160 research outputs found

    Beta cell extracellular vesicle miR-21-5p cargo is increased in response to inflammatory cytokines and serves as a biomarker of type 1 diabetes

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    AIMS/HYPOTHESIS: Improved biomarkers are acutely needed for the detection of developing type 1 diabetes, prior to critical loss of beta cell mass. We previously demonstrated that elevated beta cell microRNA 21-5p (miR-21-5p) in rodent and human models of type 1 diabetes increased beta cell apoptosis. We hypothesised that the inflammatory milieu of developing diabetes may also increase miR-21-5p in beta cell extracellular vesicle (EV) cargo and that circulating EV miR-21-5p would be increased during type 1 diabetes development. METHODS: MIN6 and EndoC-Ī²H1 beta cell lines and human islets were treated with IL-1Ī², IFN-Ī³ and TNF-Ī± to mimic the inflammatory milieu of early type 1 diabetes. Serum was collected weekly from 8-week-old female NOD mice until diabetes onset. Sera from a cross-section of 19 children at the time of type 1 diabetes diagnosis and 16 healthy children were also analysed. EVs were isolated from cell culture media or serum using sequential ultracentrifugation or ExoQuick precipitation and EV miRNAs were assayed. RESULTS: Cytokine treatment in beta cell lines and human islets resulted in a 1.5- to threefold increase in miR-21-5p. However, corresponding EVs were further enriched for this miRNA, with a three- to sixfold EV miR-21-5p increase in response to cytokine treatment. This difference was only partially reduced by pre-treatment of beta cells with Z-VAD-FMK to inhibit cytokine-induced caspase activity. Nanoparticle tracking analysis showed cytokines to have no effect on the number of EVs, implicating specific changes within EV cargo as being responsible for the increase in beta cell EV miR-21-5p. Sequential ultracentrifugation to separate EVs by size suggested that this effect was mostly due to cytokine-induced increases in exosome miR-21-5p. Longitudinal serum collections from NOD mice showed that EVs displayed progressive increases in miR-21-5p beginning 3 weeks prior to diabetes onset. To validate the relevance to human diabetes, we assayed serum from children with new-onset type 1 diabetes compared with healthy children. While total serum miR-21-5p and total serum EVs were reduced in diabetic participants, serum EV miR-21-5p was increased threefold compared with non-diabetic individuals. By contrast, both serum and EV miR-375-5p were increased in parallel among diabetic participants. CONCLUSIONS/INTERPRETATION: We propose that circulating EV miR-21-5p may be a promising marker of developing type 1 diabetes. Additionally, our findings highlight that, for certain miRNAs, total circulating miRNA levels are distinct from circulating EV miRNA content

    Machine Learning Based Analytics for the Significance of Gait Analysis in Monitoring and Managing Lower Extremity Injuries

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    This study explored the potential of gait analysis as a tool for assessing post-injury complications, e.g., infection, malunion, or hardware irritation, in patients with lower extremity fractures. The research focused on the proficiency of supervised machine learning models predicting complications using consecutive gait datasets. We identified patients with lower extremity fractures at an academic center. Patients underwent gait analysis with a chest-mounted IMU device. Using software, raw gait data was preprocessed, emphasizing 12 essential gait variables. Machine learning models including XGBoost, Logistic Regression, SVM, LightGBM, and Random Forest were trained, tested, and evaluated. Attention was given to class imbalance, addressed using SMOTE. We introduced a methodology to compute the Rate of Change (ROC) for gait variables, independent of the time difference between gait analyses. XGBoost was the optimal model both before and after applying SMOTE. Prior to SMOTE, the model achieved an average test AUC of 0.90 (95% CI: [0.79, 1.00]) and test accuracy of 86% (95% CI: [75%, 97%]). Feature importance analysis attributed importance to the duration between injury and gait analysis. Data patterns showed early physiological compensations, followed by stabilization phases, emphasizing prompt gait analysis. This study underscores the potential of machine learning, particularly XGBoost, in gait analysis for orthopedic care. Predicting post-injury complications, early gait assessment becomes vital, revealing intervention points. The findings support a shift in orthopedics towards a data-informed approach, enhancing patient outcomes.Comment: 13 pages, 6 figure

    Environmental DNA captures elasmobranch diversity in a temperate marine ecosystem

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    Abstract: Many sharks, skates, and rays (elasmobranchs) are highly threatened by the activities of commercial fisheries, and a clear understanding of their distributions, diversity, and abundance can guide protective measures. However, surveying and monitoring elasmobranch species can be highly invasive or resourceā€intensive, and utilization of nonā€invasive environmental DNAā€based methods may overcome these problems. Here, we studied spatial and seasonal variation in the elasmobranch community of the Western English Channel using environmental DNA (eDNA) collected from surface and bottom waters periodically over an annual cycle (2017ā€“2018). In total we recovered 13 elasmobranch species within eDNA samples, and the number of transformed eDNA reads was positively associated with species (hourly) catch data resolved from 105ā€year time series trawl data (1914ā€“2018). These results demonstrate the ability of eDNA to detect and semiā€quantitatively reflect the prevalence of historically dominant and rare elasmobranch species in this region. Notably, eDNA recorded a greater number of species per sampling event than a conventional trawl survey in the same area over the same sampling years (2017ā€“2018). Several threatened species were recovered within the eDNA, including undulate ray, porbeagle shark, and thresher shark. Using eDNA, we found differences in elasmobranch communities among sampling stations and between seasons, but not between sampling depths. Collectively, our results suggest that nonā€invasive eDNAā€based methods can be used to study the spatial and seasonal changes in the diversity and abundance of whole elasmobranch communities within temperate shelf habitats. Given the threatened status of many elasmobranchs in humanā€impacted marine environments, eDNA analysis is poised to provide key information on their diversity and distributions to inform conservationā€focused monitoring and management

    Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss

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    Arthritogenic alphaviruses including Ross River virus (RRV), Sindbis virus, and chikungunya virus cause worldwide outbreaks of musculoskeletal disease. The ability of alphaviruses to induce bone pathologies remains poorly defined. Here we show that primary human osteoblasts (hOBs) can be productively infected by RRV. RRV-infected hOBs produced high levels of inflammatory cytokine including IL-6. The RANKL/OPG ratio was disrupted in the synovial fluid of RRV patients, and this was accompanied by an increase in serum Tartrate-resistant acid phosphatase 5b (TRAP5b) levels. Infection of bone cells with RRV was validated using an established RRV murine model. In wild-type mice, infectious virus was detected in the femur, tibia, patella, and foot, together with reduced bone volume in the tibial epiphysis and vertebrae detected by microcomputed tomographic (Ī¼CT) analysis. The RANKL/OPG ratio was also disrupted in mice infected with RRV; both this effect and the bone loss were blocked by treatment with an IL-6 neutralizing antibody. Collectively, these findings provide previously unidentified evidence that alphavirus infection induces bone loss and that OBs are capable of producing proinflammatory mediators during alphavirus-induced arthralgia. The perturbed RANKL/OPG ratio in RRV-infected OBs may therefore contribute to bone loss in alphavirus infection

    Hanging Out, Messing Around, and Geeking Out

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    The tenth-anniversary edition of a foundational text in digital media and learning, examining new media practices that range from podcasting to online romantic breakups. Hanging Out, Messing Around, and Geeking Out, first published in 2009, has become a foundational text in the field of digital media and learning. Reporting on an ambitious three-year ethnographic investigation into how young people live and learn with new media in varied settingsā€”at home, in after-school programs, and in online spacesā€”it presents a flexible and useful framework for understanding the ways that young people engage with and through online platforms: hanging out, messing around, and geeking out, otherwise known as HOMAGO. Integrating twenty-three case studiesā€”which include Harry Potter podcasting, video-game playing, music sharing, and online romantic breakupsā€”in a unique collaborative authorship style, Hanging Out, Messing Around, and Geeking Out combines in-depth descriptions of specific group dynamics with conceptual analysis. Since its original publication, digital learning labs in libraries and museums around the country have been designed around the HOMAGO mode and educators have created HOMAGO guidebooks and toolkits. This tenth-anniversary edition features a new introduction by Mizuko Ito and Heather Horst that discusses how digital youth culture evolved in the intervening decade, and looks at how HOMAGO has been put into practice. This book was written as a collaborative effort by members of the Digital Youth Project, a three-year research effort funded by the John D. and Catherine T. MacArthur Foundation and conducted at the University of California, Berkeley, and the University of Southern California

    SARS-like WIV1-CoV poised for human emergence

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    The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome (MERS)-CoV highlights the continued risk of cross-species transmission leading to epidemic disease. This manuscript describes efforts to extend surveillance beyond sequence analysis, constructing chimeric and full-length zoonotic coronaviruses to evaluate emergence potential. Focusing on SARS-like virus sequences isolated from Chinese horseshoe bats, the results indicate a significant threat posed by WIV1-CoV. Both full-length and chimeric WIV1-CoV readily replicated efficiently in human airway cultures and in vivo, suggesting capability of direct transmission to humans. In addition, while monoclonal antibody treatments prove effective, the SARS-based vaccine approach failed to confer protection. Together, the study indicates an ongoing threat posed by WIV1-related viruses and the need for continued study and surveillance

    Use of conventional and alternative treatment strategies for a case of low back pain in a F/A-18 aviator

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    BACKGROUND: Low back pain can diminish jet pilot concentration and function during flight and be severe enough to ground pilots or cause decreased flying time. The objective of this case report is to present an example of the integration of chiropractic care with conventional treatments for the management of low back pain in a F/A-18 aviator. CASE PRESENTATION: The patient had insidious severe low back pain without radiation or neurological deficit, resulting in 24 hours of hospitalization. Spinal degeneration was discovered upon imaging. Four months later, it still took up to 10 minutes for him to get out of bed and several minutes to exit the jet due to stiffness and pain. He had discontinued his regular Marine Corps fitness training due to pain avoidance. Pain severity ranged from 1.5ā€“7.1 cm on a visual analog scale. His Roland Morris Disability Questionnaire score was 5 out of 24. The pilot's pain was managed with the coordinated efforts of the flight surgeon, physiatrist, physical therapist, and doctor of chiropractic. Following this regimen he had no pain and no functional disability; he was able to fly multiple training missions per week and exercise to Marine Corps standards. CONCLUSION: A course of care integrating flight medicine, chiropractic, physical therapy, and physiatry appeared to alleviate pain and restore function to this F/A-18 aviator with low back pain

    Supporting good practice in the provision of services to people with comorbid mental health and alcohol and other drug problems in Australia: describing key elements of good service models

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    <p>Abstract</p> <p>Background</p> <p>The co-occurrence of mental illness and substance use problems (referred to as "comorbidity" in this paper) is common, and is often reported by service providers as the expectation rather than the exception. Despite this, many different treatment service models are being used in the alcohol and other drugs (AOD) and mental health (MH) sectors to treat this complex client group. While there is abundant literature in the area of comorbidity treatment, no agreed overarching framework to describe the range of service delivery models is apparent internationally or at the national level. The aims of the current research were to identify and describe elements of good practice in current service models of treatment of comorbidity in Australia. The focus of the research was on models of service delivery. The research did not aim to measure the client outcomes achieved by individual treatment services, but sought to identify elements of good practice in services.</p> <p>Methods</p> <p>Australian treatment services were identified to take part in the study through a process of expert consultation. The intent was to look for similarities in the delivery models being implemented across a diverse set of services that were perceived to be providing good quality treatment for people with comorbidity problems.</p> <p>Results</p> <p>A survey was designed based on a concept map of service delivery devised from a literature review. Seventeen Australian treatment services participated in the survey, which explored the context in which services operate, inputs such as organisational philosophy and service structure, policies and procedures that guide the way in which treatment is delivered by the service, practices that reflect the way treatment is provided to clients, and client impacts.</p> <p>Conclusions</p> <p>The treatment of people with comorbidity of mental health and substance use disorders presents complex problems that require strong but flexible service models. While the treatment services included in this study reflected the diversity of settings and approaches described in the literature, the research found that they shared a range of common characteristics. These referred to: service linkages; workforce; policies, procedures and practices; and treatment.</p
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