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Pharmacometric methods in clinical toxicology: an application to paracetamol overdose
Full text linkPharmacometric methods have been highlighted in clinical toxicology studies in recent years. These methods provide a quantitative understanding of the relationship between physiology and related pathologies and pharmacology. Drug overdose is an important public health problem in the area of clinical toxicology and paracetamol overdose, either intentional or unintentional, is the leading cause of acute liver failure in many countries. However, there is a lack of a comprehensive understanding of the mechanisms of hepatotoxicity and optimal treatment strategies under various paracetamol overdose scenarios as a whole. The overall aim of this thesis was to apply pharmacometric methods in clinical toxicology to understand the injury caused by drug overdose and its treatment, using paracetamol overdose as a motivating example.
A general semi-mechanistic model for cell death and biomarker release from injured tissues was developed (Chapter 2). Three components were included: (1) natural tissue turnover, (2) biomarker release after cell death and its movement from tissue to blood, (3) different insult mechanisms. The general model has sufficient flexibility to quantify various kinetic behaviours of biomarker release after tissue damage in a variety of clinical toxicology and pharmacology studies. The developed model is the first general mathematical representation of biomarker release after cellular insult and provides a new framework to facilitate a better understanding of the underlying mechanisms of toxicity events and injury processes in drug overdose.
The importance of sulfation in understanding the risk of liver toxicity secondary to paracetamol overdose was emphasised (Chapter 3). A thought model simulation illustrated that insufficient sulfation led to a shift in metabolism of paracetamol to toxic oxidation pathway and patients with low sulfate reserves may be at higher risk of paracetamol toxicity. Serum sulfate, a measurable substrate on the causal path of paracetamol hepatotoxicity, was proposed as a novel predictor for paracetamol toxicity and its treatment.
A population pharmacokinetic model for plasma concentrations of immediate-release (IR) and modified-release (MR) paracetamol and its major metabolites was developed (Chapter 4). MR paracetamol showed a slow absorption after a supratherapeutic dose intake. Model simulations showed that errors may exist in toxicity assessment based on the 150mg/L nomograms for overdose with MR paracetamol. These findings support the key update in the latest guidelines for Australia and New Zealand, where the nomogram line was no longer recommended for interpreting MR paracetamol overdose.
A 54-state quantitative systems pharmacology (QSP) model for paracetamol overdose and its rescue was developed by integrating key model components investigated in this thesis (Chapter 2 to Chapter 4) as well as prior knowledge from the literature. This unique QSP model provided a quantitative understanding of the whole causal pathway of paracetamol-induced hepatotoxicity and its treatment with the antidote N-acetylcysteine (NAC) in both IR and MR paracetamol. Various mechanisms that may affect paracetamol hepatotoxicity were explored and two subpopulations with different susceptibilities to N-acetyl-para-benzoquinone imine (NAPQI) toxicity were identified for the first time. This work identified a knowledge gap in paracetamol hepatotoxicity and further studies are needed to address this issue.
A utility analysis was performed to explore the optimal NAC regimens in various paracetamol overdose scenarios based on the QSP model simulations. Key attributes including the efficacy of protecting liver injury and the side effects caused by high exposure were considered in the utility function. It was found that slow input or impaired elimination of paracetamol could be the driving factors for NAC prolonged infusion, suggesting that larger dose or longer duration of NAC infusion is required in treating MR paracetamol overdose or massive overdose.
In conclusion, pharmacometric methods applied in this thesis provided quantitative and mechanistic insights to drug overdose induced toxicity, using paracetamol overdose as an example. A new general framework to understand and quantify biomarker release behaviours after tissue injury was developed and can be adopted in various clinical toxicology studies. The QSP model for paracetamol overdose and rescue improved the understanding of mechanisms in paracetamol-induced hepatotoxicity and its treatment with the antidote NAC. An important future work is to optimise NAC regimens in various paracetamol overdose scenarios
Ko au te awa, ko te awa ko au: The Connection Between Kāi Tahu/Kāti Māmoe Identity and Cultural Landscapes in Murihiku
No full textFor takata whenua, landscapes tell the stories of our whakapapa and experiences as whānau, hapū, and iwi. How we see how whenua interacts with these identities comes down to personal interpretation, where our experiences as takata whenua influence, but do not necessarily dictate, the connection between our Māoritaka and the whenua.
Using qualitative research methods, data was retrieved from unpublished manuscripts written by the authors Nana, Marna Dunn, in c. 2000. Interviews were also conducted with a selection of her descendants. These individuals are mana whenua of Makāti (Chaslands Mistake), located on the Catlins coast. Using this data, this research has investigated the connection that Dunn, her tīpuna, and her descendants, have to Makāti, and how this connection influences, and is influenced by, their Kāi Tahutaka/Kāti Māmoetaka. This research centres around the methodology of autoethnography, where the author embraces the self-reflective perspective of the subject matter. The author acknowledges the connection between the self and the research, and uses this for their benefit.
Māori protest movements from Parihaka in the nineteenth century, Takaparawhā (Bastion Point) in the 1970s, and Ihumātao since 2016, illustrate that pre-colonial connections to the whenua are still crucial for Māori. This research will demonstrate how these contemporary connections to the whenua fit into a Kāi Tahu/Kāti Māmoe context, using Makāti and the Dunn whānau as a case study. It is generally agreed that Māori kaupapa surrounding the whenua differs from a European viewpoint. This research will explore how Kāi Tahu and Kāti Māmoe specifically view the landscape, and how this does or does not connect with their Kāi Tahu/Kāti Māmoe identity
Challenges to implementing outcome measures in Nepal
No full textPatient-reported outcome measures (PROMs) are essential to evidence-based practice but their implementation is a significant challenge in low- and middle-income countries. In this thesis, I aimed to understand how the use and acceptability of PROMs can be improved in Nepal.
First, I sought to understand context-specific barriers and facilitators to outcome measure use in Nepal. I conducted focus group discussions with 24 physiotherapists and an online survey of 125 physiotherapists. Major barriers reported were lack of time, inadequate outcome measures in local languages, and inability to follow-up with patients. Participants expressed a need for external regulation and data transparency.
Second, I explored if the Patient-Specific Functional Scale (PSFS) might be useful in Nepal. This is assessed using two main criteria: (a) is the measure acceptable and feasible for use; and (b) does it have sufficient measurement properties. The PSFS is a PROM where patients nominate activities they have difficulty performing and rate them on a scale of 0-10. However, in a previous study from Nepal I found up to 64% of participants made errors in a 0-10 pain scale; verbal and faces scales were better understood. Hence, I hypothesised that an alternative verbal response scale might make the Nepali version of the PSFS (i.e. PSFS-NP) more acceptable. Therefore, I developed two verbal response scales for the PSFS-NP (i.e. v-PSFS) after interviewing 42 individuals. I then pre-tested the v-PSFS and PSFS-NP on 119 individuals. I found that although the verbal scales were more preferred (50% versus 12%), there was no difference in error rates between numeric (34%) and verbal scales (32% and 36%). Higher error rates were associated with greater age, fewer years of education, and inexperience with numeric scales.
Next, I sought to assess the measurement properties of PSFS in non-musculoskeletal conditions in two studies. So for the third study, I analysed the content validity of the PSFS in neurological and cardiopulmonary conditions by comparing data from the PSFS in study two with the International Classification of Functioning, Disability and Health (ICF), the ICF core sets and validated condition-specific measures. I found that the PSFS predominantly assesses the Activities and Participation component of the ICF, 31% to 79% of the responses in the PSFS overlap with condition-specific outcome measures, and the Brief Core Sets covered 40%-71% of participants' responses whereas the Comprehensive Core Sets covered 67%-100% of responses.
Lastly, I updated the previous systematic review on measurement properties and current uses of the PSFS using the COSMIN guideline. After searching 11 databases, two independent reviewers screened all records, extracted data, and performed risk of bias assessments and GRADE assessments. Of 985 articles screened, 57 articles on measurement properties and 255 articles on the use of PSFS were included. The PSFS demonstrated ‘sufficient’ test-retest reliability in musculoskeletal (22 studies, 845 participants, low to moderate-quality) and non-musculoskeletal conditions (6 studies, 197 participants, very low-quality), ‘insufficient’ construct validity as a measure of physical function (21 studies, 2 945 participants, low to moderate-quality evidence), and ‘sufficient’ responsiveness (32 studies, 13 770 participants, moderate to high-quality evidence). The PSFS was used in 87 unique health conditions, some without prior evidence of validity.
The findings in this thesis highlight the context-specific challenges and future needs for the implementation of PROMs in Nepal, especially the need for guidelines. Additionally, one out of three participants in the study made errors in using the PSFS despite a verbal scale and even with an interview format; error rates were higher among participants with low literacy. The findings call for actions to identify ways to improve the validity of using PROMs in people with low literacy. I discuss alternatives that might be useful based on previous literature
Heritage Buildings: A Tool for Supporting the Revitalisation of Central Business Districts in Aotearoa New Zealand?
Full text linkAside from a few landmark buildings, the bulk of Aotearoa New Zealand’s built heritage is made up of commercial and industrial heritage buildings which pepper the country’s central business district (CBD) streetscapes. Yet, these ‘good old buildings’ have a vast history of being gravely undervalued in terms of their heritage value and place within a CBD environment. To the naked eye, their often less grand appearance and sometimes outdated functions have caused many over time to simply dismiss them as barriers to progress or unworthy of protection. However, driven by key paradigm shifts within the heritage conservation discipline, new perceptions regarding their value have recently begun to emerge. Whereby cities are starting to see their collections of commercial and industrial heritage buildings as resources they can use to support wider strategies aimed at revitalising their CBDs.
This research focuses on exploring this evolving relationship between heritage conservation and the planning process by investigating the role heritage buildings play in supporting the revitalisation of CBDs in Aotearoa New Zealand’s lower South Island. To do this, the research looks at the three cities of the lower South Island – Timaru, Dunedin and Invercargill. Due to a history of low development pressure, each of the three cities has a CBD that is still heavily defined by the character of their commercial and industrial heritage buildings. However, this same lack of development pressure has meant that in recent years their CBDs have received fewer upgrades, leaving areas in need of a facelift. As a response each city now currently has a City Centre Revitalisation Plan (CCRP) in place aimed at breathing new life back into their CBDs. Whilst each CCRP emphasises the importance of conserving heritage buildings, each city has taken a different approach to what role they have given their buildings within wider revitalisation efforts.
Using qualitative methods in the form of key informant interviews and site observations, the research found that commercial and industrial heritage buildings are valuable resources for supporting CBD revitalisation. It was revealed that if local authorities focus on giving not only their individual heritage buildings, but wider collections a new use and value, they have the potential to make contributions to the social, economic and environmental dimensions of a city. These benefits were observed in practice in each of the three case study locations. Timaru is fostering a sense of place by using its heritage buildings in the creation of a heritage hub and as a canvas for street art; Dunedin is using its heritage buildings to spur economic activity by creating points of difference across four quarters of their CBD; and Invercargill is using the intervention of façadism in an attempt to create a vibrant CBD underpinned by both historic and modern fabric. However, this research also uncovered that there are a number of challenges which impact the role heritage buildings play in revitalisation efforts. Namely, each city has been mostly successful in keeping their heritage buildings but struggle to encourage owners to go the extra mile in undertaking further visual or functional enhancements to their buildings
Effect of Coenzyme Q10 and MitoQ on Mitochondrial Function in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome
Full text linkIntroduction
Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex and severe condition with unknown aetiology which affects over 20,000 people in New Zealand. Only in the last 20 years has it been considered to have a biological basis as opposed to being a psychiatric condition, and this has been strongly confirmed in the last 5 years. However, no specific aetiology or treatments have been found. There are reports the essential component of the electron transport chain, Coenzyme Q10 (CoQ10), is decreased in plasma and in peripheral blood mononuclear cells (PBMCs) of patients with ME/CFS, and that there may be contributing or exacerbating dysfunctions in mitochondrial and metabolic pathways. CoQ10, and the modified analogue that targets the molecule to mitochondria, MitoQ, have been investigated as potential therapies in ME/CFS. The aim of this research is to investigate the relationship between CoQ10 levels and mitochondrial function in ME/CFS and investigate the impact of CoQ10 and MitoQ on mitochondrial function.
Methods
Two ME/CFS cohorts totalling 23 participants were investigated in this research study, and there were 22 age/sex matched healthy controls. Plasma and purified PBMCs from the participants were analysed using an ELISA kit that could detect CoQ10.The mitochondrial functions of the participants were measured with a mitochondrial ‘stress test’ on the Seahorse Analyzer, before and after incubation with CoQ10 and MitoQ.
Results
Surprisingly, there was no significant difference in plasma or PBMC CoQ10 levels between the ME/CFS patients and the controls as previously reported, although the well-established decrease with age was seen in ME/CFS and control cohorts. PBMC CoQ10 levels however, of both patients and controls showed an association with their mitochondrial function. Incubation of CoQ10 in PBMCs enhanced the mitochondrial functions in ME/CFS in patients, however, the analogue MitoQ incubation, at the concentration used, caused major uncoupling of electron transfer from oxidative phosphorylation. An exploratory longitudinal supplementation study with the nutraceutical MitoQ in one patient showed an improvement in mitochondrial function by two months that was sustained through to month four, but then returned to pre -supplementation levels, possibly as a result of the stress of surgery.
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Discussion
Our results demonstrate that plasma or PBMC CoQ10 concentration is not a distinct biomarker for ME/CFS, despite the low levels reported in other studies. The results from the incubation of PBMCs suggest CoQ10 can act to restore mitochondrial respiration in ME/CFS, which may result in positive clinical benefits, especially in individuals with low CoQ10. Given that the levels of CoQ10 can be influenced indirectly by lifestyle factors, and ME/CFS is a severely fatiguing illness that affects lifestyle practices, the study needs to be repeated with closer consideration given to confounding variables such as exercise and diet, and with larger cohorts. MitoQ needs to be tested in vitro at a much lower concentration range than that chosen for this study to avoid this undesirable uncoupling that masks any possible positive effects on functions involved in energy production. Further, a larger longitudinal supplementary study of MitoQ would be of benefit to investigate its potential in ME/CFS.
Conclusion
ME/CFS patients of a New Zealand cohort do not have lower plasma or immune cell concentrations of CoQ compared with an age/gender matched healthy controls as previously reported for another cohort. Differences in the bioenergetic capacity of mitochondria for the New Zealand ME/CFS patient group compared with the healthy controls were: increased rate of basal but decreased rate of maximum oxygen consumption, decreased ATP production, decreased spare respiratory capacity that would impact on the ability to respond to stress, and an increase in proton leak. These changes suggest there is a dysfunction in mitochondrial energy production in ME/CFS
Patient preferences for dose tapering of biologics in rheumatoid arthritis treatment: A discrete choice experiment approach
No full textBackground and objective: Tapering of biologics dose is a safe and feasible approach for people with rheumatoid arthritis (RA) in remission. However, the appeal of tapering needs to be balanced against the risks of disease flare-up. Little is currently known about how the preferences of people with RA would influence their decision to accept biologics tapering. This thesis aimed to elicit and evaluate the preferences of people with RA for biologics tapering.
Methods: This thesis employed a three-phased mixed-methods study design. In phase 1, people with RA were invited to participate in focus groups (FGs) (n=43) and individual interviews (n=2) to explore their perspectives towards biologics tapering. Thematic analysis was applied to generate themes of what patients considered in their choice of tapering biologic. The next phase described the development of a discrete choice experiment (DCE) survey according to good research practices, which was piloted among patients (n=16). Think aloud (TA) procedures and FGs were employed to establish the feasibility of a DCE as an instrument to elicit preferences for tapering of biologics. In phase 3, participants with RA (n=142) completed an online DCE survey consisting of 14 scenarios, asking their preferences when given three hypothetical treatment options involving varying frequency of biologics dosing, chances of adverse effects, chances of regaining disease control and healthcare service-related features. Preference weights were estimated using a panel mixed logit model.
Results: Thematic analysis revealed five overarching themes describing: (i) fear of the uncertain outcomes of tapering, (ii) prioritising quality of life from continuing biologics over the risk of adverse effects, (iii) inconvenience of taking biologics regularly, (iv) assurance of prompt access to healthcare after disease flare and (v) preferences for involvement in decision-making. The themes were used to guide the subsequent phase of developing attributes for DCE. Findings from TA and FG data indicated the DCE was well-received by participants and was an acceptable instrument to elicit preferences. Most participants understood the context of a DCE, were able to engage with the choice task while employing various decision-making strategies when making their choice. Feedback received were used to improve and prepare the DCE for the next phase. In phase 3, the DCE data revealed that two attributes with the greatest impact on the preferences for tapering were frequency of biologics dosing (mean relative importance:1.0, 95%CI 0.79-1.20) and the chance of disease flare (mean relative importance:0.64, 95%CI 0.49-0.79). Time to see the rheumatology team after a flare was ranked the least important among the seven attributes. Participants were willing to accept a 25.3% to 50.2% increase in the chance of disease flare in exchange for reducing the frequency of treatment, the chance of serious infection and skin cancer. The predicted uptake of biologic tapering was high among people with RA, suggesting biologics tapering was a favoured option.
Conclusions: This thesis addresses an important research gap about how people with RA make decisions and trade-offs between the benefits and risks of tapering their biologics. The evidence presented provides novel insights that have implications for clinical practice and policy making about biologic tapering
The experiences of internationally qualified nurses working in a publicly-funded tertiary hospital in New Zealand: A qualitative descriptive study
Full text linkIn most developed countries, the need for Registered Nurses has seen a dramatic increase. Thus, these countries turn overseas to attract migrant nurses into their workforce, especially for tertiary hospitals that are consistently understaffed. Although numerous studies have explored the experiences of such nurses in developed nations, there has been limited research done in the New Zealand context, especially in the acute public hospital setting. The aim of this research is to explore and describe the experiences of Internationally Qualified Nurses (IQNs) working in a publicly-funded tertiary hospital in New Zealand. The qualitative descriptive method was used to illuminate the IQNs’ experiences working in a New Zealand public hospital. A purposive sampling using maximum variation and snowball sampling methods was utilised to recruit IQNs employed in the tertiary hospital. From 12 one-on-one, semi- structured face-to-face interviews, which were analysed using Braun and Clarke’s method of thematic analysis, the following three themes, Hospital navigation, The ambivalent nurse and The outsider, were found. This study concludes that while IQNs encounter issues in their new work environment, they remain integral to the safe and effective delivery of nursing care, especially within the New Zealand hospital setting
The Rakiura Dune Restoration Programme (1999-2021): Lessons Learned from 21 Years of Operations, Monitoring & Research
Full text linkThis book was prepared to celebrate 21 years of dune restoration on Rakiura (Stewart Island)
by the Department of Conservation and former government agencies. The focus is the period
since aerial spray operations commenced at Doughboy Bay in February 1999; however, the
foundation for this work was laid in the early 1980s, during a period of ground control of
marram grass (Ammophila arenaria) on Whenua Hou (Codfish Island), and beaches on the
the northeast coast of Rakiura. The Rakiura Dune Restoration Programme has since evolved to
encompass almost all the major dune systems on Rakiura, making it the largest and longest-running
coastal dune restoration programme in the world
Forcing Neural Networks to Behave Using Interpretability Methods
Full text linkArtificial neural networks are excellent machine learning models but are often referred to as “black boxes”, meaning that the reasoning behind their decisions is obscured. The field of neural network interpretability attempts to explain why these models make the decisions they do. In my research I combine methods for interpreting neural network decisions with the neural network training process to develop networks that learn to solve problems in a specified way. Rather than training neural networks only to maximise prediction accuracy, I train the networks while enforcing a constraint that the network’s behaviour interpretation matches our human expectations, with the goal of improving our ability to understand and trust neural networks. Finally, I explore an alternative training objective that seeks to replicate the effects of this guided training method but without the need for a predefined set of human expectations
Double Vision: Comparing Community Aspirations to Council Objectives for the Future of New Plymouth
Full text linkThis thesis explores the alignment of community aspirations for long-term built
environment objectives with the vision set out by Council officers through district planning
documents. It looks in detail at the aspects of city centres, growth and housing for the city of
New Plymouth, and how the aspirations of the Council and the community coalesce or diverge.
In the context of a shifting urban atmosphere, the ongoing impacts on the COVID-19 pandemic,
online retailing, national policy statements and the climate crisis must all be considered when
looking to the future of cities. The particular challenge of aligning community expectations
with expert planning measures is at the core of consultation efforts in the formal planning
process. A qualitative questionnaire (community survey) and key informant interviews were
used to gauge community aspirations and a policy analysis and interviews to establish the
Council vision. The results of the community survey show the diversity of views within even a
small city like New Plymouth. Strong interest in a wider range of housing types, including
medium density apartments and one- or two-bedroom dwellings currently lacking in the city,
are juxtaposed with a continuing desire for rural lifestyle living. The low-key urban lifestyle
offered by New Plymouth city appeals in contrast to larger urban centres like Wellington,
Hamilton and Auckland. However, the expected growth of the city boundary to accommodate
further single-family dwellings has put the character of the ‘small city’ into question. Council
continues to face pressures to unlock land for residential development. The ailing city centre,
in no way unique to New Plymouth, was the focus of several suggested solutions, from
evolution to revolution. New Plymouth locals expressed a variety of expectations, though
overall aspirations are for increased social capacity and green space in the city centre. These
findings are expected to be of use to New Plymouth District Council and related agencies in
providing a greater understanding of community perspectives on the expectations and
challenges for the future of New Plymouth’s urban form