Inhibiting influenza virus replication using novel and established antiviral compounds

Circulating influenza viruses have the potential to cause pandemics, as seen in 2009 with the emergence of a novel H1N1 virus that rapidly disseminated worldwide. In such an event, huge reliance is placed upon antiviral drugs for the prophylaxis and treatment of influenza infections. To date, only two different classes of antiviral drug are licensed for the treatment of influenza and only one of these, oseltamivir, has been stockpiled by major world governments in preparation for an influenza pandemic. However, widespread resistance to this drug has been documented in seasonal circulating strains, which emerged in the absence of intense drug use and predominated over drug-sensitive phenotypes. Furthermore, examples of oseltamivir resistant viruses have been found sporadically in pandemic A/H1N1 2009 influenza strains. The need for novel antivirals is therefore essential for effective infection control of influenza viruses in future years. A potential source of novel therapies are licensed compound libraries. We begin with the screening of two compound libraries, resulting in the identification of several compounds which inhibited influenza virus replication in vitro. After completing a traditional library screen, a novel approach to high-throughput compound screening using reporter plasmids expressed in a stable cell line was attempted. Although these cell-lines did not prove maintainable in the long-term, this work resulted in the generation of a reporter plasmid that is directly initiated by influenza infection in vitro and is thus a useful tool for assaying polymerase fitness of different influenza strains. The investigation then focused on one of the newly discovered hits and attempted to identify the spectrum of activity of this compound, a glycosylation inhibiting molecule, which was shown to be efficacious against influenza A strains only. The drug was shown to have low toxicity and proved active against the recently emerged pandemic influenza virus. The thesis then documents the effects of a common oseltamivir-resistant mutation, H275Y, on the neuraminidase protein of a representative 2009 pandemic influenza virus. This mutation was well tolerated in vitro by the virus and did not handicap replication in a human airway epithelial model. However, subtle impediments to the neuraminidase activity of the mutant were observed biochemically which may suggest why this mutation has not emerged more readily in the field

Sacrifice in the Eucharist in the texts of the fathers from the New Testament to the council of Chalcedon

This thesis examines the evidence for the notion of Eucharistic Sacrifice which is found in the original texts of all the principal Fathers and ecclesiastical authors of the Early Church. The period covered is from the time of the writing of the New Testament to the Council of Chalcedon in 451 A.D. Each of the principal Fathers is examined in historical order, as far as this is possible, except when there is another link between them such as their city of origin. Apart from a few exceptions, the texts are presented in their Greek or Latin original in the footnotes, but an English translation is supplied for every case in the main text of the thesis. The aim of the thesis is not to provide an exhaustive analysis of the above data, but to present them in an orderly way and to make initial exploratory comments on the texts themselves and of the work of various scholars. The final conclusion resulting from this exercise is that, although there is indisputable evidence that the notion of Eucharistic sacrifice was widely upheld by Patristic authors, its actual content varied from author to author and presents a richness which it is not easy to classify

Evaluating Outcome Measures in Veterinary Physiotherapy with Particular Reference to the Treatment of Canine and Equine Joint Cases

Background: Veterinary physiotherapists provide postoperative care, rehabilitation, sports maintenance, and aged maintenance for their patients. Outcome measures are extensively used within human medicine, including physiotherapy, but a widely accepted issue in veterinary physiotherapy practice is that outcome measures lack sufficient evaluation with regard to intra- and inter-clinician comparisons. This project aimed to determine the quality of outcome measures being used in canine and equine physiotherapy practice and any disparities external factors cause. Methods: A structured scoping literature review consolidated current understanding and limitations. This was combined with a survey of qualified veterinary physiotherapists (n=40). Statistical analysis comprised descriptive statistics and Chi Squared analyses. Results: Key observations generated include (1) a lack of differences in application of outcome measures between veterinary physiotherapists with and without a human physiotherapy background, (2) enhanced utilisation of outcome measures by members of a registration body and (3) an overall skew towards subjective, rather than objective, outcome measure use. Limitations: Sample size and time for a secondary survey further exploring limitations. Conclusion: Recommendations on enhancing outcome measures in clinical practice include several technical measures, e.g. goniometers and pain scoring, and profession-wide initiatives, including the introduction of comprehensive CPD resources and reviews of regulatory and education bodies

Evaluating Outcome Measures in Veterinary Physiotherapy with Particular Reference to the Treatment of Canine and Equine Joint Cases

Background: Veterinary physiotherapists provide postoperative care, rehabilitation, sports maintenance, and aged maintenance for their patients. Outcome measures are extensively used within human medicine, including physiotherapy, but a widely accepted issue in veterinary physiotherapy practice is that outcome measures lack sufficient evaluation with regard to intra- and inter-clinician comparisons. This project aimed to determine the quality of outcome measures being used in canine and equine physiotherapy practice and any disparities external factors cause. Methods: A structured scoping literature review consolidated current understanding and limitations. This was combined with a survey of qualified veterinary physiotherapists (n=40). Statistical analysis comprised descriptive statistics and Chi Squared analyses. Results: Key observations generated include (1) a lack of differences in application of outcome measures between veterinary physiotherapists with and without a human physiotherapy background, (2) enhanced utilisation of outcome measures by members of a registration body and (3) an overall skew towards subjective, rather than objective, outcome measure use. Limitations: Sample size and time for a secondary survey further exploring limitations. Conclusion: Recommendations on enhancing outcome measures in clinical practice include several technical measures, e.g. goniometers and pain scoring, and profession-wide initiatives, including the introduction of comprehensive CPD resources and reviews of regulatory and education bodies

Reporting outcome measures in veterinary physiotherapy with particular reference to the treatment of canine and equine joint cases in the UK

Background: Outcome measures are extensively used within human physiotherapy, but a widely accepted issue in veterinary physiotherapy is that outcome measures lack sufficient evaluation and standardisation in terms of how they are implemented. This cross‐sectional study aimed to provide clarity on (1) the current selection of outcome measures in canine and equine physiotherapy and (2) investigate external influences on outcome measure selection, including comparative literature availability, professional memberships and background. Methods: A structured scoping literature review consolidated current understanding and limitations. This informed a survey of qualified veterinary physiotherapists (n = 40). The statistical analysis comprised descriptive statistics. Results: Key observations included (1) a lack of difference in outcome measure application between veterinary physiotherapists with and without a human physiotherapy background, (2) enhanced outcome measure utilisation by registry body members and (3) an overall skew towards subjective, rather than objective, outcome measure use. Limitations: The study was limited by the absence of a defined veterinary physiotherapist population and subsequent convenience sample size. Conclusion: The apparent skew towards subjective outcome measures highlights objective outcome measure underutilisation and the need for a more extensive evidence base. In conclusion, there is a need to develop comprehensive professional development resources promoting the use of repeatable outcome measures such as goniometers and the Liverpool osteoarthritis scoring

An evaluation of Bradfordizing effects

The purpose of this paper is to apply and evaluate the bibliometric method Bradfordizing for information retrieval (IR) experiments. Bradfordizing is used for generating core document sets for subject-specific questions and to reorder result sets from distributed searches. The method will be applied and tested in a controlled scenario of scientific literature databases from social and political sciences, economics, psychology and medical science (SOLIS, SoLit, USB Köln Opac, CSA Sociological Abstracts, World Affairs Online, Psyndex and Medline) and 164 standardized topics. An evaluation of the method and its effects is carried out in two laboratory-based information retrieval experiments (CLEF and KoMoHe) using a controlled document corpus and human relevance assessments. The results show that Bradfordizing is a very robust method for re-ranking the main document types (journal articles and monographs) in today’s digital libraries (DL). The IR tests show that relevance distributions after re-ranking improve at a significant level if articles in the core are compared with articles in the succeeding zones. The items in the core are significantly more often assessed as relevant, than items in zone 2 (z2) or zone 3 (z3). The improvements between the zones are statistically significant based on the Wilcoxon signed-rank test and the paired T-Test

The Open-Fracture Patient Evaluation Nationwide (OPEN) study: epidemiology of open fracture care in the UK

Aims Understanding of open fracture management is skewed due to reliance on small-number lower limb, specialist unit reports and large, unfocused registry data collections. To address this, we carried out the Open Fracture Patient Evaluation Nationwide (OPEN) study, and report the demographic details and the initial steps of care for patients admitted with open fractures in the UK. Methods Any patient admitted to hospital with an open fracture between 1 June 2021 and 30 September 2021 was included, excluding phalanges and isolated hand injuries. Institutional information governance approval was obtained at the lead site and all data entered using Research Electronic Data Capture. Demographic details, injury, fracture classification, and patient dispersal were detailed. Results In total, 1,175 patients (median age 47 years (interquartile range (IQR) 29 to 65), 61.0% male (n = 717)) were admitted across 51 sites. A total of 546 patients (47.1%) were employed, 5.4% (n = 63) were diabetic, and 28.8% (n = 335) were smokers. In total, 29.0% of patients (n = 341) had more than one injury and 4.8% (n = 56) had two or more open fractures, while 51.3% of fractures (n = 637) occurred in the lower leg. Fractures sustained in vehicle incidents and collisions are common (38.8%; n = 455) and typically seen in younger patients. A simple fall (35.0%; n = 410) is common in older people. Overall, 69.8% (n = 786) of patients were admitted directly to an orthoplastic centre, 23.0% (n = 259) were transferred to an orthoplastic centre after initial management elsewhere, and 7.2% were managed outwith specialist units (n = 81). Conclusion This study describes the epidemiology of open fractures in the UK. For a decade, orthopaedic surgeons have been practicing in a guideline-driven, network system without understanding the patient features, injury characteristics, or dispersal processes of the wider population. This work will inform care pathways as the UK looks to the future of trauma networks and guidelines, and how to optimize care for patients with open fractures

Does function fit structure? A ground truth for non-invasive neuroimaging.

There are now a number of non-invasive methods to image human brain function in-vivo. However, the accuracy of these images remains unknown and can currently only be estimated through the use of invasive recordings to generate a functional ground truth. Neuronal activity follows grey matter structure and accurate estimates of neuronal activity will have stronger support from accurate generative models of anatomy. Here we introduce a general framework that, for the first time, enables the spatial distortion of a functional brain image to be estimated empirically. We use a spherical harmonic decomposition to modulate each cortical hemisphere from its original form towards progressively simpler structures, ending in an ellipsoid. Functional estimates that are not supported by the simpler cortical structures have less inherent spatial distortion. This method allows us to compare directly between magnetoencephalography (MEG) source reconstructions based upon different assumption sets without recourse to functional ground truth

Physiotherapy for adults with joint hypermobility syndrome: A pilot randomised controlled trial

Background: Joint Hypermobility Syndrome (JHS) is a heritable disorder associated with laxity and pain in multiple joints. Physiotherapy is the mainstay of treatment but there is little research investigating its effectiveness. The aim of this study was therefore to conduct a pilot randomised controlled trial (RCT) to determine the feasibility of conducting a future definitive RCT. Methods: A comprehensive physiotherapy intervention was developed in conjunction with patients and healthcare professionals. It was then piloted and refined on the basis of patient and physiotherapist feedback. A parallel two-arm pilot RCT in two UK secondary care NHS Trusts compared 'Advice' against 'Advice & Physiotherapy'. Inclusion criteria were: >16 years, a diagnosis of JHS, and no other musculoskeletal conditions causing pain. The Advice intervention was a one-off session, supplemented by advice booklets from the Hypermobility Syndromes Association and Arthritis Research UK. All patients could ask questions specific to their circumstances and received tailored advice. Participants were then randomly allocated to 'Advice' (no further advice or physiotherapy) or 'Advice & Physiotherapy' (an additional six 30 minute sessions over 4 months). The Physiotherapy intervention was supported by a patient handbook and delivered on a one-to-one patient-therapist basis. It aimed to increase patients’ physical activity through developing knowledge, understanding and skills to better manage their condition. The primary outcome related to the feasibility of conducting a future definitive RCT. Qualitative interviews with patients and physiotherapists therefore formed a major component of data collection. Secondary outcomes included clinical measures (physical function, pain, global status, self-reported joint count, quality of life, exercise self-efficacy and adverse events); resource use (to estimate cost-effectiveness); and an estimate of the value of information from a future RCT. Outcomes were recorded at baseline, 4 months (at the end of physiotherapy) and 7 months (3 months following physiotherapy). Results: A total of n=29 participants were recruited to the pilot RCT. Recruitment was challenging, primarily due to a perceived lack of equipoise between Advice and Physiotherapy. The qualitative evaluation provided very clear guidance to inform a future RCT, including enhancement of the Advice intervention. Some patients reported that the Advice intervention was useful and the Physiotherapy intervention was evaluated very positively. The rate of return of questionnaires was low within the Advice group but reasonable in the Physiotherapy group. The Physiotherapy intervention showed evidence of promise in terms of primary and secondary clinical outcomes. The Advice arm experienced more adverse events. The value of information estimate indicated the potential for high value from a future RCT. Conclusion: A future definitive RCT of physiotherapy for JHS seems feasible, although the Advice intervention should be made more robust to address perceived equipoise and subsequent attrition