Background: Lung cancer has a dreadful prognosis and is the leading cause of cancer deaths in the world and in the UK. The UK survival rates are particularly poor when compared with survival in other countries in Europe. More than two-thirds of people with lung cancer in the UK are diagnosed at a late stage when curative treatment is no longer possible. Since lung cancer survival rates are higher with earlier diagnosis, there is need to diagnose cases earlier. This suggests a potential to examine and if possible, modify the care pathway for people with lung cancer to achieve earlier diagnosis. Aim: The overall aim of this thesis was to explore the patient characteristics and interactions in primary care before the diagnosis of lung cancer, as a means of identifying the features that are predictive of lung cancer and the potential for earlier diagnosis. To achieve this aim, it was necessary to investigate and validate the use of lung cancer data from The Health Improvement Network. Methods: The Health Improvement Network (THIN) database of United Kingdom general practice records, was used to identify and study the characteristics of cases of lung cancer in the UK. To ensure that THIN was a valid source of lung cancer information for research, a study was done to assess the completeness and representativeness of the lung cancer data in THIN by comparing the lung cancer patient characteristics, incidence and survival in THIN with the UK National Cancer Registry and the National Lung Cancer Audit Database. Experian's Mosaic Public Sector variable linked into THIN database was then used to identify detailed profiles of the UK sectors of society where lung cancer incidence was highest as a means of exploring the potential of using this geo-demographic tool to facilitate disease ascertainment. Two case-control datasets were developed from the database using the identified cases of lung cancer. The first dataset was matched on age, sex and general practice and it was used to carry out three studies in this thesis. The first study was a pilot study of methods to identify the socio-demographic and clinical features independently associated with lung cancer as well as to identify the timing of these clinical features before lung cancer was diagnosed. This was followed by two studies to examine separate hypotheses on the variation in lung cancer risk firstly between smokers of different socioeconomic status, then between smokers with and without a recorded history of depression, as socioeconomic deprivation and depression are both associated with increased prevalence of cigarette smoking. The second case-control dataset was matched only on practice and this dataset expanded on the methods from the pilot study to identify the socio-demographic factors including age and sex, as well as the early clinical features that are predictive of lung cancer. This was followed by a study which used the identified predictors to develop and validate a risk-prediction model for lung cancer. The model validation was carried out using another dataset of patients in a more recent version of THIN with records spanning a time period after the last date of records for patients used for the earlier studies in the thesis. Results: A study population of 12,135 patients with incident lung cancer were identified from the 1st of January 2000 to the 28th of July 2009. The overall incidence of lung cancer, median survival and general lung cancer patient characteristics in THIN were similar to other national lung cancer databases - The National Lung Cancer Audit Data and the UK National Lung Cancer Registry data from the Office of National Statistics. Mosaic™ classifications identified wider variations in lung cancer incidence than existing markers of socioeconomic deprivation and therefore allowed more detailed classifications of the UK sectors of society where lung cancer incidence was highest. For example the incidence rate in Mosaic Public Sector™ type I50 (Cared-for pensioners) was 31.2 times higher (IRR 31.2; 95% CI 21.9-44.5) than the incidence rate in Mosaic Public Sector™ type B10 (Upscale new owners). With regards to the risk of lung cancer among smokers from different socioeconomic groups, stratified analyses of the association between smoking and lung cancer by Townsend deprivation quintiles showed that the risks of lung cancer were similar in smokers of different socioeconomic status. Depression was associated with a 30% increased risk of lung cancer (odds ratio 1.30; 95% CI 1.24-1.38) which was completely explained by smoking. Cigarette smoking was more common and levels of consumption were higher among depressed compared to non-depressed individuals. Stratified analyses of the association between smoking and lung cancer by depression showed that there was no difference in lung cancer risk among depressed and non-depressed smokers. Socio-demographic features - age, sex, socioeconomic status and smoking, increase in the frequency of general practice consultations as well as early records of presentation for symptoms of cough, haemoptysis, dyspnoea, weight loss, lower respiratory tract infections, non-specific chest infections, chest pain, hoarseness, upper respiratory tract infections and Chronic Obstructive Pulmonary Disease (COPD) were found to be independently associated with lung cancer 4 to 12 months before diagnosis. A risk prediction model was developed with these variables, and on validation using an independent THIN dataset of 1,826,293 patients, the model performed well with an area under the curve statistic of 0.88. Conclusions: Routine electronic data in THIN are a valid source of lung cancer information for research. Mosaic™ identifies greater incidence differentials than standard area-level measures and as such could be used as a tool for public health programmes to ascertain future cases more effectively. Neither socioeconomic deprivation nor a history of depression increases an individuals' vulnerability to the carcinogenic effects of cigarette smoke. The increase in lung cancer risk among more deprived individuals and those with depression is largely explained by the greater cigarette consumption by these groups of people. Smoking cessation interventions targeted to these groups of people are needed to reduce the lung cancer-related health inequalities associated with deprivation and depression. A combination of patients' age, sex, socioeconomic characteristics, smoking status and early stage symptoms in general practice aid earlier identification of patients at increased risk of lung cancer. The model developed using these variables performed substantially better than the current NICE referral guidelines and all comparable models, being able to predict lung cancer early enough to make detection at a potentially curable stage feasible by allowing general practitioners to better risk-stratify their patients.

Hyperpolarized noble gas MRI using 3He and 129Xe has allowed void space imaging of the lungs for several years. Hyperpolarized 83Kr MRI has also been shown to provide an MRI contrast sensitive to the surface-to-volume ratio and chemistry of synthetic porous systems. Ex vivo animal models of pulmonary diseases and in vitro experiments were used in this thesis to examine three methodological advances allowing for the measurement of pulmonary physiological parameters using 129Xe and 83Kr. The 83Kr quadrupolar property was explored in a rat model of pulmonary surface-to-volume ratio degradation, i.e. emphysema. The surface quadrupolar relaxation (SQUARE) of the noble gas provided maps of the longitudinal relaxation in control and emphysematous rat lungs. The relaxation observations were regionally correlated to the histological measurements of the alveolar degradation. The 129Xe solubility in the lungs, blood, and more generally liquids, was the basis for the design of a new biosensor composed of a cryptophane cage tethered to a paramagnetic agent. The depolarization of the 129Xe atoms encapsulated by the cryptophane, followed by chemical exchange with the surrounding medium was investigated in vitro. This model biosensor will lead to a future switchable biosensor that will be deactivated by the enzymatic cleavage of the encapsulating cage and the paramagnetic agent. Finally, the 129Xe solubility was further utilised to study the gas transfer through ex vivo rat lungs after blood replacement by a perfluorocarbon emulsion. The large chemical shift separating the 129Xe peaks for the gas phase, the tissue and the perfluorocarbon emulsion, allowed for a selective excitation of each phase and the independent observation of their signal build-up after inhalation. This mechanism will be used as a biomarker for gas transfer impairment in animal models of pulmonary fibrosis.

Background: The United Kingdom (UK) has poor lung cancer survival rates compared to other countries, and this is partly explained by differences in early mortality. In order to diagnose lung cancer at an earlier stage in the UK there is a pressing need to understand the management process from the recognition of symptoms by people with lung cancer, through the initial interactions with primary care to the referral to secondary care and the choice of the subsequent treatment plan. Objectives: The aim of this thesis is to use mixed methods to identify some of the factors which may affect the diagnosis and prognosis in patients with lung cancer in the United Kingdom across the whole patient pathway. Methods: Prospectively collected clinical data were used in conjunction with qualitative methodology. Primary care records were obtained from The Health Improvement Network, alongside data from the National Lung Cancer Audit (NLCA), linked to Hospital Episode Statistics and Office for National Statistics datasets. Case-control and cohort studies were conducted using multivariable logistic regression to look at independent associations with early mortality, likelihood of receiving surgery and place of death. Survival analyses were performed using Kaplan Meier curves and Cox regression and validation studies used area under the receiver operating curves (AUC). The Framework approach was used to identify themes and sub-themes arising from focus group interviews. Results: Mixed methods were used to look at barriers to early diagnosis and attitudes towards lung cancer screening in a high risk population. A number of key practical and emotional barriers which may impact on screening uptake were identified, alongside the issue of smoking stigma and blame. Primary care data were used to look at predictors of early (0-90 day) mortality in the UK. Thirty per cent of patients with lung cancer died within 90 days of diagnosis. Increasing age, male sex, socioeconomic deprivation, rural versus urban location and current smoking were all independently associated with early death. Patients who had poorer prognosis did interact with primary care before diagnosis, suggesting missed opportunities to identify them earlier. NLCA data linked to organisational audit data highlighted inequities between Trusts, in particular with regards to variability in the workload of specialists and differences in access to diagnostic and therapeutic modalities. On site access to positron emission computed tomography, stereotactic ablative radiotherapy and video-assisted thoracoscopic lobectomy were independently associated with increased likelihood of receiving surgery for lung cancer. Records for patient who developed brain metastases following radical surgical treatment for lung cancer were reviewed. Those with more advanced disease stage, younger age and adenocarcinoma sub-type were more likely to develop metastases and modelling suggested that 71% may have been visible pre-operatively had magnetic resonance imaging of the brain been performed as part of the staging process. An internal and external validation was performed to assess the ability of two risk scoring systems to predict 90 day post-operative mortality. AUC values for internal and external validation of the NLCA score and validation of Thoracoscore were 0.68 (95% CI 0.63-0.72), 0.60 (95% CI 0.56-0.65) and 0.60 (95% CI 0.54-0.66) respectively. Post-hoc analysis was performed using NLCA records on 15554 surgical patients to derive summary tables for 30 and 90 day mortality, stratified by procedure type, age and performance status. Linked NLCA data were used to look at place of death from lung cancer. Thirty-five per cent of patients with lung cancer die in acute hospital beds, with male sex, old age (≥ 85 years), socioeconomic deprivation, WHO performance status 4 at diagnosis and emergency route to diagnosis all independently associated with increased likelihood of death in this setting. There is marked geographical variation in place of death, particularly with regard to provision of hospice services. Conclusions: The studies described in this thesis use prospectively collected data to provide a snapshot of different aspects of the lung cancer patient journey which may impact on prognosis, alongside qualitative methodology to try to determine reasons for diagnostic delay and attitudes towards screening programmes. There remain some important clinical questions about lung cancer care and outcomes which need to be looked at to provide a greater understanding of where the inequities in the lung cancer patient pathway in the UK lie and to try to address modifiable factors with an aim to improve outcomes.

Clinicians use several oxygen-based indices in intensive care units as surrogates to determine the condition of the patient’s lung and verify monitoring progress. Examples of these oxygen indices include the ratio of arterial oxygen tension to inspired oxygen fraction (PaO2/FiO2 ratio); arterial/alveolar oxygen tension ratio (PaO2/PAO2); alveolar–arterial oxygen tension difference (PA-aO2); respiratory index (RI= (PA-aO2)/PaO2), and content-based venous admixture (Qs/Qt). One of the issues with this approach is that these indices fail to take into consideration several additional external pulmonary physiological factors and, as such, these indices could potentially mislead clinicians. This thesis explores the nature of the oxygen-tension-based indices response and examined the effect that varying certain external pulmonary factors, such as FiO2, PaCO2, Hb, respiratory rate, oxygen consumption, cardiac output, and respiratory quotient, had on PaO2 using virtual subjects and patients’ data to quantify oxygenation defect through a combination of mathematics, different diseases, and pathophysiology. There were one or two approaches that could lead us to the answer, and many dead end routes. Eventually, the research produced a new index that was compared and validated using two approaches. First, on virtual subjects with lung pathologies that were commonly seen in the intensive care unit and then on real clinical data that was obtained from the intensive care unit. The results of these validation investigations indicated that the proposed index is more robust and resistant to variations in certain external pulmonary factors than the PaO2/FiO2 ratio. As such, there is a strong indication that it may help to improve the quality of patient care provided. The feasibility of manually calculating and applying this newly proposed index in the ICU is an issue that merits further exploration. Theoretically, if the newly proposed index was found to be practicable, it could improve the healthcare provided; reduce the cost of unnecessary blood work, and save time and effort. However, due to the time it takes to calculate crPaO2 manually, the use of medical technology and computer applications is desirable.

Bibliography: leaves 217-244. Tachykinins are implicated in the mediation of airway inflammatory responses and may have roles in airway remodeling and healing. The actions of tachykinins are mediated by specific receptors, designated NK1, NK2 and NK3. Tachykinin degredation, an important mechanism for limiting the effects of these peptides, is principally mediated by neutral endopeptidase (NEP). This thesis investigates the role of tachykinins, in vivo, in an ovine model and in human airway epithelium. Results show that the nett effect of tachykinins in the airway will depend on the relative balance between the expression of receptors, tachykinins and NEP. Assessment of these molecules in the airway epithelium from subjects with normal lungs or chronic bronchitis showed that preprotachykinin-A gene expression was relatively higher in the disease group whereas NEP and NK1 receptor levels were unchanged. These studies provide new insights into the role of tachykinins in airways disease.

1 v. (various paging) : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (D.Sc.)--University of Adelaide, 1981

There is limited study of the relationship between current farming exposures and childhood asthma, respiratory symptoms, and lung function. This thesis examined the prevalence of asthma in children living on and off farms and the risk of asthma and respiratory symptoms of children exposed to farming activities as well as the relationship between participation in selected farm related activities and lung function values in school age children.<p>The analysis for this thesis was based on data collected from a cross-sectional study conducted in 2004 of 636 children ages 6-13 from an agricultural community in rural Saskatchewan. Parents on behalf of children completed a questionnaire of respiratory health and environmental exposures. Asthma was defined as doctor diagnosis of asthma. Respiratory symptoms were determined by report of cough, wheeze, phlegm. Individual farming activities assessed were; haying, harvesting, moving or playing with hay bales, feeding livestock, cleaning or playing in barns, cleaning pens, and emptying or filling grain bins. The health assessment, conducted at the schools with children, included measurements of height, weight, skin prick test for atopy and lung function (FEV1, FVC, FEV 25-75, FEV1/FVC ratio).<p>There were 553 subjects with questionnaire data for a response rate of 86.9%. Of those subjects participating in the study, lung function was available for 532 subjects. The overall prevalence of asthma was 18.8% and the prevalence of respiratory symptoms was 39.8%. The prevalence of asthma or respiratory symptoms did not differ between children who lived on farms or in towns. <p>After adjusting for significant or clinically important risk factors, children who were exposed to emptying and filling of grain bins were more likely to have asthma (OR=2.42, 95%CI:1.19-4.92). Children with respiratory symptoms were more likely to be exposed to haying activities (OR=1.92, 95% CI:1.03-3.56), playing on or near hay bales (OR=1.93, 95%CI:1.2 -2.96) or cleaning pens (OR=2.55, 95% CI:1.04-6.26). Lung function variables were not associated with participation in any of the seven farming activities tested.<p>Although there were no differences in the prevalence of asthma and respiratory symptoms between farming and non-farming children, certain farming practices may be important in the etiology of asthma and related respiratory symptoms in children.

There is limited study of the relationship between current farming exposures and childhood asthma, respiratory symptoms, and lung function. This thesis examined the prevalence of asthma in children living on and off farms and the risk of asthma and respiratory symptoms of children exposed to farming activities as well as the relationship between participation in selected farm related activities and lung function values in school age children.<p>The analysis for this thesis was based on data collected from a cross-sectional study conducted in 2004 of 636 children ages 6-13 from an agricultural community in rural Saskatchewan. Parents on behalf of children completed a questionnaire of respiratory health and environmental exposures. Asthma was defined as doctor diagnosis of asthma. Respiratory symptoms were determined by report of cough, wheeze, phlegm. Individual farming activities assessed were; haying, harvesting, moving or playing with hay bales, feeding livestock, cleaning or playing in barns, cleaning pens, and emptying or filling grain bins. The health assessment, conducted at the schools with children, included measurements of height, weight, skin prick test for atopy and lung function (FEV1, FVC, FEV 25-75, FEV1/FVC ratio).<p>There were 553 subjects with questionnaire data for a response rate of 86.9%. Of those subjects participating in the study, lung function was available for 532 subjects. The overall prevalence of asthma was 18.8% and the prevalence of respiratory symptoms was 39.8%. The prevalence of asthma or respiratory symptoms did not differ between children who lived on farms or in towns. <p>After adjusting for significant or clinically important risk factors, children who were exposed to emptying and filling of grain bins were more likely to have asthma (OR=2.42, 95%CI:1.19-4.92). Children with respiratory symptoms were more likely to be exposed to haying activities (OR=1.92, 95% CI:1.03-3.56), playing on or near hay bales (OR=1.93, 95%CI:1.2 -2.96) or cleaning pens (OR=2.55, 95% CI:1.04-6.26). Lung function variables were not associated with participation in any of the seven farming activities tested.<p>Although there were no differences in the prevalence of asthma and respiratory symptoms between farming and non-farming children, certain farming practices may be important in the etiology of asthma and related respiratory symptoms in children.

Thesis (M.P.H.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 90-95).

Thesis--PlanA (M.S.)--University of Wisconsin--Stout, 2002. / Includes bibliographical references.