Search results for: Tracy Wangechi Maina

Authors: Sukumar Namineni, Tracy O'Connor, Ulrich Kalinke, Percy Knolle, Mathias Heikenwaelder

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The liver is one of the pivotal organs in vertebrate animals, serving a multitude of functions such as metabolism, detoxification and protein synthesis and including a predominant role in innate immunity. The innate immune mechanisms pertaining to liver in controlling viral infections have largely been attributed to the Kupffer cells, the locally resident macrophages. However, all the cells of liver are equipped with innate immune functions including, in particular, the hepatocytes. Hence, our aim in this study was to elucidate the innate immune contribution of hepatocytes in viral clearance using mice lacking Ikkβ specifically in the hepatocytes, termed IkkβΔᴴᵉᵖ mice. Blockade of Ikkβ activation in IkkβΔᴴᵉᵖ mice affects the downstream signaling of canonical NF-κB signaling by preventing the nuclear translocation of NF-κB, an important step required for the initiation of innate immune responses. Interestingly, infection of IkkβΔᴴᵉᵖ mice with lymphocytic choriomeningitis virus (LCMV) led to strongly increased hepatic viral titers – mainly confined in clusters of infected hepatocytes. This was due to reduced interferon stimulated gene (ISG) expression during the onset of infection and a reduced CD8+ T-cell-mediated response. Decreased ISG production correlated with increased liver LCMV protein and LCMV in isolated hepatocytes from IkkβΔᴴᵉᵖ mice. A similar phenotype was found in LCMV-infected mice lacking interferon signaling in hepatocytes (IFNARΔᴴᵉᵖ) suggesting a link between NFkB and interferon signaling in hepatocytes. We also observed a failure of interferon-mediated inhibition of HBV replication in HepaRG cells treated with NF-kB inhibitors corroborating our initial findings with LCMV infections. Collectively, these results clearly highlight a previously unknown and influential role of hepatocytes in the induction of innate immune responses leading to viral clearance during a systemic viral infection with LCMV-WE.

Keywords: CD8+ T cell responses, innate immune mechanisms in the liver, interferon signaling, interferon stimulated genes, NF-kB signaling, viral clearance

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Authors: Faith Maina

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Slender leaf (Crotalaria brevidens and Crotalaria ochroleuca), African indigenous vegetables, are an important source of nutrients, income and traditional medicines in Kenya. However, their production is constrained by poor quality seed, due to lack of standardized agronomic and storage practices. Factors that affect the quality of seed in storage include the duration of storage, seed moisture, temperature, relative humidity, oxygen pressure during storage, diseases, and pests. These factors vary with the type of storage method used. The aim of the study was to investigate the effect of various storage methods on seed quality of slender leaf and recommend the best methods of seed storage to the farmers in Western Kenya. Seeds from various morphotypes of slender leaf that had high germination percentage (90%) were stored in pots, jars, brown paper bags and polythene bags in Kakamega and Siaya. Other seeds were also stored in a freezer at the University of Eldoret. In Kakamega County average room temperature was 23°C and relative humidity was 85% during the storage period of May to July 2006. Between December and February 2006 the average room temperature was 26°C while relative humidity was 80% in the same county. In Siaya County, the average room temperature was 25°C and relative humidity was 80% during storage period of May to July 2006. In the same county, the average temperature was 28°C and relative humidity 65% during the period of December and February 2006. Storage duration was 90 days for each season. Seed viability and vigour, was determined for each storage method. Data obtained from storage experiments was subjected to ANOVA and T-tests using Statistical Analysis Software (SAS). Season of growth and storage methods significantly influenced seed quality in Kakamega and Siaya counties. Seeds from the long rains season had higher seed quality than those grown during the short rains season. Generally, seeds stored in pots, brown paper bags, jars and freezer had higher seed quality than those stored in polythene bags. It was concluded that in order to obtain high-quality seeds farmers should store slender leaf seeds in pots or brown paper bags or plastic jars or freezer.

Keywords: Crotalaria sp, seed, quality, storage

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Authors: David C. Boettiger, Tracy Kuo Lin, Maram Almansour, Mariam M. Hamza, Reem Alsukait, Christopher H. Herbst, Nada Altheyab, Ayman Afghani, Faisal Kattan

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Background The number of people aged greater than 65 years per 100 people aged 20–64 years is expected to almost double in The Kingdom of Saudi Arabia (KSA) between 2020 and 2030. We therefore aimed to quantify the growing non-communicable disease (NCD) burden in KSA between 2020 and 2030, and the impact this will have on the national health budget. Methods Ten priority NCDs were selected: ischemic heart disease, stroke, type 2 diabetes, chronic obstructive pulmonary disease, chronic kidney disease, dementia, depression, osteoarthritis, colorectal cancer, and breast cancer. Age- and sex-specific prevalence was projected for each priority NCD between 2020 and 2030. Treatment coverage rates were applied to the projected prevalence estimates to calculate the number of patients incurring treatment costs for each condition. For each priority NCD, the average cost-of-illness was estimated based on published literature. The impact of changes to our base-case model in terms of assumed disease prevalence, treatment coverage, and costs of care, coming into effect from 2023 onwards, were explored. Results The prevalence estimates for colorectal cancer and stroke were estimated to almost double between 2020 and 2030 (97% and 88% increase, respectively). The only priority NCD prevalence projected to increase by less than 60% between 2020 and 2030 was for depression (22% increase). It is estimated that the total cost of managing priority NCDs in KSA will increase from USD 19.8 billion in 2020 to USD 32.4 billion in 2030 (an increase of USD 12.6 billion or 63%). The largest USD value increases were projected for osteoarthritis (USD 4.3 billion), diabetes (USD 2.4 billion), and dementia (USD 1.9 billion). In scenario analyses, our 2030 projection for the total cost of managing priority NCDs varied between USD 29.2 billion - USD 35.7 billion. Conclusions Managing the growing NCD burden in KSA’s aging population will require substantial healthcare spending increases over the coming years.

Keywords: aging, non communicable disease, costs, Saudi Arabia

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Authors: Amanda J. Burridge, Keith J. Edwards, Paul A. Wilkinson, Tom Batstone, Erik H. Murchie, Lorna McAusland, Ana Elizabete Carmo-Silva, Ivan Jauregui, Tracy Lawson, Silvere R. M. Vialet-Chabrand

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The rate of genetic progress in wheat production must be improved to meet global food security targets. However, past selection for domestication traits has reduced the genetic variation in modern wheat cultivars, a fact that could severely limit the future rate of genetic gain. The genetic variation in agronomically important traits for the wild relatives and progenitors of wheat is far greater than that of the current domesticated cultivars, but transferring these traits into modern cultivars is not straightforward. Between the elite cultivars of wheat, photosynthetic capacity is a key trait for which there is limited variation. Early screening of wheat wild relative and progenitors has shown differences in photosynthetic capacity and efficiency not only between wild relative species but marked differences between the accessions of each species. By identifying wild relative accessions with improved photosynthetic traits and characterising the genetic variation responsible, it is possible to incorporate these traits into advanced breeding programmes by wide crossing and introgression programmes. To identify the potential variety of photosynthetic capacity and efficiency available in the secondary and tertiary genepool, a wide scale survey was carried out for over 600 accessions from 80 species including those from the genus Aegilops, Triticum, Thinopyrum, Elymus, and Secale. Genotype data were generated for each accession using a ‘Wheat Wild Relative’ Single Nucleotide Polymorphism (SNP) genotyping array composed of 35,000 SNP markers polymorphic between wild relatives and elite hexaploid wheat. This genotype data was combined with phenotypic measurements such as gas exchange (CO₂, H₂O), chlorophyll fluorescence, growth, morphology, and RuBisCO activity to identify potential breeding material with enhanced photosynthetic capacity and efficiency. The data and associated analysis tools presented here will prove useful to anyone interested in increasing the genetic diversity in hexaploid wheat or the application of complex genotyping data to plant breeding.

Keywords: wheat, wild relatives, pre-breeding, genomics, photosynthesis

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Authors: Denise Ben-Porath, Tracy Masterson

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In the past, individuals who struggled with and sought treatment for mental health difficulties were stigmatized. However, the current generation holds more open attitudes around mental health issues. Indeed, public figures such as Demi Lovato, Naomi Osaka, and Simone Biles have taken to social media to break the silence around mental health, discussing their own struggles and the benefits of treatment. Thus, there is considerable reason to believe that this generation would hold fewer stigmatizing attitudes toward mental health difficulties and treatment compared to previous ones. In this study, we explored possible changes in stigma on mental health diagnosis and treatment seeking behavior between two generations: Gen Z, the current generation, and Gen X, those born between 1965-1980. It was hypothesized that Gen Z would hold less stigmatizing views on mental illness than Gen X. To examine possible changes in stigma attitudes between these two generations, we conducted a cross-generational cohort design by using the same methodology employed 20 years ago from the Ben-Porath (2002) study. Thus, participants were randomly assigned to read one of the following four case vignettes employed in the Ben-Porath (2002) study: (a) “Tom” who has received psychotherapy due to depression (b) “Tom” who has been depressed but received no psychological help, (c) “Tom” who has received medical treatment due to a back pain, or (d) “Tom” who had a back pain but did not receive medical attention. After reading the vignette, participants rated “Tom” on various personality dimensions using the IFQ Questionnaire and answered questions about their frequency of social media use and willingness to seek mental health treatment on a scale from 1-10. Identical to the results 20 years prior, a significant main effect was found for diagnosis with “Tom” being viewed in more negative terms when he was described as having depression vs. a medical condition (back pain) [F (1, 376) = 126.53, p < .001]. However, in the study conducted 20 years earlier, a significant interaction was found between diagnosis and help-seeking behavior [F (1, 376) = 8.28, p < .005]. Specifically, “Tom” was viewed in the most negative terms when described as depressed and seeking treatment. Alternatively, the current study failed to find a significant interaction between depression and help seeking behavior. These findings suggest that while individuals who hold a mental health diagnosis may still be stigmatized as they were 20 years prior, seeking treatment for mental health issues may be less so. Findings are discussed in the context of social media use and its impact on destigmatization.

Keywords: stigma, mental illness, help-seeking, social media

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Authors: Emily Moore, Dora Amos, Tracy Ellimah, Natasha Parrott

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Postoperative haematoma is a well-recognised complication of thyroid surgery with an incidence of 1-5%. Haematoma formation causes progressive airway obstruction, necessitating emergency bedside haematoma evacuation in up to ¼ of patients. ENT UK, BAETS and DAS have developed consensus guidelines to improve perioperative care, recommending that all healthcare staff interacting with patients undergoing thyroid surgery should be trained in managing post-thyroidectomy haematoma. The aim was to assess the effectiveness of a hybrid simulation model in improving clinician’s confidence in dealing with this surgical emergency. A hybrid simulation was designed, consisting of a standardised patient wearing a part-task trainer to mimic a post-thyroidectomy haematoma in a real patient. The part-task trainer was an adapted C-spine collar with layers of silicone representing the skin and strap muscles and thickened jelly representing the haematoma. Both the skin and strap muscle layers had to be opened in order to evacuate the haematoma. Boxes have been implemented into the appropriate post operative areas (recovery and surgical wards), which contain a printed algorithm designed to assist in remembering a sequence of steps for haematoma evacuation using the ‘SCOOP’ method (skin exposure, cut sutures, open skin, open muscles, pack wound) along with all the necessary equipment to open the front of the neck. Small-group teaching sessions were delivered by ENT and anaesthetic trainees to members of the multidisciplinary team normally involved in perioperative patient care, which included ENT surgeons, anaesthetists, recovery nurses, HCAs and ODPs. The DESATS acronym of signs and symptoms to recognise (difficulty swallowing, EWS score, swelling, anxiety, tachycardia, stridor) was highlighted. Then participants took part in the hybrid simulation in order to practice this ‘SCOOP’ method of haematoma evacuation. Participants were surveyed using a Likert scale to assess their level of confidence pre- and post teaching session. 30 clinicians took part. Confidence (agreed/strongly agreed) in recognition of post thyroidectomy haematoma improved from 58.6% to 96.5%. Confidence in management improved from 27.5% to 89.7%. All participants successfully decompressed the haematoma. All participants agreed/strongly agreed, that the sessions were useful for their learning. Multidisciplinary team simulation teaching is effective at significantly improving confidence in both the recognition and management of postoperative haematoma. Hybrid simulation sessions are useful and should be incorporated into training for clinicians.

Keywords: thyroid surgery, haematoma, teaching, hybrid simulation

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Authors: Keith Diamond, Tracy Collier, Ciara Sterling, Ben Kraal

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The increased frequency and intensity of disaster events in the Asia-Pacific region is likely to require organisations to better understand how their initiatives, and the support they provide to their customers, intersect with other organisations aiming to support communities in achieving disaster resilience. While there is a growing awareness that disaster response and recovery rebuild programmes need to adapt to more integrated, community-led approaches, there is often a discrepancy between how programmes intend to work and how they are collectively experienced in the community, creating undesired effects on community resilience. Following Australia’s North Queensland Monsoon Disaster of 2019, this research set out to understand and evaluate how the service and support ecosystem impacted on the local community’s experience and influenced their ability to respond and recover. The purpose of this initiative was to identify actionable, cross-sector, people-centered improvements that support communities to recover and thrive when faced with disaster. The challenge arose as a group of organisations, including utility providers, banks, insurers, and community organisations, acknowledged that improving their own services would have limited impact on community wellbeing unless the other services people need are also improved and aligned. The research applied human-centred service design methods, typically applied to single products or services, to design a new way to understand a whole-of-community journey. Phase 1 of the research conducted deep contextual interviews with residents and small business owners impacted by the North Queensland Monsoon and qualitative data was analysed to produce community journey maps that detailed how individuals navigated essential services, such as accommodation, finance, health, and community. Phase 2 conducted interviews and focus groups with frontline workers who represented industries that provided essential services to assist the community. Data from Phase 1 and Phase 2 of the research was analysed and combined to generate a systems map that visualised the positive and negative impacts that occurred across the disaster response and recovery service ecosystem. Insights gained from the research has catalysed collective action to address future Australian disaster events. The case study outlines a transformative way for sectors and industries to rethink their corporate social responsibility activities towards a cross-sector partnership model that shares responsibility and approaches disaster response and recovery as a single service that can be designed to meet the needs of communities.

Keywords: corporate social responsibility, cross sector partnerships, disaster resilience, human-centred design, service design, systems change

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Authors: Jade V. Rushby, Tony Loughland, Tracy L. Durksen, Hoa Nguyen, Robert M. Klassen

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This paper reports a study investigating the development and implementation of an online multi-session ‘scenario-based learning’ (SBL) program administered to preservice teachers in Australia. The transition from initial teacher education to the teaching profession can present numerous cognitive and psychological challenges for early career teachers. Therefore, the identification of additional supports, such as scenario-based learning, that can supplement existing teacher education programs may help preservice teachers to feel more confident and prepared for the realities and complexities of teaching. Scenario-based learning is grounded in situated learning theory which holds that learning is most powerful when it is embedded within its authentic context. SBL exposes participants to complex and realistic workplace situations in a supportive environment and has been used extensively to help prepare students in other professions, such as legal and medical education. However, comparatively limited attention has been paid to investigating the effects of SBL in teacher education. In the present study, the SBL intervention provided participants with the opportunity to virtually engage with school-based scenarios, reflect on how they might respond to a series of plausible response options, and receive real-time feedback from experienced educators. The development process involved several stages, including collaboration with experienced educators to determine the scenario content based on ‘critical incidents’ they had encountered during their teaching careers, the establishment of the scoring key, the development of the expert feedback, and an extensive review process to refine the program content. The 4-part SBL program focused on areas that can be challenging in the beginning stages of a teaching career, including managing student behaviour and workload, differentiating the curriculum, and building relationships with colleagues, parents, and the community. Results from prior studies implemented by the research group using a similar 4-part format have shown a statistically significant increase in preservice teachers’ self-efficacy and classroom readiness from the pre-test to the final post-test. In the current research, professional teaching identity - incorporating self-efficacy, motivation, self-image, satisfaction, and commitment to teaching - was measured over six weeks at multiple time points: before, during, and after the 4-part scenario-based learning program. Analyses included latent growth curve modelling to assess the trajectory of change in the outcome variables throughout the intervention. The paper outlines (1) the theoretical underpinnings of SBL, (2) the development of the SBL program and methodology, and (3) the results from the study, including the impact of the SBL program on aspects of participating preservice teachers’ professional identity. The study shows how SBL interventions can be implemented alongside the initial teacher education curriculum to help prepare preservice teachers for the transition from student to teacher.

Keywords: classroom simulations, e-learning, initial teacher education, preservice teachers, professional learning, professional teaching identity, scenario-based learning, teacher development

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Authors: Tracy L. F. Worley

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This presentation explores the environment that has limited leadership opportunities for Black women in cinema and advocates for autonomy among Black women filmmakers that is facilitated by strong internal and external networks and cooperative opportunities. Early images of African Americans in motion pictures were often conceptualized from the viewpoint of a White male director and depicted by White actors. The black film evolved in opposition to this context, leading to a Black film aesthetic. The oppositional context created in response to racist, misogynistic, and sexist representations in motion pictures sets the tone for female filmmakers of every hue – but especially for African American women. For them, the context of a male gaze, and for all intents and purposes, a White male gaze, forces them to create their own aesthetic. Theoretically, men and women, filmmakers and spectators have different perspectives across race, ethnicity, and gender. Two feminist theorists, bell hooks and Mary Ann Doane, suggest that female filmmakers are perceived as disparate from male filmmakers and that women, in general, are defined by what men see. Mary Ann Doane, a White feminist film theorist, has focused extensively on female spectatorship and women (White) in general as the object of the male gaze. Her discussion of the female body, male perception of it, and feminism in the motion picture industry support the suggestion that comprehending the organization and composition of Hollywood is critical to understanding women’s roles in the industry. Although much of her research addresses the silent film era and women’s roles then, Doane suggests that across cinematic periods, the theory assigned to “cinematic apparatus” is formulated within a context of sexuality. Men and women are viewed and treated differently in cinema (in front of and behind the camera), with women’s attractiveness and allure photographed specifically for the benefit of the “spectatorial desire” of the male gaze. Bell Hooks, an African American feminist writer and theorist with more than 30 published books and articles on race, gender, class, and culture in feminism and education, suggests that women can overcome the male gaze by using their “oppositional gaze” to transform reality and establish their own truth. She addresses gender within the context of race by acknowledging the realities faced by African American women and the fact that the feminist movement was never intended to include Black women. A grounded theory study led to the development of a leadership theory that explains why African American women are disproportionately represented in a mainstream motion picture leadership. The study helped to reveal the barriers to entry and illuminated potential strategies that African American female motion picture directors might pursue to reduce this inequity. Using semi-structured interviews as the primary means for data collection, the lived experiences of African American female directors and organizational leadership’s perceived role in the perpetuation of negative female imagery in major motion pictures led to the identification of support strategies for African American female motion picture directors that counter social stereotyping and validate the need for social networking in the mainstream.

Keywords: African American, cinema, directors, filmmaking, leadership, women

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Authors: Zi Y. Kang, Tracy D. Cassidy, Tom Cassidy

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3D apparel CAD is one of the remarkable products in advanced technology which enables intuitive design, visualisation and evaluation of garments through stereoscopic drape simulation. The progressive improvements of 3D apparel CAD have led to the creation of more realistic clothing simulation which is used not only in design development but also in presentation, promotion and communication for fashion as well as other industries such as film, game and social network services. As a result, 3D clothing technology is becoming more ubiquitous in human culture and lives today. This study considers that such phenomenon implies that the technology has reached maturity and it is time to inspect the status of current technology and to explore its potential uses in ways to create cultural values to further move forward. For this reason, this study aims to generate virtual costumes as culturally significant objects using 3D apparel CAD and to assess its capability, applicability and attitudes of the audience towards clothing simulation through comparison with physical counterparts. Since the access to costume collection is often limited due to the conservative issues, the technology may make valuable contribution by democratization of culture and knowledge for museums and its audience. This study is expected to provide foundation knowledge for development of clothing technology and for expanding its boundary of practical uses. To prevent any potential damage, two replicas of the costumes in the 1860s and 1920s at the Museum of London were chosen as samples. Their structural, visual and physical characteristics were measured and collected using patterns, scanned images of fabrics and objective fabric measurements with scale, KES-F (Kawabata Evaluation System of Fabrics) and Titan. Commercial software, DC Suite 5.0 was utilised to create virtual costumes applying collected data and the following outcomes were produced for the evaluation: Images of virtual costumes and video clips showing static and dynamic simulation. Focus groups were arranged with fashion design students and the public for evaluation which exposed the outcomes together with physical samples, fabrics swatches and photographs. The similarities, application and acceptance of virtual costumes were estimated through discussion and a questionnaire. The findings show that the technology has the capability to produce realistic or plausible simulation but expression of some factors such as details and capability of light material requires improvements. While the use of virtual costumes was viewed as more interesting and futuristic replacements to physical objects by the public group, the fashion student group noted more differences in detail and preferred physical garments highlighting the absence of tangibility. However, the advantages and potential of virtual costumes as effective and useful visual references for educational and exhibitory purposes were underlined by both groups. Although 3D apparel CAD has sufficient capacity to assist garment design process, it has limits in identical replication and more study on accurate reproduction of details and drape is needed for its technical improvements. Nevertheless, the virtual costumes in this study demonstrated the possibility of the technology to contribute to cultural and knowledgeable value creation through its applicability and as an interesting way to offer 3D visual information.

Keywords: digital clothing technology, garment simulation, 3D Apparel CAD, virtual costume

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Authors: Lynn Sheridan, Dennis Alonzo, Hoa Nguyen, Andy Gao, Tracy Durksen

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Disruptions to teaching (e.g., COVID-related) have increased work demands for teachers. There is an opportunity for research to explore evidence-informed steps to support teachers. Collective evidence informs data on teachers’ personal attributes (e.g., self-efficacy beliefs) in the workplace are seen to promote success in teaching and support teacher engagement. Teacher engagement plays a role in students’ learning and teachers’ effectiveness. Engaged teachers are better at overcoming work-related stress, burnout and are more likely to take on active roles. Teachers’ commitment is influenced by a host of personal (e.g., teacher well-being) and environmental factors (e.g., job stresses). The job demands-resources model provided a conceptual basis for examining how teachers’ well-being, and is influenced by job demands and job resources. Job demands potentially evoke strain and exceed the employee’s capability to adapt. Job resources entail what the job offers to individual teachers (e.g., organisational support), helping to reduce job demands. The application of the job demands-resources model involves gathering an evidence-base of and connection to personal attributes (job resources). The study explored the association between constructs (resilience, adaptability, commitment, self/collective efficacy) and a teacher’s engagement with the job. The paper sought to elaborate on the model and determine the associations between key constructs of well-being (resilience, adaptability), commitment, and motivation (self and collective-efficacy beliefs) to teachers’ engagement in teaching. Data collection involved online a multi-dimensional instrument using validated items distributed from 2020-2022. The instrument was designed to identify construct relationships. The participant number was 170. Data Analysis: The reliability coefficients, means, standard deviations, skewness, and kurtosis statistics for the six variables were completed. All scales have good reliability coefficients (.72-.96). A confirmatory factor analysis (CFA) and structural equation model (SEM) were performed to provide measurement support and to obtain latent correlations among factors. The final analysis was performed using structural equation modelling. Several fit indices were used to evaluate the model fit, including chi-square statistics and root mean square error of approximation. The CFA and SEM analysis was performed. The correlations of constructs indicated positive correlations exist, with the highest found between teacher engagement and resilience (r=.80) and the lowest between teacher adaptability and collective teacher efficacy (r=.22). Given the associations; we proceeded with CFA. The CFA yielded adequate fit: CFA fit: X (270, 1019) = 1836.79, p < .001, RMSEA = .04, and CFI = .94, TLI = .93 and SRMR = .04. All values were within the threshold values, indicating a good model fit. Results indicate that increasing teacher self-efficacy beliefs will increase a teacher’s level of engagement; that teacher ‘adaptability and resilience are positively associated with self-efficacy beliefs, as are collective teacher efficacy beliefs. Implications for school leaders and school systems: 1. investing in increasing teachers’ sense of efficacy beliefs to manage work demands; 2. leadership approaches can enhance teachers' adaptability and resilience; and 3. a culture of collective efficacy support. Preparing teachers for now and in the future offers an important reminder to policymakers and school leaders on the importance of supporting teachers’ personal attributes when faced with the challenging demands of the job.

Keywords: collective teacher efficacy, teacher self-efficacy, job demands, teacher engagement

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Authors: Katarzyna Lubecka, Kirsty Flower, Megan Beetch, Lucinda Kurzava, Hannah Buvala, Samer Gawrieh, Suthat Liangpunsakul, Tracy Gonzalez, George McCabe, Naga Chalasani, James M. Flanagan, Barbara Stefanska

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Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, is the second leading cause of cancer death worldwide. Late onset of clinical symptoms in HCC results in late diagnosis and poor disease outcome. Approximately 85% of individuals with HCC have underlying liver cirrhosis. However, not all cirrhotic patients develop cancer. Reliable early detection biomarkers that can distinguish cirrhotic patients who will develop cancer from those who will not are urgently needed and could increase the cure rate from 5% to 80%. We used Illumina-450K microarray to test whether blood DNA, an easily accessible source of DNA, bear site-specific changes in DNA methylation in response to HCC before diagnosis with conventional tools (pre-diagnostic). Top 11 differentially methylated sites were selected for validation by pyrosequencing. The diagnostic potential of the 11 pyrosequenced probes was tested in blood samples from a prospective cohort of cirrhotic patients. We identified 971 differentially methylated CpG sites in pre-diagnostic HCC cases as compared with healthy controls (P < 0.05, paired Wilcoxon test, ICC ≥ 0.5). Nearly 76% of differentially methylated CpG sites showed lower levels of methylation in cases vs. controls (P = 2.973E-11, Wilcoxon test). Classification of the CpG sites according to their location relative to CpG islands and transcription start site revealed that those hypomethylated loci are located in regulatory regions important for gene transcription such as CpG island shores, promoters, and 5’UTR at higher frequency than hypermethylated sites. Among 735 CpG sites hypomethylated in cases vs. controls, 482 sites were assigned to gene coding regions whereas 236 hypermethylated sites corresponded to 160 genes. Bioinformatics analysis using GO, KEGG and DAVID knowledgebase indicate that differentially methylated CpG sites are located in genes associated with functions that are essential for gene transcription, cell adhesion, cell migration, and regulation of signal transduction pathways. Taking into account the magnitude of the difference, statistical significance, location, and consistency across the majority of matched pairs case-control, we selected 11 CpG loci corresponding to 10 genes for further validation by pyrosequencing. We established that methylation of CpG sites within 5 out of those 10 genes distinguish cirrhotic patients who subsequently developed HCC from those who stayed cancer free (cirrhotic controls), demonstrating potential as biomarkers of early detection in populations at risk. The best predictive value was detected for CpGs located within BARD1 (AUC=0.70, asymptotic significance ˂0.01). Using an additive logistic regression model, we further showed that 9 CpG loci within those 5 genes, that were covered in pyrosequenced probes, constitute a panel with high diagnostic accuracy (AUC=0.887; 95% CI:0.80-0.98). The panel was able to distinguish pre-diagnostic cases from cirrhotic controls free of cancer with 88% sensitivity at 70% specificity. Using blood as a minimally invasive material and pyrosequencing as a straightforward quantitative method, the established biomarker panel has high potential to be developed into a routine clinical test after validation in larger cohorts. This study was supported by Showalter Trust, American Cancer Society (IRG#14-190-56), and Purdue Center for Cancer Research (P30 CA023168) granted to BS.

Keywords: biomarker, DNA methylation, early detection, hepatocellular carcinoma

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