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Assessing medication appropriateness in older adults and recommending therapeutic alternatives in individuals with dementia
No full textOlder adults comprise a significant proportion of the population of New Zealand (NZ) and are known to be prescribed the highest number of medications. Several medications have to be prescribed with caution in older adults due to their compromised biological functions that can impact and reduce drug clearance. Potentially inappropriate medications (PIMs) may be defined as the prescription of drugs where the risks outweigh the clinical benefits or there may be under-prescribing of beneficial treatments. Over the last 3 decades, the global prevalence of prescribing PIMs has been reported from 5.2% to over 85%. PIMS may be identified by the application of criterion based explicit screening tools, of which the Beers criteria are commonly used to assess potentially inappropriate prescribing of medications in older adults.
The overarching aim of the thesis was to assess medication appropriateness in older adults and suggest therapeutic alternatives for the currently prescribed medications with anticholinergic properties in individuals with dementia.
In the first phase of our project, a literature review of the existing tools for reducing PIMS was undertaken to assess the merits and demerits of each tool with a view to suggest methods to reduce inappropriate prescribing which include medication review for each individual, deprescribing, and developing guidelines for appropriate prescribing. Through the literature review of existing explicit and implicit tools for identifying PIMS prescription, we could substantiate that the Beers criteria is a comprehensive screening tool that has been validated by a systematic literature review, evaluated by a Delphi consensus, and has shown good predictor validity in different settings. Hence, the Beers criteria was utilized for all the analytical studies conducted thereafter.
We observed a high prevalence of prescription of potentially inappropriate medications in community dwelling older adults in NZ utilizing the Beers criteria and the PHARMS- interRAI-HC dataset. The International Resident Assessment Instrument-Home Care (interRAI-HC) is a standardized and internationally validated comprehensive geriatric risk assessment for older adults living in the community with complex care needs. In NZ a standardized interRAI-HC has been implemented for conducting all community care assessments in older adults needing publicly funded long-term community services or aged residential care. The ubiquitous nature of the interRAI-HC assessment accounts for numerous social, psychological, and clinical risk factors when examining health outcomes in older adults. The interRAI-HC database is linked to several NZ Ministry of Health national collections, including prescription use [the Pharmaceutical Claims Data Mart (PHARMS database)], hospital discharges (National Minimum Dataset), mortality data, and laboratory collections. The Pharmaceutical Claims Data Mart (PHARMS) is utilized by the Pharmaceutical Management Agency (PHARMAC) and the Ministry of Health, NZ to remunerate pharmacists for dispensing medications that are publicly funded, as well as to help PHARMAC in its management of the national budget of medications. The Ministry of Health provides PHARMS extracts with individual‐level prescription data along with the unique encrypted National Health Index (NHI) number for each individual.
We then analysed the factors associated with prescribing PIMS, and found that there was a higher probability of prescribing PIMs in males, individuals aged 65-75 years, NZ Europeans, those who were prescribed a greater number of medications, and those who reported poor self-health, compared to their counter-parts. Individuals diagnosed with certain disorders like dementia, insomnia, depression, cancer, anxiety; or those who were hospitalized were more likely to be prescribed PIMs than the other individuals.
Dementia is one of the principal syndromes linked with disability and dependence among older adults, and is a major challenge to individuals, communities, and societies worldwide. The global incidence of dementia is expected to rise to 81 million by 2040, primarily due to the progressive nature of the disorder, which involves worsening neurocognitive impairment and loss of basic functions in daily life. In 2016, the estimated prevalence of dementia in NZ was more than 62,000, which is predicted to increase to 170,000 in 2050. In one of our studies utilizing the PHARMS and interRAI-HC linked dataset, we observed that the prevalence of dementia was 13%, which was diagnosed by the Minimum Dataset Cognitive Performance Scale. 67% of the individuals with dementia were prescribed PIMs, and the medications with anticholinergic properties (MAP) constituted 60%.
MAP bind to the muscarinic receptors and block acetylcholine neurotransmission, which regulates many central nervous system (CNS) and peripheral nervous system (PNS) actions MAP are prescribed excessively for Parkinson’s disease, depression, overactive bladder, allergies, inflammatory bowel disorders, and epilepsy. MAP are specifically associated with negative outcomes in older adults diagnosed with dementia, such as worsening of cognitive function, sustained cognitive defects, and increased mortality. They are notorious for their central side effects such as impaired concentration, confusion, attention deficit, and impairment of memory, and peripheral side effects, which include dry mouth, constipation, urinary retention, and bowel obstruction. MAP may also inhibit the potential benefits of cholinesterase inhibitors such as Donepezil, Rivastigmine, and Galantamine, which is the main pharmacological class, currently approved for the management of dementia.
Based on the current literature review of the anticholinergic burden (ACB) scales and serum anticholinergic activity of various medications, we collated known information of the level of anticholinergic activity for medications listed in the NZ formulary, and developed recommendations for prescribers, focussing on pharmacological alternatives for the currently prescribed MAP for older adults with dementia presenting with co-morbidities. Medications were classified according to the ATC-DDD methodology. We sorted all the medications based on the high/moderate anticholinergic activity, and their low/no anticholinergic activity substitutes. To achieve an adequately comprehensive range of medications, all the existing scales measuring the anticholinergic activity of various medications were utilized. The current intervention was an attempt to identify medications with high or moderate anticholinergic activity (HOMAA) and substitute a low or no anticholinergic activity (LONAA) alternative for them wherever possible, according to the therapeutic classification of medications. The ACB is the cumulative effect of prescription of MAP to each individual. The tool was applied to the New Zealand’s PHARMS and interRAI-HC linked dataset to test the amendment in the ACB. Of the 75,410 community dwelling older adults aged 65 and above, 17 % were diagnosed with dementia. Almost half of these individuals were prescribed at least one MAP. Using a Paired-Samples Test, we compared the results of the ACB before and after the theoretical intervention of the pharmacological alternatives to MAP. By incorporation of the recommendations, we observed a significant reduction of the ACB by 0.49 (95% CI, 0.47-0.51).
The implementation of the recommendations for prescribing therapeutic alternatives to anticholinergic medications in this vulnerable population along with an awareness created among prescribers has the potential to reduce untoward effects associated with the prescription of these medications, slower cognitive decline, and decrease the risk of mortality; supporting individuals with dementia to live longer independently
Health and wellbeing of under-five year olds in New Zealand 2017
No full textKeeping their children healthy and safe is one of the most important responsibilities parents and caregivers have. It requires knowledge and skills that are acquired in a number of ways: from families and friends, through cultural heritage, at school, from health professionals, through reading, and through audio-visual media, such as television, radio and the internet.
The knowledge and skills people need to meet the complex demands of health and healthcare systems in a modern society have been conceptualised as health literacy.1 Being health literate means having the knowledge, skills, motivation and confidence to accurately assess the health of yourself, your family and your community, to understand the factors that influence health at each of these levels, to take responsibility for health, and to act appropriately.1 It means being able to make well-informed decisions on personal health matters like nutrition, choice of healthcare providers, preventive interventions such as immunisation and screening, and treatment options for health problems.1 It also means being able to form informed opinions on public health issues, such as air pollution, the safety of the water supply, workplace health and safety, the quality of food offered in school canteens, the location of liquor outlets, and the social and economic determinants of health, and being able to use political processes to affect government policy relating to such matters.1-3
When faced with a personal health problem, a health literate person can recognise symptoms that warrant medical attention, seek and obtain help from the health system, make an informed choice if they are offered treatment options, and understand and follow the advice and treatment plan they are given. They can, for example, use the information on the label to determine the correct dose of liquid medicine to give their child4, or understand informed consent documents.5 They can carry out health-related tasks requiring numeracy skills, such as understanding food labels6, measuring blood sugar7, and comparing the risks of different treatment options8. They can make a phone call to make an appointment with a healthcare provider, arrange time off work to attend the appointment, get themselves to the health service, and interact confidently with health professionals by answering questions, providing a history, and asking questions about things they do not understand.9
According to the World Health Organisation, health literacy is one of the three key elements of health promotion, together with healthy cities and good governance.10 As will be explained further, many people have poor health literacy and this is a major contributor to poor health outcomes and to health inequities between different population groups. In their 2015 discussion paper Health literacy: A necessary element for achieving health equity11, Logan et al. made the following three key points about health literacy and health disparities:
Health literacy is intrinsically linked to both an individual’s and a community’s socioeconomic context, and is a powerful mediator of the social determinants of health
Health literacy interventions are viable options among other evidence-based strategies to address social adversity and environmental health determinants and should be considered when assessing meaningful actions to address health disparities
Health literacy interventions and practices contribute to reducing health disparities, which fosters health equity and social justice.
This article discusses the research on health literacy and its relation to health outcomes, the research on interventions to improve health outcomes for people with low health literacy, and how the health system can reduce the health literacy demands it places on patients and better serve patients with low health literacy
Distribution, population structure, social organisation, and behaviour of sperm whales off the Kaikoura Coast
No full textThe distribution, population structure, social organisation, and behaviour ofsperm whales (Physeter macrocephalus) was investigated off the Kaikoura coast between spring 1990 and summer 1992. Acoustic surveys of uniform coverage design, stereophotogrammetry, and identification photographs were used to carry out this investigation.
The abundance of whales peaked in winter, when significantly more whales were heard during acoustic surveys. Data collected on seasonal distribution and habitat partitioning between large and small males indicate an inshore peak in abundance of large males during winter. Whaling data gathered in this area and knowledge of local fishing trends suggest that this may be in response to movements of groper.
The development of a simple, accurate, boat-based stereophotogrammetry system allowed us to make size estimates for 41 individually identified sperm whales. Length estimates for these whales ranged from 8.69 metres to 14.95 metres with median 95% confidence limits of± 0.46 metres.
Likely sex, age, and maturity levels were assigned for all measured and identified whales in the population. These assignments were based on our length estimates, presence or absence of a dorsal callus and an age/length key. Dorsal calluses were observed on 24.4% of whales believed to be females, immatures and pubertal males. Our data indicate that the population of sperm whales off the Kaikoura coast was largely comprised of young males between the ages of about 10 and 20 years. Most of the whales were in the age range of pubertal males, with five males being in the sexually mature age range, and three in the socially mature age range. There were also a few small whales whose sizes suggest they may be females or immature males.
Associations among whales were weak. The majority of encounters were with single whales. Large groups were rarely seen, and whales seen in groups tended to be of similar size. Breaches, lobtails, and codas, which are believed to serve in social communication, were very infrequent.
The whales appeared to be spending most of their time feeding. Dives lasting an average of 40 minutes were typically followed by a c. 10 minute resting period at the surface. Whales approached while at the surface sometimes exhibited avoidance reactions to approaching vessels by turning away or shallow diving
Prolific structures in combinatorial classes
No full textUnder what circumstances might every extension of a combinatorial structure contain more copies of another one than the original did? This property, which we call prolificity, holds universally in some cases (e.g., finite linear orders) and only trivially in others (e.g., permutations). Integer compositions, or equivalently layered permutations, provide a middle ground. In that setting, there are prolific compositions for a given pattern if and only if that pattern begins and ends with 1. For each pattern, there are methods that identify conditions that allow classification of the texts that are prolific for the pattern. This notion is also extendable to other combinatorial classes. In the context of permutations that are sums of cycles we can also establish minimal elements for the set of prolific permutations based on the bijective correspondence between these permutations and compositions, with a slightly different containment order. We also take a brief step into the more general world of permutations that avoid the pattern 321 and attempt to establish some preliminary results
Activation of the cardiac non-neuronal cholinergic system prevents type-1 diabetes-induced cardiovascular dysfunction
No full textThe cardiac non-neuronal cholinergic system (cNNCS) is a newly described system where the cardiomyocytes possess the ability to synthesise and release acetylcholine (ACh) that acts in an auto-/paracrine manner to induce cardioprotective effects. In this study, we determined the effects of type-1 diabetes mellitus (T1DM) on the expression of the cNNCS components namely choline acetyltransferase (ChAT), choline transporter-1 (CHT-1: rate-limiting step of ACh synthesis), vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) which synthesise, release and degrade acetylcholine (ACh) respectively. Secondly, we determine the potential therapeutic effect of activation of the cNNCS in preventing T1DM induced cardiovascular dysfunction. T1DM was chemically induced by injection of low dose streptozotocin (STZ, 50mg/kg, i.p) over five consecutive days in C57Bl6 mice (T1DM; n=6) by our collaborator Prof Yoshihiko Kakinuma at Nippon Medical School, Japan. Age-matched healthy mice served as controls (ND; n=6). To determine the effects of activation of the cNNCS on T1DM, mice with cardiomyocyte-specific overexpression of the ChAT gene in the ventricles were injected with STZ to induce T1DM (ChAT-TG-T1DM; n=6). The western blotting analysis demonstrated that CHT-1 expression in T1DM mice at 16-weeks after STZ injection was significantly decreased. Interestingly, the western blotting analysis in T1DM mice compared to ND mice showed marked impairment in the downstream targets of pro-survival AKT pathway such as pAkt/Akt (activate mammalian target of rapamycin 1/2 to reduce fibrosis) and Bcl-2 (anti-apoptotic protein) at all time points. Further, evaluating apoptosis (determined by TUNEL positive nuclei) and fibrosis (determined by Picro-Sirius staining) showed a significant increase in apoptotic and fibrotic area at all time points. All these consequently resulted in T1DM-induced cardiac dysfunction, as reflected by the manifestation of both diastolic (reduced ejection fraction, increased end-diastolic volume) and systolic dysfunction (increased end-systolic volume). However, at the same time, western blot analysis in ChAT-TG-T1DM mice compared to T1DM mice resulted in a significant increase in CHT-1 along with an increase in pAkt and Bcl-2 expression. Moreover, apoptosis and fibrosis were significantly decreased in ChAT-TG-T1DM mice compared to T1DM mice preventing cardiac dysfunction. In conclusion, our results provide the first evidence that the cNNCS is altered in the T1DM heart and activation of the cNNCS prevented the alterations, to improve cardiac function and reduce apoptosis and fibrosis. Taken together, targeting cNNCS to increase the availability of ACh can be a potential therapeutic intervention, which will prevent the development of cardiac dysfunction in type 1 diabetic heart
Biomimetic leg design and passive dynamics of Dolomedes aquaticus
No full textSpiders provide working models for agile, efficient miniature passive-dynamic robots. Joints are extended by haemoplymph (hydraulic) pressure and flexed by muscle-tendon systems. Muscle contraction in the prosoma leads to an increase in hydraulic pressure and subsequently leg extension. Analysis of body kinematics the New Zealand fishing spider, Dolomedes aquaticus indicates that elastic plates around the joints absorb energy from the ground reaction force when the force vector points backwards (i.e. would decelerate the spider’s body in the direction of locomotion) and release it to provide forward thrust as the leg swings backwards. In addition to improving energy efficiency, this mechanism improves stability by passively absorbing energy from unpredictable foot-ground impacts during locomotion on uneven terrain. These principles guided an iterative design methodology using a combination of 3D modelling software and 3D printing techniques. I compared and contrasted compliant joints made of a variety of plastic materials. The final 3D-printed spider leg prototype has a stiff ABS exoskeleton joined by a compliant polypropylene backbone. The entire structure envelopes a soft silicone pneumatic bladder. FEA analysis was used to determine the ideal shape and behavior of the pneumatic bladder to actuate the exoskeleton. The spider leg can be flexed and contracted depending on the input pressure. To laterally actuate this pneumatic spider leg I designed and developed a fabrication system that uses vacuum injection molding to produce an integrated mesh sleeve/elastomer pneumatic actuator. I designed an apparatus to measure pressure and contraction of silicone and latex pneumatic muscles when inflated. I analyzed the non-linear pressure-contraction relationships of silicone versus latex pneumatic muscles, and also derived force-contraction relationships. From efficiency studies, both media muscles proved to be inefficient and the measuring apparatus needs to be more robust to prevent leaking air. The fabrication process still offers the possibility of a quick and efficient method of creating pneumatic muscles. A spider-like robot that implements these pneumatic muscles and pneumatic leg design could be used to explore the efficiency and stability of passive dynamic legged locomotion in spider-like robots
Profiling the pregnancy-specific glycoprotein genes in pre-eclampsia.
No full textBackground: Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is characterised by reduced placental cell invasion into the maternal arteries. Lack of invasion causes insufficient transformation of arteries which disrupts blood flow to the fetus. PE is a leading cause of maternal and fetal death, yet the pathogenesis is not fully elucidated. PE establishes in the early stages of pregnancy but is only diagnosed after 20 weeks gestation due to late onset of symptoms, making early prediction and prevention difficult. Recently, the pregnancy-specific glycoprotein (PSG) genes were proposed as a potential biomarker for early detection of PE and have been hypothesised to have roles in facilitating invasion.
This study aimed to determine if PSG gene expression is downregulated in the PE placenta. Further, expression of PSG genes in first trimester was interrogated to address the role of PSG genes in invasion.
Methods: The NanoString, nCounter platform quantified PSG4, PSG9 and PSG11 gene expression in PE placentae, control (term) placentae (>36 weeks gestation), and first trimester placentae (<13 weeks gestation). The promoter regions of the PSG genes were interrogated using targeted bisulfite sequencing (TBS) on the iSeq platform to quantify DNA methylation.
Main findings: A lower mean expression for each PSG gene was observed in the PE placenta compared to term but this was not statistically significant. PSG9 and PSG11 were significantly upregulated in the invasive period of first trimester compared to term. Supporting these findings, it was confirmed that PSG genes were aberrantly expressed in invasive melanoma cell lines compared to somatic tissues. However, DNA methylation at the promoter of the PSG genes did not inversely correlate with gene expression.
Conclusion: PSG genes may not be implicated in the pathogenesis of PE. However, PSG genes are upregulated in first trimester which may provide insight into how these genes contribute to early placental development. These findings provide further scope to investigate the role of PSG genes in invasion
Impact of carbon monoxide releasing oCOm-21 on the NLRP3 inflammasome
No full textDuring cardiac bypass procedure, the heart is subjected to repeat cycles of ischaemia reperfusion injury (IRI). This is highly detrimental to clinical outcomes in patients, presenting as myocardial dysfunction and contributing to extensive organ injury, morbidity and mortality. Pro-inflammatory signalling has been identified as a key contributor in the pathogenesis of cardiac remodelling. This IRI-linked signalling mechanism has been identified to involve the NLRP3 inflammasome to produce myocardial inflammation and dysfunction. Carbon monoxide (CO), a secondary messenger, has repeatedly been established to act through vasodilatory, anti-inflammatory, anti-thrombotic and anti-apoptotic pathways to provide protection. Recent research highlighted the capability of CO releasing compounds to reduce injury associated with the inflammasome. Therefore, this study aimed to test whether a novel organic CO releasing molecule, oCOm-21, could produce an anti-inflammatory effect by reducing NLRP3 levels within both non-hypertrophic and moderately hypertrophic CYP1a1-Ren2 rat hearts undergoing IRI.
Histology was performed to evaluate the damage in both non-hypertrophic and moderately hypertrophic hearts. The vehicle controls in both groups sustained more extensive damage than oCOm-21 treated hearts. Results obtained from immunofluorescence staining indicated that non-hypertrophic hearts treated with 3 µM and 10 µM of oCOm-21 had a 2.0- and 3.0-fold decrease in NLRP3 respectively, when compared to the vehicle hearts (P 0.05). Western blotting with densitometry analysis however, failed to show a significant decrease in NLRP3 levels between vehicle control and oCOm-21 treated hearts (P > 0.05).
These preliminary results strengthen the hypothesis that IRI evokes an inflammatory response, resulting in cardiac damage, which may be attenuated with oCOm-21 via the inhibition of inflammasomes. Although the immunohistochemical results demonstrates a promising link between CO and NLRP3 inhibition, the lack of reproducibility with western blotting requires additional research
Memory function in borderline personality disorder
No full textBorderline Personality Disorder (BPD) is a severe psychiatric condition that involves impairment in multiple areas of psychological functioning including disturbed cognition, impulsivity, and intense unstable relationships. Memory deficits are not recognised as a core symptom of BPD, but BPD patients have long been suspected of having inaccurate perceptions, disturbed memory processes, and an increased tendency to generate false memories about past events, interpersonal perceptions, and social interactions. The overarching goal of my PhD was to investigate potential memory differences in people with features of BPD. In particular, I examined whether people with more BPD symptoms would be more susceptible to false memories or would exhibit irregularities in autobiographical memory. In addition, I also compared the traditional conceptualisation of BPD with the alternative model of personality disorders in predicting memory performance.
A total of 300 university students were recruited to participate in the main experiment. Participants were asked to complete a series of psychological assessments that measured various aspects of personality and psychopathology. In addition, each participant took part in a false memory procedure, the Deese/Roediger-McDermott (DRM) paradigm, using word lists that were developed in the course of preliminary research (Chapter 4). Participants were also asked to report about both their earliest personal memory and a memory that reflected an important turning point in their lives (see Chapter 5 for the complete Method). I then examined how BPD features are associated with false memory (Chapter 6) and how dissociation is associated with false memory (Chapter 7). In the final two empirical chapters, I investigated how BPD features are related to the qualities of autobiographical narratives (Chapter 8) and how borderline symptoms are reflected in the nature of narrative identity (Chapter 9).
Overall, I found that 1) using the BPD traditional model, BPD symptoms were correlated with higher false memory for positive information, and in the alternative model of BPD, identity impairment and anxiousness were correlated with the overall false memory score; 2) irrespective of BPD, experiencing trauma and dissociation, as well as lower levels of intelligence, were associated with higher false memory; 3) trauma and dissociation mediated the relation between BPD and false memory; 4) both the traditional and alternative models of BPD were correlated with negative affect in turning-point memories, but not in earliest memories; 5) relying on the traditional model of BPD, I found no correlation between over-general memories and BPD, however, using the alternative model, over-general turning-point memories were associated with higher BPD-related impairment in self-direction; 6) participants with features of BPD were more likely to rate their earliest memories as more negative in valence and less coherent; 7) participants with features of BPD were more likely to rate their turning-point memories as negative in valence, to describe them from a 3rd-person perspective, and to reflect higher distancing, greater emotional intensity, and less accessibility; 8) participants with higher features of BPD also reported turning point memories that were also less likely to reflect their sense of agency, agency fulfilment, intimacy and empathy; and 9) narrative identity, but not narrative intimacy and coherence, was the dominant predictor of BPD features. Overall, I also found that both the traditional and alternative models of BPD predict the expected qualities of memory, with the alternative model of BPD doing better in determining which diagnostic subtypes of BPD predict the trajectories of false memory. Taken together, the current findings not only have important theoretical implications for understanding memory differences in BPD, but they also have practical implications in clinical settings
Kinetics of Passive Demethylation
No full textDNA methylation is an epigenetic modification established during cellular differentiation, and when removed by either active or passive means, can substantially improve the efficiency by which induced pluripotent stem cells are created for the sake of regenerative medicine. During the ‘active’ removal of DNA methylation, the Ten-Eleven Translocation (TET) enzymes catalyse the oxidation of cytosine methylation (5mC) to 5-hydroxymethylcytosine (5hmC) and further derivatives. Unpublished work from the Hore laboratory and collaborators has shown that TET differentially targets particular CG-containing hexamer motifs for rapid demethylation but leaves others unaffected.
Currently, it is unclear if ‘passive’ epigenetic memory loss, whereby demethylation results from the inhibition or inactivation of the DNA methylation maintenance machinery, also shows a preference for certain CG-containing hexamers. DNMT1 typically acts to maintain DNA methylation by catalysing the addition of methyl groups on hemimethylated DNA, enabling the transmission of methylation after DNA replication or repair. A cytosine-analogue called decitabine, which is also used in cancer treatment, can be utilised to block DNMT1 activity.
In this project, I used bisulfite sequencing data from decitabine-treated mouse embryonic stem cell samples to determine the kinetics of demethylation at all 256 CG-containing hexamers over a 48-hour period. A bioinformatic pipeline was implemented for the extraction and analysis of CG-containing hexamers from trimmed and mapped sequencing reads. Demethylation rates from these hexamers were examined both within and outside of CpG islands (CGI) and my analysis was performed in both absolute and relative terms according to similar experiments performed recently. In doing so, I found that once starting methylation levels and genomic location were taken into account, passive demethylation of DNA showed no preference to certain CG-containing hexamers, in stark contrast to that of active DNA demethylation.
In studying the kinetics of passive demethylation, I was able to answer a fundamental biological question regarding the mechanism by which passive demethylation occurs. However, in an applied sense, the value of this work will help to assess merits and risks of DNA demethylation strategies for the efficient creation of induced pluripotent stem cells that are safe for clinical use