High pressure rheology: a probe for formulation development

The development of new routes for therapeutic delivery such as controlled or sustained delivery systems, is time and cost consuming. This is because it is necessary to perform multiple in vitro dissolution studies to investigate the release profiles of all the formulations in the early stages of development. This thesis aims to investigate the potential use of rheology as a pre-screening tool to aid formulation development by reducing the number of in vitro studies that need to be performed. The hypothesis being that rheology could be used to assess the homogeneity and processability of a formulation, with the expectation that a homogeneous formulation would exhibit consistent release profiles on a batch-to-batch basis. Recent advances in pharmaceutical research have identified supercritical carbon dioxide (scCO2) as a potential green solvent alternative for the production of microparticles that promote the sustained release of APIs (active pharmaceutical ingredients) from a polymer matrix. Mild conditions are necessary to preserve the integrity of the API and carbon dioxide (CO2) is well documented to be able to reduce the viscosity of polymers at low temperatures. In order to quantify this, a robust and reliable rheology method was established to measure the polymer melt viscosity in the presence of CO2. First, the viscosity of the single polymers: polycaprolactone (PCL112) and poly(D,L-lactide) (PLA11), in their molten states was measured at ambient pressure and in the presence of CO2. For simplicity these measurements were made at elevated temperature (80-90 °C), where the samples were already molten at ambient pressure. However, this method was not suitable for formulations containing thermosensitive APIs, such as proteins or peptides, because they degrade at temperatures above physiological conditions (> 40 °C). Therefore, the method was adapted for use at lower temperatures by exposing the polymers to 140 bar of CO2 at 40 °C, without preheating. Although CO2 is known to reduce the viscosity of polymers it has been shown that the polymer melt viscosity remains relatively high, hindering the incorporation and even distribution of the drug. Additives such as plasticisers can be used to optimise the viscosity and processing parameters of a pharmaceutical formulation. Poly(ethylene glycol) (PEG) has been employed extensively as a polymeric plasticiser for Poly(lactic acid) (PLA) and as an excipient in pharmaceutical formulations. It was thought that by combining both the plasticising effects of CO2 and PEG it would be possible to further reduce the viscosity of PLA. This was not the case; however, a reduction in the time taken for the samples to reach their saturation viscosity was observed. The effect of the mode of PEG incorporation was also investigated, where PEG as a blended excipient was compared to PEG as a covalently linked entity in a block copolymer. The plasticising effect was found to have similar efficiency regardless of the incorporation method. Finally, a series of formulations containing a model protein drug, bovine serum albumin (BSA) encased in a polymer matrix were produced using a CO2 mixing procedure. The influence of the composition of the polymer matrix was investigated and a mix of PD,LLA and PLGA was found to be the most suitable. The effect of BSA content, BSA particle size and polymer ratio on the rheological properties and the release profiles was evaluated. A content assay and micro Raman spectroscopy were performed to assess the API content and the homogeneity of the formulations. It was expected that a formulation that can be readily processed will have a homogenous distribution of API and would exhibit consistent release profiles on a batch-to-batch basis. An in vitro dissolution study was performed on the formulations and the results were compared to the rheological data. It was found that if the rheology of a formulation could be measured and analysed and the viscosity was sufficiently low, then this formulation should exhibit consistent release profiles across different batches. Overall, this thesis aims to determine whether high pressure rheology can be used as an aid for formulation development. The data show that it is possible to measure the viscosity of complex formulations in a robust and reliable manner. These preliminary data suggest there is a general correlation between the rheological properties of a formulation and the consistency of its in vitro release

Can a combination of poly(ethylene glycol) and dense phase carbon dioxide improve processing of polylactide? A high pressure rheology investigation

High temperature melts or use of organic solvents are not practicable approaches for encapsulating protein based or thermally labile drugs into degradable polymers. Here, we demonstrate that poly(ethylene glycol) (PEG) in combination with supercritical carbon dioxide (scCO2) can dramatically reduce the viscosity of polymer melts allowing enhanced uptake of CO2 into poly(D,L-lactide) (PLA). Both PEG and CO2 are approved excipients in drug delivery and it is well documented that individually both are effective plasticisers. Using high pressure rheology techniques (scCO₂ at 14 MPa) we demonstrate a synergistic impact leading to significantly lower processing temperatures with PEG employed as both a blended additive and as a component of a block copolymer

Effect of supercritical CO2 on the copolymerization behavior of cyclohexene oxide/CO2 and copolymer properties with DMC/salen-Co(III) catalyst system

The copolymerization of cyclohexene oxide (CHO) and carbon dioxide (CO2) was carried out under supercritical CO2 (scCO2) conditions to afford poly (cyclohexene carbonate)(PCHC) in high yield. The scCO2 provided not only the C1 feedstock but also proved to be a very efficient solvent and processing aid for this copolymerization system. Double metal cyanide (DMC) and salen-Co(III) catalysts were employed, demonstrating excellent CO2/CHO copolymerization with high yield and high selectivity. Surprisingly, our use of scCO2 was found to significantly enhance the copolymerization efficiency and the quality of the final polymer product. Thermally stable and high molecular weight (MW) copolymers were successfully obtained. Optimization led to excellent catalyst yield (656 wt/wt, polymer/catalyst) and selectivity (over 96% toward polycarbonate) that were significantly beyond what could be achieved in conventional solvents. Moreover, detailed thermal analyses demonstrated that the PCHC copolymer produced in scCO2 exhibited higher glass transition temperatures (Tg ~114 8C) compared to polymer formed in dense phase CO2 (Tg~77 8C), and hence good thermal stability. Additionally, residual catalyst could be removed from the final polymer using scCO2, pointing toward a green method that avoids the use of conventional volatile organic based solvents for both synthesis and work-up

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

High pressure rheology: a probe for formulation development

The development of new routes for therapeutic delivery such as controlled or sustained delivery systems, is time and cost consuming. This is because it is necessary to perform multiple in vitro dissolution studies to investigate the release profiles of all the formulations in the early stages of development. This thesis aims to investigate the potential use of rheology as a pre-screening tool to aid formulation development by reducing the number of in vitro studies that need to be performed. The hypothesis being that rheology could be used to assess the homogeneity and processability of a formulation, with the expectation that a homogeneous formulation would exhibit consistent release profiles on a batch-to-batch basis. Recent advances in pharmaceutical research have identified supercritical carbon dioxide (scCO2) as a potential green solvent alternative for the production of microparticles that promote the sustained release of APIs (active pharmaceutical ingredients) from a polymer matrix. Mild conditions are necessary to preserve the integrity of the API and carbon dioxide (CO2) is well documented to be able to reduce the viscosity of polymers at low temperatures. In order to quantify this, a robust and reliable rheology method was established to measure the polymer melt viscosity in the presence of CO2. First, the viscosity of the single polymers: polycaprolactone (PCL112) and poly(D,L-lactide) (PLA11), in their molten states was measured at ambient pressure and in the presence of CO2. For simplicity these measurements were made at elevated temperature (80-90 °C), where the samples were already molten at ambient pressure. However, this method was not suitable for formulations containing thermosensitive APIs, such as proteins or peptides, because they degrade at temperatures above physiological conditions (> 40 °C). Therefore, the method was adapted for use at lower temperatures by exposing the polymers to 140 bar of CO2 at 40 °C, without preheating. Although CO2 is known to reduce the viscosity of polymers it has been shown that the polymer melt viscosity remains relatively high, hindering the incorporation and even distribution of the drug. Additives such as plasticisers can be used to optimise the viscosity and processing parameters of a pharmaceutical formulation. Poly(ethylene glycol) (PEG) has been employed extensively as a polymeric plasticiser for Poly(lactic acid) (PLA) and as an excipient in pharmaceutical formulations. It was thought that by combining both the plasticising effects of CO2 and PEG it would be possible to further reduce the viscosity of PLA. This was not the case; however, a reduction in the time taken for the samples to reach their saturation viscosity was observed. The effect of the mode of PEG incorporation was also investigated, where PEG as a blended excipient was compared to PEG as a covalently linked entity in a block copolymer. The plasticising effect was found to have similar efficiency regardless of the incorporation method. Finally, a series of formulations containing a model protein drug, bovine serum albumin (BSA) encased in a polymer matrix were produced using a CO2 mixing procedure. The influence of the composition of the polymer matrix was investigated and a mix of PD,LLA and PLGA was found to be the most suitable. The effect of BSA content, BSA particle size and polymer ratio on the rheological properties and the release profiles was evaluated. A content assay and micro Raman spectroscopy were performed to assess the API content and the homogeneity of the formulations. It was expected that a formulation that can be readily processed will have a homogenous distribution of API and would exhibit consistent release profiles on a batch-to-batch basis. An in vitro dissolution study was performed on the formulations and the results were compared to the rheological data. It was found that if the rheology of a formulation could be measured and analysed and the viscosity was sufficiently low, then this formulation should exhibit consistent release profiles across different batches. Overall, this thesis aims to determine whether high pressure rheology can be used as an aid for formulation development. The data show that it is possible to measure the viscosity of complex formulations in a robust and reliable manner. These preliminary data suggest there is a general correlation between the rheological properties of a formulation and the consistency of its in vitro release

SNP-based breeding for broiler resistance to ascites and evaluation of correlated production traits

Background The goal of this study was to evaluate marker-assisted selection (MAS) in broiler chickens using previously mapped gene regions associated with ascites syndrome incidence. The second-generation MAS products were assessed for impact on ascites phenotype and whether there were associated changes in important production traits. Previously, we used whole genome resequencing (WGR) to fine-map 28 chromosomal regions as associated with ascites phenotype in our experimental ascites broiler line (Relaxed, REL) based on a hypobaric chamber challenge. Genotypes for single nucleotide polymorphisms (SNPs) in mapped regions on chromosomes 2 and 22, were used for MAS in our REL line. After two generations, birds homozygous for the genotypes associated with resistance for both chromosomal regions were established. The MAS F2 generation was then compared to the REL line for ascites susceptibility and 25 production traits. Results Selection based on SNPs in the carboxypeptidase Q (CPQ, Gga2) and leucine rich repeat transmembrane neuronal 4 (LRRTM4, Gga22) gene regions resulted in a sex- and simulated altitude- dependent reduction of ascites incidence in two F2 cohorts of the MAS line. Comparisons of the F2 MAS and REL lines for production traits when reared at ambient pressure found no significant negative impacts for feed intake (FI), feed conversion ratio (FCR), or deboned part yields for either sex for two F2 cohorts. There were, however, improvements in the MAS for full-trial body weight gain (BWG), FCR, absolute and relative tender weights, and relative drumstick weight. Conclusions These results validate the mapping of the 28 chromosomal regions and demonstrate that fine mapping by WGR is an effective strategy for addressing a complex trait; it also stands as the first successful SNP-based selection program against a complex disease trait, such as ascites. The MAS line is comparable and, in some instances, superior, in growth performance to the REL control while being more resistant to ascites. This study indicates that MAS based on WGR can provide significant breeding potential in agricultural systems

Content analysis of the journal of student research: exploring the research culture of a university

Research article with tables.The purpose of this project was to gain better understanding of the research culture of the university by conducting a content analysis of the articles in the university student journal. The University of Wisconsin-Stout Journal of Student Research had its inception twelve years ago. An analysis of its contents has yet to be conducted. In order to gain greater understanding of the research culture at this university, the faculty-researcher and student-researchers co-conducted a content analysis of the university-based journal. Reported are findings from the following areas: total number of articles, authoring practices, advising patterns, count by department, attention to ethics, identification of article type, and content areas within articles. Implications for the journal, as well as student, faculty advisors/authors, and the larger university community are discussed.University of Wisconsin--Stout. Research Service

Perceptions of drug users regarding Hepatitis C screening and care: a qualitative study

Abstract Background Illicit drug users have a high prevalence of HCV and represent the majority of newly infected persons in the U.S. Despite the availability of effective HCV treatment, few drug users have been evaluated or treated for HCV. Racial and ethnic minorities have a higher incidence and prevalence of HCV and higher HCV-related mortality. Factors contributing to poor engagement in care are incompletely understood. Methods Fourteen mixed-gender focus groups of either African American or Latino/a drug users (N = 95) discussed barriers to HCV testing and treatment. Themes were identified through content analysis of focus group discussions. Results Many drug users were tested for HCV in settings where they were receiving care. Outside of these settings, most were unaware of voluntary test sites. After testing HCV positive, drug users reported not receiving clear messages regarding the meaning of a positive HCV test, the impact of HCV infection, or appropriate next steps including HCV clinical evaluations. Many drug users perceived treatment as unimportant because they lacked symptoms, healthcare providers minimized the severity of the diagnosis, or providers did not recommend treatment. Mistrust of the motivations of healthcare providers was cited as a barrier to pursuing treatment. Social networks or social interactions were a source of HCV-related information and were influential in shaping drug users perceptions of treatment and its utility. Conclusion Drug users perceived a paucity of settings for self-initiated HCV testing and poor provider-patient communication at test sites and during medical encounters. Notably, drug users reported having an unclear understanding about the meaning of a positive HCV test, the health implications of HCV infection, the importance of clinical evaluations and monitoring, and of treatment options for HCV. Efforts to improve the delivery of clinical messages about HCV infection for drug users at test settings and clinical encounters are needed

Successful partnerships with third sector organisations to enhance the student experience: A partnership evaluation

There is limited research surrounding academic partnerships and more research is needed to educate universities, and the private, public and third sectors about the benefits and limitations of such partnerships. The aim of this study was to outline the unique partnership between Macmillan Cancer Support and De Montfort University and to evaluate the progress of this partnership. A qualitative approach was employed which involved interviews with nine members of the partnership’s steering group. Interviews were transcribed and analysed using thematic analysis. The results showed that a partnership between a university and a third sector charity can have mutual benefits for all those involved, particularly for students and those affected by cancer. Furthermore, the module to develop volunteering among families affected cancer, created through this partnership is now being considered by other universities as a way of providing holistic and non-traditional lecture based learning experiences. Recommendations are made for future partnerships between third sector charities and universities