Pharmaceutical Co-crystals; Screening Optimisation, Utility and Performance

Co-crystallisation is currently a ‘hot topic’ in pharmaceutical development among other fields. Modification of the physicochemical properties of the parent material by inclusion of a second component within the crystal structure, with the potential to lead to large improvements in useful attributes, being the key reason for the interest in co-crystals. Being able to efficiently utilise co-crystallisation to ameliorate problem properties of drugs or other compounds would be a boon to many industries, the pharmaceutical being an ideal example. Limitations in current ability to predict co-crystal formation and potential property modification presents a great opportunity for development in this research area. The work presented in this thesis encompasses the optimisation of a high-throughput ultrasonication based physical co-crystal screen paired with a computational pre-screen, the application of this optimised screen and the analysis of both co-crystalline and co-amorphous materials resulting from the screening. An initial optimisation of a manual physical co-crystal screen was later transferred to an automated screen implemented on a robotics platform. The implementation of the screen and subsequent analysis of products led to the discovery of the stabilisation of an amorphous form of highly polymorphic compound, ROY, through a predicted co-former interaction. The interactions responsible for the stabilisation were further investigated in the ROY:pyrogallol co-amorphous material and it was found that certain analogues of pyrogallol exhibit the same behaviour with ROY depending on the presence and position of specific functionality. Implementation of the optimised co-crystal screen to the antiprotozoal drug ornidazole led to the detection of 23 hits and the crystal structure of the 1:1 co-crystal of ornidazole and 5nitroisophthalic acid being determined by single crystal X-ray diffraction. Characterisation of this co-crystal found that it crystallised much more readily than pure ornidazole, potentially improving its processing characteristics, but that unexpectedly had a lower intrinsic dissolution rate than either of the parent components. In comparison, formulation and characterisation of the already known zafirlukast:piperazine co-crystals showed that large improvements in dissolution rates and oral bioavailability in relation to the parent drug are possible. Specifically, the 1:1 zafirlukast:piperazine co-crystal showed a large increase in dissolution rate in vitro and an accompanying six-fold increase in in vivo oral bioavailability

Manifestos

31 pages. A Great Bear Pamphlet; no. 8. CONTENTS : Word power / Alison Knowles -- Answers to manifesto puzzle -- Rainbow manifesto / Ay-o -- Western civilization is done with ... / Philip Corner -- Manifesto of the W.E.B. DuBois Clubs -- Take care of the world / Oyvind Fahlström -- A proposition, a problem, a danger and a hunch / Robert Filliou -- We hold ... / John Giorno -- Manifesto / [Robert Watts] -- Lettuce manifesto / Al Hansen -- A Something Else manifesto / Dick Higgins -- Once, the task of the artist was ... / Allan Kaprow -- Cybernated art is very important ... ; Utopian laser TV station / Nam June Paik -- And I open my mouth ... / Diter Rot -- Program / Jerome Rothenberg -- Instead of bombs ... / Wolf Vostell -- abeeiillmmmsttwy / [Emmett Williams]. Stapled binding. Gift of Richard Liebler. 2nd copy gift of Estera Milman, RISD Class of 1970. Estera Milman (RISD BFA Painting/Printmaking and Film, 1970) scholar of post-World War II avant-garde art. Founded Alternative Traditions in Contemporary Art (ATCA) at the University of Iowa, 1982, and served as its director until 2000. She is the author of many books, articles, interviews, and exhibition catalogs on Fluxus and No!art. In December 2018 she donated a selection of books from her library to the Fleet Library at RISD. Curated title for Fleet Library Special Collections exhibition By Hand: Women & Books Exhibit fall, 2021.https://digitalcommons.risd.edu/specialcollections_artistsbooks/1253/thumbnail.jp

Popular Entertainments

[16] pages : illustrations. A Great Bear Pamphlet (Unnumbered) Cover title. Popular entertainments, no. 1. Paper wrapper, stapled. Gift of Estera Milman, RISD Class of 1970. Estera Milman (RISD BFA Painting/Printmaking and Film, 1970) scholar of post-World War II avant-garde art. Founded Alternative Traditions in Contemporary Art (ATCA) at the University of Iowa, 1982, and served as its director until 2000. She is the author of many books, articles, interviews, and exhibition catalogs on Fluxus and No!art. In December 2018 she donated a selection books from her library to the Fleet Library at RISD. Curated title for Fleet Library Special Collections exhibition By Hand: Women & Books Exhibit fall, 2021.https://digitalcommons.risd.edu/specialcollections_artistsbooks/1266/thumbnail.jp

Pastoral lease assessment using geospatial analysis

Seven remote sensing based Vegetation Indices (NDSVI, STVI-3, NDVI, Green + Red, Red, Land Monitor and STVI-1) were tested for their potential to discriminate between “poor” and “good” range condition assessments in Western Australia’s pastoral rangelands. Indices were computed using the Australian Greenhouse Office National Carbon Accounting System (AGO NCAS) repository of calibrated Landsat TM/ETM+ mosaics. Discrimination potential was assessed at two levels of stratification – station level (identical to the stratification used to collect the traverse data), and functional group level (an aggregation of similar land systems)

Developing a flexible automated continuous downstream processing system for research to clinical supply

Continuous manufacturing has gained a lot of attention over the last 10-15 years for numerous reasons such as the potential for higher efficiencies, reduced cost of goods, and improved product quality. However, the adoption of these technologies has been slow due to concerns over operating these processes in a GMP manufacturing environment. Some of these concerns relate to the operation of multiple continuous unit operations in an integrated process sequence. This presentation will highlight these concerns and show how these issues were addressed by developing an overarching automated and modular platform which can be easily reconfigured for processing most products. The developed automation platform is the result of a project funded by Innovate UK that brings together a number of biopharmaceutical companies including Allergan, AstraZeneca, Fujifilm Diosynth Biotechnologies and GSK to identify and address these issues. One objective of the project is to develop a flexible automated biologics downstream process consisting of multiple unit operations that can be rapidly reconfigured for manufacturing different products. To that end the process has been design with modularity in mind with each module having common inputs and outputs. The automation software has also been developed in a way that most typical downstream processes can be implemented in the system with little to no software updates. The ability to rapidly reconfigure the process has been demonstrated by using the system to produce three products with different process sequences. Another issue that inhibits the adoption of continuous technologies is the concern over simultaneously operating multiple unit operations. This presentation will detail how the automation software was developed to control both the key unit operations such as chromatography and filtration steps but also intermediate operations such as feed conditioning and viral inactivation steps. The automated system reduces the complexity of downstream processes, which can have in excess of eleven unit operations, to a single user-friendly interface. Implementing this control platform enables a single operator to control the entire process. This presentation will also detail how the automation strategy has been developed to enable a single operator to deal with start-up/shutdown, perturbations in the process and mid-process equipment turnover. It will highlight the challenges that have been faced when developing this system and how these have been overcome. The aim of this project was to improve efficiency by reducing processing time when compared to the current batch process and this was demonstrated by testing the system with three different products (a MAb and a MAb fusion protein). Furthermore, this presentation with show data from the production of three products that demonstrates comparability between the continuous process and the original batch processes. It will then detail how this was used to demonstrate the production of a large-scale clinical batch run

Pleasure and meaningful discourse: an overview of research issues

The concept of pleasure has emerged as a multi-faceted social and cultural phenomenon in studies of media audiences since the 1980s. In these studies different forms of pleasure have been identified as explaining audience activity and commitment. In the diverse studies pleasure has emerged as a multi-faceted social and cultural concept that needs to be contextualized carefully. Genre and genre variations, class, gender, (sub-)cultural identity and generation all seem to be instrumental in determining the kind and variety of pleasures experienced in the act of viewing. This body of research has undoubtedly contributed to a better understanding of the complexity of audience activities, but it is exactly the diversity of the concept that is puzzling and poses a challenge to its further use. If pleasure is maintained as a key concept in audience analysis that holds much explanatory power, it needs a stronger theoretical foundation. The article maps the ways in which the concept of pleasure has been used by cultural theorists, who have paved the way for its application in reception analysis, and it goes on to explore the ways in which the concept has been used in empirical studies. Central to our discussion is the division between the ‘public knowledge’ and the ‘popular culture’ projects in reception analysis which, we argue, have major implications for the way in which pleasure has come to be understood as divorced from politics, power and ideology. Finally, we suggest ways of bridging the gap between these two projects in an effort to link pleasure to the concepts of hegemony and ideology

Incongruous consultation behaviour: results from a UK-wide population survey

<p>Abstract</p> <p>Background</p> <p>Symptom characteristics are strong drivers of care seeking. Despite this, incongruous consultation behaviour occurs and has implications for both individuals and health-care services. The aim of this study was to determine how frequently incongruous consultation behaviour occurs, to examine whether it is more common for certain types of symptoms and to identify the factors associated with being an incongruous consulter.</p> <p>Methods</p> <p>An age and sex stratified random sample of 8,000 adults was drawn from twenty UK general practices. A postal questionnaire was used to collect detailed information on the presence and characteristics of 25 physical and psychological symptoms, actions taken to manage the symptoms, general health, attitudes to symptom management and demographic/socio-economic details. Two types of incongruous consultation behaviour were examined: i) consultation with a GP for symptoms self-rated as low impact and ii) no consultation with a GP for symptoms self-rated as high impact.</p> <p>Results</p> <p>A fifth of all symptoms experienced resulted in consultation behaviour which was incongruous based on respondents' own rating of the symptoms' impact. Low impact consultations were not common, although symptoms indicative of a potentially serious condition resulted in a higher proportion of low impact consultations. High impact non-consultations were more common, although there was no clear pattern in the type of associated symptoms. Just under half of those experiencing symptoms in the previous two weeks were categorised as an incongruous consulter (low impact consulter: 8.3%, high impact non-consulter: 37.1%). Employment status, having a chronic condition, poor health, and feeling that reassurance or advice from a health professional is important were associated with being a low impact consulter. Younger age, employment status, being an ex-smoker, poor health and feeling that not wasting the GPs time is important were associated with being a high impact non-consulter.</p> <p>Conclusions</p> <p>This is one of the first studies to examine incongruous consultation behaviour for a range of symptoms. High impact non-consultations were common and may have important health implications, particularly for symptoms indicative of serious disease. More research is now needed to examine incongruous consultation behaviour and its impact on both the public's health and health service use.</p

Comparing nuclear power trajectories in Germany and the UK: from ‘regimes' to ‘democracies’ in sociotechnical transitions and Discontinuities

This paper focuses on arguably the single most striking contrast in contemporary major energy politics in Europe (and even the developed world as a whole): the starkly differing civil nuclear policies of Germany and the UK. Germany is seeking entirely to phase out nuclear power by 2022. Yet the UK advocates a ‘nuclear renaissance’, promoting the most ambitious new nuclear construction programme in Western Europe.Here,this paper poses a simple yet quite fundamental question: what are the particular divergent conditions most strongly implicated in the contrasting developments in these two countries. With nuclear playing such an iconic role in historical discussions over technological continuity and transformation, answering this may assist in wider understandings of sociotechnical incumbency and discontinuity in the burgeoning field of‘sustainability transitions’. To this end, an ‘abductive’ approach is taken: deploying nine potentially relevant criteria for understanding the different directions pursued in Germany and the UK. Together constituted by 30 parameters spanning literatures related to socio-technical regimes in general as well as nuclear technology in particular, the criteria are divided into those that are ‘internal’ and ‘external’ to the ‘focal regime configuration’ of nuclear power and associated ‘challenger technologies’ like renewables. It is ‘internal’ criteria that are emphasised in conventional sociotechnical regime theory, with ‘external’ criteria relatively less well explored. Asking under each criterion whether attempted discontinuation of nuclear power would be more likely in Germany or the UK, a clear picture emerges. ‘Internal’ criteria suggest attempted nuclear discontinuation should be more likely in the UK than in Germany– the reverse of what is occurring. ‘External’ criteria are more aligned with observed dynamics –especially those relating to military nuclear commitments and broader ‘qualities of democracy’. Despite many differences of framing concerning exactly what constitutes ‘democracy’, a rich political science literature on this point is unanimous in characterising Germany more positively than the UK. Although based only on a single case,a potentially important question is nonetheless raised as to whether sociotechnical regime theory might usefully give greater attention to the general importance of various aspects of democracy in constituting conditions for significant technological discontinuities and transformations. If so, the policy implications are significant. A number of important areas are identified for future research, including the roles of diverse understandings and specific aspects of democracy and the particular relevance of military nuclear commitments– whose under-discussion in civil nuclear policy literatures raises its own questions of democratic accountability

Diagnosis of Tuberculosis in the Wild Boar (Sus scrofa): A Comparison of Methods Applicable to Hunter-Harvested Animals

To obtain robust epidemiological information regarding tuberculosis (TB) in wildlife species, appropriate diagnostic methods need to be used. Wild boar (Sus scrofa) recently emerged as a major maintenance host for TB in some European countries. Nevertheless, no data is available to evaluate TB post-mortem diagnostic methods in hunter-harvested wild boar. METHODOLOGY/PRINCIPAL FINDINGS: Six different diagnostic methods for TB were evaluated in parallel in 167 hunter-harvested wild boar. Compared to bacteriological culture, estimates of sensitivity of histopathology was 77.8%, gross pathology 72.2%, PCR for the MPB70 gene 66.7%, detection of acid-fast bacilli (AFB) in tissue contact smears 55.6% and in histopathology slides 16.7% (estimated specificity was 96.7%, 100%, 100%, 94.4% and 100%, respectively). Combining gross pathology with stained smears in parallel increased estimated sensitivity to 94.4% (94.4% specificity). Four probable bacteriological culture false-negative animals were identified by Discriminant Function Analysis. Recalculating the parameters considering these animals as infected generated estimated values for sensitivity of bacteriology and histopathology of 81.8%, gross pathology 72.7%, PCR for the MPB70 gene 63.6%, detection of AFB in tissue contact smears 54.5% and in histopathology slides 13.6% (estimated specificity was 100% for gross pathology, PCR, bacteriology and detection of AFB in histopathology slides, 96.7% for histopathology and 94.4% for stained smears). CONCLUSIONS/SIGNIFICANCE: These results show that surveys for TB in wild boar based exclusively on gross pathology considerably underestimate prevalence, while combination of tests in parallel much improves sensitivity and negative predictive values. This finding should thus be considered when planning future surveys and game meat inspection schemes. Although bacteriological culture is the reference test for TB diagnosis, it can generate false-negative results and this should be considered when interpreting data.This study was funded by laboratory funds from Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript

Intermedial Relationships of Radio Features with Denis Mitchell’s and Philip Donnellan’s Early Television Documentaries

Writing of the closure in early 1965 of the Radio Features Department, Asa Briggs identifies one of the reasons for the controversial decision as ‘the incursion of television, which was developing its own features.’ ‘[Laurence] Gilliam and his closest colleagues believed in the unique merits of “pure radio”. The screen seemed a barrier’ (The History of Broadcasting in the United Kingdom, Vol. 5, p. 348). Rather than the screen being ‘a barrier’ for them, a number of the creators of the emerging television documentary were from the late 1950s onwards able to transfer and transform distinctive techniques of ‘pure radio’ into highly effective visual forms. Two key figures were the producers of ‘poetic’ documentaries Denis Mitchell and Philip Donnellan, who employed layered voices, imaginative deployments of music and effects, and allusive juxtapositions of sound and image, to develop an alternative (although always marginal) tradition to the supposedly objective approaches of current affairs and, later, verité filmmakers. And a dozen years after the dismemberment of the Features Department, Donnellan paid tribute to it in his glorious but little-seen film Pure Radio (BBC1, 3 November 1977). Taking important early films by Mitchell and Donnellan as case studies, this paper explores the impact of radio features on television documentaries in the 1950s and early 1960s, and assesses the extent to which the screen in its intermedial relationships with ‘pure radio’ was a barrier or, in the work of certain creators, an augmentation