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Item Restricted An Exploration of the Psychological Well-Being of Orphans in Saudi Arabia: Insights from Service Providers and Orphans(Saudi Digital Library, 2026) AlGhuraibi, Dulal; Nikparvar, FatemehAbstract The problem being studied was the susceptibility of Saudi Arabian orphans to experience psychological distress, attributed to factors such as parental loss, mistreatment, and abandonment. However, cultural, social, and familial contexts may pose distinctive challenges, emphasizing the need for targeted research and support systems. This qualitative case study explored service providers' and orphans' perspectives regarding how experiencing parental death or abandonment and living in an orphanage affects psychological well-being in Saudi Arabia. Data was collected via semi-structured interviews with six orphans and six service providers until data saturation was achieved. Guided by Bronfenbrenner’s Ecological Systems Theory, the research employed Interpretative Phenomenological Analysis (IPA) to provide an in-depth understanding of participants’ lived experiences and contextual factors influencing their well- being. Findings revealed that orphans in institutional care often experience emotional disconnection and loneliness, coupled with a strong desire for belonging, recognition, and genuine care. Despite their isolation, many demonstrated resilience and self-reliance, drawing on inner strength, faith, and aspirations for a better future, though these strengths often coexisted with unresolved grief and emotional pain. Service providers, meanwhile, faced significant challenges within institutional settings, including limited resources, structural constraints, and emotional burnout. They described the difficulty of balancing professional boundaries with authentic emotional engagement, while emphasizing the importance of building trust and providing mentorship that fosters growth and hope. Overall, the themes illustrate the emotional complexity of orphan life and the demanding nature of caregiving within institutional contexts, offering a foundation for further discussion and practical recommendations. Keywords: Orphan, Service provider, Well-being, Saudi Arabia2 0Item Restricted DEVELOPMENT AND CHARACTERIZATION OF MEMBRANES FOR BIOMEDICAL AND ELCTROCHEMICAL APPLICATIONS(Saudi Digital Library, 2026) Alarwa, Najem; Metin, UzThis dissertation focuses on developing polymeric membranes for two distinct applications. 1) Exosome isolation: Exosomes are nano-sized membrane-bound vesicles secreted by cells and present in body fluids. Exosomes play a critical role in intercellular communication by transforming information to maintain physiological homeostasis. Recent studies indicated that exosomes derived from mesenchymal stem cells (MSCs) are considered potential therapeutics for many diseases. One of the key challenges is to obtain efficient exosome isolation with high yield and purity. To address this challenge, a stimulus-responsive polymer-based membrane was developed to isolate MSC-derived exosomes directly from culture media in a single step, without any pretreatment. The membrane was obtained by modifying the surface of a sulfonated polysulfone support with subsequent polyelectrolyte layers and a temperature- and pH-responsive cationic pentablock copolymer (PBC) via electrostatic interactions. A total exosome yield of ~3x1011 particles/mL and total exosomal protein concentration of ~2000 µg/mL were obtained with a purity of ~8x109 particles/µg protein at 37 ˚C and pH 7.4, which was higher than the conventionally used isolation methods. The isolated exosomes demonstrated enhanced cell migration on 3T3 cells and neurite outgrowth on PC12-TrkB cells, confirming biological activity. Therefore, the PBC-modified membrane could be a simple and viable alternative to isolate exosomes with high yield and purity. 2) Vanadium redox flow battery (VRFB): VRFB utilizes vanadium ions in different oxidation states to store and release energy. Currently, perfluorosulfonic acid membranes, such as Nafion117, are widely used in VRFBs. However, Nafion-based membranes are costly, suffer from vanadium-ion crossover, and raise environmental concerns. Therefore, in this dissertation, poly(styrene-isobutylene-styrene) triblock copolymer-based proton exchange membranes with varying sulfonation degrees were developed as an alternative. The 34%-S-SIBS membrane exhibited physicochemical and proton-transfer properties that were better than or at least comparable to those of Nafion117. Moreover, the coulombic, voltage, and energy efficiencies of 34%-S-SIBS, along with its stable cycling performance, were on par with Nafion117. To further enhance performance, S-SIBS was blended with polyvinylidene fluoride or graphene. The modified membranes demonstrated performance that was at least as good as, and in some cases better than, Nafion117, providing a cost-effective alternative.4 0Item Restricted Swimming of Zooplankton and their Interaction with Langmuir Circulation(Saudi Digital Library, 2026) Aldaddi, Abdullah; Murphy, DavidThis dissertation aims to study three fields related to biological fluid mechanics: Shell-less pteropod swimming and mysid interaction with Langmuir cells both with and without the presence of prey. For the first exploration we worked with gymnosomes; gymnosomes are holoplanktonic marine creatures that can be found throughout the open ocean. They are commonly known as sea angels, and swim in the water by flapping a pair of muscular and flexible wings to generate thrust. They feed on thecosomatous pteropods and are consumed by larger animals. Swimming is vital for sea angels to hunt, avoid predators, mate, ascend to the surface, or sink to deeper layers. Nevertheless, limited studies have examined the kinematics and fluid dynamics of sea angels. This dissertation spotlights the hydrodynamics and kinematics of a subtropical gymnosome Pneumoderma atlantica using a non-intrusive technique known as time-resolved 2D micro–Particle Image Velocimetry (PIV), and also compares the 3D wing kinematics with a morphologically similar polar species Clione antarctica, which are larger and swim in higher viscosity waters. The second and third studies explore the impact of Langmuir Circulation on zooplankton swimming behavior and spatial distribution. Langmuir Circulation is an oceanic phenomenon induced by wind and surface-wave interactions. Langmuir cells are characterized by a series of counter-rotating, parallel vortices that form in the upper water layer. The downwelling and upwelling regions transfer momentum, mass, heat and concentrate food particles and plankton. Upward swimming zooplankton, such as mysids, accumulate in regions known as Stommel Retention Zones (SRZs) within these Langmuir cells when they match the downwelling flow speed. To explore this phenomenon, a laboratory facility generates a 2D model of Langmuir cell, which is used to investigate the mysid spatial distribution and swimming trajectories in Langmuir cells at different flow strengths. The shrimp-like crustaceans are strong swimmers and their spatial distributions and swimming behaviors are found to vary with the flow strength. Finally, I examine how the 2D counter-rotating Langmuir turbulence may influence the trophic interactions of mysids. I examine the variation of the spatial distribution of mysids by the presence of prey at different flow strengths.6 0Item Restricted Azeotropic Refrigerant Mixtures Separation using Ionic Liquid Entrainers(Saudi Digital Library, 2026) Arishi, Abdulrhman Mohammed; Shiflett, Mark BHydrofluoroolefins (HFOs) represent the next-generation in refrigerant technology, poised to revolutionize the industry due to having substantially lower global warming potential (GWP) and zero ozone-depleting potential (ODP). These characteristics position HFOs as the ideal replacements for hydrofluorocarbons (HFCs), which have been widely used in air-conditioning and refrigeration systems since the early 1990’s but are now being phased out due to concerns over having a high GWP. As the industry transitions to HFO refrigerants, there will remain millions of systems that will continue to have useful life and require servicing. Many HFOs are not drop-in replacements for HFCs, so refrigerant producers have developed HFO/HFC blends to meet the demands of the service industry and in some cases for new equipment. This strategy aims to reduce the overall GWP of the blend by using lower GWP HFC refrigerants mixed with HFOs while ensuring that the thermophysical properties are a close match with the HFC being replaced and compatible with existing equipment. This is especially critical for equipment that might not perform optimally or may even be incompatible when using pure HFOs. However, blending HFCs with HFOs introduces its own set of challenges, most notably the formation of azeotropic mixtures. These mixtures present difficulties during the recycling and reclamation processes of the refrigerants. Consequently, there is a pressing need for the development of highly efficient separation techniques to address this issue. One promising solution to this problem is extractive distillation, wherein an ionic liquid (IL) is employed as an entrainer. This method has shown significant promise in effectively separating azeotropic mixtures. The suitability of an IL as an entrainer is determined based on its selectivity and strong affinity towards specific components within the mixture. The selection of the most appropriate IL for a given gas mixture is influenced by several factors, including the desired purity levels of the separated products and the associated energy and cost implications of the separation process. To evaluate the performance of various ILs in this context, comprehensive simulations were conducted using an equilibrium-based and rate-based models in ASPEN Plus, as well as vapor pressure estimations and thermal stability analysis were carried out. Different imidazolium and phosphonium-based ILs were modeled to determine the effectiveness of separating azeotropic refrigerant mixtures including, R-410A, R-450A, R-456A, R-513A, R-515B, and R-516A, which are commonly used in refrigeration systems. The results of the simulation revealed notable differences among the ILs in terms of overall heat duties, the number of stages required for separation (NT), operating pressure (P), solvent-to-feed ratio (S/F), and reflux ratio (RR). A rate-based model simulation, incorporating experimentally measured mixture properties, was developed to replicate the performance of the pilot extractive distillation column for separating R-410A. In addition, the vapor pressure of ILs were estimated using non-isothermal TGA at temperatures above 298.15 K. Thermal stability of the ILs were analyzed and discussed to identify and avoid degradation conditions. These findings underscore the importance of carefully selecting the appropriate solvent for optimizing energy efficiency and economic feasibility for a more sustainable separation process.5 0Item Restricted INSULIN RESISTANCE, BEHAVIORAL, AND PSYCHOLOGICAL PATHWAYS TO COGNITIVE AGING IN OLDER U.S. ADULTS(Saudi Digital Library, 2026) Alshayhan, Ali; Merchant, AnwarABSTRACT Introduction: Metabolic dysfunction, depressive symptoms, and physical activity are key and independent interrelated determinants of cognitive aging, yet the temporal ordering and causal pathways linking these factors remain incompletely understood. Specifically, metabolic dysfunction may act as both a risk factor for cognitive decline and as an exposure-induced mediator-outcome confounder when examining behavioral and psychological pathways. This dissertation used longitudinal data from the Health and Retirement Study (HRS) to examine the role of metabolic dysfunction, depressive symptoms, and physical activity in shaping later-life cognitive performance using advanced causal mediation methods. Methods: We analyzed nationally representative longitudinal data from U.S. adults aged 50 years and older participating in the HRS between 2014 and 2020. Metabolic dysfunction was indexed by the triglyceride-glucose (TyG) index derived from fasting biomarkers. Cognitive performance was measured using the validated 27-point Langa–Weir cognitive score. Aim 1 examined whether TyG predicted subsequent cognitive performance over 2 and 4 year follow-ups using multivariable regression incorporating survey weights. Aims 2 and 3 applied the Recanting Twins (RT) causal mediation framework using the crumble package in R to estimate path-specific effects on the additive scale in the presence of exposure-induced mediator-outcome confounding. Aim 2 examined the pathways linking physical activity (2014) to cognition through depressive symptoms and metabolic dysfunction (2016). Aim 3 examined pathways v linking depressive symptoms (2014) to cognition through physical activity and metabolic dysfunction (2016). Results: In aim 1, higher TyG levels were associated with poorer subsequent cognitive performance, with stronger and more consistent associations emerging over the longer 4-year follow-up. Continuous modeling detected modest short-term associations, whereas quartile-based differences were more consistent at longer follow-up among participants in the highest TyG quartile (Q4). In aim 2, physically active individuals had higher cognitive performance at both follow-ups. The largest contribution to the total effect (ATE:2018: 0.195 [95% CI: 0.19, 0.2]; 2020: 0.505 [95% CI: 0.476, 0.533] was the direct pathway from physical activity to cognitive performance independent of depressive symptoms and metabolic dysfunction (P1: A→Y, 2018: 0.122 [95% CI: 0.119, 0.126]; 2020: 0.366 [95% CI: 0.331, 0.400]), and the indirect pathways through depressive symptoms (P4: A→M→Y, 2018: 0.06 [95% CI: 0.029, 0.091]; 2020: 0.124 [95% CI: 0.09, 0.158]) were significant also at both follow-ups. The pathways involving metabolic dysfunction were only significant at the longer follow-up and were smaller in magnitude. The extent by which the exposure-induced mediator-outcome confounding component attributable to TyG index was not distinguishable from zero. In aim 3, elevated depressive symptoms predicted cognitive decline at both follow-ups (ATE:2018: -0.413 [95% CI: - 0.447, -0.379]; 2020: -0.733 [95% CI: (-0.756, -0.71]). The direct pathway independent of physical activity and metabolic dysfunction accounted for the largest portion of the total effect (P1: A→Y, 2018: -0.371 [95% CI: -0.380, -0.362]; 2020: -0.651 [95% CI: - 0.673, -0.629]). Also, the behavioral pathway through physical activity was significant at both follow-ups (P4: A→M→Y, 2018: -0.041 [95% CI: -0.0753, -0.007]; 2020: -0.062 vi [95% CI: -0.069, -0.056]). The metabolic pathways emerged only at the longer follow-up and were modest in magnitude. The exposure-induced mediator-outcome confounding component attributed to metabolic dysfunction was small but statistically significant. Conclusion: This dissertation demonstrates that metabolic dysfunction, depressive symptoms, and physical activity jointly shape cognitive aging through temporally evolving pathways. Metabolic dysfunction predicts later cognitive performance and plays a modest but increasingly detectable role in behavioral and psychological mediation pathways over longer follow-up and, in the depressive-physical activity-cognitive performance pathways, the TyG index representing the metabolic dysfunction acted as a an exposure-induced mediator-outcome confounding. Physical activity and depressive symptoms exerted strong direct behavioral and psychological effects on cognition, highlighting mental health and physical activity as key targets for intervention. These findings provide causal evidence that improving depressive symptoms, promoting physical activity, and addressing metabolic dysfunction may collectively contribute to preserving cognitive health in the aging population.3 0Item Restricted The Dual Factor Model (DFM) of Mental Health Among Appalachian Youth(Saudi Digital Library, 2026) Bashatah, Mawyah; Zullig, Keith; Kristjansson, Alfgeir; Davis, Steve; Huebner, ScottBackground. Adolescent mental health is a critical public health concern, particularly in rural Appalachian communities where rates of depression, anxiety, and substance use exceed national averages and access to mental health resources remain severely limited. Traditional mental health frameworks rely predominantly on the identification and reduction of psychopathological symptoms, neglecting the independent contributions of positive well-being to adolescent risk and resilience. The Dual-Factor Model (DFM) of mental health offers a more comprehensive alternative by simultaneously assessing subjective well-being (SWB) and psychopathology, classifying individuals into four distinct groups: Complete mental health, Vulnerable, Symptomatic but content, and Troubled. Despite the DFM’s growing utility in academic and behavioral research, its application to substance use outcomes, environmental protective factors, and educator perceptions in the rural Appalachian population are largely unexplored. Aims. This dissertation aimed to: (Aim 1) test whether DFM of mental health classifications significantly differentiate adolescent substance use behavior among Appalachian middle school students; (Aim 2) examine whether five contextual and environmental protective factors (school connectedness, community safety, neighborhood ties, collective efficacy, and organized leisure time activities) differ significantly across DFM mental health classification in this population; and (Aim 3) explore middle school teachers’ subjective perspectives on the interplay between student mental health, life satisfaction, and substance use risk in rural West Virginia (WV) using Q-methodology. Methods. (Aim 1 and 2) Spring 2022 cross-sectional data from the Young Mountaineer Health Study (YMHS; N = 1698), a NIH-funded prospective cohort study of Appalachian adolescents across five West Virginia counties, were used. Psychopathology was measured using the Oregon Adolescent Depression Project Conduct Disorder Screen (OADP-CDS) and 13 anxiety and depression items from the Symptom Checklist – 90 (SCL-90). SWB was measured using the Brief Multidimensional Students’ Life Satisfaction Scale (BMSLSS). Participants were classified into the four DFM groups using established T-score cutoffs. In Aim1, linear regression models examined associations between DFM group relationship and substance use while controlling for gender, race, and family socioeconomic status. Chi-square tests and a series of one-way ANOVAs with Tukey post hoc comparisons were also applied to various substance use outcomes to assess group differences. In Aim 2, a series of one-way ANOVAs with Tukey post hoc comparisons examined differences across the five contextual variables by DFM group. For Aim 3, a purposive sample of 12 middle school teachers were recruited from the five YMHS counties and completed a 41-statement Q-sort instrument. Statements were drawn from a structured concourse informed by the DFM and life satisfaction domains. Data was analyzed using principal component analysis (PCA) with Varimax rotation in Kade software. Results. (Aim 1) DFM group membership significantly differentiated by substance use across all outcomes. The Troubled group consistently reported the highest substance use risk, followed by the Vulnerable and Symptomatic groups, with the Complete group reporting the lowest prevalence of use. Notably, the Vulnerable and Symptomatic groups did not differ statistically from each other on any substance use measure, suggesting that low SWB, regardless of psychopathology level, elevates behavioral risk. (Aim 2) Significant DFM group differences emerged across all five contextual variables. SWB emerged as the primary organizing variable: adolescents with high SWB consistently reported stronger school connectedness, greater perceived community safety, more robust neighborhood ties, and higher participation in leisure activities. Critically, the Vulnerable group clustered with the Troubled group on nearly all measures, despite the absence of clinical psychopathology, underscoring independent risks associated with diminished well-being. (AIM 3) Four distinct teacher viewpoint factors emerged: Factor 1 (Strong Support System) emphasized parental guidance as the primary protective factor; Factor 2 (Multiple risk Factors and Uncertainty) reflected perceived powerlessness and unpredictability of substance use risk; Factor 3 (Importance of Environment; the largest group) endorsed a comprehensive ecological view centering on positive school climate, peer relationships, and family support; and Factor 4 (Importance of Mental Health) highlighted teachers’ roles in detecting use and attending to individual student dynamics. Consensus statements across all factors reflect shared recognition that mental health and life satisfaction jointly influence substance use vulnerability. Conclusion. This dissertation applied the DFM of mental health to a set of interconnected public health questions in a rural Appalachian youth population, employing a multi-method approach that moved from individual classification (Aim 1) to environmental context (Aim 2), to educator perspectives (Aim 3). Across all three aims, SWB consistently emerged as a critical and independently actionable construct, one that was associated with both behavioral risk and engagement with protective environmental resources, and that educators intuitively recognized even without formal DFM training. The Vulnerable group’s alignment with the Troubled group across both behavioral and contextual outcomes highlights a persistent gap in symptom-focused screening frameworks. Together, these findings support a prevention model that promotes positive indicators of mental health alongside the reduction of psychopathological symptoms, and that engages teachers as informed frontline partners in culturally responsive, school-based prevention efforts for Appalachian youth.5 0Item Restricted Inhibition of Clostridium perfringens by Natural Products(Saudi Digital Library, 2026) Alfattani, Safa Qutub; Sarker, Mahfuzur RClostridium perfringens is a Gram-positive, anaerobic, spore-forming bacterium that produces up to 20 distinct toxins and is responsible for various gastrointestinal (GI) and histotoxic diseases in humans and animals. C. perfringens strains may be categorized into seven toxinotypes (A-G) based on the toxins they generate. C. perfringens type F strains that generate C. perfringens enterotoxin (CPE) induce food poisoning (FP) and non-foodborne (NFB) illnesses in humans and livestock animals, leading to significant annual economic losses in the United States. C. perfringens displays several distinctive traits that allow to induce a wide array of diseases in various hosts: i) it is anaerobic organism that can grow in circumstances with relatively limited exposure to air or low oxygen levels, such as soil, sewage, and the GI system of humans and animals; ii) it owns the ability to form spores that resist heat and other harsh stresses in environment; iii) over favorable conditions, C. perfringens spores can quickly turn to vegetative cells through a procedure known as germination; and iv) it can release a range of toxins under different settings. In addition to these intrinsic virulence properties, external factors such as improper cooking, improper chilling, and storing meat and poultry products at abusive temperatures may significantly contribute to the incidence of C. perfringens type F food poisoning outbreaks. The possibility of obtaining foodborne infections is typically minimized by widely employed food preservation techniques, such as heat processing. Even so, inhibiting highly heat-resistant spores is a significant issue; consequently, alternative solutions to traditional thermal processing technologies must be implemented immediately. The initial study investigated the inactivation ability of several natural products as antimicrobial agents against the spore growth of C. perfringens type F (FP) isolates. Our findings revealed that garlic, onion juice, and undiluted essential oil constituents (EOCs) of clove, rosemary, and peppermint exhibited the highest activity. Therefore, we examined the inhibitory effects of these products on all forms in the life cycle of C. perfringens FP strains, including spore germination, spore outgrowth, and vegetative growth, in laboratory media and chicken meat. Clove and peppermint oils demonstrated efficacy against C. perfringens spore germination in a nutrient-rich medium. Furthermore, EOCs, but not garlic and onion juice, blocked the spore outgrowth of C. perfringens in laboratory medium. Interestingly, EOCs at 0.5% completely prevented the vegetative growth of FP isolates during a 6 h incubation under laboratory medium. However, even at 4-fold higher concentrations (2%), EOCs could not inactivate C. perfringens spore growth in contaminated chicken meat stored under abusive conditions. Although some natural products inhibited C. perfringens spore germination, outgrowth, and vegetative growth under laboratory-controlled conditions, no such inhibitory activity was observed when these products were applied to C. perfringens spore-inoculated chicken meat. Our earlier study has shown considerable inhibitory effects of medicinal plants, including essential oils of clove, rosemary, and peppermint, against vegetative cells of C. perfringens, hence raising their application in traditional medicine and industrial practices in developing countries. EOs have gained increased attention across multiple sectors, particularly as natural substances, with their value as food preservatives having been previously proven. Their distinctive chemical structure facilitates a broad spectrum of biological and antimicrobial activity. In the second study, we assessed the possible effect of EOs, including clove, rosemary, and peppermint, which had previously been shown to have activity against selected FP strains of C. perfringens in laboratory media. The three evaluated oils markedly lowered intracellular ATP levels during the initial 3 h, as estimated using the BacTiter-Glo reagent, and damaged the cellular membrane, as illustrated by the release of compounds absorbing at 260 nm, protein leakage, and the uptake of crystal violet dye. Subsequent research using a scanning electron microscope (SEM) revealed cellular membrane disruption in oil-treated cells. In conclusion, as natural products, essential oils may utilize their anti-C. perfringens activities by disrupting the cytoplasmic membrane, hence modifying bacterial cell membrane permeability and resulting in the release of certain cellular components. Recent research has elucidated potential mechanisms of action of essential oils against C. perfringens; however, their in vivo efficacy has yet to be determined. In the third study, a mixture of lactic acid (lactate) and the antimicrobial peptide nisin was evaluated to assess their combined inactivation effect against a collection of FP strains of C. perfringens, with a focus on spore germination and outgrowth in cooked meat products. Results showed that, among the tested concentrations, a mixture comprising 0.02% nisin, which is the acceptable level, and (0.5-1) % calcium lactate was determined to be the most effective combination for inhibiting spore germination and outgrowth in meat products, depending on the meat product under examination. Our findings suggest that the combination of nisin and calcium lactate may offer a promising alternative approach for controlling C. perfringens spore growth in meat products. Consequently, the objective of this work is to integrate low concentrations of antimicrobials to ensure the safety and efficacy of meat products and to inhibit C. perfringens proliferation under adverse conditions. Together, this dissertation presents observations on several inactivation techniques designed for controlling spore growth of C. perfringens FP isolates in both laboratory medium and cooked meat as a model system. These include methodologies for applying natural antimicrobials recognized as generally recognized as safe (GRAS)-listed antimicrobial agents in food products, as well as the identification of their target sites within the cells of C. perfringens, which provides insights into developing new treatment options to inactivate spore formation. The integration of these practices should successfully reduce the risk of C. perfringens related to foodborne diseases.13 0Item Restricted Hypertensive Kidney Disease and The Role of Toll-Like Receptor 4(Saudi Digital Library, 2026) Almarshood, Hebah; Sen, UtpalIntroduction: Hypertension is one of the leading causes of kidney disease. Persistently high, uncontrolled blood pressure (BP) can constrict the blood vessels within the kidneys, impairing their ability to regulate fluids and eliminate waste. This deterioration of renal function can result in serious health complications. Moreover, hypertension can initiate a self-perpetuating cycle of innate immune activation, which contributes to structural changes and worsens kidney dysfunction. Research from our laboratory and others has identified toll-like receptors (TLRs) as key mediators in this immune response associated with hypertensive kidney injury. Of the thirteen known TLRs in mammals, TLR4 plays a particularly significant role: its activation during hypertension triggers a range of cellular responses, some of which are pathological and contribute to kidney damage. Conversely, studies have shown that genetic mutation (beneficial) or pharmacological inhibition of TLR4 can limit organ injury, including kidney damage, in hypertensive models. Despite these findings, the precise mechanisms by which TLR4 contributes to hypertensive kidney damage and dysfunction remain unclear. Objectives: The main objective of this dissertation was to investigate whether hypertension, via the stress response, activates TLR4, subsequently triggering inflammatory pathways, tissue remodeling, and kidney dysfunction. A further objective was to determine if mutation or inhibition of TLR4 can mitigate pathological kidney remodeling and dysfunction associated with hypertension. Methods: In vivo experiments were conducted using both female and male C3H/HeOuJ and C3H/HeJ mice, aged 10–12 weeks. The C3H/HeOuJ mice possess normal TLR4 function (designated TLR4N in this study), whereas C3H/HeJ mice carry a spontaneous mutation in the TLR4 gene (designated TLR4M). Hypertension and related pathologies were induced in these mice by infusing them with angiotensin II (Ang-II, 1000 ng/kg/min) using Alzet mini-osmotic pumps for four weeks. Physiological and pathological parameters, including systolic and mean arterial pressure (MAP) and kidney function as indicated by glomerular filtration rate (GFR), were monitored throughout and at the conclusion of the 4-week period. At the end of the experiments, kidneys were collected for biochemical, histological, protein, and mRNA analyses. For the in vitro model, mouse kidney mesangial cells were cultured in a humidified incubator at 37°C with 5% CO2 until they reached 60% to 70% confluence, displaying a uniform density. Cells were seeded in DMEM/F-12 (50/50) medium supplemented with 5% fetal bovine serum, antibiotics, and L-glutamine. In a 6-well plate, the cells were pre-treated with 200 nM TAK-242 (a TLR4 inhibitor) for one hour, followed by exposure to 200 nM Angiotensin-II for 24 hours. Subsequently, the cells were collected for further laboratory analysis. Appropriate controls were used in all experiments. Results: Results showed that Ang II significantly elevated blood pressure in TLR4N mice, whereas TLR4M mice were resistant to this increase under the same Ang II treatment. In TLR4N mice, hypertension also led to a significant upregulation of TLR4 expression in the kidney, increased levels and activity of matrix metalloproteinases (MMPs), and reduced levels of their natural inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs). Similar results were observed in in vitro experiments with mesangial cells. Additionally, TLR4N hypertensive mice exhibited elevated inflammatory markers, increased apoptosis, and pyroptosis in the kidneys, all of which were mediated by activation of the NF-κB signaling pathway. Moreover, TLR4N mice displayed increased collagen genes expression, glomerular hypercellularity, reduced renal blood flow, higher resistive index, and impaired renal function following Ang II-induced hypertension. Notably, all these adverse changes were mitigated in TLR4M mice subjected to the same hypertensive regimen. Summary and Conclusion: Hypertension activates the TLR4 receptor, triggering a cascade of immune responses that disrupts the balance of MMPs and TIMPs in the renal vasculature. This activation also drives pyroptosis and apoptosis via the NF-kB signaling pathway, ultimately leading to impaired kidney function. Conversely, TLR4 mutation or inhibition offers targeted strategies to mitigate vascular damage and enhance renal function in hypertension. Together, these findings indicate that hypertension promotes kidney remodeling and dysfunction through TLR4 activation, while TLR4 mutation (TLR4M) or inhibition confers protection against renal remodeling and improves kidney function in hypertensive conditions. Further research is required to validate these model-based findings in preclinical and clinical studies.8 0Item Restricted APPLICATION OF ELECTRONIC EVIDENCE RULES IN CIVIL AND COMMERCIAL LITIGATION IN SAUDI ARABIA(Saudi Digital Library, 2026) Alshamrani, Arwa; Wright, Ronald FThe increasing use of digital technologies in commercial and civil transactions has led to a growing reliance on electronic evidence in judicial proceedings. In response to these developments, Saudi Arabia has introduced legislative reforms, most notably the Evidence Law and related regulations, to regulate the admissibility and evaluation of electronic evidence. Despite this legal framework, questions remain regarding how these rules operate in judicial practice. This study examines the application of electronic evidence rules in civil and commercial litigation in Saudi Arabia. It combines doctrinal legal analysis with qualitative empirical research in order to explore both the legal framework governing electronic evidence and its practical implementation in the courts. The doctrinal component analyzes the relevant statutory provisions and their relationship to evidentiary principles in Islamic jurisprudence. The empirical component relies on qualitative interviews conducted with judges and attorneys who have professional experience in civil and commercial litigation. The findings suggest that Saudi law formally recognizes electronic evidence as a legitimate means of proof and adopts a generally flexible approach to admissibility. At the same time, the practical evaluation of electronic evidence often depends on judicial discretion, technical understanding, and contextual interpretation. The study further identifies a range of procedural and practical challenges in the judicial handling of electronic evidence. Together, these findings contribute to a clearer understanding of how electronic evidence operates within contemporary Saudi judicial practice.6 0Item Restricted ASSESSING AND MITIGATING RISK OF QT INTERVAL PROLONGATION(Saudi Digital Library, 2026) Alzahrani, Mofareh Abdulrahman Ali; Tisdale, James EBackground: Torsades de pointes (TdP) is associated with the electrocardiogram abnormality known as QT interval prolongation and is associated with sudden cardiac death, which is a catastrophic outcome. TdP is most commonly caused by drugs; more than 200 available medications may cause QT prolongation and TdP. Risk factors are important for the development of QT prolongation and TdP; drug-induced TdP is extremely rare in the absence of risk factors. Significant evidence exists linking older age and female sex to QT interval lengthening and identifying both as independent risk factors for QT interval prolongation and TdP. Mechanisms of lengthening of ventricular repolarization with advancing age are likely, in large part, related to changes in serum sex hormone concentrations. The difference in ventricular repolarization between women and men, and the increased susceptibility to drug-induced lengthening of ventricular repolarization and risk of TdP, is due in large part to the effects of sex hormones. Older age is an independent risk factor for QT interval prolongation and TdP. However, independent risk factors for QT interval prolongation within this high-risk population have not been identified. In a retrospective case-control study using multiple large electronic medical records databases, our first Aim was to identify independent risk factors for QT interval prolongation in older adults. Furthermore, female sex is an independent risk factor for QT interval prolongation and TdP. We have shown previously that administration of oral progesterone attenuates drug-induced QT interval lengthening in healthy premenopausal women during the menses phase of the menstrual cycle, when serum estradiol concentrations are low. However, estradiol lengthens the QT interval and could offset the protective effects of progesterone. For the second Aim, we conducted a randomized, double-blind, placebo-controlled, crossover design study to determine the efficacy of oral progesterone to diminish drug-induced QTc interval lengthening in premenopausal women during the ovulation phase of the menstrual cycle, when serum estradiol concentrations are high; then, for the third Aim, we determined the influence of oral progesterone on drug-induced increases in dispersion of repolarization (represented by Tpeak-Tend) and lengthening of early [represented by heart rate-corrected J-Tpeak (J-Tpeakc)] versus late ventricular repolarization (Tpeak-Tend). Methods: To achieve Aim one, we conducted a retrospective case-control study by obtaining a limited dataset using electronic health records from the Regenstrief Institute Data Core from January 2004 to December 2024. After applying our inclusion and exclusion criteria, 230,670 patients aged 65-105 years were eligible for the final analysis. Then we applied the least absolute shrinkage and selection operator regression (LASSO) model for independent risk factors selection, multiple logistic regression (MLR) model to estimate odds ratios and 95% confidence intervals for the association between the predictors and the outcome, and prediction error assessment such as, accuracy and area under the receiver operating characteristic curve [AUC-ROC (c-statistic)] to evaluate the regression model performance. We defined QT interval prolongation as Bazett’s heart rate-corrected QT (QTcB) interval >500 ms, or >550 ms for patients with a QRS >120 ms. To achieve Aims two and three, eighteen premenopausal female volunteers, aged 21-40 years, were randomized in a double-blind, placebo-controlled crossover-design fashion to receive oral progesterone 400 mg or a matching placebo once daily for 7 days, timed to the ovulation phase of the menstrual cycle (median between-phase washout = 41 days). On day 8, intravenous ibutilide 0.003 mg/kg was infused over 10 minutes. ECG intervals were recorded during and for 8 hours post-infusion. Results: With regard to Aim one, the following independent risk factors for QT interval prolongation were identified for older adults: male sex; age ≥80 years; taking one QT interval-prolonging drug; taking two or more QT interval-prolonging drugs; pharmacokinetic drug-drug interactions (DDI) perpetrated by inhibitors of CYP450 enzymes metabolizing QT interval-prolonging drugs; hypocalcemia; hypokalemia; hypomagnesemia; loop diuretics; acute decompensated heart failure (ADHF); sepsis and septic shock, any-stroke including ischemic stroke and hemorrhagic stroke; acute kidney injury (AKI); acute coronary syndrome (ACS); mood disorder including depression and bipolar disorder; hyperparathyroidism; epilepsy; heart failure with preserved ejection fraction (HFpEF); heart failure with reduced ejection fraction (HFrEF); anorexia; hypothyroidism; diabetes mellitus (DM); hypoxia; cancer; hypertension; arrhythmia; chronic kidney disease (CKD); amyloidosis; rheumatoid arthritis; sleep apnea; systemic lupus erythematosus; liver disease; obesity; schizophrenia; chronic ischemic heart disease (CIHD); bradycardia; tobacco use; and drug abuse. With respect to Aim 2, baseline (pre-ibutilide) Fridericia-corrected QT (QTF) in the progesterone and placebo phases was not significantly different. The maximum ibutilide-associated QTF and area under the effect curve during and for 1-hour post-ibutilide infusion (AUEC0-1.17) was significantly lower during the progesterone phase. For Aim 3, baseline (pre-ibutilide) J-Tpeakc were similar in the progesterone and placebo phases, but maximum J-Tpeakc, maximum % change from pretreatment value, and J-Tpeakc AUEC0-1.17 were significantly lower during progesterone treatment compared to placebo, as were pre-ibutilide Tpeak-Tend, maximum Tpeak-Tend, and Tpeak-Tend AUEC0-1.17. Conclusions: We identified multiple independent risk factors for QT interval prolongation and TdP in older adults. These risk factors can help clinicians identify older adults who are at higher risk for QT interval prolongation, which may guide treatment and monitoring decisions. Future research will include incorporating these independent risk factors into a risk score that can be developed and validated for this high-risk population, who can be targeted for amelioration of these modifiable risk factors and therapeutic substitution, where feasible and appropriate. This will improve medication safety in this vulnerable patient population. In addition, we have shown that oral progesterone attenuates drug-induced lengthening of ventricular repolarization in premenopausal women, regardless of menstrual cycle phase, and in the presence of high serum estradiol concentrations. This research suggests that pre-menopausal women who require therapy with QT interval-prolonging drugs and who have risk factors for drug-induced QT interval prolongation and torsades de pointes could be prescribed oral progesterone to lower their risk, regardless of the phase of the menstrual cycle. This hypothesis requires testing in future studies.9 0