 police officers. The information collected was analyzed using interpretive description. The results showed that participants were motivated to participate in the trial by altruism, and that the participants experienced some concerns about their participation. They stated that altruism in the fight against HIV infection was the main reason for enrolling in the trial. However, young participants were seriously concerned about a possible loss of close relationships if they enrolled in the HIV vaccine trial. Both men and women feared the effect of the trial on their reproductive biology, and they feared interference with pregnancy norms. They were unsure about risks such as the risks of acquiring HIV infection and of suffering physical harm, and they were unsure of the intentions of the researchers conducting the trial. Further, enrolling in the trial required medical examination, and this led some participants to fear that unknown diseases would be revealed. Other participants, however, saw an opportunity to obtain free health services.\ud We have shown that specific fears are important concerns when recruiting volunteers to an HIV vaccine trial. More knowledge is needed to determine participants' views and to ensure that they understand the conduct of the trial and the reasons it is being carried out

Effects of ethanol on NMDA receptor-mediated functions in primary cultures of cerebellar granule cells

Primary cultures of cerebellar granule cells were used to investigate the effects of acute and chronic exposure of ethanol on NMDA receptor functions and to examine the possible sites of interaction between ethanol and the NMDA receptor. Activation of NMDA receptors induced elevation of free cytoplasmic Ca2+, Ca2+ influx, activation of protein kinase C and neurotoxicity. Acutely added ethanol potently inhibited these NMDA receptormediated functional responses, although the existence of ethanol-sensitive and -insensitive neurons was observed. Glycine, as a necessary co-agonist, was required for full activation of the NMDA receptors and also to demonstrate the inhibitory actions of ethanol. However, glycine and ethanol did not share the same regulatory site at the NMDA receptor. Spermidine, a polyamine site agonist, dramatically potentiated NMDA-induced neurotoxicity. The potentiating effect of spermidine was not altered by ethanol, indicating that ethanol and spermidine produce their effects acting at different sites within the NMDA receptor complex. In contrast, the neuroprotective action of ethanol on NMDA-induced cell death was significantly reduced by spermidine, suggesting that the spermidine enhancement of NMDA receptor function is so potent that it could mask the inhibitory action of ethanol on other sites within the NMDA receptor. When homoquinolinic acid (HQ), a NR2A-13 subunit-selective agonist, was used as agonist, the NMDA receptor- mediated neurotoxicity was more pronounced. Ethanol antagonized the neurotoxic effects of HQ in a competitive- 1 i ke manner in contrast to the noncompetitive reduction of NMDA-induced neurotoxicity suggesting the existence of a novel site of interaction between ethanol and the NMDA receptor. Enhancement of several NMDA receptor functions was observed in cell cultures chronically exposed to intoxicating concentrations of ethanol. Thus, NMDA-induced neurotoxicity and elevation of cytoplasmic free Ca2+ were clearly potentiated. However, the NMDA-induced 45Ca2+ influx was not altered by chronic ethanol, suggesting that chronic exposure to ethanol mainly affects the ability of neurons to utilize free cytoplasmic Ca2+. Furthermore, the potentiation of NMDA-mediated functional responses following chronic ethanol treatment was not accompanied by changes in the number or affinity of NMDA receptor antagonist [3 HIMK-801 binding sites, indicating that the conductance of the NMDA receptor-controlled cation channel was not affected. Finally, chronic ethanol treatment failed to alter the expression of NMDA receptor subunit mRNAs and levels of the membrane- bound NMDA receptor subunits (NR1 and NR2A-C). Stimulation of NMDA receptors enhanced AP-1 transcription factor DNA binding activity. The NMDA- induced AP-1 DNA binding activity was strongly suppressed by acutely added ethanol, but was significantly potentiated in neurons chronically exposed to ethanol. There was no significant difference in the levels of AP-1 activity between control and ethanol-treated cells in the absence of NMDA receptor agonist, suggesting that the observed enhancement was entirely due to altered NMDA receptor sensitivity in chronic ethanol-treated cells. In the absence of agonist, the constitutively expressed AP-1 complexes consisted mainly of jun D proteins, while in cells challenged with NMDA there was a pronounced expression of both jun D and c-Fos proteins. Protein composition of AP-1 complexes was not affected by chronic ethanol treatment. In conclusion, acutely applied ethanol strongly inhibited many NMDA receptor-mediated processes. Ethanol may produce its effects by interacting with the NMDA receptor at a novel site identified by HO, as well as at a site associated with the polyamine modulatory site. Chronic exposure to ethanol enhanced some of the NMDA receptor-mediated functional responses without concomitant changes in the expression of NMDA receptor subunits. It is suggested that the observed enhancement of NMDA receptor functions may be a consequence of adaptive changes in the signalling pathways down-stream of the NMDA receptors, possibly by modulating gene expression. However, it remains to be clarified whether the enhanced activity of NMDA-induced AP-1 transcription factor following chronic ethanol exposure in vitro is of importance for long-term neuroadaptive changes associated with the development of ethanol tolerance and dependence in vivo