Saudi Cultural Missions Theses & Dissertations
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Item Restricted The effect of senolytics on cardiac remodelling and repair after injury induced by isoproterenol(King's College London, 2024-04) Altuwaijri, Ahmed; Ellison-Hughes, GeorginaSenescent cells accumulate during ageing and contribute to tissue deterioration, including in the heart. Senescent cells negatively affect an organ's microenvironment by refusing to die and producing a pro-inflammatory senescence-associated secretory phenotype (SASP). Genetic or pharmacologic clearance of senescent cells by senolytics has been shown to improve cardiac recovery and remodelling in aged mice. Moreover, senolytics have improved cardiac recovery after cardiac injury and in heart failure models in aged and young adult mice. Isoproterenol (ISO) has been widely used to induce cardiac injury in rodents, but it is unknown if ISO induces senescence and whether increased senescent cells in the heart contribute to cardiac deterioration and pathophysiology. This PhD aimed to first establish a cardiac injury model which led to increased senescence in the hearts of young adult mice by ISO. Second, to investigate the effects of the senolytics, dasatanib+quercetin (D+Q) on cardiac recovery and remodelling after ISO-injury in young adult and aged mice. To establish the dose of ISO that induced senescence with cardiac injury, ISO 150 mg/kg or 100 mg/kg was subcutaneously administered to ~12-week-old male mice (n=3 per group) for six consecutive days. Echocardiography was conducted from baseline to day 7. On day 7 after ISO, hearts were excised in order to analyse cardiac injury and cellular senescence. Results indicated that 100 mg/kg and 150 mg/kg ISO induced injury mainly in the apex of the heart. However, SA-β-gal staining was evident only in the apex of the ISO 150 mg/kg group. Therefore, ISO 150 mg/kg was chosen over the ISO 100 mg/kg dose. To establish the timeline of increased senescence after ISO-injury, 150 mg/kg ISO was subcutaneously administered to ~12-week-old male mice (n= 3-9 per group) for six consecutive days. Echocardiography was conducted at baseline, day 7 and 14 following ISO administration. Mice were sacrificed and hearts were excised for analysis of cardiac injury and senescence on days 7, 10 and 14. ISO 150 mg/kg successfully induced cardiac injury and senescence that lasted for 14 days. The peak of senescence was observed on day 10 following ISO. Next, ISO 150 mg/kg was subcutaneously administered to ~12-week-old male mice for six consecutive days. On day 10 after ISO, D+Q (5 mg/kg, 50 mg/kg) were administered by oral gavage for five consecutive days. Echocardiography was performed at baseline, day 7 post-ISO, and day 28 after the last D+Q dose. The hearts were excised on day 28 following the last D+Q dose to investigate cardiac injury and cellular senescence. Young adult mice treated with D+Q showed better cardiac recovery and remodelling after ISO injury. D+Q enhanced cardiac function, reduced hypertrophy, and reduced senescence markers. However, levels of collagen and DNA damage were unaffected by D+Q treatment. Aged male mice had four cycles of D+Q (5 mg/kg, 50 mg/kg) via oral gavage. Each cycle was composed of 3 days on and 12 days off. After that, aged mice hearts were injured by subcutaneous injection of 50 mg/kg ISO for six consecutive days. Echocardiography was performed at baseline, 24 hours after D+Q, and 28 days after the last ISO dose. The hearts were excised on day 28 following the last ISO dose to investigate cardiac injury, cellular senescence and remodelling. D+Q did not enhance cardiac function in the aged mice before ISO injury. However, D+Q improved cardiac recovery and survival after ISO injury. In the ISO-injured aged mice, D+Q enhanced cardiac function, reduced hypertrophy, reduced fibrosis, reduced DNA damage and senescence markers, and increased cardiomyocyte DNA synthesis. Clearance of the senescent cells and their SASP factors by D+Q senolytics improved cardiac function and recovery after ISO injury in aged and young adult male mice. These findings encourage the use of senolytics as a potential adjunct therapy for cardiac injury and deterioration with ageing. Senolytics could be used to improve the microenvironment of the heart so that it is more resilient to damage and can recover more effectively.24 0Item Restricted Body Weight and Mortality Risk in Community-Dwelling Older Adults(Monash University, 2024-02-21) Alharbi, Tagrid Abdullah; Owen, Alice; Freak Poli, Rosanne; Ryan, Joanne; Gasevic, DanijelaBackground: Overweight and obesity, generally defined by body mass index (BMI) ≥ 25 kg/m² or large waist circumference (abdominal obesity), is increasingly prevalent among older adults worldwide, however studies of excess weight and the link with mortality risk in older adults have reported mixed findings. Weight change may be a better indicator of mortality risk in older individuals, but large community-based longitudinal studies of older individuals are needed. Aims: To systematically review the association between weight change and all-cause mortality risk in adults aged ≥ 65 years, and to examine the association of weight status, abdominal obesity and weight change with the risk of mortality in community-dwelling older adults aged ≥ 65 years. Methods: A systematic review and meta-analysis conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines to examined the evidence that weight change (loss, gain and fluctuation, measured by weight or BMI) is associated with all-cause mortality. Secondary data analysis was performed using longitudinal data on community-dwelling individuals from the ESPIRIT (France, N=2,017) and ASPREE/ALSOP sub-studies (Australia, N=14,853). The association of self-reported weight loss, objectively measured weight change (loss and gain), weight status, and abdominal obesity with all-cause mortality over a 17-year follow-up period in the ESPIRIT study was explored using Cox proportional-hazard regression. To broaden understanding of the association between BMI in early (at age 18 years) and later (age ≥70 years) adulthood, and their impact on later-life mortality (over a median of 4.7 years in the ASPREE/ALSOP sub-study), Cox proportional-hazard regression was applied. Furthermore, the socio-demographic, lifestyle, and clinical characteristics associated with change in weight status between early (age 18 years) and late (age ≥ 70 years) adulthood were identified. Results: From the systematic review, weight change, particularly weight loss, was found to be associated with a 59% increased risk of mortality compared to stable weight. Longitudinal data analyses found that abdominal obesity was linked to a 49% increased mortality risk compared to non-abdominal obesity, but being overweight was associated with a 20% decreased risk compared to a normal BMI. Self-reported weight loss of >3 kg at baseline was associated with a 52% increase in mortality risk for men only; but both men and women with ≥ 5% objectively measured weight loss had a 24% increased risk of all-cause mortality. Obesity at 18 years, but not in older age, was associated with a 35% increased risk of mortality in later life. Compared to participants with a normal BMI, obesity at both early adulthood and later life was associated with 99% increase in the risk of all-cause mortality. Obesity in early and/or late adulthood was also associated with a higher risk of adverse clinical risk characteristics. Conclusion: Weight change and weight status are important predictors of mortality risk in older adults. These results highlight the importance of healthcare providers monitoring weight in older adults to detect weight loss at it is early stages, enabling more effective interventions aimed at maintaining stable weight and reducing risk of premature mortality.45 0Item Restricted Pre-Hospital Trauma Assessment and Management of Older Patients and their Association with Patient Outcomes: Challenges and Barriers(Saudi Digital Library, 2023-12-12) Harthi, Naif; Goodacre, Steve; Sampson, FionaBACKGROUND: Saudi Arabia faces an increasing prehospital healthcare burden from older people with injuries, but little is known about their characteristics and current treatment. METHODS: This was a sequential explanatory mixed-methods design, preceded by a scoping review on the prehospital geriatric trauma care. A retrospective quantitative study was conducted using registry data from older patients (≥55 years) admitted by ambulances from 01/08/2017 to 31/10/2021 at a major trauma centre in Saudi Arabia. A qualitative study was conducted using a purposive sample of Saudi paramedics and ambulance technicians from Riyadh and Makkah using online semi-structured interviews and analysed using the framework method. The quantitative and qualitative findings were integrated. RESULTS: The quantitative study recruited 452 eligible cases and found most of them were admitted with low falls (53.7%), normal physiology, and extremities injuries (53.1%). The study identified no significant predictors of in-hospital death (p>0.05 for all predictors), although statistical power was limited. The qualitative study recruited twenty participants and identified that they reported age-related challenges including physiological changes, polypharmacy, and communication difficulties. They all wanted training and guidelines to improve their knowledge. They reported struggling with communication difficulties, inaccurate adverse outcomes predictions, difficult intravenous cannulations, and cultural restrictions affecting care provision for female patients. I identified organisational barriers (e.g. lack of shared patient records and lack of guidelines) and cultural barriers (e.g. barriers to assessing women, attitudes towards older people, and attitudes towards paramedics) that influenced implementation of knowledge. This study also found that the participants' perceptions aligned with the retrospective study’s cohort, and they acknowledged the difficulty of predicting death in older trauma patients. CONCLUSION: Ambulance clinicians in Saudi Arabia want guidelines and training in managing older trauma patients but these need to take into account the characteristics of older trauma patients and the cultural barriers that I identified.15 0