Saudi Cultural Missions Theses & Dissertations
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Item Restricted Advanced physiological monitoring of the cardiorespiratory system in healthy subjects and patients with sleep-disordered breathing(King's College London, 2024) Alsharifi, Abdulaziz; Steier, JoergIn this thesis, advanced physiological monitoring of the cardiorespiratory system was examined with the aim to improve outcomes for patient care in the management of respiratory conditions. The load:capacity ratio of the respiratory system was introduced as an indicator that reflects respiratory efficiency, the balance between the physiological load on the respiratory system and the capacity of the respiratory muscles. While Neural Respiratory Drive (NRD) represents a crucial component in assessing respiratory efficiency and its fundamental role in maintaining stable breathing, the load;capacity ratio provides insights into the ability to meet physiological demands, modulate symptoms, and maintain quality of sleep. Three integrated research projects examined different aspects of the load: capacity ratio of the respiratory system. The first study investigated levels of NRD, particularly the electromyographic (EMG) activity of the diaphragm, and its association with the perception of breathlessness, aiming to determine the minimally clinically important difference (MCID) in its activation. NRD, as measured by the respiratory muscle pump EMG, is a marker for inspiratory effort and closely correlates with work of breathing and symptoms, such as breathlessness. A systematic review and meta-analysis were undertaken to determine the MCID of NRD measurement using anchor-based and distribution-based methods. The systematic review identified 21 eligible studies involving 483 adult participants. NRD was primarily defined as the maximal root mean square of the diaphragm EMG as a percentage of maximum (EMGdi %max). In healthy individuals, the absolute range of EMGdi at rest was 6.0 to 16.6 %max, and 56.9 to 71.0 %max during exercise, with a mean difference of 53.3 [95% CI: 49.4; 57.1] %max. In COPD patients, the absolute range of EMGdi at rest was between 12 and 18 %max, and 59 to 72 %max during exercise, with a mean difference of 48.5 [95% CI: 44.8; 52.1] %max. The MCID of EMGdi %max, associated with a clinically large effect size, was 2.43% [95% CI: 1.96; 2.91] in normal subjects and 2.76% [95% CI: 1.92; 3.61] for COPD patients. For the Borg score, the MCID was approximately one unit for both healthy subjects and COPD patients. The second project focused on physiological experiments examining the effects of submental electrical stimulation and chemoreceptor stimulation in normal subjects during head-down tilt conditions while breathing different gas mixtures (room air, hypercapnic, and hypoxic). This research highlighted the importance of the load:capacity ratio in understanding the impact of loading the cardiorespiratory system and sensitising the baro- and chemoreceptors. Using an experimental model of baroreceptor loading induced by head-down tilt, the cardiorespiratory responses were measured during 50° head-down tilt combined with submental electrical stimulation and different gas conditions (hypercapnia, hypoxia, normoxia). The study involved 13 healthy subjects. Analysis from a three-way ANOVA indicated that blood pressure decreased significantly with transcutaneous electrical stimulation, and different gas conditions and postures similarly impacted blood pressure control. Additionally, there was increased minute ventilation with electrical stimulation, and an interaction effect between gas condition and posture on minute ventilation. The third project assessed the feasibility of remote monitoring to improve adherence to non-invasive ventilation (NIV) in patients with sleep-disordered breathing and hypercapnic respiratory failure. The study investigated remote monitoring of home mechanical ventilation (HMV) for treating chronic hypercapnic respiratory failure in patients with Obstructive Sleep Apnoea/Obesity Hypoventilation Syndrome (OSA/OHS). The primary aim was to assess whether remote monitoring could improve and optimise NIV adherence, test patients' willingness to use remote monitoring devices, and evaluate the associated healthcare resource usage and symptom improvement. In total, 32 participants were enrolled and randomly assigned to the intervention (remote monitoring) or usual care arm. The groups were similar in age, gender, and body mass index. While NIV usage in the intervention arm showed an initial improvement at the 6-week follow-up, the primary outcome of average nocturnal NIV adherence at 12 weeks was similar in both groups. Quality of life outcomes did not differ significantly between the intervention and usual care groups at the end of the trial. However, one severe adverse event with acute-on-chronic hypercapnic respiratory failure requiring hospitalization due to NIV non-adherence occurred in the control group. In conclusion, this thesis demonstrated various aspects of assessing the load:capacity ratio and the importance and complexities of understanding the underlying physiology in the context of advanced cardiorespiratory monitoring. The MCID associated with the sensation of breathlessness for the diaphragm EMG was described. A sensitization effect of electrical stimulation on the baroreceptors, impacting blood pressure, was proven. Furthermore, while the value of remote monitoring in patients with OSA/OHS requires further assessment, regular review of cardiorespiratory parameters contributes to the provision of safe follow-up surveillance in this cohort. Each project underlined the relevance of a deeper pathophysiological understanding for the management and treatment of cardiorespiratory conditions. These findings could be used to improve respiratory care by focusing on patient-based, clinically relevant outcomes and optimising healthcare delivery for clinical trials and regular clinical services for patients with respiratory conditions and sleep-disordered breathing.6 0Item Restricted The role of IL-17 in CD95L-driven nonapoptotic pathology during respiratory disease(University of Liverpool, 2024-07) ALAidarous, Sondus; Stewart, JamesCD95L can induce a pathological nonapoptotic pathway and promote Th17 migration when cleaved from the cell surface by proteases. The targeted inhibition of this nonapoptotic pathway by blocking the calcium-inducing domain to impede IL-17 migration could be of therapeutic benefit in inflammation, as seen in a murine lupus model. We aimed to investigate the CD95L nonapoptotic pathway and factors involved in the cleavage of CD95L in the context of SARS-CoV-2 infection and pulmonary fibrosis. Three approaches were used: in vitro studies, in vivo murine models and human clinical sample-based studies. In vitro, the Jurkat cell line was stimulated with PHA, LPS, recombinant MMP9 and mouse sera to optimise conditions for the expression and cleavage of CD95L. MMP9 was investigated as a putative cleavage factor of CD95L and was found at higher levels in naïve lung supernatant than in serum. In a SARS-CoV-2 murine model, the effect of inhibitory peptide treatment on mice intranasally infected with 104 PFU SARS-CoV-2 was assessed. IL-17 serum levels in the peptide-treated group were significantly lower than in the control group, yet this difference did not translate to disease progression, measured by viral load, weight loss, histopathology and survival. IL-17 and sCD95L levels were tested in SARS-CoV-2 patient samples from a biobank cohort and healthy control samples. There was no difference between the groups, and sCD95L was undetectable in the SARS-CoV-2 patient group. Our hypothesis on pulmonary fibrosis was tested through a model of bleomycin-induced fibrosis in BALB/c mice across 36 days. Animals were challenged with 4x105 of murine gammaherpesvirus (MHV) intranasally to aid fibrosis development on day 0. Bleomycin was administered twice at 40 mg/kg on day 8 and day 17. Inhibitory peptide treatment, control peptide treatment or mock treatment was given the day after bleomycin administration. Post-mortem, cardiac bleeds and lung and liver tissue were collected. IL-17, MMP9 and sCD95L were measured by ELISA. Right lungs were processed using Trizol for qPCR, and left lungs, along with livers, were prepared for histopathology. No difference was found between groups in terms of IL-17, MMP9 or sCD95L serum levels, gene expression of il-17 or ccr6, fibrosis scores based on Masson’s trichrome staining, and weight loss or survival rate. However, a significant correlation was seen between weight loss and the fibrosis score. In human pulmonary fibrosis serum samples, IL-17 levels were barely detectable and did not differ from those in healthy controls. Interestingly, sCD95L levels were significantly higher and MMP9 levels were significantly lower than in healthy controls. In summary, blocking the calcium-inducing domain could reduce IL-17 levels but did not affect disease progression in a SARS-CoV-2 model. Moreover, these findings could not be translated to other respiratory diseases, like pulmonary fibrosis.38 0Item Restricted Do Respiratory Influences on Cardiovascular Regulation Provide Early Markers of Hypertension in Young Adults with Family History of Hypertension?(2023-05-05) Al Enazi, Fahad; Marshall, Janice; Coney, AndrewBackground: Hypertension is well-known leading cause of the majority of cardiovascular diseases. Individuals with a parental history of hypertension (FH+) have a two-fold greater risk of developing hypertension than those without parental hypertension (FH-). Objective: This PhD project had three main aims. First, to elucidate whether young normotensive adult FH+ already have disturbed autonomic regulation of arterial blood pressure (ABP) relative to FH- at rest and in response to everyday stressors such as postural manoeuvres and environmental stressors. Second, to investigate whether slow breathing normalises autonomic dysregulation in FH+. Third, to assess whether slow breathing acutely or following training reduces ABP and restores autonomic regulation in normotensives and hypertensives. Methods: The first and second aims were explored by recording arterial blood pressure (ABP), a range of haemodynamic variables, heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS), in young normotensive FH+ and FH- men and women at rest, during and following acute mental stress (Stroop colour-word test) and during acute slow breathing at 6 breaths/minute. The third aim was evaluated by a systematic review and meta-analysis on the effects of device- and non-device guided slow breathing acutely and by training for ≥4 weeks on ABP and autonomic regulation of ABP in normotensives and hypertensives. Results and Conclusion: The experimental studies showed no differences between FH+ and FH- at rest. However, FH+ showed exaggerated increases in ABP and total peripheral resistance to mental stress relative to FH-. On the other hand, HRV, which mainly reflects vagal influences on the heart, was reduced during mental stress in FH+ and FH- and consistent with inhibition of the baroreceptor reflex being a characteristic of the defence response, vagal BRS was also reduced in FH+ and FH-. However, sympathetic BRS to a fall in ABP assessed by the squat to stand test was depressed by mental stress in FH- but not FH+. These findings provide novel evidence that sympathetic control of ABP is disturbed in young adult FH+ such that repeated exposure to mental stressors would be expected to increase their risk of hypertension. Acute slow breathing reduced ABP in both FH+ and FH- but reduced TPR in FH- only. Concomitantly, HRV was increased in both groups, while vagal BRS was increased in FH+ only. Theses novel results suggest that FH+ are more resistant to the ability of slow breathing to reduce sympathetic tone, but that vagal influence are normalised. Importantly, the systematic review and meta-analysis, demonstrated that slow breathing is effective in both hypertensives and normotensives in lowering ABP, enhancing HRV, and improving BRS, at least in normotensives. Thus, collectively the results indicate that slow breathing training should help to reduce abnormal autonomic regulation in young FH+ by increasing vagal regulation of the heart and decreasing sympathetic activity to the heart and vasculature, so lowering their future risk of hypertension.26 0