994 research outputs found

    30th European Congress on Obesity (ECO 2023)

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    This is the abstract book of 30th European Congress on Obesity (ECO 2023

    Paediatric Injury from Powered Off-Road Vehicles

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    Background Powered off-road vehicles, such as quad-bikes and two-wheeled motorcycles, are popularly used recreationally by children, and are also used in a variety of farming and agricultural contexts. However, crashes can result in serious injuries and deaths, and as such are an important public health concern for Australian children. Compared to adults, children have different riding patterns, injury causes and risk factors relating to their level of development, as well as different patterns of injury outcomes and severity. Aims This work aims to investigate paediatric quad-bike and motorcycle riding patterns and behaviours, along with risk factors, injury severity, outcomes and potential avenues for injury prevention counter-measures. The work consists of five related studies. Methods and Results The first study was a survey of paediatric off-road vehicle riders, which was undertaken to characterise patterns of use, rider behaviours, experience and attitudes. Recreational motorcycle riding was most common, with children having high rates of previous riding experience and often participating in ‘structured’ riding within organised motorsports competitions and events. There was a small proportion of ‘unstructured’ riding in the context of agriculture or on private properties. Riders generally rode frequently and used helmets and other protective gear. The second study examined a group of children admitted to a paediatric hospital as a result of injury sustained from an off-road vehicle crash. In-depth crash investigation techniques examined injury mechanisms and related them to injury outcomes, along with rider, environmental and vehicular risk factors. A variety of recurring mechanisms emerged, particularly loss-of-control events leading to impacts with the ground or vehicle. A wide range of injuries were also observed, particularly to the extremities. A case-control component of the study identified a lower rider to vehicle weight ratio as a factor associated with higher crash risk. The third and fourth studies used large, linked population-level hospital admission and mortality datasets. The first of these examined injury epidemiology and outcomes for paediatric off-road vehicle crashes across New South Wales over a 17-year time period. The outcomes for different vehicle types were compared. The findings demonstrated the large burden of injury caused by ORV crashes in terms of hospital admissions and operative interventions. Furthermore, although on an individual level, quad-bike injuries were associated with higher injury severity, the far greater number of two-wheeled off-road motorcycle crash admissions suggest that motorcycles should be an injury prevention priority. The second linked data study examined the subset of children who have multiple hospital admissions following off-road vehicle crashes. Children who re-present to hospital repeatedly are a particularly vulnerable group, prone to more serious injury, and higher overall costs to the healthcare system. ‘Recidivist’ riders were compared to non-recidivists across various demographic, vehicle and injury outcome factors, highlighting the areas in which potential recidivists may be identified or targeted for injury prevention interventions. The fifth study was a systematic review of injury prevention countermeasures delivered through clinical environments such as hospitals and Emergency Departments, centred around the concept of the ‘Teachable Moment’: that children may be more receptive or amenable to behaviour change after sustaining an injury. The strengths and weaknesses of interventions that apply this model were identified, which may inform potential interventions pertaining to off-road crashes. The review found that multi-modal approaches combining face-to-face counselling or teaching, supplemented with other forms of written or visual communication, often paired with the provision of safety equipment and accurate monitoring as the most effective means of intervention. However, injury prevention programs are often limited by short-term and largely self-reported outcome measures, so research and programs applying these findings to off-road vehicle riders should be designed with robust design methods and appropriate measures of behaviour change, knowledge gain or injury reduction. Conclusion The results of the project overall demonstrate that off-road vehicle injuries are a large and important cause of injury, disability and death for Australian children. An overarching theme of this project is to demonstrate that children who participate in off-road riding are a unique and vulnerable population. Riding patterns are largely recreational, and the resultant injuries are common, spanning the spectrum of severity. Factors associated with worse injury outcomes and recidivism are explored, which, along with the review of injury prevention countermeasures delivered in clinical settings, may help re-prioritise and target injury prevention resources and research. Ultimately the goal of this project, as with any injury research, is to try to prevent or mitigate the severity off-road crashes. The studies investigate various aspects of paediatric off-road riding and provide important foundational knowledge for researchers and clinicians to work towards real-world applications and interventions

    The Use of Skeletal Muscle to Amplify Action Potentials in Transected Peripheral Nerves

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    Upper limb amputees suffer with problems associated with control and attachment of prostheses. Skin-surface electrodes placed over the stump, which detect myoelectric signals, are traditionally used to control hand movements. However, this method is unintuitive, the electrodes lift-off, and signal selectivity can be an issue. One solution to these limitations is to implant electrodes directly on muscles. Another approach is to implant electrodes directly into the nerves that innervate the muscles. A significant challenge with both solutions is the reliable transmission of biosignals across the skin barrier. In this thesis, I investigated the use of implantable muscle electrodes in an ovine model using myoelectrodes in combination with a bone-anchor, acting as a conduit for signal transmission. High-quality readings were obtained which were significantly better than skin-surface electrode readings. I further investigated the effect of electrode configurations to achieve the best signal quality. For direct recording from nerves, I tested the effect of adsorbed endoneural basement membrane proteins on nerve regeneration in vivo using microchannel neural interfaces implanted in rat sciatic nerves. Muscle and nerve signal recordings were obtained and improvements in sciatic nerve function were observed. Direct skeletal fixation of a prosthesis to the amputation stump using a bone-anchor has been proposed as a solution to skin problems associated with traditional socket-type prostheses. However, there remains a concern about the risk of infection between the implant and skin. Achieving a durable seal at this interface is therefore crucial, which formed the final part of the thesis. Bone-anchors were optimised for surface pore size and coatings to facilitate binding of human dermal fibroblasts to optimise skin-implant seal in an ovine model. Implants silanised with Arginine-Glycine-Aspartic Acid experienced significantly increased dermal tissue infiltration. This approach may therefore improve the soft tissue seal, and thus success of bone-anchored implants. By addressing both the way prostheses are attached to the amputation stump, by way of direct skeletal fixation, as well as providing high fidelity biosignals for high-level intuitive prosthetic control, I aim to further the field of limb loss rehabilitation

    Comparative analysis of metallated phthalocyanines for photodynamic therapy of solid tumors

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    Photodynamic therapy (PDT) comprises the administration of a photosensitizer (PS) and its accumulation within the tumor site, followed by irradiation with light of a specific wavelength. Consequently, singlet oxygen and other reactive oxygen/nitrogen species (ROS/RNS) are produced from bioavailable oxygen at the tumor’s microenvironment and are responsible for the tumor’s eradication. PDT works effectively in certain types of cancer, but poorly in tumors that reside in internal organs and organ structures such as the pancreas and biliary tree. Moreover, adverse effect such as skin phototoxicity is a major obstacle to more widespread clinical applicability. To that end, we encapsulated a second-generation of PS into liposomal carriers that are targeted to the tumor interstitium after intravenous administration. Therefore, this doctoral thesis describes essentially the evaluation and comparison between lipophilic metallated-phthalocyanines (ZnPC and AlPC) encapsulated in interstitially-targeted liposomes (ITLs), and their corresponding hydrophilic derivatives (ZnPCS4 and AlPCS4). To do so, we initiated the doctoral research through our first study by performing an attritional assessment in vitro using A431 cells as a template for tumor cells with a dysfunctional P53 tumor suppressor gene and epidermal growth factor receptor (EGFR) overexpression. As a methodology for our investigations, we have first assessed the dark toxicity as a function of PS concentration using the water-soluble tetrazolium salt (WST-1) and sulforhodamine B dyes as an indication of the cell viability. Using the same principle, we then drew the LC50 values for each PS through PDT at 671 nm and a light exposure of 15 J/cm2 following 1 hour of PS exposure. We continued our research looking into a time-dependent uptake and intracellular distribution of the PS, and we finalized our first study with the assessment of the mode of cell death as well as the cell cycle arrest at 24 hours after PDT. Through this research we observed that, in the absence of illumination, AlPC and ZnPC in ITLs were not toxic to cells up to a 1.5 μM PS concentration and exposure for up to 72 h, but for AlPCS4 and ZnPCS4, the dark toxicity was at 5 μM and at 2.5 μM, respectively. However, PDT of cells photosensitized with ZnPC, AlPC, and AlPCS4 yielded LC50 values of 0.13 μM, 0.04 μM, and 0.81 μM, respectively (24 hours post-PDT based on sulforhodamine B assay). The uptake of all PSs was observed as early as 1 min after PS addition to cells and increased in amplitude during a 2-h incubation period. ZnPCS4 did not induce notable phototoxicity, which was echoed in the mode of cell death and cell cycle arrest data. However, AlPCS4 induced considerable necrosis in addition to apoptosis, whereby most of the cell death had already manifested as early as 2 h after PDT. Cell death signaling coincided with a reduction in cells in the G0/G1 phase (ZnPC, AlPC, AlPCS4) and cell cycle arrest in the S-phase (ZnPC, AlPC, AlPCS4) and G2 phase (ZnPC and AlPC). With the intention of validating our previous research, we have moved forward with the investigations through a second study by using our comparative model with the four metallated-phthalocyanines in a human cholangiocarcinoma cell line and tumor-comprising cells (endothelial cells, fibroblasts, and macrophages), as a representation of the tumor’s microenvironment. In addition to all parameters assessed in the previous study, we went one step further and evaluated the systemic toxicity of each PS in zebrafish and in chicken embryos, and while using BALB/c nude mice as our in vivo model, we researched for signs of skin phototoxicity. A pilot study on PDT efficacy was also performed in BALB/c nude mice bearing human triple-negative breast cancer (MDA-MB-231) xenografts. The key findings were that photodynamically active PSs (all except ZnPCS4) were able to effectively photosensitize cancer cells and non-cancerous cells. In addition, PSs in study did not induced any notable systemic toxicity in zebrafish and chicken embryos. However, ITL-delivered ZnPC and ZnPCS4 were associated with skin phototoxicity, while the aluminum containing PSs did not exert any detectable sign of cutaneous phototoxicity. Last but not least, ITL-delivered ZnPC and AlPC are equally effective in their tumor-killing capacity in human tumor breast cancer xenografts, and superior to other non-phthalocyanine PSs when appraised on a per mole administered dose basis. In summary, the research on the applications of ZnPCS4 for oncological PDT will be discontinued in our group as it failed the attrition step regarding phototoxicity and it showed alarming signs of cutaneous phototoxicity. It is therefore concluded that AlPC and its derivative AlPCS4 are the least toxic and most effective PSs to employ with respect to ITLs as part of the comprehensive tumor targeting and PS delivery platform.A terapia fotodinâmica (do inglês PDT) baseia-se essencialmente na administração de um fotossensibilizador e da sua acumulação no local do tumor, seguido de irradiação com luz de comprimento de onda específico. Consequentemente, o oxigénio singleto e outras espécies reativas de oxigénio/nitrogénio (ROS/RNS) são produzidos a partir de oxigénio biodisponível no microambiente do tumor, e são os principais responsáveis pela erradicação do tumor por meio de três mecanismos distintos: 1) morte celular por apoptose/necrose/autofagia; 2) rutura microvascular do tumor mediado por trombose; e 3) uma resposta anti-tumoral do sistema imunitário. PDT funciona de forma eficaz em certos tipos de cancro, mas menos eficaz em tumores que se alojam em órgãos internos e estruturas de órgãos, como por exemplo: o pâncreas e a árvore biliar. Além disso, efeitos adversos como a fototoxicidade da pele, são um grande obstáculo para uma ampla aplicabilidade no setor clínico. Os pacientes precisam de residir em ambientes escuros durante semanas após a terapia, para se protegerem da luz solar, o que é anti-ético nos casos em que os pacientes têm apenas alguns meses de vida. Nesse sentido, o objetivo da presente tese consiste na investigação de fotonanomedicamentos mais adequados para estes pacientes. Para esse fim, foram encapsulados fotossensibilizadores de segunda geração em transportadores lipossomais que são direcionados ao interstício do tumor após administração intravenosa. Os ftalocianine metalados, como o ftalocianine de zinco lipofílico (ZnPC) e o ftalocianine de alumínio (AlPC), bem como seus derivados tetrassulfonados hidrofílicos (ZnPCS4 e AlPCS4), atestam todos os requisitos clínicos para uso em PDT. No entanto, até o momento não houve comparação direta para determinar qual desses fotossensibilizadores é o mais fototóxico para as células tumorais e, portanto, merece mais desenvolvimento pré-clínico e clínico. Esses estudos serão conduzidos de forma a que permita a seleção do fotossensibilizador ideal para o desenvolvimento de uma terceira e quarta geração de fotossensibilizadores (por exemplo, co-encapsulamento de inibidores de vias de sobrevivência de células tumorais com fotossensibilizadores de segunda geração). A presente tese descreve a avaliação e a comparação entre os ftalocianines metalados (ZnPC e AlPC) encapsulados em lipossomas com alvo para o interstício tumoral (ITLs), e os seus equivalentes hidrofílicos (ZnPCS4 e AlPCS4). Para isso, iniciamos a investigação através de uma avaliação in vitro usando células A431 como modelo para células tumorais, com uma disfunção no gene supressor tumoral P53 e superexpressão do receptor de factor de crescimento epidermal (EGFR). Como metodologia numa primeira abordagem foi avaliada a toxicidade no escuro (sem luz de ativação para a PDT) em função da concentração de fotossensibilizadores, utilizando os corantes WST-1 e sulforrodamina B como indicação da viabilidade celular. Seguiu-se o registo da captura celular em detrimento do tempo de exposição com os fotossensibilizadores, e também da sua distribuição a nível intracelular. Ambos os parâmetros foram determinados através da técnica de citometria de fluxo e de microscopia confocal, usando a fluorescência intrínseca dos fotossensibilizadores. Os valores de LC50 foram então estabelecidos para cada PS a um cumprimento de onda de 671 nm e uma exposição radiante de 15 J/cm2, após 1 hora de exposição com os fotossensibilizadores. Finalizamos o nosso primeiro estudo com a avaliação da morte celular em função do tempo pós-PDT, e também com a análise do ciclo celular 24 horas após a PDT. Através desta investigação observamos que, na ausência de iluminação, AlPC e ZnPC em ITLs não foram tóxicos para as células até uma concentração de 1,5 μM (exposição por até 72 h). No entanto, AlPCS4 e ZnPCS4 demonstraram toxicidade no escuro na ordem dos 5 μM e dos 2,5 μM, respetivamente. A absorção de todos os fotossensibilizadores foi observada tão cedo quanto 1 min após a adição de fotossensibilizadores às células, e aumentou em amplitude durante um período de incubação de 2 h. Porém, após 60 min de incubação com os fotossensibilizadores, todo o espaço não nuclear da célula foi fotossensibilizado, com a acumulação dos fotossensibilizadores em múltiplas estruturas subcelulares, especialmente no caso de AlPC e AlPCS4. A PDT de células fotossensibilizadas com ZnPC, AlPC e AlPCS4 foi capaz de produzir valores de LC50 na ordem dos 0,13 μM, 0,04 μM e 0,81 μM, respetivamente (24 horas após PDT, com base no ensaios com sulforrodamina B). O ZnPCS4 não foi capaz de induzir fototoxicidade, o que foi igualmente observado nos resultados obtidos na análise da morte celular e também do ciclo celular. Nas 4 h após PDT, a morte celular resumiu-se principalmente à apoptose para ZnPC e AlPC, que foi gradualmente aumentada em células fotossensibilizadas com AlPC durante 8 h. Por sua vez, as células tratadas com ZnPC recuperaram nas 8 h após PDT em comparação com 4 h pós-PDT. O AlPCS4 foi capaz de induzir a morte celular de forma significativa por necrose para além da apoptose, sendo que a maior parte da morte celular já se havia manifestado 2 h após a PDT. Durante o período de 8 h, a morte celular por via necrótica que era inicialmente a mais predominante, mas foi perdendo para a morte celular apoptótica tardia. A sinalização de morte celular coincidiu com redução de células na fase G0/G1 (ZnPC, AlPC, AlPCS4) e com a redução da atividade celular na fase S (ZnPC, AlPC, AlPCS4) e fase G2 (ZnPC e AlPC) do ciclo celular. A interrupção do ciclo celular foi mais profunda em células que foram incubadas com AlPC e submetidas a PDT. Com a intenção de validar resultados prévios, foram delineadas experiências utilizando o nosso modelo comparativo com os quatro ftalocianines metalados numa linhagem representativa da população celular num tumor (células endoteliais, fibroblastos e macrófagos), e também utilizando células de colangiocarcinoma humano como representante de células cancerígenas. Para além de todos os parâmetros avaliados no estudo anterior, optou-se por dar um passo em frente na investigação, e foi avaliada também a toxicidade sistémica de cada fotossensibilizador em embriões de peixe-zebra (Danio rerio) e galinha (Gallus gallus domesticus). Além disso, determinou-se o risco de fototoxicidade da pele usando murganhos (Mus musculus) BALB/c nude como modelo in vivo. Um estudo piloto sobre a eficácia da PDT também foi realizado em murganhos nude BALB/c portadores de xenoenxertos humanos de cancro de mama triplo negativo (MDA-MB-231). Como principais resultados observou-se que todos os fotossensibilizadores ativos (exceto ZnPCS4) foram capazes de fotossensibilizar efetivamente células cancerígenas e células não cancerosas. Além disso, os fotossensibilizadores em estudo não induziram nenhuma toxicidade sistémica significativa em embriões de peixe-zebra e galinha. No entanto, ZnPCS4 e ZnPC em ITLs foram associados à fototoxicidade da pele, enquanto os fotossensibilizadores contendo alumínio não exerceram nenhuma fototoxicidade detetável no tecido cutâneo. Por último, ZnPC e AlPC encapsulados em ITLs são igualmente eficazes em reduzir o volume tumoral de xenoenxertos de cancro da mama humano em murganhos nude BALB/c, e foram superiores a outros fotossensibilizadores fora do grupo dos ftalocianines quando avaliados em detrimento da dose administrada por mol. Em resumo, as investigações envolvendo o ZnPCS4 para terapia fotodinâmica oncológica serão descontinuadas no nosso grupo, já que ZnPCS4 demonstrou-se menos eficaz comparativamente aos restantes fotossensibilizadores em estudo. Por outro lado, ZnPCS4 revelou também sinais alarmantes de fototoxicidade cutânea. Deste modo, através das investigações incluídas na presente tese de doutoramento concluímos que AlPC e o seu derivativo hidrofílico AlPCS4 são os fotossensibilizadores menos tóxicos e mais eficazes. Assim sendo, pretendem-se continuar com estes dois fotossensibilizadores em futuros estudos rumo ao desenvolvimento de uma plataforma integrando os ITLs juntamente com outro agente quimioterápico para o tratamento eficaz de tumores sólidos através da PDT

    Evaluating footwear “in the wild”: Examining wrap and lace trail shoe closures during trail running

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    Trail running participation has grown over the last two decades. As a result, there have been an increasing number of studies examining the sport. Despite these increases, there is a lack of understanding regarding the effects of footwear on trail running biomechanics in ecologically valid conditions. The purpose of our study was to evaluate how a Wrap vs. Lace closure (on the same shoe) impacts running biomechanics on a trail. Thirty subjects ran a trail loop in each shoe while wearing a global positioning system (GPS) watch, heart rate monitor, inertial measurement units (IMUs), and plantar pressure insoles. The Wrap closure reduced peak foot eversion velocity (measured via IMU), which has been associated with fit. The Wrap closure also increased heel contact area, which is also associated with fit. This increase may be associated with the subjective preference for the Wrap. Lastly, runners had a small but significant increase in running speed in the Wrap shoe with no differences in heart rate nor subjective exertion. In total, the Wrap closure fit better than the Lace closure on a variety of terrain. This study demonstrates the feasibility of detecting meaningful biomechanical differences between footwear features in the wild using statistical tools and study design. Evaluating footwear in ecologically valid environments often creates additional variance in the data. This variance should not be treated as noise; instead, it is critical to capture this additional variance and challenges of ecologically valid terrain if we hope to use biomechanics to impact the development of new products

    Biomechanics of Contemporary Implants and Prosthesis: Modeling, Experiments, and Clinical Application

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    Modern medicine is now more oriented towards patient-based treatments. Taking into account individual biological features allows for increasing the quality of the healing process. Opportunities for modern hardware and software allow not only the complex behavior of implants and prostheses to be simulated, but also take into account any peculiarities of the patient. Moreover, the development of additive manufacturing expands the opportunities for materials. Technical limits for composite materials, biomaterials, and metamaterials are decreasing. On the other hand, there is a need for more detailed analyses of biomechanics research. A deeper understanding of the technological processes of implants, and the mechanobiological interactions of implants and organisms will potentially allow us to raise the level of medical treatment. Modern trends of the biomechanics of contemporary implants and prostheses, including experimental and mathematical modeling and clinical application, are discussed in this book

    Femoral neck anteversion: measurement, predictors, and effects on musculoskeletal function

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    Total femoral torsion and other lower limb geometry parameters show substantial inter-individual variation and contribute to clinical outcomes such as hip dysplasia, hip and knee osteoarthritis, atypical fractures, and disadvantageous kinematics. This thesis aimed to identify appropriate methods to assess femoral torsion. Thereafter, to investigate its determinants and relationship to other aspects of lower limb geometry and muscle function. The literature review identified the clinical importance of femoral torsion, a lack of standardisation in femoral torsion measurement, and the strength and weaknesses of current methods whilst highlighting the need for quick and accurate techniques employable in children. The first study proved the concept of a new three-dimensional biomedical imaging device using a standard ultrasound device, with a linear array probe, coupled with a coordinate-measuring system. This achieved only poor-to-moderate test-retest reliability for femoral torsion (ICC=0.329; CI -0.542-0.843) and femoral length (ICC=0.615; CI -0.071-0.919) respectively but identified a number of potential avenues for improvement of the technique. The second study characterised lower limb geometry in individuals with X-linked hypophosphatemia (XLH) and controls and found large differences in several parameters of lower limb geometry between the two groups. The identification of ~ 18° smaller intertrochanteric rather than shaft torsion in these individuals can inform surgical guidelines. The third study explored the associations of long-term power exercise with lower limb geometry in young and older adults. Only small associations were observed with training and age as effects on femoral bowing in the order of magnitude of ~2°. The ability to alter skeletal geometry through exercise throughout adulthood seems limited, reinforcing the importance of childhood physical activity for lifelong skeletal health. This thesis presented novel insights and methodologies regarding the characterisation of lower limb geometry on three planes and the relationship between the different shape parameters, informing future surgical procedures. It also added new evidence of skeletal shape adaptations to chronic exercise in adulthood and impaired phosphate metabolism
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