Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a non-neoplastic pulmonary disease that is characterized by the formation of scar tissue within the lungs in the absence of any known provocation. IPF is a rare disease which affects approximately 5 million persons worldwide. The prevalence is estimated to be slightly greater in men (20.2/100,000) than in women (13.2/100,000). The mean age at presentation is 66 years. IPF initially manifests with symptoms of exercise-induced breathless and dry coughing. Auscultation of the lungs reveals early inspiratory crackles, predominantly located in the lower posterior lung zones upon physical exam. Clubbing is found in approximately 50% of IPF patients. Cor pulmonale develops in association with end-stage disease. In that case, classic signs of right heart failure may be present. Etiology remains incompletely understood. Some environmental factors may be associated with IPF (cigarette smoking, exposure to silica and livestock). IPF is recognized on high-resolution computed tomography by peripheral, subpleural lower lobe reticular opacities in association with subpleural honeycomb changes. IPF is associated with a pathological lesion known as usual interstitial pneumonia (UIP). The UIP pattern consists of normal lung alternating with patches of dense fibrosis, taking the form of collagen sheets. The diagnosis of IPF requires correlation of the clinical setting with radiographic images and a lung biopsy. In the absence of lung biopsy, the diagnosis of IPF can be made by defined clinical criteria that were published in guidelines endorsed by several professional societies. Differential diagnosis includes other idiopathic interstitial pneumonia, connective tissue diseases (systemic sclerosis, polymyositis, rheumatoid arthritis), forme fruste of autoimmune disorders, chronic hypersensitivity pneumonitis and other environmental (sometimes occupational) exposures. IPF is typically progressive and leads to significant disability. The median survival is 2 to 5 years from the time of diagnosis. Medical therapy is ineffective in the treatment of IPF. New molecular therapeutic targets have been identified and several clinical trials are investigating the efficacy of novel medication. Meanwhile, pulmonary transplantation remains a viable option for patients with IPF. It is expected that, during the next decade, considerable progress will be made toward the understanding and treatment of this devastating illness

Maturation, playing position and genetic variation: injury risk factors in high-level youth soccer

The negative impact of injury on the development of youth soccer players (YSP) means that efforts must be made to prevent and control their occurrence. Although a range of risk factors have been investigated in YSP, they remain poorly understood due to limitations with previous studies (as discussed in Chapter Two). Greater understanding of the factors affecting injury risk could help identify and improve management of ‘at risk’ players, thus improving the likelihood of them reaching their full potential of a professional contract. Accordingly, the overriding aim of this thesis was to investigate the association of potentially key risk factors with injury risk in a large cohort of high-level YSP from academies within eight professional clubs from four different countries, across two continents. For all four experimental chapters in this thesis, injuries were prospectively recorded over the course of a single season in high-level YSP to determine (i) whether the rate of these injuries varied in YSP between different nations; (ii) if maturation status, playing position and/or genetic variation were associated with injury risk in YSP. The injury audit (Chapter Three) revealed that non-contact injuries to skeletal muscle were amongst those frequently recorded, with most injuries located in the lower limb. The Under-14 (U14) and U16 age groups suffered relatively more severe injuries, with minimal differences in injury rate between nations. Thus, Chapter Three indicated that more severe injuries occurred around the timing of biological maturation, suggesting an association of maturation status with injury in YSP. When this hypothesis was tested directly in Chapter Four, maturation status (pre-, mid- and post- peak height velocity [PHV], estimated by maturity offset) was indeed associated with injury risk, where soft-tissue, ligament/tendon and thigh injuries were more prevalent in post-PHV than pre- and mid-PHV, and muscle injuries were more prevalent in post- than pre-PHV. With all injuries combined, post-PHV missed more days in the season than pre-PHV. Thus, the results from this chapter strongly suggest that post-PHV are at greatest risk of injury, and miss more of the season due to injury than pre- and mid- PHV. Having identified a maturation-dependent link with injury risk in YSP, Chapter Five investigated whether there was an association between playing positon and injuries solely in post-PHV YSP (due to the greater prevalence and severity of injuries in post- vs. pre-PHV, and the fact that playing position is more firmly defined at post-PHV). Prevalence and severity did not differ between outfield positions, but relatively fewer goalkeepers suffered thigh injuries than lateral and forward players combined. These data indicate injury prevention strategies should be similar for outfield players in post-PHV, but should focus on preventing thigh injuries particularly for lateral and forward players. Finally, the results from Chapter Six showed that three single nucleotide polymorphisms (SNPs), i.e. COL5A1 rs12722, EMILIN1 rs2289360 and VEGFA rs2010963, were associated with injury prevalence in pre- and post-PHV combined, and that more SNPs were individually associated with injury risk in post- vs. pre-PHV. When combining those SNPs that were individually associated with injury risk, injured YSP demonstrated a worse polygenic profile (in terms of more ‘at risk’ genotypes) than uninjured YSP regarding non-contact and non-contact soft-tissue injuries, while pre- and post-PHV YSP had similar polygenic profiles. These data indicate a maturation-dependent influence of individual SNPs on injury, i.e. the environment likely interacts with genetic predisposition for injury more so in post-PHV YSP, when the intensity of training/match-play is greater than it is for pre-PHV YSP. The results from this thesis clearly identify post-PHV as being at higher risk of injury than their biologically younger counterparts, and that injury risk is similar between countries in this under-researched and important population. The results also show that playing position in physically mature YSP has minimal influence on injury risk but that genetic variation appears to be linked with the likelihood of suffering certain injuries, as well as the severity of those injuries. These novel findings could be used to help identify and manage ‘at risk’ YSP in order to reduce the burden of injury, thus increasing the chance of talented YSP reaching their full potential of a professional playing career

PRAGMATIC RANDOMISED TRIAL OF LOW VERSUS HIGH VOLUME INITIATED TRANSANAL IRRIGATION THERAPY IN ADULTS WITH CHRONIC CONSTIPATION: A FEASIBILITY STUDY

Background Chronic Constipation (CC) is common in adults. The effect of symptoms on quality-of-life (QOL) is significant. Trans-anal irrigation therapy has become a widely-used treatment despite a lack of robust evidence. A randomised comparison of two different methods of irrigation (the CapaCiTY 02 study) will provide valuable evidence of superiority of one system over the other. This study aims to evaluate the feasibility of conducting CapaCiTY 02. Data presented are interim findings from a single study site nested within the large multi-centre CapaCiTY 02 study. Methods This study was a mixed methods study involving a) a systematic review and meta-analysis of current literature data for trans-anal irrigation in chronic constipation, b) a randomised controlled trial, and c) a qualitative study of the patient experience. Participants in the trial were randomised to either high volume (HV) or low volume (LV) irrigation and underwent standardised physiological investigations. Data from the first 10 months of data collection at the Durham site were used for the feasibility study. Data were collected according to a standardised outcomes framework. The primary outcome was reduction in PAC-QOL, measured at 3 months. Qualitative interviews using a phenomenological framework were undertaken to explore the nature of the participants’ lived experience of irrigation. Descriptive analysis of data enabled assessment of study feasibility. Results The meta-analysis of seven eligible studies reported a positive response to treatment rate of 50.4%. Trial recruitment nationally was slower than anticipated. However the recruitment rate at the Durham site met the target for individual sites. A total of 19 participants were recruited at Durham, of whom 11 reached the primary outcome visit (3 months). The overall reduction in mean PAC-QOL at three months was 0.39 (SD 0.44), with a difference between groups of 0.04. Some outcome data were incompletely recorded. Of the 19 participants, 5 (29%) discontinued treatment, after a mean time of 51 days (SD 35.2). Qualitative interviews (n=5 at 3 months, n=3 at 6 months) identified important themes regarding participants’ experiences of irrigation training and home use. Discussion Collaboration between participating sites, combined with protocol amendments, has allowed measures to be taken to improve recruitment and recording of outcomes. This study demonstrates that the proposed methodology is feasible and acceptable to a majority of patients. The qualitative study provided a broader context to the quantitative study findings

First steps in optimizing breast screening in Mongolia: Understanding radiologists’ performance in reading mammograms and mammographic breast density

Advanced diagnoses of breast cancer have become a serious public health issue in Mongolia. Whilst mammography has been proven to be an effective screening approach for breast cancer and well established amongst developed countries, such program has not been introduced in Mongolia. In addition in Mongolia, a lack of research around breast cancer continues to exist. The purpose of this thesis is to understand mammographic diagnostic accuracy and mammographic breast density (MD) in Mongolia, both of which are important considerations, which will inform a future national screening program. To address this aim, three studies were conducted; the first two were radiologists’ performance studies in reading mammograms with different levels of difficulty. The mammographic detection of Mongolian radiologists (case sensitivity of 63% and lesion sensitivity of 34%) was substantially lower compared with that of Australian radiologists. The third study investigated the MD features of 1985 Mongolian women using the Breast Imaging Reporting and Data system (BI-RADS) density categories. The majority of women (58%) were found to have low-density categories (category A and B) and significant associations were observed between MD; age (OR = 6.8, 95% CI: 5.5, 8.0), weight (OR = 4.5, 95% CI: 3.4, 6.0) and BMI (OR=13.2, 95% CI: 8.6, 20.0). Findings from this research have demonstrated that mammographic diagnostic accuracy is sub-optimal in Mongolia. Moreover, images with different levels of difficulty did not alter the reading performance of Mongolian radiologists suggesting the need for improving breast cancer detection skills urgently. The output of this work also demonstrated that low density was predominant in Mongolia. The results will impact on health policy around screening in Mongolia. They will inform educational strategies that are needed to transform diagnostic efficacy and will provide a good basis for decision making around screening modality choices

Clinical and imaging biomarkers of audiovestibular function in infratentorial superficial siderosis

Disabling hearing loss is known to affect over 400 million people worldwide while the lifetime prevalence of dizziness can be as high as 40%. Rare causes for hearing and balance impairment are often understudied. Infratentorial (classical) superficial siderosis (iSS) is a rare but sometimes disabling complex neurological condition most often associated with hearing and balance impairment, and myelopathy. Olfactory loss has been reported but not yet systematically studied. iSS results from a chronic low-grade and low volume bleeding into the cerebrospinal fluid and the deposition of iron-degradation products (predominantly haemosiderin) in the subpial layers of the central nervous system, with predilection for the cerebellum and the vestibulocochlear nerves. Magnetic resonance imaging (MRI) allows haemosiderin to be visualised in-vivo and is the mainstream diagnostic modality. Due to the assumed rarity of iSS (prevalence of 0.03-0.14%), our research opportunities are limited. Few dedicated studies describe iSS-related audiovestibular (AV) findings, often limited to case-series, with mixed findings. There is currently no robust evidence that the radiological haemosiderin appearances correlate with the objective clinical tests. This project focuses on phenotyping the AV function in iSS and identifies predominantly retrocochlear hearing loss with features suggestive of central auditory dysfunction, and mixed vestibular (predominantly cerebellar) dysfunction. This work introduces and validates an imaging rating scale aiming to capture the anatomical extent of haemosiderin deposits visualised on MRI in a standardised and reproducible way. The scale demonstrates excellent reliability and good validity, with the scores correlating with hearing thresholds. This project estimates the prevalence of MRI-defined iSS in a large UK Biobank sample, similar to other rare neurootological disorders. Using patient/self-report measures, this work captures markedly low health-states of individuals with iSS and identifies possible iSS-specific auditory characteristics. Finally, the work identifies high prevalence of olfactory dysfunction in individuals with iSS

Neonatal Mortality in the Cape Town Metro West Geographical Service Area 2014-2017

Background Each neonatal death counts, as recognised by the Every Newborn Action Plan (ENAP). This is an important aspect in attaining the third Sustainable Development Goal by 2030. Accurate neonatal mortality data as well as an understanding of the causality and context is essential to plan interventions to reduce neonatal deaths and attain the third Sustainable Development Goals (SDG) of a neonatal mortality rate of less than 12 per 1000 livebirths by 2035. Objectives The objectives of this study were: (i) to determine neonatal mortality occurring in and out of health facilities in the Metro West GSA using the three audit programmes; Perinatal Problem Identification Programme (PPIP), Child Healthcare Problem Identification Programme (Child PIP) and Forensic Pathology Services (ii) to ascertain the cause of death specific neonatal mortality (iii) to describe the avoidable factors in each death as coded by the three audit programmes (iv) to make recommendations for the alignment of existing audit databases to obtain accurate neonatal statistics for the Metro West GSA. Methods This was a retrospective descriptive study of neonatal deaths undertaken in the public healthcare setting in the Cape Town Metro West GSA from January 2014 till December 2017. Existing data from PPIP, Child PIP and the CDR/FPS was used. Neonatal deaths were defined as in the first 28 days of life where there had been signs of life at delivery and a birthweight greater than 500g. Neonatal deaths were excluded where birth had occurred outside of the GSA or in the private health care setting. The audit data with regards to cause of death and avoidable or modifiable factors was obtained for each death. Results From a total of 134843 live deliveries, 1243 neonatal deaths were identified: 976(78%) from PPIP, 58(5%) from Child PIP and 209 (17%) from CDR/FPS. Sixteen per cent of the deaths occurred outside of healthcare facilities. The neonatal mortality rate (NMR) for PPIP was 7.2, Child PIP 0.43 and CDR 1,6 per 1000 livebirths. When the audit systems were combined, the annual NMR over the study period varied from 8.05 to 10.1 with a mean of 9.2 per 1000 livebirths over the entire period. Seventy-eight per cent of the deaths occurred in the early neonatal period with a mean early neonatal mortality rate of 7.2 per 1000 livebirths. The mean late NMR was 2 per 1000 livebirths. Where all neonatal deaths were considered for those more than 500g, the main cause of death was immaturity related, then infection related followed by congenital disorders and then hypoxia related. Seventy-four per cent of deaths occurred in those less than 2500g at birth and 41% were less than 1000g and defined as extremely low birthweight. In the group of neonates greater than 1000g, the main cause of death was infection related deaths, closely followed by congenital disorders and then hypoxia, followed by immaturity. Most of infection related deaths were collected by the CDR and Child PIP. A third of Child PIP and PPIP deaths and half of the CDR deaths were coded as avoidable. The prevalence of deaths due to abandonment either by passive or active neonaticide contributed towards the higher proportion of preventable deaths in the CDR group. Conclusions The burden of deaths due to immaturity is high and may be attributed to the finding that 41% of neonatal deaths were in the ELBW group. Current viability criteria that aim at optimum use of resources may improve survival amongst this group. Infection related deaths were shown by this study to have a greater burden than recorded from PPIP data; most of these deaths were derived from Child PIP and CDR data. Also, where 10% of neonatal deaths were sudden unexpected deaths (SUDIs), a better understanding and definition of this group is urgently required as many of these deaths were subsequently found to be secondary to lower respiratory infections. It is further relevant that where 20% of CDR deaths or 3% of all the study deaths were due to active and passive neonaticide, this entity should be monitored and investigated. The study showed that the GSA has achieved the SDG for NMR of less than 12 per 1000 livebirth. However, a mean NMR of 9.2 per 1000 livebirths is not comparable to other upper middle-income countries. As 38% of the deaths were coded as avoidable, appropriate programmes to address these factors could reduce the NMR to 5.7 per 1000 livebirths. A strong recommendation from this study would be to use all three audit systems to calculate the NMR, understand the causes of neonatal deaths and plan programmes to improve neonatal survival in this GSA

New technology in radiological diagnosis: An investigation of diagnostic image quality in digital displays of radiographs

Digital radiology is undergoing rapid evolution. Its objectives can be summarized as the creation within the modern radiology department - and indeed within the entire hospital - of a harmonious, integrated, electronic network capable of handling all diagnostic radiological images, obviating the need for conventional film-based radiology. One of the limiting factors in the introduction and exploitation of digital technology is the issue of image display quality: if electronic display systems are to be widely used for primary radiological diagnosis, it is essential that the diagnostic quality of the displayed images should not be compromised. From the perspective of the practising radiologist, this study examines the performance of the first two commercially available digital radiological display systems to be purchased and installed in a British hospital. This work incorporates an extensive observer performance investigation of image quality from existing 1024- and 1280-line display systems, and suggests that displayed images digitized at a pixel size of 210?m show a significant reduction in diagnostic performance when compared with original film. Such systems appear to be unsuitable for primary radiological diagnosis of subtle lesions. Some of the physical properties of such systems, some relevant methodological issues, and the relationship between image quality and other factors influencing the development acceptance and implementation of digital technology, have also been investigated; the results are presented. This is a controversial subject, and conflicting views have been expressed in the British literature concerning the issue of whether or not the technology is now ready for total system implementation; the view of this author is that careful testing of display systems, and of every other component of digital networks, should precede their entry into clinical use

Studies on benign hepatic and pancreatic pathology

Background Malignant pathologies of hepatic and pancreatic lesions have been widely reported. However, benign pancreatic and hepatic pathologies are infrequently focused on owing to their innocuous nature. The significance of indeterminate liver lesions (ILL) and a novel pancreatic entity - intraductal tubulopapillary neoplasm (ITPN) are explored. With the escalating incidence of obesity, a better understanding of fat distribution, metabolism, and its clinical implications are critical to managing pancreatitis. Visceral adipose tissue (VAT) and sarcopenia are valued as contributors to prognosis and outcomes in these patients. Objective The pathologies of ILL and ITPN pose a diagnostic conundrum and have created a management dilemma for clinicians. This thesis examines the characteristics and natural history of these pathologies, and attempt to provide current strategies to aid diagnosis and management. This thesis also focuses on the impact of VAT and sarcopenia in pancreatitis. The main purpose is to highlight the current data available and identify gaps in knowledge surrounding these pathologies. Design The four papers contributing to this thesis include a retrospective cohort study, a review and two systematic reviews. The retrospective cohort study consisted of a retrospective analysis of prospectively collected data from a single institution for eight years. The systematic reviews utilised NCBI PubMed, EMBASE as data sources and selected all studies published since 2000. Results The results cover an overview of clinical, radiological, histopathological, and molecular features, as well as the prognosis and up to date management of ILL and ITPN. The cohort study concluded that small (<15 mm) hepatic lesions discovered incidentally in patients with no known primary malignancy and risk factors are virtually always benign, with a 1% risk of malignancy. The review on ITPN discovered that the diagnosis of ITPN is invariably made post-operatively and is considered to be a precursor lesion to carcinomas but has a favourable prognosis. The systematic review on VAT identified 11 studies. Nine studies showed a statistically significant association between VAT and the severity of AP. Four studies found VAT to be a risk factor for acute pancreatitis. Two studies showed VAT is associated with an increased risk of local complications and two other studies showed a correlation between VAT and mortality. The systematic review on sarcopenia in chronic pancreatitis (CP) analysed six studies. The prevalence of sarcopenia in CP from all studies ranged from 17-62%. Sarcopenia was associated with a reduced quality of life, increased hospitalisation, and reduced survival. Conclusion This thesis provides the foundation for further work to be undertaken on these surgically challenging diseases. There is a need for a classification system, which stratifies ILLs by malignant potential based on a standardized and evidence-based approach. Further studies are essential to elucidate the natural history of ITPN to guide the best treatment strategy and determine survival. The systematic reviews established that VAT and sarcopenia have significant prognostic values and should be incorporated into prognostic scores of pancreatitis and future prospective analyses. A multidisciplinary approach in an experienced hepatobiliary and pancreatic centre is recommended for the management of these challenging benign pathologies.Thesis (MPhil) -- University of Adelaide, Adelaide Medical School, 202