Search results for: Nick Curzen

Authors: Florian Misoc, Cyril Okhio, Joshua Tolbert, Nick Carlin, Thomas Ramey

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This project is focused on designing a Stirling engine system for a solar-thermal-electrical system that can supply electric power to a single residential unit. Since Stirling engines are heat engines operating any available heat source, is notable for its ability to generate clean and reliable energy without emissions. Due to the need of finding alternative energy sources, the Stirling engines are making a comeback with the recent technologies, which include thermal energy conservation during the heat transfer process. Recent reviews show mounting evidence and positive test results that Stirling engines are able to produce constant energy supply that ranges from 5kW to 20kW. Solar Power source is one of the many uses for Stirling engines. Using solar energy to operate Stirling engines is an idea considered by many researchers, due to the ease of adaptability of the Stirling engine. In this project, the Stirling engine developed was designed and tested to operate from biomass source of energy, i.e., wood pellets stove, during low solar radiation, with good results. A 20% efficiency of the engine was estimated, and 18% efficiency was measured, making it suitable and appropriate for residential applications. The effort reported was aimed at exploring parameters necessary to design, build and test a ‘Solar Powered Stirling Engine (SPSE)’ using Water (H₂O) as the Heat Transfer medium, with Nitrogen as the working gas that can reach or exceed an efficiency of 20%. The main objectives of this work consisted in: converting a V-twin cylinder air compressor into an alpha-type Stirling engine, construct a Solar Water Heater, by using an automotive radiator as the high-temperature reservoir for the Stirling engine, and an array of fixed mirrors that concentrate the solar radiation on the automotive radiator/high-temperature reservoir. The low-temperature reservoir is the surrounding air at ambient temperature. This work has determined that a low-cost system is sufficiently efficient and reliable. Off-the-shelf components have been used and estimates of the ability of the Engine final design to meet the electricity needs of small residence have been determined.

Keywords: stirling engine, solar-thermal, power inverter, alternator

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Authors: Nick Woodier, Paul Sampson, Iain Moppett

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Background: For years, healthcare across the world has recognised that patients are coming to harm from the very processes meant to help them. In response, healthcare tells itself that it needs to ‘be more like aviation.’ Aviation safety is highly regarded by those in healthcare and is seen as an exemplar. Specifically, healthcare is keen to learn from how aviation uses near misses to make their industry safer. Healthcare is rife with near misses; however, there has been little progress addressing them, with most research having focused on reporting. Addressing the factors that contribute to near misses will potentially help reduce the number of significant, harm patientsafety incidents. While the healthcare literature states the need to learn from aviation’s use of near misses, there is nothing that describes how best to do this. The authors, as part of a larger study of near-miss management in healthcare, sought to learn from aviation to develop principles for how healthcare can identify, report, and learn from near misses to improve patient safety. Methods: A Grounded Theory (GT) methodology, augmented by a scoping review, was used. Data collection included interviews, field notes, and the literature. The review protocol is accessible online. The GT aimed to develop theories about how aviation, amongst other safety-critical industries, manages near misses. Results: Twelve aviation interviews contributed to the GT across passenger airlines, air traffic control, and bodies involved in policy, regulation, and investigation. The scoping review identified 83 articles across a range of safety-critical industries, but only seven focused on aviation. The GT identified that aviation interprets the term ‘near miss’ in different ways, commonly using it to specifically refer to near-miss air collisions, also known as Airproxes. Other types of near misses exist, such as health and safety, but the reporting of these and the safety climate associated with them is not as mature. Safety culture in aviation was regularly discussed, with evidence that culture varies depending on which part of the industry is being considered (e.g., civil vs. business aviation). Near misses are seen as just one part of an extensive safety management system, but processes to support their reporting and their analysis are not consistent. Their value alone is also questionable, with the challenge to long-held beliefs originating from the ‘common cause hypothesis.’ Conclusions: There is learning that healthcare can take from how parts of aviation manage and learn from near misses. For example, healthcare would benefit from a formal safety management system that currently does not exist. However, it may not be as simple as ‘healthcare should learn from aviation’ due to variation in safety maturity across the industry. Healthcare needs to clarify how to incorporate near misses into learning and whether allocating resources to them is of value; it was heard that catastrophes have led to greater improvements in safety in aviation.

Keywords: aviation safety, patient safety, near miss, safety management systems

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Authors: Rostyslav Horbay, Nick Korolis, Vahid Anvari, Rostyslav Stoika

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Introduction: Giant cancer cells (GCC) are common in all types of cancer, especially after poor therapy. Some specific features of such cells include ~10-fold enlargement, drug resistance, and the ability to propagate similar daughter cells. We used murine NK/Ly lymphoma, an aggressive and fast growing lymphoma model that has already shown drastic changes in GCC comparing to parental cells (chromatin condensation, nuclear fragmentation, tighter OXPHOS/cellular respiration coupling, multidrug resistance). Materials and methods: In this study, we compared morpho-functional changes of GCC that predominantly show either a cytostatic or a cytotoxic effect after treatment with drugs. We studied the effect of a combined cytostatic/cytotoxic drug treatment to determine the correlation of drug efficiency and GCC formation. Doses of G1/S-specific drug paclitaxel/PTX (G2/M-specific, 50 mg/mouse), vinblastine/VBL (50 mg/mouse), and DNA-targeting agents doxorubicin/DOX (125 ng/mouse) and cisplatin/CP (225 ng/mouse) on C57 black mice. Several tests were chosen to estimate morphological and physiological state (propidium iodide, Rhodamine-123, DAPI, JC-1, Janus Green, Giemsa staining and other), which included cell integrity, nuclear fragmentation and chromatin condensation, mitochondrial activity, and others. A single and double factor ANOVA analysis were performed to determine correlation between the criteria of applied drugs and cytomorphological changes. Results: In all cases of treatment, several morphological changes were observed (intracellular vacuolization, membrane blebbing, and interconnected mitochondrial network). A lower gain in ascites (49.97% comparing to control group) and longest lifespan (22+9 days) after tumor injection was obtained with single VBL and single DOX injections. Such ascites contained the highest number of GCC (83.7%+9.2%), lowest cell count number (72.7+31.0 mln/ml), and a strong correlation coefficient between increased mitochondrial activity and percentage of giant NK/Ly cells. A high number of viable GCC (82.1+9.2%) was observed compared to the parental forms (15.4+11.9%) indicating that GCC are more drug resistant than the parental cells. All this indicates that the giant cell formation and its ability to obtain drug resistance is an expanding field in cancer research.

Keywords: ANOVA, cisplatin, doxorubicin, drug resistance, giant cancer cells, NK/Ly lymphoma, paclitaxel, vinblastine

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Authors: Ageliki I. Katsarou, Andriana C. Kaliora, Antonia Chiou, Apostolos Papalois, Nick Kalogeropoulos, Nikolaos K. Andrikopoulos

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Chronic inflammation plays a pivotal role in CVD development, while phytochemicals have been shown to reduce CVD risk. Several studies have correlated olive oil consumption with CVD prevention and CVD risk reduction. However, the effect of individual olive oil macro- or micro-constituents and possible synergisms among them needs to be further elucidated. Herein, extra virgin olive oil (EVOO) lipidic and polar phenolics fractions were evaluated for their effect on inflammatory markers in cholesterol-fed rats. Oils combining different characteristics as to their polar phenolic content and lipid profile were used. Male Wistar rats were fed for 9 weeks on either a high-cholesterol diet (HCD) or a HCD supplemented with oils, either commercially available, i.e. EVOO, sunflower oil (SO), or modified as to their polar phenol content, i.e. phenolics deprived-EVOO (EVOOd), SO enriched with the EVOO phenolics (SOe). Post-intervention, aorta and blood samples were collected. HCD induced dyslipidemia, manifested by serum total cholesterol and low-density lipoprotein cholesterol elevation. Additionally, HCD resulted in higher adhesion molecules’ levels in rat aorta. In the case of E-selectin, this increase was attenuated by HCD supplementation with EVOO and EVOOd, while no alterations were observed in SO and SOe groups. No differences were observed between pairs of commercial and modified oils, indicating that oleates may be the components responsible for aorta E-selectin levels lowering. The same was true for vascular adhesion molecule-1 (VCAM-1); augmentation in cholesterol-fed animals was attenuated by EVOO and EVOOd diets, highlighting oleates effect. In addition, VCAM-1 levels were higher in SO group compared to the respective SOe, indicating that in the presence of phenolic compounds linoleic acid have become less prone to oxidation. Intercellular adhesion molecule-1 (ICAM-1) levels were higher in cholesterol-fed rats, however not affected by any of the oils supplemented during the intervention. Overall, EVOO was found superior in regulating adhesion molecule levels in rat aorta compared to SO. EVOO and EVOOd exhibited analogous effects on all adhesion molecules assessed, indicating that EVOO major constituents (oleates) improve E-selectin and VCAM-1 levels in rat aorta, independently from phenolics presence. Further research is needed to elucidate the effect of phenolics and oleates in other tissues.

Keywords: extra virgin olive oil, cholesterol-fed rats, polar phenolics, adhesion molecules

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Authors: Ageliki I. Katsarou, Andriana C. Kaliora, Antonia Chiou, Apostolos Papalois, Nick Kalogeropoulos, Nikolaos K. Andrikopoulos

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Oxidative stress is a major mechanism underlying CVDs while inflammation, an intertwined process with oxidative stress, is also linked to CVDs. Extra virgin olive oil (EVOO) is widely known to play a pivotal role in CVD prevention and CVD reduction. However, in most studies, olive oil constituents are evaluated individually and not as part of the native food, hence potential synergistic effects as drivers of EVOO beneficial properties may be underestimated. In this study, EVOO lipidic and polar phenolics fractions were evaluated for their effect on inflammatory (TNF-alpha) and oxidation (malondialdehyde/MDA) markers, in cholesterol-fed rats. Thereat, oils with discernible lipidic profile and polar phenolic content were used. Wistar rats were fed on either a high-cholesterol diet (HCD) or a HCD supplemented with oils, either commercially available, i.e. EVOO, sunflower oil (SO), or modified as to their polar phenol content, i.e. phenolics deprived-EVOO (EVOOd), SO enriched with the EVOO phenolics (SOe). After 9 weeks of dietary intervention, heart and blood samples were collected. HCD induced dylipidemia shown by increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-c) and triacylglycerols. Heart tissue has been affected by dyslipidemia; oxidation was indicated by increase in MDA in cholesterol-fed rats and inflammation by increase in TNF-alpha. In both cases, this augmentation was attenuated in EVOO and SOe diets. With respect to oxidation, SO enrichment with the EVOO phenolics brought its lipid peroxidation levels as low as in EVOO-fed rats. This suggests that phenolic compounds may act as antioxidant agents in rat heart. A possible mechanism underlying this activity may be the protective effect of phenolics in mitochondrial membrane against oxidative damage. This was further supported by EVOO/EVOOd comparison with the former presenting lower heart MDA content. As for heart inflammation, phenolics naturally present in EVOO as well as phenolics chemically added in SO, exhibited quenching abilities in heart TNF-alpha levels of cholesterol-fed rats. TNF-alpha may have played a causative role in oxidative stress induction while the opposite may have also happened, hence setting up a vicious cycle. Overall, diet supplementation with EVOO or SOe attenuated hypercholesterolemia-induced increase in MDA and TNF-alpha in Wistar rat hearts. This is attributed to phenolic compounds either naturally existing in olive oil or as fortificants in seed oil.

Keywords: extra virgin olive oil, hypercholesterolemic rats, MDA, polar phenolics, TNF-alpha

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Authors: Brooke Sweeney, David White, Felix Amparano, Nick A. Clark, Amy R. Beck, Mathew Lindquist, Lora Edwards, Julie Vandal, Jennifer Lisondra, Katie Cox, Renee Arensberg, Allen Cummins, Jazmine Cedeno, Jason D. Fraser, Kelsey Dean, Helena H. Laroche, Cristina Fernandez

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Background: National organizations call for standardized pre-surgical requirements and education to optimize postoperative outcomes. Since 2017 our surgery program has used defined protocols and educational curricula pre- and post-surgery. In response to patient outcomes, our educational content was refined to include quizzes to assess patient knowledge and surgical preparedness. We aim to optimize adolescent pre-bariatric surgery preparedness by improving overall aggregate pre-surgical assessment performance from 68% to 80% within 12 months. Methods: A multidisciplinary improvement team was developed within the weight management clinic (WMC) of our tertiary care, free-standing children’s hospital. A manual has been utilized since 2017, with limitations in consistent delivery and patient uptake of information. The curriculum has been improved to include quizzes administered during WMC visits prior to bariatric surgery. The initial outcome measure is the pre-surgical quiz score of adolescents preparing for bariatric surgery. Process measure was the number of questions answered correctly to test the questions. Baseline performance was determined by a patient assessment survey of pre-surgical preparedness at patient visits. Plan-Do-Study-Act cycles (PDSA) included: 1) creation and implementation of a refined curriculum, 2) development of 5 new quizzes based upon learning objectives, and 3) improving provider-lead teaching and quiz administration within clinic workflow. Run charts assessed impact over time. Results: A total of 346 quiz questions were administered to 34 adolescents. The outcome measure improved from a baseline mean of 68% to 86% following PDSA 2 cycles, and it was sustained. Conclusion/Implication: Patient/family comprehension of surgical preparedness improved with standardized education via team member-led teaching and assessment using quizzes during pre-surgical clinic visits. The next steps include launching redesigned teaching materials with modules correlated to quizzes and assessment of comprehension and outcomes post-surgically.

Keywords: bariatric surgery, adolescent, clinic, pre-bariatric training

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Authors: Nick Woodier, Iain Moppett

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Background: It is estimated that one in ten patients admitted to hospital will suffer an adverse event in their care. While the majority of these will result in low harm, patients are being significantly harmed by the processes meant to help them. Healthcare, therefore, seeks to make improvements in patient safety by taking learning from other industries that are perceived to be more mature in their management of safety events. Of particular interest to healthcare are ‘near misses,’ those events that almost happened but for an intervention. Healthcare does not have any guidance as to how best to manage and learn from near misses to reduce the chances of harm to patients. The authors, as part of a larger study of near-miss management in healthcare, sought to learn from the UK nuclear sector to develop principles for how healthcare can identify, report, and learn from near misses to improve patient safety. The nuclear sector was chosen as an exemplar due to its status as an ultra-safe industry. Methods: A Grounded Theory (GT) methodology, augmented by a scoping review, was used. Data collection included interviews, scenario discussion, field notes, and the literature. The review protocol is accessible online. The GT aimed to develop theories about how nuclear manages near misses with a focus on defining them and clarifying how best to support reporting and analysis to extract learning. Near misses related to radiation release or exposure were focused on. Results: Eightnuclear interviews contributed to the GT across nuclear power, decommissioning, weapons, and propulsion. The scoping review identified 83 articles across a range of safety-critical industries, with only six focused on nuclear. The GT identified that nuclear has a particular focus on precursors and low-level events, with regulation supporting their management. Exploration of definitions led to the recognition of the importance of several interventions in a sequence of events, but that do not solely rely on humans as these cannot be assumed to be robust barriers. Regarding reporting and analysis, no consistent methods were identified, but for learning, the role of operating experience learning groups was identified as an exemplar. The safety culture across nuclear, however, was heard to vary, which undermined reporting of near misses and other safety events. Some parts of the industry described that their focus on near misses is new and that despite potential risks existing, progress to mitigate hazards is slow. Conclusions: Healthcare often sees ‘nuclear,’ as well as other ultra-safe industries such as ‘aviation,’ as homogenous. However, the findings here suggest significant differences in safety culture and maturity across various parts of the nuclear sector. Healthcare can take learning from some aspects of management of near misses in nuclear, such as how they are defined and how learning is shared through operating experience networks. However, healthcare also needs to recognise that variability exists across industries, and comparably, it may be more mature in some areas of safety.

Keywords: culture, definitions, near miss, nuclear safety, patient safety

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Authors: Chen Yuan, Nick Green, Stuart Blackburn

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The investment casting process offers a great freedom of design combined with the economic advantage of near net shape manufacturing. It is widely used for the production of high value precision cast parts in particularly in the aerospace sector. Various combinations of materials have been used to produce the ceramic moulds, but most investment foundries use a silica based binder system in conjunction with fused silica, zircon, and alumino-silicate refractories as both filler and coarse stucco materials. However, in the context of advancing alloy technologies, silica based systems are struggling to keep pace, especially when net-shape casting titanium alloys. Study has shown that the casting of titanium based alloys presents considerable problems, including the extensive interactions between the metal and refractory, and the majority of metal-mould interaction is due to reduction of silica, present as binder and filler phases, by titanium in the molten state. Cleaner, more refractory systems are being devised to accommodate these changes. Although yttria has excellent chemical inertness to titanium alloy, it is not very practical in a production environment combining high material cost, short slurry life, and poor sintering properties. There needs to be a cost effective solution to these issues. With limited options for using pure oxides, in this work, a silica-free magnesia spinel MgAl₂O₄ was used as a primary coat filler and alumina as a binder material to produce facecoat in the investment casting mould. A comparison system was also studied with a fraction of the rare earth oxide Y₂O₃ adding into the filler to increase the inertness. The stability of the MgAl₂O₄/Al₂O₃ and MgAl₂O₄/Y₂O₃/Al₂O₃ slurries was assessed by tests, including pH, viscosity, zeta-potential and plate weight measurement, and mould properties such as friability were also measured. The interaction between the face coat and titanium alloy was studied by both a flash re-melting technique and a centrifugal investment casting method. The interaction products between metal and mould were characterized using x-ray diffraction (XRD), scanning electron microscopy (SEM) and Energy Dispersive X-Ray Spectroscopy (EDS). The depth of the oxygen hardened layer was evaluated by micro hardness measurement. Results reveal that introducing a fraction of Y₂O₃ into magnesia spinel can significantly increase the slurry life and reduce the thickness of hardened layer during centrifugal casting.

Keywords: titanium alloy, mould, MgAl₂O₄, Y₂O₃, interaction, investment casting

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Authors: Gracie Tredget, Raymond McGrath, Karen Ang, Julie Williams, Nick Sevdalis, Fiona Gaughran, Jorge Aria de la Torre, Ioannis Bakolis, Andy Healey, Zarnie Khadjesari, Euan Sadler, Natalia Stepan

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Background: Preventable physical health problems have been found to increase morbidity rates amongst adults living with serious mental illness (SMI). Community mental health clinicians have a role in identifying, and preventing physical health problems worsening, and supporting primary care services to administer routine physical health checks for their patients. However, little is known about how mental health staff perceive and approach their role when providing physical healthcare amongst patients with SMI, or the impact these attitudes have on routine practice. Methods: The present study involves a prospective service evaluation specific to Adult Community Mental Health Services at South London and Maudsley NHS Foundation Trust (SLaM). A qualitative methodology will use semi-structured interviews, focus groups and observations to explore attitudes, perceptions and experiences of staff, patients, and carers (n=64) towards physical healthcare, and barriers or facilitators that impact upon it. 1South London and Maudsley NHS Foundation Trust, London, SE5 8AZ, UK 2 Centre for Implementation Science, King’s College London, London, SE5 8AF, UK 3 Psychosis Studies, King's College London, London, SE5 8AF, UK 4 Department of Biostatistics and Health Informatics, King’s College London, London, SE5 8AF, UK 5 Kings Health Economics, King's College London, London, SE5 8AF, UK 6 Behavioural and Implementation Science (BIS) research group, University of East Anglia, Norwich, UK 7 Department of Nursing, Midwifery and Health, University of Southampton, Southampton, UK 8 Mind and Body Programme, King’s Health Partners, Guy’s Hospital, London, SE1 9RT *[email protected] Analysis: Data from across qualitative tasks will be synthesised using Framework Analysis methodologies. Staff, patients, and carers will be invited to participate in co-development of recommendations that can improve routine physical healthcare within Adult Community Mental Health Teams at SLaM. Results: Data collection is underway at present. At the time of the conference, early findings will be available to discuss. Conclusions: An integrated approach to mind and body care is needed to reduce preventable deaths amongst people with SMI. This evaluation will seek to provide a framework that better equips staff to approach physical healthcare within a mental health setting.

Keywords: severe mental illness, physical healthcare, adult community mental health, nursing

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Authors: Josie West

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This paper focuses on the conflicts and utility of Marxist Feminist frames for sex work research, drawing on findings uncovered through in-depth interviews with online sex workers, alongside critical discourse analysis of media and political commentary. It brings the critical perspective of women into digital workerism and gig economy dialogue who, despite their significant presence within online work, have been overlooked. The autonomist Marxist concept of class composition is adopted to unpack the social, technical and political composition of this often-invisible segment of the service sector. Autonomism makes visible the perspective of workers engaged in processes of mobilization and demobilizaiton. This allows researchers to find everyday forms of resistance which occur within and outside trade unions. On the other hand, Marxist feminist arguments about invisibility politics can generate unhelpful allegories about sex work as domestic labour within the reproductive sphere. Nick Srnicek’s development of Marx’s notion of infrastructure rents helps theorize experiences of unpaid labour within online sex work. Moreover, debates about anti-work politics can cause conflict among sex workers fighting for the labour movement and those rejecting the capitalist work ethic. This illuminates’ tensions caused by white privilege and differing experiences of sex work. The monopolistic and competitive nature of sex work platforms within platform capitalism, and the vulnerable position of marginalised workers within stigmatized/criminalised markets, complicates anti-work politics further. This paper is situated within the feminist sex wars and the intensely divisive question of whether sex workers are victims of the patriarchy or symbols of feminist resistance. Camgirls are shown to engage in radical tactics of resistance against their technical composition on popular sex work platforms. They also engage in creative acts of resistance through performance art, in an attempt to draw attention to stigma and anti-criminalization politics. This sector offers a fascinating window onto grassroots class-action, alongside education about ‘whorephobia.’ A case study of resistance against Only Fans, and a small workers co-operative which emerged during the pandemic, showcases how workers engage in socialist and political acts without the aid of unions. Workers are victims of neoliberalism and simultaneous adopters of neoliberal strategies of survival. The complex dynamics within unions are explored, including tensions with grass-roots resistance, financial pressures and intersecting complications of class, gender and race.

Keywords: autonomist marxism, digital labor, feminism, neoliberalism, sex work, platform capitalism

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Authors: Muteb Alotaibi, Graham Clarke, Nick Malleson

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The Hajj religious festival at Mina in Saudi Arabia has always presented the opportunity for injuries or deaths. For example, in 1990, a stampede killed 1426 pilgrims, whilst in 1997, 343 people were killed and 1500 injured due to a fire fuelled by high winds sweeping through the tent city in Mina.Many more minor incidents have occurred since then. It is predicted that 5 million pilgrims will soon perform the ritual at Mina (which is, in effect, a temporary city built each year in the desert), which might lead in the future to severe congestion and accidents unless the research is conducted on actions that contribute positively to improving the management of the crowd and facilitating the flow of pilgrims safely and securely. To help prevent further disasters, it is important to first plan better, more accessible locations for emergency services across Mina to ensure a good service for pilgrims. In this paper, we first use a Location Allocation Model (LAM) within a network GIS to examine the optimal locations for key services in the temporary city of Mina. This has been undertaken in relation to the location and movement of the pilgrims during the six day religious festival. The results of various what-if scenarios have been compared against the current location of services. A major argument is that planners should be flexible and locate facilities at different locations throughout the day and night. The use of location-allocation models in this type of comparative static mode has rarely been operationalised in the literature. Second, we model pilgrim movements and behaviours along with the most crowded parts of the network. This has been modelled using an agent-based model. This model allows planners to understand the key bottlenecks in the network and at what usage levels the paths become critically congested. Thus the paper has important implications and recommendations for future disaster planning strategies. This will enable planners to see at what stage in the movements of pilgrims problems occur in terms of potential crushes and trampling incidents. The main application of this research was only customised for pedestrians as the concentration only for pedestrians who move to Jamarat via foot. Further, the network in the middle of Mina was only dedicated for pedestrians for safety, so no Buses, trains and private cars were allowed in this area to prevent the congestion within this network. Initially, this research focus on Mina city as ‘temporary city’ and also about service provision in temporary cities, which is not highlighted in literature so far. Further, it is the first study which use the dynamic demand to optimise the services in the case of day and night time. Moreover, it is the first study which link the location allocation model for optimising services with ABM to find out whether or not the service location is located in the proper location in which it’s not affecting on crowd movement in mainstream flow where some pilgrims need to have health services.

Keywords: ABM, crowd management, hajj, temporary city

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Authors: Ivana Knezevic, Kenneth D. Candido, N. Nick Knezevic

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Background: While pain intensity scales remain generally accepted assessment tool, and the numeric pain rating score is highly subjective, we nevertheless rely on them to make a judgment about treatment effects. Misinterpretation of pain can lead practitioners to underestimate or overestimate the patient’s medical condition. The purpose of this study was to analyze how the numeric rating pain scores given by patients with low back pain correlate with their functional activity levels. Methods: We included 100 consecutive patients with radicular low back pain (LBP) after the Institutional Review Board (IRB) approval. Pain scores, numeric rating scale (NRS) responses at rest and in the movement,Oswestry Disability Index (ODI) questionnaire answers were collected 10 times through 12 months. The ODI questionnaire is targeting a patient’s activities and physical limitations as well as a patient’s ability to manage stationary everyday duties. Statistical analysis was performed by using SPSS Software version 20. Results: The average duration of LBP was 14±22 months at the beginning of the study. All patients included in the study were between 24 and 78 years old (average 48.85±14); 56% women and 44% men. Differences between ODI and pain scores in the range from -10% to +10% were considered “normal”. Discrepancies in pain scores were graded as mild between -30% and -11% or +11% and +30%; moderate between -50% and -31% and +31% and +50% and severe if differences were more than -50% or +50%. Our data showed that pain scores at rest correlate well with ODI in 65% of patients. In 30% of patients mild discrepancies were present (negative in 21% and positive in 9%), 4% of patients had moderate and 1% severe discrepancies. “Negative discrepancy” means that patients graded their pain scores much higher than their functional ability, and most likely exaggerated their pain. “Positive discrepancy” means that patients graded their pain scores much lower than their functional ability, and most likely underrated their pain. Comparisons between ODI and pain scores during movement showed normal correlation in only 39% of patients. Mild discrepancies were present in 42% (negative in 39% and positive in 3%); moderate in 14% (all negative), and severe in 5% (all negative) of patients. A 58% unknowingly exaggerated their pain during movement. Inconsistencies were equal in male and female patients (p=0.606 and p=0.928).Our results showed that there was a negative correlation between patients’ satisfaction and the degree of reporting pain inconsistency. Furthermore, patients talking opioids showed more discrepancies in reporting pain intensity scores than did patients taking non-opioid analgesics or not taking medications for LBP (p=0.038). There was a highly statistically significant correlation between morphine equivalents doses and the level of discrepancy (p<0.0001). Conclusion: We have put emphasis on the patient education in pain evaluation as a vital step in accurate pain level reporting. We have showed a direct correlation with patients’ satisfaction. Furthermore, we must identify other parameters in defining our patients’ chronic pain conditions, such as functionality scales, quality of life questionnaires, etc., and should move away from an overly simplistic subjective rating scale.

Keywords: pain score, functionality scales, low back pain, lumbar

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Authors: Hollie Ashworth, Sarah Heath, Nick Bryan, Liam Abrahamsen, Simon Kellet

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Sellafield has a number of fuel storage ponds, some of which have been open to the air for a number of decades. This has caused corrosion of the fuel resulting in a release of some activity into solution, reduced water clarity, and accumulation of sludge at the bottom of the pond consisting of brucite (Mg(OH)2) and other uranium corrosion products. Both of these phases are also present as colloidal material. 90Sr and 137Cs are known to constitute a small volume of the radionuclides present in the pond, but a large fraction of the activity, thus they are most at risk of challenging effluent discharge limits. Organic molecules are known to be present also, due to the ponds being open to the air, with occasional algal blooms restricting visibility further. The contents of the pond need to be retrieved and safely stored, but dealing with such a complex, undefined inventory poses a unique challenge. This work aims to determine and understand the sorption-desorption interactions of 90Sr and 137Cs to brucite and uranium phases, with and without the presence of organic molecules from chemical degradation and bio-organisms. The influence of organics on these interactions has not been widely studied. Partitioning of these radionuclides and organic molecules has been determined through LSC, ICP-AES/MS, and UV-vis spectrophotometry coupled with ultrafiltration in both binary and ternary systems. Further detailed analysis into the surface and bonding environment of these components is being investigated through XAS techniques and PHREEQC modelling. Experiments were conducted in CO2-free or N2 atmosphere across a high pH range in order to best simulate conditions in the pond. Humic acid used in brucite systems demonstrated strong competition against 90Sr for the brucite surface regardless of the order of addition of components. Variance of pH did have a small effect, however this range (10.5-11.5) is close to the pHpzc of brucite, causing the surface to buffer the solution pH towards that value over the course of the experiment. Sorption of 90Sr to UO2 obeyed Ho’s rate equation and demonstrated a slow second-order reaction with respect to the sharing of valence electrons from the strontium atom, with the initial rate clearly dependent on pH, with the equilibrium concentration calculated at close to 100% sorption. There was no influence of humic acid seen when introduced to these systems. Sorption of 137Cs to UO3 was significant, with more than 95% sorbed in just over 24 hours. Again, humic acid showed no influence when introduced into this system. Both brucite and uranium based systems will be studied with the incorporation of cyanobacterial cultures harvested at different stages of growth. Investigation of these systems provides insight into, and understanding of, the effect of organics on radionuclide partitioning to brucite and uranium phases at high pH. The majority of sorption-desorption work for radionuclides has been conducted at neutral to acidic pH values, and mostly without organics. These studies are particularly important for the characterisation of legacy wastes at Sellafield, with a view to their safe retrieval and storage.

Keywords: caesium, legacy wastes, organics, sorption-desorption, strontium, uranium

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Authors: Jing Zhang, Yvonne Reinwald, Nick Poulson, Alicia El Haj, Chung See, Mike Somekh, Melissa Mather

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Biomedical imaging of native tissue using light offers the potential to obtain excellent structural and functional information in a non-invasive manner with good temporal resolution. Image contrast can be derived from intrinsic absorption, fluorescence, or scatter, or through the use of extrinsic contrast. A major challenge in applying optical microscopy to in vivo tissue imaging is the effects of light attenuation which limits light penetration depth and achievable imaging resolution. Recently Selective Plane Illumination Microscopy (SPIM) has been used to map the 3D distribution of fluorophores dispersed in biological structures. In this approach, a focused sheet of light is used to illuminate the sample from the side to excite fluorophores within the sample of interest. Images are formed based on detection of fluorescence emission orthogonal to the illumination axis. By scanning the sample along the detection axis and acquiring a stack of images, 3D volumes can be obtained. The combination of rapid image acquisition speeds with the low photon dose to samples optical sectioning provides SPIM is an attractive approach for imaging biological samples in 3D. To date all implementations of SPIM rely on the use of fluorescence reporters be that endogenous or exogenous. This approach has the disadvantage that in the case of exogenous probes the specimens are altered from their native stage rendering them unsuitable for in vivo studies and in general fluorescence emission is weak and transient. Here we present for the first time to our knowledge a label-free implementation of SPIM that has downstream applications in the clinical setting. The experimental set up used in this work incorporates both label-free and fluorescent illumination arms in addition to a high specification camera that can be partitioned for simultaneous imaging of both fluorescent emission and scattered light from intrinsic sources of optical contrast in the sample being studied. This work first involved calibration of the imaging system and validation of the label-free method with well characterised fluorescent microbeads embedded in agarose gel. 3D constructs of mammalian cells cultured in agarose gel with varying cell concentrations were then imaged. A time course study to track cell proliferation in the 3D construct was also carried out and finally a native tissue sample was imaged. For each sample multiple images were obtained by scanning the sample along the axis of detection and 3D maps reconstructed. The results obtained validated label-free SPIM as a viable approach for imaging cells in a 3D gel construct and native tissue. This technique has the potential use in a near-patient environment that can provide results quickly and be implemented in an easy to use manner to provide more information with improved spatial resolution and depth penetration than current approaches.

Keywords: bioimaging, optics, selective plane illumination microscopy, tissue imaging

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Authors: Nick Toossi, Joseph Hartland

Abstract:

Background: Malawi is an example of a low resource setting which faces a chronic shortage of doctors and other medical staff. This shortfall is made up for by clinical officers (COs), who are para-medicals trained for 4 years. The literature suggests to improve outcomes surgical skills training specifically should be promoted for COs in district and mission hospitals. Accordingly, the primary author was tasked with developing a basic surgical skills teaching package for COs of Mulanje Mission Hospital (MMH), Malawi, as part of a 4th year medical student External Student Selected Component field trip. MMH is a hospital based in the South of Malawi near the base of Mulanje Mountain and works in an extremely isolated environment with some of the poorest communities in the country. Traveling to Malawi the medical student author performed an educational needs assessment to develop and deliver a bespoke basic surgical skills teaching package. Methodology: An initial needs assessment identified the following domains: basic surgical skills (instrument naming & handling, knot tying, suturing principles and suturing techniques) and perineal repair. Five COs took part in a teaching package involving an interactive group simulation session, overseen by senior clinical officers and surgical trainees from the UK. Non-organic and animal models were used for simulation practice. This included the use of surgical skills boards to practice knot tying and ox tongue to simulate perineal repair. All participants spoke and read English. The impact of the session was analysed in two different ways. The first was via a pre and post Single Best Answer test and the second a questionnaire including likert’s scales and free text response questions. Results: There was a positive trend in pre and post test scores on competition of the course. There was increase in the mean confidence of learners before and after the delivery of teaching in basic surgical skills and simulated perineal repair, especially in ‘instrument naming and handling’. Whilst positively received it was discovered that learners desire more frequent surgical skills teaching sessions in order to improve and revise skills. Feedback suggests that the learners were not confident in retaining the skills without regular input. Discussion: Skills and confidence were improved as a result of the teaching provided. Learner's written feedback suggested there was an overall appetite for regular surgical skills teaching in the clinical environment and further opportunities to allow for deliberate self-practice. Surgical mentorship schemes facilitating supervised theatre time among trainees and lead surgeons along with improving access to surgical models/textbooks were some of the simple suggestions to improve surgical skills and confidence among COs. Although, this study is limited by population size it is reflective of the small, isolated and low resource environment in which this healthcare is delivered. This project does suggest that current surgical skills packages used in the UK could be adapted for employment in low resource settings, but it is consistency and sustainability that staff seek above all in their on-going education.

Keywords: clinical officers, education, Malawi, surgical skills

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Authors: Rosina U. Ndukwe, Diane Crone, Nick Cavill

Abstract:

Active transport (i.e. walking to school, cycle to work schemes etc.) is an effective approach with multiple social and environmental benefits for transforming urban environments into active urban environments. Although walking and cycling often remain on the margins of urban planning and infrastructure, there are new approaches emerging, along with policy intervention relevant for the creation of sustainable urban active environments conductive to active travel, increasing physical activity levels of involved communities and supporting social inclusion through more active participation. SPAcE - Supporting Policy and Action for Active Environments is a 3 year Erasmus+ project that aims to integrate active transport programmes into public policy across the EU. SPAcE focuses on cities/towns with recorded low physical activity levels to support the development of active environments in 5 sites: Latvia [Tukums], Italy [Palermo], Romania [Brasov], Spain [Castilla-La Mancha] and Greece [Trikala]. The first part of the project involved a review of good practice including case studies from across the EU and project partner countries. This has resulted in the first output from the project, an evidence of good practice summary with case study examples. In the second part of the project, working groups across the 5 sites have carried out co-production to develop Urban Active Environments (UActivE) Action Plans aimed at influencing policy and practice for increasing physical activity primarily through the use of cycling and walking. Action plans are based on international evidence and guidance for healthy urban planning. Remaining project partners include Universities (Gloucestershire, Oxford, Zurich, Thessaly) and Fit for Life programme (National physical activity promotion program, Finland) who provide support and advice incorporating current evidence, healthy urban planning and mentoring. Cooperation and co-production with public health professionals, local government officers, education authorities and transport agencies has been a key approach of the project. The third stage of the project has involved training partners in the WHO HEAT tool to support the implementation of the Action Plans. Project results show how multi-agency, transnational collaboration can produce real-life Action Plans in five EU countries, based on published evidence, real-life experience, consultation and collaborative working with other organisations across the EU. Learning from the processes adopted within this project will demonstrate how public health, local government and transport agencies across the EU, can work together to create healthy environments that have the aim of facilitating active behaviour, even in times of constrained public budgets. The SPAcE project has captured both the challenges and solutions for increasing population physical activity levels, health and wellness in urban spaces and translating evidence into policy and practice ensuring innovation at policy level. Funding acknowledgment: SPAcE (www.activeenvironments.eu) is co-funded by the Sport action of the ERASMUS+ programme.

Keywords: action plans, active transport, SPAcE, UActivE urban active environments, walking and cycling

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Authors: Nalika S. Rajapaksha, James Airton, Amina Aboobakar, Nick Chappell, Andy Dyer

Abstract:

Nutrient pollution and their impact on water quality is a key concern in England. Many water quality issues originate from multiple sources of pollution spread across the catchment. The river water quality in England has improved since 1990s and wastewater effluent discharges into rivers now contain less phosphorus than in the past. However, excess phosphorus is still recognised as the prevailing issue for rivers failing Water Framework Directive (WFD) good ecological status. To achieve WFD Phosphorus objectives, Wastewater Treatment Works (WwTW) permit limits are becoming increasingly stringent. Nevertheless, in some rural catchments, the apportionment of Phosphorus pollution can be greater from agricultural runoff and other sources such as septic tanks. Therefore, the challenge of meeting the requirements of watercourses to deliver WFD objectives often goes beyond water company activities, providing significant opportunities to co-deliver activities in wider catchments to reduce nutrient load at source. The aim of this study was to apply the United Utilities' Catchment Systems Thinking (CaST) strategy and pilot an innovative permitting approach - Catchment Nutrient Balancing (CNB) in a rural catchment in Cumbria (the River Petteril) in collaboration with the regulator and others to achieve WFD objectives and multiple benefits. The study area is mainly agricultural land, predominantly livestock farms. The local ecology is impacted by significant nutrient inputs which require intervention to meet WFD obligations. There are a range of Phosphorus inputs into the river, including discharges from wastewater assets but also significantly from agricultural contributions. Solely focusing on the WwTW discharges would not have resolved the problem hence in order to address this issue effectively, a CNB trial was initiated at a small WwTW, targeting the removal of a total of 150kg of Phosphorus load, of which 13kg were to be reduced through the use of catchment interventions. Various catchment interventions were implemented across selected farms in the upstream of the catchment and also an innovative polonite reactive filter media was implemented at the WwTW as an alternative to traditional Phosphorus treatment methods. During the 3 years of this trial, the impact of the interventions in the catchment and the treatment works were monitored. In 2020 and 2022, it respectively achieved a 69% and 63% reduction in the phosphorus level in the catchment against the initial reduction target of 9%. Phosphorus treatment at the WwTW had a significant impact on overall load reduction. The wider catchment impact, however, was seven times greater than the initial target when wider catchment interventions were also established. While it is unlikely that all the Phosphorus load reduction was delivered exclusively from the interventions implemented though this project, this trial evidenced the enhanced benefits that can be achieved with an integrated approach, that engages all sources of pollution within the catchment - rather than focusing on a one-size-fits-all solution. Primarily, the CNB approach and the act of collaboratively engaging others, particularly the agriculture sector is likely to yield improved farm and land management performance and better compliance, which can lead to improved river quality as well as wider benefits.

Keywords: agriculture, catchment nutrient balancing, phosphorus pollution, water quality, wastewater

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Authors: Wiam El Kheir, Anais Dumais, Maude Beaudoin, Bernard Marcos, Nick Virgilio, Benoit Paquette, Nathalie Faucheux, Marc-Antoine Lauzon

Abstract:

The high infiltrative pattern of glioblastoma multiforme cells (GBM) is the main cause responsible for the actual standard treatments failure. The tumor high heterogeneity, the interstitial fluid flow (IFF) and chemokines guides GBM cells migration in the brain parenchyma resulting in tumor recurrence. Drug delivery systems emerged as an alternative approach to develop effective treatments for the disease. Some recent studies have proposed to harness the effect CXC-lchemokine-ligand-12 to direct and control the cancer cell migration through delivery system. However, the dynamics of the brain environment on the delivery system remains poorly understood. Nanoparticles (NPs) and hydrogels are known as good carriers for the encapsulation of different agents and control their release. We studied the release of CXCL12 (free or loaded into NPs) from an alginate-based hydrogel under static and indirect perfusion (IP) conditions. Under static conditions, the main phenomena driving CXCL12 release from the hydrogel was diffusion with the presence of strong interactions between the positively charged CXCL12 and the negatively charge alginate. CXCL12 release profiles were independent from the initial mass loadings. Afterwards, we demonstrated that the release could tuned by loading CXCL12 into Alginate/Chitosan-Nanoparticles (Alg/Chit-NPs) and embedded them into alginate-hydrogel. The initial burst release was substantially attenuated and the overall cumulative release percentages of 21%, 16% and 7% were observed for initial mass loadings of 0.07, 0.13 and 0.26 µg, respectively, suggesting stronger electrostatic interactions. Results were mathematically modeled based on Fick’s second law of diffusion framework developed previously to estimate the effective diffusion coefficient (Deff) and the mass transfer coefficient. Embedding the CXCL12 into NPs decreased the Deff an order of magnitude, which was coherent with experimental data. Thereafter, we developed an in-vitro 3D model that takes into consideration the convective contribution of the brain IFF to study CXCL12 release in an in-vitro microenvironment that mimics as faithfully as possible the human brain. From is unique design, the model also allowed us to understand the effect of IP on CXCL12 release in respect to time and space. Four flow rates (0.5, 3, 6.5 and 10 µL/min) which may increase CXCL12 release in-vivo depending on the tumor location were assessed. Under IP, cumulative percentages varying between 4.5-7.3%, 23-58.5%, 77.8-92.5% and 89.2-95.9% were released for the three initial mass loadings of 0.08, 0.16 and 0.33 µg, respectively. As the flow rate increase, IP culture conditions resulted in a higher release of CXCL12 compared to static conditions as the convection contribution became the main driving mass transport phenomena. Further, depending on the flow rate, IP had a direct impact on CXCL12 distribution within the simulated brain tissue, which illustrates the importance of developing such 3D in-vitro models to assess the efficiency of a delivery system targeting the brain. In future work, using this very model, we aim to understand the impact of the different phenomenon occurring on GBM cell behaviors in response to the resulting chemokine gradient subjected to various flow while allowing them to express their invasive characteristics in an in-vitro microenvironment that mimics the in-vivo brain parenchyma.

Keywords: 3D culture system, chemokines gradient, glioblastoma multiforme, kinetic release, mathematical modeling

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Authors: Jennifer Wheeldon, Nick de Viggiani, Nikki Cotterill

Abstract:

Background: Urinary and fecal incontinence affect a significant proportion of older adults aged 65 and over who permanently reside in residential and nursing home facilities. Incontinence symptoms have been linked to comorbidities, an increased risk of infection and reduced quality of life and mental wellbeing of residents. However, continence care provision can often be poor, further compromising the health and wellbeing of this vulnerable population. Objectives: To identify experiences and perceptions of continence care provision in older adult residential care settings and to identify factors that help or hinder good continence care provision. Settings included both residential care homes and nursing homes for older adults. Methods: A qualitative evidence synthesis using systematic review methodology established the current evidence-base. Data from 20 qualitative and mixed-method studies was appraised and synthesized. Following the review process, 10* qualitative interviews with staff working in older adult residential care settings were conducted across six* sites, which included registered managers, registered nurses and nursing/care assistants/aides. Purposive sampling recruited individuals from across England. Both evidence synthesis and interview data was analyzed thematically, both manually and with NVivo software. Results: The evidence synthesis revealed complex barriers and facilitators for continence care provision at three influencing levels: macro (structural and societal external influences), meso (organizational and institutional influences) and micro (day-to-day actions of individuals impacting service delivery). Macro-level barriers included negative stigmas relating to incontinence, aging and working in the older adult social care sector, restriction of continence care resources such as containment products (i.e. pads), short staffing in care facilities, shortfalls in the professional education and training of care home staff and the complex health and social care needs of older adult residents. Meso-level barriers included task-centered organizational cultures, ageist institutional perspectives regarding old age and incontinence symptoms, inadequate care home management and poor communication and teamwork among care staff. Micro-level barriers included poor knowledge and negative attitudes of care home staff and residents regarding incontinence symptoms and symptom management and treatment. Facilitators at the micro-level included proactive and inclusive leadership skills of individuals in management roles. Conclusions: The findings of the evidence synthesis study help to outline the complexities of continence care provision in older adult care homes facilities. Macro, meso and micro level influences demonstrate problematic and interrelated barriers across international contexts, indicating that improving continence care in this setting is extremely challenging due to the multiple levels at which care provision and services are impacted. Both international and national older adult social care policy-makers, researchers and service providers must recognize this complexity, and any intervention seeking to improve continence care in older adult care home settings must be planned accordingly and appreciatively of the complex and interrelated influences. It is anticipated that the findings of the qualitative interviews will shed further light on the national context of continence care provision specific to England; data collection is ongoing*. * Sample size is envisaged to be between 20-30 participants from multiple sites by Spring 2023.

Keywords: continence care, residential and nursing homes, evidence synthesis, qualitative

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral, dental, and general health and well-being; where it normally bathes the oral cavity acting as a clearing agent. This becomes more apparent when the amount and quality of saliva are significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the 5th most common malignancy worldwide, during which the salivary glands are included within the radiation field/zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely as they become malnourished and experience a significant decrease in their QoL. Accordingly, the formulation of a radio-protection/-prevention modality and development of an alternative Rx to restore damaged salivary gland tissue is eagerly awaited and highly desirable. Objectives: Assess the pre-clinical radio-protective effect and reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs, followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: cancer, head and neck, oncology, drug development, drug delivery systems, nanotechnology, nanoncology

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Authors: Ziyad S. Haidar

Abstract:

Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

Procedia PDF Downloads 88