Filters
Availability
Publication Year
Resource Type
Faculty
School/Institute
Publication Search Results
Sort
Results per page
1 - 10 of 35
-
(2018)ThesisCardiovascular disease is the leading cause of morbidity and mortality globally. Left ventricular (LV) and left atrial (LA) dysfunction are both independent predictors of adverse cardiac outcomes. LV and LA structural and functional remodelling can result from increased LV wall stress consequent to chronic pressure overload. The studies in this thesis aimed to examine the alterations in LV and LA mechanics in chronic pressure overload conditions, especially focusing on early detection of subtle and subclinical abnormalities using newer echocardiographic techniques. Aortic stenosis (AS) and hypertension, the two most common cardiovascular conditions associated with chronic pressure overload, have been chosen for evaluation. Myocardial fibres are organised in layers with subendocardial strain being significantly higher than subepicardial strain in all three (longitudinal, circumferential and radial) axes. There was progressive global longitudinal strain (GLS) and global circumferential strain (GCS) impairment with increasing AS severity. Subendocardial longitudinal strain correlated better with indices of AS severity than other strain parameters. The degree of aortic valve calcification correlated with AS severity as well as strain impairment, with stronger correlation with GLS than GCS. There was no correlation between the degree of myocardial fibrosis assessed on histopathology and AS severity or LV strain impairment in patients undergoing surgical aortic valve replacement (AVR). For AS patients who were managed conservatively, there was progressive strain impairment, detectable earlier in subendocardial than subepicardial layer, and earlier in GLS than GCS. LV GLS improvement was detected from 3 months after AVR, with GCS improvement detected from 6 months post-surgery. Hypertensive patients, compared with normotensive patients, had impaired LV GLS at rest and at low-dose dobutamine, and impaired GCS at low-dose dobutamine despite preserved GCS at rest. They also had impaired LV GLS contractile reserve (CR) to inotropic stimulation, despite normal LVEF at rest and normal LV CR assessed by LVEF. Furthermore, hypertensive patients had impaired LA reservoir, conduit and atrial contractile strains, in addition to more prolonged electromechanical delay (EMD) in the absence of LA enlargement. LA EMD correlated significantly with all 3 LA phasic strains, with LA atrial contractile strain being an independent correlate of LA EMD.
-
(2017)ThesisThe main component of treatment for locally advanced rectal cancer is neoadjuvant chemoradiation, which carries morbidity. Hence, biomarkers are urgently needed to better select patients to undergo this therapy. This work evaluates selected, rational and primarily biologically-based biomarker changes during chemoradiation. These include circulating tumour cell (CTC)-based, serum and solid tissue biomarkers, as well as patient-related biomarkers such as quality of life. Novel aspects include tracking of CTCs during chemoradiation, description of microRNA (miRNA) profiles in CTCs, tracking changes in miRNA expression during treatment, comparison of miRNA profiles across tissue types and correlation of biological and patient-related markers. CTCs were found in almost two-thirds of patients with locally advanced rectal cancer. Overall, CTC counts fell during chemoradiation. Patients with a complete pathological response to treatment had lower CTCs at baseline. We report a positive correlation between CEA and CTC counts, and between CTC counts and the neutrophil-lymphocyte ratio. We found that natural killer cell counts were reduced in locally advanced rectal cancer tissue compared to normal tissue and this correlated with tumour regression. Rectal tissue lymphocyte counts increased with neoadjuvant chemoradiotherapy, with the CD8 subset most likely responsible. Upregulated polo-like kinase 1 expression in the periphery of the primary tumour tissue correlates with inferior survival in rectal cancer. Hypothesis-generating correlations were found between CTCs and quality of life. MicroRNA profiles exist in CTCs, serum and solid tissue and were compared between treatment time-points. miR-542-3p in CTCs was upregulated during chemoradiation. Out of 112 candidates, 13 serum miRNAs were differentially expressed between patients and controls and 11 were also altered with treatment. Comparing across tissue types, miR-1183, miR-125b-1*, miR-223, miR-375 were differentially expressed from pre- to post-treatment in both serum and solid tissue. miR-195 and miR-342-3p in CTCs, and serum miR-720 and mir-628-5p may be promising markers of non-response. In solid tissue, miR-25 was downregulated only in responders. We believe that a comprehensive profile incorporating these novel biomarkers will help us better understand the disease process during neoadjuvant chemoradiation in locally advanced rectal cancer, and can potentially serve as an adjunct to conventional histopathological variables.
-
(2017)ThesisPancreatic cancer (PC) is the fourth leading cause of cancer related deaths with a 5-year survival rate as low as 5%. It is now acknowledged that the desmoplastic / stromal reaction, a characteristic feature of PC, contributes to progression of this cancer, by facilitating local growth and distant metastasis. Our laboratory was the first to demonstrate that pancreatic stellate cells (PSCs), i) produce the collagenous stroma of PC, and ii) interact closely with cancer cells to facilitate cancer progression. A candidate growth factor pathway that may mediate this PSC-cancer cell interaction is the hepatocyte growth factor (HGF) /c-MET (receptor for HGF) pathway. This thesis studies the effects of inhibiting HGF and c-MET, in the presence and absence of chemotherapy, on PC progression using (i) an orthotopic model of PC (in vivo approach), and (ii) human PC cells (AsPC-1) and PSCs (hPSCs) in culture (in vitro approach). My novel data have demonstrated that HGF inhibition (with neutralising antibody AMG102) as well as c-MET inhibition (using Compound A, a small molecule c-MET inhibitor), either singly or together were as effective as standard chemotherapy (gemcitabine) in inhibiting local tumour growth. Combining either HGF or c-MET inhibition with gemcitabine also reduced tumour growth. However, the combination of all three approaches (HGF inhibition + c-MET inhibition + chemotherapy) reduced tumour growth most, and more importantly, virtually eliminated metastasis. Another important observation was that gemcitabine treatment by itself failed to prevent metastasis, but instead, induced epithelial-mesenchymal transition and stemness (as assessed by increased expression of stem cell markers) in a sub-population of cancer cells. In vitro studies demonstrated that hPSC secretions not only induce proliferation and migration, but also inhibit apoptosis of cancer cells. These effects were countered by pre-treatment of hPSC secretions with HGF inhibitor or c-MET inhibitor indicating a key role for the HGF/c-MET pathway in PSC-PC interactions. The above findings suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC, which could be used with existing treatment modalities as a multi-pronged approach, to significantly improve the clinical outcome of patients with pancreatic cancer.
-
(2014)ThesisThis thesis examined the central concepts of left ventricular (LV) deformation and functional reserve in patients with diabetes (DM). The studies evaluated LV systolic contractile reserve (CR) and coronary microvascular function and identified determinants and patterns of coronary microvascular dysfunction. LV diastolic reserve and its relationship with endothelial function and impact of strict metabolic control on LV mechanics were studied. LV systolic CR at low dose dobutamine of ≥10% identified an index of microcirculatory resistance (IMR) of <25 with 100% accuracy. There was differential involvement of coronary vascular beds in patients with vascular risk factors: DM patients had worse microvascular function in the anterior circulation than patients without DM. The opposite was observed in those without DM. DM patients with dyslipidaemia, hypertension, worse glycaemic control and higher body mass index had worse microvascular function, whereas those treated with metformin had better microvascular function. Flow mediated dilatation (FMD) of the brachial artery was an independent predictor of LV diastolic reserve and exercise capacity. Patients with DM had impaired ability to improve LV diastolic function and maintain normal LV pressures with exercise. This is demonstrated by a higher increase in E/e , after adjusting for differences in the resting values, with the increase in the ratio persisting up to 10 minutes into recovery. Patients with DM and hypertension, longer duration of insulin therapy, worse glycaemic control, worse renal function and lower septal e had more impaired diastolic reserve. Patients with DM have impaired LV systolic and diastolic function manifested by an impaired LV global longitudinal strain of -14.9±3.2% and septal e velocities of 6±2 cm/sec, respectively, despite a normal LV ejection fraction. Improvements in glycaemic control over a 12-month period were associated with improvements in LV systolic and diastolic function measured by LV ejection fraction as well as GLS and septal e velocities. There were significant linear relationships between improvement in HbA1c and improvement in LV systolic and diastolic function. Furthermore, improvements in systolic function and HbA1c were associated with improvement in exercise tolerance. Improving glycemic control appears to be beneficial in reversing to some degree the cardiotoxic effects of hyperglycemia.
-
(2014)ThesisRandomised controlled trials (RCTs) provide clinicians with the best evidence for interventions, but are subject to systematic errors (bias) when methodology is not optimal. These biases occur at any time from the inception, execution, data collection, analysis, and dissemination of results. Performing RCTs for surgical interventions is additionally challenging, given the relative complexities of surgical interventions and patients, and the culture of surgical training. This thesis examined the epidemiology and quality characteristics of RCTs of surgical interventions. A systematic search was conducted to locate recently published surgical RCTs and meta-analyses, in order to attain a sample that would be reflective of the current state of surgical evidence. Data was piloted and collected according to a proforma. The first study assessed the epidemiology and methodological quality of surgical RCTs, and compared these characteristics with what is known about general medical RCTs. The second study assessed reporting quality by compliance with the Consolidated Standards of Reporting Trials (CONSORT) statement. The third study investigated the association between methodological quality and treatment effects in surgical RCTs. The fourth and fifth studies examined patterns of outcome reporting. The association between statistical significance and reporting of outcomes (outcome reporting bias) was explored. The extent to which outcomes measured in surgical RCTs are patient important was also assessed. Finally, the sixth study assessed the epidemiology, reporting and methodological quality of meta-analyses of surgical RCTs. The results show that there is substantial room for improvement in the conduct and reporting of RCTs of surgical interventions. Inadequate methodology was common, and was associated with an exaggeration of treatment effects. There was concerning evidence of unreported outcomes, and complete outcome reporting was associated with statistical significance. Only two thirds of primary outcomes were patient important. If the truth about surgical interventions is to be discerned, the conduct and reporting of surgical trials must improve. Much of this responsibility lies with study authors, but journal editors and reviewers, and the funders of research also have an important role. Existing guidelines need to be promoted and imposed, and existing multicentre models for the conduct of surgical trials should be further explored.
-
(2015)ThesisBackground: Stricturing and fistulizing intestinal complications are largely responsible for the significant morbidity of Crohn’s disease (CD). The inability to predict the development of these complicated phenotypes of CD (CCD) remains the bottleneck to evaluating the efficacy of early escalation therapies, which could change the natural history of CD. Proteomic methodologies may be able to identify important mechanisms in these pathologies. This thesis comprised a series of studies conducted under the framework of the biomarker development pipeline to examine the low-mass serum proteome of the behavioural phenotypes of CD. Methods: Untargeted and targeted Mass Spectrometry (MS) was used for global metabolite profiling and quantification of immunoregulating Kynurenine Pathway (KP) metabolites in proof-of-principle metabolomics studies. In a discovery phase proteomics study, in-solution electrophoresis was used to enrich the low-mass (<25kDa) serum fraction of CD behavioural phenotypes for untargeted MS analysis. Elements affecting accuracy in Multiple Reaction Monitoring (MRM) MS assays were evaluated in research assay optimisation phase study, and MRM and immunoblotting were used in qualification phase proteomics studies to quantify discovery phase-identified biomarker candidates in cross-sectional and longitudinal cohorts. Results: Proof-of-principle metabolomic studies demonstrated the ability of MS to identify unique plasma profiles between distinct pathologies of intestinal inflammation. Th1/17 inflammatory metabolites Angiotensin IV, diphthamide and GM3 gangliosides were associated with CD and KP metabolite Quinolinic acid was increased in CD and correlated with biochemical and clinical measures of disease activity. In discovery phase proteomics study, a low-mass serum profile typified by an overabundance of epithelial component proteins was identified in CCD. In research assay optimisation, peptide-centric matrix effects that caused deleterious effects on quantitative accuracy in MRM assays were identified, and a novel Reverse-Polynomial Dilution (RPD) calibration technique that reduced error in multiplexed MRM assays was established. Finally, a serological biomarker candidate panel with discriminative ability for intestinal complications in CD was demonstrated in qualification phase. Conclusions: An enrichment of serological epithelial component proteins in CCD was identified in this work that can classify CCD against intestinal and Th1/17 systemic inflammation controls. These proteins may be serological biomarkers of transmural intestinal tissue integrity that could predict progression to CCD.
-
(2012)ThesisPolycystic Ovarian Syndrome (PCOS) has the clinical manifestations of irregular menstrual cycles, anovulatory infertility, amenorrhoea, insulin resistance, polycystic ovaries, androgen disturbance, hirsutism and/or acne. The condition affects an estimated 5 to 10% of women of reproductive age (Hull 1987; Polson 1988; Lo 2006), although this varies depending on the diagnostic criteria used (Michelmore 1999). Farquhar et al. (1994) suggested the prevalence of PCOS to be 21% in a New Zealand study. Due to the lack of uniformed definition of PCOS, the prevalence of PCOS can have a highly variable prevalence estimates, ranging from 2.2% to 26% . (Nidhi 2011) Through researches, evidence suggests the potential usefulness of acupuncture in the treatment of the PCOS disorder (Ku 2001; Petti 1998; Ulett 1998). It was postulated that beta-endorphin and various neuropeptides (like protein pro-opiomelanocortin) within the nervous system may be implicated in producing the effects of acupuncture. Aleem (1987) revealed the presence of beta-endorphin in the follicular fluid of both normal and polycystic ovaries. Stener-Victorin (2000) s study suggested that acupuncture may have a role in ovulation induction. Further details of current acupuncture studies in PCOS can be found in Chapter Four. Acupuncture is currently used in public hospitals in China for the treatment of PCOS. Clinical studies conducted in China have suggested that the effectiveness of using acupuncture may be significant. However, the methodological quality of those trials was poor with limited long-term follow-up. The present study aimed to evaluate the action of body acupuncture on menstrual pattern through a pilot study (Stage II) and a randomised controlled study (Stage V). However, in order to plan the RCT properly from Chinese medicine point of view, it was important to first standardise the Chinese medicine syndrome differentiation for PCOS or otherwise an inaccurate clinical response may be obtained. This was achieved by utilising a questionnaire (Stage III) as a tool development in this study. In addition to understanding the needs of Chinese women with PCOS, an epidemiological data was performed in Stage IV, so as to attempting to address their needs in the RCT stage. An effective CM treatment protocol would then be proposed to serve as a guide for the clinical acupuncture management of adult women with PCOS. The findings are promising and further studies are required. The design for this doctoral program study composed of the following 6 stages: 1. Stage I Comprehensive systematic literature review of current acupuncture treatment for PCOS patients in human studies in all available Chinese and English Literature. This stage has been published as Cochrane Systematic Review paper; 2. Stage II Pilot Clinical Study involving real body acupuncture group; 3. Stage III Development of Traditional Chinese Medicine (TCM) Syndrome Differentiation Diagnostic Questionnaire (Tool) for PCOS according to the results of comprehensive literature review in stage I and also the National Disease Criteria set by the State Administration of Traditional Chinese Medicine in the Peoples Republic of China; This is important as to standardise the CM diagnosis of PCOS in Stage V; 4. Stage IV Collection of Epidemiological data among Asian women of PCOS, to ascertain the psychological needs of Chinese women with PCOS; and to attempting to fulfil this in Stage V; 5. Stage V Randomised Single Blinded Acupuncture Clinical Trial involving a) real body acupuncture group; b) placebo (sham) body acupuncture group; For this study, there are two types of outcome measures that are under consideration. The primary outcome measure was the return of menstruation from amenorrhea while the secondary measures were the changes in LH, FSH concentration, LH: FSH Ratio, Progesterone, Oestrogen and Androgenic hormone concentration; 6. Stage VI Investigation of the Mechanism of Acupuncture Treatment on the Management of PCOS. Based on the findings from Stage One, various case studies suggested that there may be a role for acupuncture in regulating menstruation pattern in PCOS but there was nil randomised controlled trial identified to assess the efficacy of action of acupuncture in treatment of PCOS when this project was proposed. Furthermore, preliminary evidence from the literature review suggested that acupuncture may be useful in regulating menstrual pattern in women with PCOS. This confirms the importance of this research project as to fill in the gap of current medical understanding of using acupuncture in women with PCOS. From the descriptive analysis that was performed in Stage Three, it can be concluded that the syndrome diagnostic questionnaire that developed in this project could possibly be a useful tool in Chinese medicine syndrome differentiation for women with PCOS. It is warranted for further analysis and tested for internal validity. In Stage Four, a total of 57 patients agreed to participate were interviewed. All patients responded to all 4 questions (Cronback s alpha > 0.9) asked thus for this study it has a 100% response rate. Among all the factors of concern, most of interviewed subject expressed problems of having PCOS as : difficulty to control weight, frustration about difficulty to reduce weight, frustrated due to PCOS and its related medical problems, unable to conceive and menstrual irregularity, as well as pressure from workplace. Based on the results from pilot study in Stage Two (11 subject recruited) and the RCT in Stage Five (146 subjects recruited), acupuncture can be recommended as effective menstrual regulation intervention for PCOS. In Stage V, the inter-menstrual days in the control group is 302.45 day and 348.32 days pre and post treatment respectively (p=0.001). In the interventional group, the mean inter-menstrual days are 297.69 and 33.82 days pre and post treatment respectively (p=0.000). There is no menstrual pattern change in the control group pre and post treatment. Acupuncture demonstrated statistically significant difference toward hormonal profiles before and after the real body acupuncture intervention among women with PCOS. Within the interventional group, it can be seen that there are six treatment outcomes that were found to have a significant differences (p<0.0001) pre and post real acupuncture intervention. ANOVA was found to be highly significance in between the control group and intervention group among the 6 treatment outcomes. These six treatments outcomes were FSH, LH, LH: FSH ratio, Progesterone, FAI, and menstruation days. There are no statistical significances (p>0.05) in prolactin, oestrogen (E2) and testosterone in both control and interventional groups. Stage V is aimed to elicit whether acupuncture can assist in return of menstruation for lady with PCOS and has complete amenorrhoea. As this is the initial aim of the study, ovulation was not chosen to be the outcome measure for this RCT. This also becomes one of the limitations for this study as we cannot definitely answer whether acupuncture can induce ovulation for lady with PCOS, although improvements were noted in the LH:FSH ratio and progesterone level. It is important to note that menstruation return may not necessary to protect the uterus from hyperplasia. Overall speaking, the results from the statistical analysis and the insights that were gathered from those results have proposed the following mechanisms in relation to Chinese and Western medicine perspective: 1. Acupuncture significantly increases β-endorphin levels for periods up to 24 hours and may have regulatory effect on FSH, LH and androgen. 2. Decrease hypothalamic-pituitary-adrenal (HPA) axis activity by inhibiting release of corticotrophin-releasing factor (CRF), causing decreased adrenocorticotrophic hormone (ACTH) release from the pituitary gland and decreased cortisol and/or dehydroepiandrostenedione (sulfate) release from the adrenal cortex. 3. β-endorphin increased levels secondary to acupuncture affects the hyperthalamic-pituitary-adrenal (HPA) axis through promoting the release of ACTH through stimulation of its precursor pro-opiomelanocortin synthesis. 4. Needle insertion into the skin and muscle may stimulate ergoreceptors and initiate afferent nerves activity. 5. If acupuncture needles were placed in the same somatic segment of the ovary, they may stimulate the oxytocin axis resulting in decreased release and secretion of ovarian androgens. In conclusion, the designed acupuncture protocol for PCOS proposes that the usage of acupuncture is effective to induce return of menstruation from oligomenorrhoea.
-
(2012)ThesisBackground: Adequate radiotherapy services provision entails systematic planning due to their high capital costs and the requirement for specialised staff. A treatment attendance (called a fraction) is a fundamental unit of productivity in a radiotherapy department. There is variation in radiotherapy fractionation practices, however, there is no evidence-based benchmark for appropriate activity. A radiotherapy utilisation model was previously constructed and estimated that 52.3% of cancer patients should receive external beam radiotherapy at least once during their illness. The next challenge is to translate an overall radiotherapy utilisation rate into a more practical estimate of radiotherapy demand. Aim: To construct an evidence-based model to estimate the optimal number of fractions for the first course of radiotherapy, building on the radiotherapy utilisation model. Methods: Evidence-based treatment guidelines, meta-analyses and randomised controlled trials were reviewed for fraction number recommendations for each indication of radiotherapy for notifiable cancers with an incidence of ≥ 1%. The previously published radiotherapy utilisation tree was adapted so that the most appropriate evidence-based fraction number was added to each branch. Epidemiological data previously used were updated. For each cancer type, the optimal fraction number was then calculated using the TreeAge software, taking into account the frequency of specific clinical conditions where radiotherapy is indicated and the recommended fraction number for each condition. One-way sensitivity analyses were performed to assess the impact of uncertainties on the model. Results: For each cancer type, the optimal number of fractions for the first course of radiotherapy ranged from 0 to 26.1 per cancer patient, and 0 to 30.8 per course. Head and neck, brain and anal cancers had the highest number of fractions per course. Overall, the optimal fraction number was 9 per cancer patient and 18 per course. Sensitivity analysis showed that this ranged from 8.6 to 9.6 per cancer patient, and 17.2 to 19.2 per course. Conclusion: These results represent the first evidence-based benchmark for radiotherapy services delivery, and allow comparisons with actual practices. The model can be used to predict workload to aid in radiotherapy services planning, and adapted to future changes in cancer incidence, stage distribution and fractionation recommendations.
-
(2018)ThesisCardiomyopathies are heterogeneous disorders that result in significant morbidity and mortality. This thesis evaluated subclinical left ventricular (LV) dysfunction in cardiomyopathy subtypes, namely radiation induced heart disease (RIHD), cardiac amyloidosis (CA) and Anderson-Fabry disease (AFD). The unifying theme of 2 dimensional (2D) LV strain imaging assessment was explored. We hypothesized that LV strain and strain rate (SR) are more sensitive markers of subclinical changes in LV global and regional function than conventional methods. RIHD was evaluated using 2D strain in a longitudinal study of left sided breast cancer patients undergoing radiotherapy; at baseline, during treatment and at 6 weeks post treatment. Reduced global longitudinal strain (GLS) was detected during radiotherapy and at 6 weeks post treatment despite preserved LVEF. A modest correlation of global strain reduction to mean heart dose was observed. Differential planar strain alterations with reduced longitudinal and radial strain and preserved circumferential strain was observed. The largest decrement of strain occurred in the LV apical segments, corresponding to segments receiving the highest radiation dose. Cardiomyopathy with increased LV wall thickness including cardiac amyloidosis (CA), hypertension and AFD were studied and compared to age and gender matched normal controls. Differential planar strain reduction occurs in CA compared to hypertension and normal controls. GLS and radial strain were reduced with preservation of circumferential strain until severe diastolic dysfunction develops. Regional heterogeneity was observed with basal and mid segmental strain reduction and relative sparing of apical strain. Longitudinal systolic SR was an independent predictor of mortality and restrictive filling pattern in CA. 2D strain detected subclinical LV dysfunction in patients with AFD patients despite preserved LVEF. Gender related differential strain reduction was observed; though diminished when compared to controls, greater reduction was seen in hemizygous males. In heterozygous females, reduced GLS was observed despite normal left ventricular wall thickness. Strain parameters were significantly decreased in patients with increased wall thickness. Our findings underscored that application of 2D strain imaging is a sensitive tool in the detection of subclinical cardiac dysfunction in asymptomatic patients. This has implications on risk stratification, preventative measures and early initiation of targeted cardio-protective treatment.
-
(2019)ThesisLong-term opioid use for chronic non-cancer pain has increased substantially. An increasing body of evidence is indicating that there has been an overestimation of benefit and an underestimation of harms, yet rates of use and dependence are not well quantified. The aims were to explore the incidence of prescription opioid use and dependence within an orthopaedic trauma and end-stage osteoarthritis population and to test a new model (a less-is-more-approach) for pain management after fracture surgery. Specifically, six studies were undertaken including five cohort studies and a single randomised trial. Main findings 1) Amongst an end-stage osteoarthritis population waitlisted for total hip or knee arthroplasty (THA; TKA) at NSW public hospitals, opioid use was common (25%) on entry to the waitlist and was associated with numerous individual characteristics; 2) Amongst a cohort including private THA and TKA patients, opioid use was common pre-operatively (17.8%) and post-operatively (41.5% 30-days, 18.1% 90-days), and pre-operative opioid use was a strong predictor of longer-term opioid post-operatively; 3): Within a non-admitted road trauma population, opioid use and dependence at 6 months was low; 3.3% and 0.8%, respectively. Opioid prescription at emergency department discharge was 33.3%; 4) Within a non-admitted fracture population, opioid use and dependence at 6 months was low; 4.2% and 1.2%, respectively. Opioid prescription at emergency department discharge was 47.4%; 5) In admitted major fracture patients, opioid use and dependence at six months after discharge was 17.6% and 8.9%, respectively. An opioid prescription upon discharge was 74%; 6) In a randomised trial, treatment with strong opioids was not superior to treatment with mild opioid after surgically managed orthopaedic fracture sub-acutely. Conclusions: Persistent opioid use after THA or TKA is common and predicted by pre-operative use, thus, more research testing mild- and non-opioid analgesics is required; Rates of opioid prescription following road trauma or fracture both in the non-hospitalised or hospitalised are high; Opioid use and dependence are low among the non-admitted populations; Admitted major trauma populations are being exposed to harms as indicated by ongoing long term use; while strong opioid use following discharge from hospital after surgically managed fractures has been found unnecessary.