Saudi Cultural Missions Theses & Dissertations
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Item Restricted The Association Between Patient-Reported Outcomes and Pulmonary Exacerbation Frequency in Patients with Alpha-1 Antitrypsin Deficiency(University of Birmingham, 2024-08) Almahmoudi, Jameelah Ahmed; Pye, AnitaIntroduction: the negative effect that pulmonary exacerbations have on alpha-1 antitrypsin deficiency patients’ lung function has been explored and proven. Nonetheless, studies addressing the association between patient-reported outcomes (PROs) and exacerbation frequency in patients with AATD are lacking. Study Aim: To analyse the association between pulmonary exacerbations, and patientreported outcomes in alpha-1 antitrypsin deficiency patients. Method: Patients’ data was extracted from The AATD cohort/registry. Information regarding patients’ demographics, genotype, smoking status, smoking rate, COPD diagnosis, and FEV1% were included. The PROs include The St. George's Respiratory Questionnaire (SGRQ), The COPD Assessment Test (CAT), Modified Medical Research Council Dyspnoea Scale (mMRC). The exacerbation frequency in the last 12 months was reported by patients. Statistical association and correlation were reported. Patients with 2 or more exacerbations were labelled as frequent exacerbators (FE), and patients with less than 2 exacerbations were labelled infrequent exacerbators (IE) in the last 12 months. Also, patients were grouped as non-exacerbators with 0 exacerbations or exacerbators with 1 or more exacerbations in the last 12 months. Results: A total of 234 patients were included in this study. The FE group (n=69) reported significantly poorer PROs when compared to the IE group (n=165), even though FEV1% was not significantly different between the two groups (p = 0.055). when comparing exacerbators to non-exacerbators, all PROs and FEV1% were significantly different with poorer results seen in the exacerbators group (p < 0.001 for SGRC and CAT and p = 0.007 for mMRC). Spearman rank correlation supported that lower FEV1% and more exacerbations are significantly correlated with poorer PROs (p ≤ 0.001 in all correlations). The regression model proved that more exacerbations and declined FEV1% are significant predictors of PROs worsening. Conclusion: Frequent exacerbations and declined FEV1% are associated with worse patientreported outcomes in patients with alpha-1 antitrypsin deficiency.13 0Item Restricted A Comparative Analysis of CVD and MSK Comorbidities in Usual COPD and AATD-COPD(University of Birmingham, 2024-08) Mousa, Hatim Hammad; Michael, NewnhamBackground: Chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency-related COPD (AATD-COPD) are complex conditions associated with cardiovascular (CVD) and musculoskeletal (MSK) comorbidities, which exacerbate the severity of the disease and impact patient outcomes. Despite their clinical relevance, the prevalence and impact of these comorbidities in AATD-COPD compared to usual COPD have not been thoroughly investigated. This study aims to address this gap by comparing the prevalence of CVD and MSK comorbidities in these two COPD populations to improve treatment approaches and patient care. Methods: This retrospective cohort analysis utilised data from the INTEGR-COPD trial and the Birmingham Alpha-1 cohort to compare the prevalence of CVD and MSK comorbidities in patients with usual COPD and AATD-COPD. Baseline characteristics, comorbidities, and pulmonary exacerbations were analysed. Non-parametric tests, including chi-square and Mann-Whitney U tests, were employed to compare categorical and continuous variables across the cohorts, respectively. Results: The study analysed 1,663 usual COPD and 754 AATD-COPD patients. CVD comorbidities were more prevalent in usual COPD (52.50%) than AATD-COPD (30.11%) (p < 0.001). Similarly, MSK comorbidities were more prevalent in usual COPD (30.07%) compared to AATD-COPD (11.41%) (p < 0.001). AATD-COPD patients were younger, had better lung function, and reported higher dyspnoea scores. Smoking status varied significantly, with higher current smokers in the usual COPD cohort. Pulmonary exacerbations were significantly more frequent in usual COPD patients with CVD than in AATD-COPD patients (p = 0.0011). Conclusion: This study highlights that usual COPD patients exhibit a higher prevalence of CVD and MSK comorbidities. Additionally, they tend to be older and have worse pulmonary outcomes compared to patients with AATD-COPD, who experience more severe dyspnoea. These findings emphasise the need for tailored clinical management approaches for both populations. Further research should explore the mechanisms and interventions to mitigate these comorbidities and improve patient outcomes.5 0Item Restricted Evaluating FEV1Q as a race-neutral measurement of lung function across three diverse populations in LMICs.(University College London (UCL), 2024-08-28) ALlayadhi, Ayadh; Hurst, JohnIntroduction The adjustment of lung function for ethnicity is controversial and has led to race-neutral approaches, such as forced expired volume in 1st second quotient (FEV1Q), which expresses FEV1 as a multiple of the theoretical lower limit of survival. It is unknown whether this lower limit is similar in diverse populations in different low- and middle-income countries (LMICs) or whether FEV1Q can accurately diagnose chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the FEV1Q as a race-neutral measure of lung function in these regions. Methods This study utilised 10660 participants’ spirometry and anthropometric data, aged ≥40 years, collected from Uganda, Nepal, and Peru, with even sex and site distribution. The assessment included: whether 1st percentiles of absolute FEV1 were similar across these populations, assessing the FEV1Q diagnostic ability for 999 COPD cases, and estimating FEV1Q decline rates under several circumstances. Results The 1st percentiles of absolute FEV1 (L) were similar to the previously reported values of 0.5 L for males and 0.4 L for females in the COPD group, while these percentiles differed in the entire population. FEV1Q had discriminative accuracy in diagnosing COPD (AUC = 0.87). Estimation of FEV1Q decline under normal conditions demonstrated 1 unit/18 years, while it declined every 12.5 years for current smokers and every 17.5 years with biomass exposure. Discussion Although this study addressed the lack of diverse populations in which FEV1Q has been assessed, and presented several strengths, it did not include follow-up measurements of lung function which limit quantifying long-term outcomes; and ethnicity/race categories were assumed based on site. This highlights the need for future longitudinal studies to assess FEV1Q utility, and shed light on other respiratory conditions. Conclusion FEV1Q is a simple and promising race-neutral measure of lung function; however, further studies are required.13 0Item Restricted The Use of Home Carbon Monoxide Monitoring as Part of a Tobacco Dependency Service for Acute Hospital Admissions with COPD and Asthma(University College London, 2024-08-27) Alshammari, Turki Faleh; Roy, KayBackground Tobacco dependency is a significant global public health challenge, affecting the NHS; UK, causing substantial morbidity and mortality, especially in COPD and asthma patients where Tobacco Dependency Services (TDS) have potential to reduce hospital admissions and improve health outcomes. NHS Long-Term Plan prioritizes COPD and smoking-related health inequalities. Although carbon monoxide monitoring (COM) is recommended for smoking cessation, its use in airway diseases has not been studied before. Aim To determine whether the iCOquit has potential value to help quit attempts in respiratory patients (asthmatics and COPD smokers) as part of the TDS in acute trusts and adds to positive experience. Methods COPD and asthma patients admitted to two London hospitals were offered the iCOquit device for home COM and remotely followed for up to 12 weeks, with motivation levels and stages of behavioural change assessed. Pre- and post-intervention surveys were conducted to assess patient experiences. Results 15 COPD and asthma patients were initially reviewed, (mean age 59 years), predominantly male (60%) and White British (80%). Initial motivation to quit smoking was high (73.3% at maximum), with 20% remaining smoke-free after 4 weeks. Patient experience was good but suggested specific technological improvements. Discussion This study introduced a novel approach to enhancing TDS within acute care settings. Initial findings suggest that the iCOquit device may be beneficial for certain patient populations and future research will focus on identifying these groups more precisely and the value of home COM in different settings, alongside a follow-up study incorporating health economic modelling to validate the clinical efficacy, cost-effectiveness, and scalability of iCOquit within the NHS. Collaboration with manufacturers will aim to enhance the device's accessibility and usability, improving data collection and decision-making processes, with the potential for broader implementation of similar digital health tools across healthcare.11 0Item Restricted The molecular basis of pathological alpha-1-antitrypsin polymerisation(University College London, 2025) Aldobiyan, Ibrahim Fahad I; Lomas, David A; Irving, James A; Orlova, Elena VAlpha-1-antitrypsin deficiency (AATD) is a rare protein misfolding disease, primarily afflicting Northern European and Iberian populations. The deficiency is due to mutations in the gene encoding alpha-1-antitrypsin which promote its misfolding and subsequent aggregation into polymeric chains within hepatocytes. This results in both gain-of- toxicity and loss-of-function phenotypes, with accumulating polymers inducing cellular damage to hepatocytes, causing liver cirrhosis in the long term. The marked reduction in circulating antitrypsin levels leads to early-onset emphysema. AATD has been studied for over half a century and the mechanism defining the polymerisation pathway in molecular detail remains elusive. Several theories have been proposed, with varying degrees of experimental support, on artificially inducedantitrypsin polymers. We propose that understanding the nature of the intermolecular linkage between the monomeric subunits of ex vivo liver-derived antitrypsin polymers is fundamental to developing therapeutics that inhibit or reverse polymerization. Such therapeutics are necessary as currently, liver transplantation is the only means of curing the condition. The principal aim of this study is to use cryo-electron microscopy (cryo-EM) with single- particle reconstruction techniques to establish the structural changes that lead to polymer formation, using material obtained from human explant tissue. Polymers are technically challenging targets due to their flexibility and heterogeneity. Decorating antitrypsin liver polymers with Fab fragments of known epitope restricted their flexibility and provided valuable orientational information, assisting particle alignment. Despite the challenging sample preparation, the structure of the monomeric subunit of alpha-1-antitrypsin has successfully been reconstructed to 4.2 Å resolution. This reconstruction, in the context of other experiments, allows conclusions to be drawn regarding the polymerisation mechanism, and its implications for the polymerisation of other members of the serpin family. It has been established that an early step in polymerisation involves a monomeric activated state, M*, with perturbations in a region known as the breach. A secondary aim of this project is to better understand the role of the breach region of AAT in the polymerisation pathway. Site-directed mutagenesis was performed on numerous sites within and around the breach. A potent small molecule polymerisation inhibitor was used to probe the effect of these mutations on the ability of antitrypsin to transition to the intermediate M* conformation and polymerise.10 0Item Restricted Association Between Chronic Airflow Obstruction and Physical Activity in A Multinational Study(Imperial College London, 2024) Alharbi, Talal; Amaral, AndreBackground Several studies have suggested that poor respiratory health may strongly impact physical activity. The aim of this study was to investigate whether people with chronic airflow obstruction are more or less likely to be physically active and to examine variations in this association across regions, sexes, and smoking statuses. Methods The data used in this study were from the general population-based Burden of Obstruction Lung Disease (BOLD) follow-up, collected from 18 different sites worldwide. A total of 3,372 participants answered the core questionnaire, provided high-quality lung function spirometry and had no missing data on relevant variables. The level of physical activity was classified into moderate, vigorous, and walking activity. We conducted comprehensive analytic modules using meta-analysis and logistic regression across different sites. The analysis assessed the impact of physical activity on the risk of airflow obstruction in both sexes, with further stratification by sexes. Result Overall, people with chronic airflow obstruction are 33% less likely to report moderate physical activity (OR: 0.67, 95% CI: 0.48 to 0.93), as compared to people without obstruction. Remarkably, the association was significant in females (OR: 0.59, 95% CI: 0.37 to 0.95) but not in males (OR: 0.78, 95% CI: 0.48 to 1.27). These results were consistent across all sites. We found no significant association between vigorous physical activity and chronic airflow obstruction. Conclusion Chronic airflow obstruction seems to have a strong effect on physical activity, particularly in females. However, it is not clear from the data whether participants with chronic airflow obstruction were already less active before developing obstruction. Anyway, integrating pulmonary rehabilitation into clinical intervention for people with chronic airflow obstruction may be important as a way to improve their health outcomes and quality of life.18 0Item Restricted Role of C-reactive protein in airway smooth muscle dysfunction relevant to obstructive lung disease.(University of Leicester, 2024-07-31) Alanazi, Amani; Saunders, RuthC-reactive protein (CRP), is an inflammation marker, often elevated in airways conditions such as asthma and COPD. This research investigated the impact of CRP on airway smooth muscle (ASM) cells, which are crucial in the airway remodelling and hyperresponsiveness which is observed in these conditions. By using primary human ASM cells, this study has shown that purified CRP reduced cell number, increased cell size and intracellular complexity, and maintained cell viability. However, these findings were not replicated with recombinant CRP, which lacks endotoxin, suggesting that endotoxin contamination in the purified CRP may have played a role. Lipopolysaccharide (LPS) treatment, an endotoxin component, resulted in increased intracellular complexity but did not completely replicate the other effects of purified CRP on ASM cells. Moreover, a CRP-neutralizing antibody did not reverse the changes induced by purified CRP, indicating the potential involvement of contaminants. The differences between purified and recombinant CRP highlight the challenges in isolating the true effects of CRP from those of other inflammatory agents. Future research will give priority to endotoxin removal or neutralization, using higher concentrations of both CRP and the neutralizing antibody. Additionally, the study will focus on exploring potential synergistic effects between CRP and LPS on ASM cells. Further investigations are needed to fully understand the role of CRP in the ASM dysfunction and the underlying mechanisms, including apoptosis, hypertrophy, and mediator secretion. In conclusion, this study suggests that CRP has the potential to contribute to ASM dysfunction but underscores the importance of strict experimental controls to distinguish its effects from potential contaminants like endotoxin. The research emphasizes the need for further exploration of the complex interplay between CRP, endotoxin, and ASM cells to elucidate their individual or combined contribution to ASM dysfunction in lung diseases.84 0Item Restricted Systemic Inflammation, Arterial Stiffness, and Vascular Endothelial Dysfunction in Patients with Chronic Lung Disease(University of Dundee, 2024-05-22) Arafah, Abdullah M.; Khan, FaiselChronic lung disease (CLD) is considered a heterogeneous, complex, and multicomponent condition. Types of CLD include bronchiectasis, chronic obstructive pulmonary disease (COPD), and asthma. Cardiovascular events and peripheral vascular disease are highly prevalent among patients who are known to have CLD. It is increasingly acknowledged that cardiovascular comorbidities contribute to the disease’s severity. The underlying mechanisms that link CLD and cardiovascular disease (CVD) are inadequately understood. Systemic inflammation is a key component that could describe the link between CLD and CVD. Changes in vascular endothelial function accompany the increased cardiovascular events in CLD. Atherosclerosis and calcification of macrovascular and microvascular lead to further decrease vascular compliance. These structural changes in the vascular wall contribute to increased arterial stiffness observed in patients with CLD. Endothelial dysfunction and arterial stiffness are early signs of vascular disease and the development of cardiovascular events. Chronic systemic inflammation plays a vital role in linking CLD to the development of endothelial dysfunction and arterial stiffness. Therefore, this study aims to investigate the association between CLD and CVD. To successfully achieve the aims of this project, four work packages were employed, including a systematic review, a retrospective study, a Mendelian randomisation study, and a cross-section study involving the BRIDGE study. The systematic review study related to arterial stiffness in patients with CLD using various pulse wave velocity (PWV) methods, which assessed and summarised the outcomes of all relevant studies regarding the link between CLD and CVD. The retrospective study analysed anonymous data from the SUMMIT study to assess the vascular function in patients with CLD in the presence of CVD and type 2 diabetes mellitus, and shows a significantly greater PWV; p-value = 0.015 and carotid intima-media thickness (CIMT) in the CLD patients; p-value = 0.001. The Mendelian randomisation study investigated potential genetic causal links between CLD and arterial stiffness, which shows a significant association; p-value = 0.021. The cross-section study and BRIDGE study utilised biomarkers to determine if there are shared pathways that contribute to the development and progression of CLD and CVD, and shows significant differences in PWV, and microvascular function; p-value = 0.001, blood biomarkers include adiponectin, VCAM-1, GDF-15, coagulation factor III, syndecan-1, and matrix metalloproteinase (MMP-10); p-value = 0.001. In conclusion, this study revealed a significant association between CLD and CVD. Therefore, monitoring CVD risk, including assessment of endothelial dysfunction and arterial stiffness, in patients with CLD might be helpful for risk stratification and for identifying future CVD pathologies and disease progression. This emphasises the need to identify and manage comorbid CLD and CVD to target new or existing therapeutic approaches to control systemic inflammation and improve overall lung and cardiovascular health.9 0Item Restricted Characteristics and Outcomes of Chronic Bronchitis in Alpha-1 Antitrypsin Deficiency Related Lung Disease: A Retrospective Longitudinal Analysis(Saudi Digital Library, 2023-10) Alsaab, Sulaiman; Turner, Alice; Ellis, PaulAbstract Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with lung disease such as early-onset emphysema and chronic obstructive pulmonary disease (COPD). The presence of chronic bronchitis may accelerate disease progression in AATD patients, but few studies have specifically examined this phenotype. Objectives: To investigate the characteristics and outcomes such as FEV1 decline, DLCO decline, exacerbations frequency, and mortality of AATD patients with chronic bronchitis compared to those without chronic bronchitis. Methods: This retrospective cohort analysis utilised clinical data from the REDcap registry for 236 PiZZ and PiSZ AATD patients. Participants were categorised based on chronic bronchitis diagnosis and genotypes. Characteristics were compared between groups. Multiple linear regression analysis, logistic regression analysis, mixed linear model, and survival analysis are done to investigate outcomes including lung function decline, exacerbation frequency, and mortality among those patients. Results: Patients with chronic bronchitis (35% of the cohort) demonstrated significantly worse baseline lung function. FEV1 decline was steeper in PiZZ chronic bronchitis patients (-1.61% predicted/year, - 52 ml/year) versus PiZZ without chronic bronchitis (-1.07% predicted/year, - 31.5 ml/year). In the PiSZ genotype, the chronic bronchitis group similarly showed accelerated decline (-1.85% predicted/year, - 64 ml/year) versus the PiSZ without chronic bronchitis (-0.67% predicted/year, - 21 ml/year). Female sex was associated with higher odds of frequent exacerbations in both PiZZ and PiSZ individuals. There was no significance in terms of mortality between the groups. Conclusion: Chronic bronchitis in AATD is associated with impaired lung function and worse clinical outcomes compared to AATD alone. This high-risk phenotype warrants additional research into tailored interventions and closer monitoring. Larger longitudinal studies are needed to confirm the results and elucidate underlying mechanisms.18 0Item Restricted High Flow Nasal Oxygen Therapy for Acute Type II Respiratory Failure in Acute Settings(Saudi Digital Library, 2023) Alnajada, Asem; Shyamsundar, Murali; Blackwood, BronaghIntroduction: In acute type 2 respiratory failure (AT2RF), carbon dioxide levels in the blood are abnormally elevated. At present, non-invasive ventilation (NIV) with bi-level positive airway pressure is the standard treatment for AT2RF. High-flow nasal therapy (HFNT), which delivers heated humidified oxygen air to the patient with a flow rate of up to 60 L/min, is proposed for treating AT2RF. HFNT has several benefits, such as washout of carbon dioxide (CO2), reduced work of breathing, comfort and tolerance. Nevertheless, these benefits need to be comprehensively evaluated using high-quality evidence. HFNT, due to its tolerability and physiological rationale, could overcome the limitations of NIV. However, the current evidence and guidelines for its use are limited and uncertain. Therefore, this thesis presented a) Systematic evidence synthesis for CO2 clearance to identify the knowledge gap and guide future study designs, b) an exploration of the current practice through the international survey, c) a single centre randomised controlled trial (RCT) conducted to determine if HFNT reduces the need for NIV and partial pressure of CO2 (PaCO2) when used as an initial oxygen delivery method in comparison to LFO. Methods: In this thesis, three main methods were used. First, a systematic review was conducted to assess the existing evidence using a predefined protocol and a systematic approach. The inclusion criteria were randomised or non-randomised controlled trials or cohort studies that recruited participants with AT2RF, tested HFNT versus NIV or low-flow oxygen (LFO), and reported PaCO2 and other clinical and patient-related outcomes. Second, an international online survey was conducted to evaluate the current practice, guidelines and audits of HFNT. Participants included medical and respiratory therapists or physiotherapists in three countries: The United Kingdom (UK), Canada, and the USA (North America, NA). Third, a randomised controlled trial (RCT) was performed that assessed the effectiveness of HFNT versus LFO on adult patients with AT2RF (PaCO2 > 6 Kpa and pH < 7.35) admitted to the emergency department to determine the clinical effects of HFNT on the CO2 clearance and the number of patients requiring NIV escalation after 6 hours of treatment. Results: In the systematic review, 727 citations were screened, and five studies met the inclusion criteria. Four studies were RCTs, and one was a cohort study. Four studies compared HFNT with NIV and one RCT compared HFNT with LFO. Of four trials evaluating HFNT versus NIV, one RCT reported a significant reduction (HFNT 6.7, 5.6 –7.7 vs NIV 7.6, 6.3 – 9.3 (Median, interquartile range (IQR)) at four hours and no significant difference at other time-points. In relation to the secondary outcomes, there were no significant differences in other blood gases between HFNT and NIV. In two RCTs, HFNT was rated more comfortable than NIV. HFNT and NIV studies reported no effects on intubation rates, dyspnoea scores, length of stay and mortality. In the RCT comparing HFNT with LFO, there was no significant difference in PaCO2, and in terms of comfort, HFNT was rated as being louder than LFO. Other outcomes relevant to the review were not reported. The international survey was completed by 488 participants in the UK and NA. The majority reported using HFNT for acute type 1 respiratory failure (UK 99%, NA 94%). In the UK, HFNT was mainly used in respiratory wards (82%), while in NA, HFNT was primarily used in emergency departments (87%). In all countries, regular audits were lacking, and respondents considered the need for guidance very important (UK 61%, NA 64%) and urgent (UK 77%, 87%). In the RCT, HFNT significantly reduced the escalation to NIV compared to LFO. No significant differences in blood gas, respiratory parameters and patient centred outcomes between treatment groups at different time-points. In dyspnoea, HFNT showed a significant difference compared to LFO. Conclusion A few studies with very low to moderate certainty have assessed the clinical effectiveness of HFNT in AT2RF. The advantages of CO2 reduction by HFNT were limited to clinically irrelevant time points. HFNT was used in clinical conditions with poor quality evidence, the practice was not extensively audited and the guidance was lacking. HFNT showed statistical significance in reducing the need for NIV compared to LFO and was better in reducing dyspnoea at an early time point. Based on the thesis results, HFNT showed potential, but due to the limitations found in the thesis, it cannot be recommended for AT2RF until clinical practice guidelines and higher-quality evidence have been conducted.27 0