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Health professions educators have the opportunity and responsibility to teach and stimulate scientific knowledge and curiosity in a context that eliminates bias towards minoritized communities and informs emerging understanding of race in research and healthcare. Through the key elements of curiosity, humility, and accountability, the authors propose methods to change the narrative that may otherwise perpetuate biases and inappropriate presentations of race as purely biological rather than a social construct. The evolution of scientific discovery has brought to question our understanding and teaching of race in health, clinical decision-making, and health outcomes. Through case presentations, the authors invite the reader to reflect on their teaching materials and apply methods to 1) decrease bias in case presentations and 2) explain racial health disparities in the context of longstanding structural racism. A Q&A section will draw on resources to advance health equity in health professions education.

Objectives: We investigated whether a Mediterranean-style diet (MedDiet) supplemented with fish oil can improve mental health in adults suffering depression. Methods: Adults with self-reported depression were randomized to receive fortnightly food hampers and MedDiet cooking workshops for 3 months and fish oil supplements for 6 months, or attend social groups fortnightly for 3 months. Assessments at baseline, 3 and 6 months included mental health, quality of life (QoL) and dietary questionnaires, and blood samples for erythrocyte fatty acid analysis. Results: n = 152 eligible adults aged 18–65 were recruited (n = 95 completed 3-month and n = 85 completed 6-month assessments). At 3 months, the MedDiet group had a higher MedDiet score (t = 3.95, P < 0.01), consumed more vegetables (t = 3.95, P < 0.01), fruit (t = 2.10, P = 0.04), nuts (t = 2.29, P = 0.02), legumes (t = 2.41, P = 0.02) wholegrains (t = 2.63, P = 0.01), and vegetable diversity (t = 3.27, P < 0.01); less unhealthy snacks (t = −2.10, P = 0.04) and red meat/chicken (t = −2.13, P = 0.04). The MedDiet group had greater reduction in depression (t = −2.24, P = 0.03) and improved mental health QoL scores (t = 2.10, P = 0.04) at 3 months. Improved diet and mental health were sustained at 6 months. Reduced depression was correlated with an increased MedDiet score (r = −0.298, P = 0.01), nuts (r = −0.264, P = 0.01), and vegetable diversity (r = −0.303, P = 0.01). Other mental health improvements had similar correlations, most notably for increased vegetable diversity and legumes. There were some correlations between increased omega-3, decreased omega-6 and improved mental health. Discussion: This is one of the first randomized controlled trials to show that healthy dietary changes are achievable and, supplemented with fish oil, can improve mental health in people with depression. Refereed/Peer-reviewed

PURPOSE: To explore how early meaningful experiential learning in community settings impacted medical students’ application of systems thinking, their perceptions of systems navigation, and their professional identity as health system change agents. METHODS: Following an immersive Health Systems Science course, first-year medical students partnered with veterans or newly arrived refugee families and served as health system patient navigators embedded within primary care teams for a year. Across two cohorts, fifty-six students participated in the elective. Three voluntary focus groups were conducted each year for a total of six groups with 50 patient navigator students. Inductive content analysis of focus group transcripts was conducted. RESULTS: Qualitative analysis produced three major themes: program impact on students, student impact on patients, and student perceptions of the role of healthcare providers. Students reported a rich understanding of social determinants of health. By improving patient awareness of health and well-being, building capacity to understand medical issues, and increasing medication adherence through teaching, students recognized their impact on patient care. The importance of interprofessional collaboration with social workers also emerged and helped shape students’ understanding of how they as physicians are part of a coordinated team working toward better patient care. CONCLUSION: The Case Western Reserve University WR2 curriculum teaches students how to address complex determinants of health and how to consider their role in dynamic health systems. This study highlights rich themes that emerged from students as they recognized the context that creates health for both individuals and communities. It underscores the role of such experiences in reinforcing systems thinking and development of change agency, both contributing to their professional identity formation as physicians.

BACKGROUND: In our effort to increase the value and academic standing of teaching, we implemented an initiative focused on scholarship in teaching. Our program was narrowly focused, project-based, peer-reviewed, resource-neutral, and open to all faculty. Faculty members are invited annually to submit a description of their educational projects in keeping with Glassick’s criteria. Our purpose was to assess the effects of this award program. METHOD: We reviewed the distribution of applications over a 3-year period and determined the academic departments, academic rank of applicants, and focus of projects. A questionnaire assessed applicants’ perceptions of the value of participation, its contribution to promotion and advancement, and its role in subsequent dissemination activities. RESULTS: Slightly fewer than half (60 of 124, 48%) of the applications submitted during 2016 through 2018 were judged by peer review to meet Glassick’s criteria for scholarship and received the award. Most applicants were junior faculty, and most applications were from the department of medicine though all departments who taught students in core clinical rotations were represented during the years studied. The projects that were awarded were more likely to be disseminated when compared with those who were not awarded. LESSONS LEARNED: Our scholarship in teaching program seemingly advanced educational scholarship among teaching faculty and provided a way of recognizing projects that advanced educational initiatives. Further efforts are required to promote support from departmental leadership, to enhance faculty participation, and to encourage success through mentoring and assistance in project preparation.

The Master Adaptive Learner (MAL) theoretical framework describes an integrated approach to learning that combines features of educational theory on self-regulated learning and aspects of quality improvement. In order to develop MAL students, it is important to pay attention to the learning environment.To describe educators' perspectives about theThematic analysis of reports by medical educators who were workshop participants at a national presentation on creating effective learning environment to develop MAL in undergraduate medical education.Three themes educators considered important in the development of the Master Adaptive Learner were Adaptive Educator, Support for Learning, and Institutional Commitment. These findings suggest that in order to support the MAL, an educational setting should provide faculty who can be flexible and adapt to the developing MAL, learning experiences that support active learning, focused on groups as well as developing individual learners. Leaders in the educational setting should demonstrate a commitment to creating a culture to support learning and provide appropriate resources to that end.Learning environments to develop master adaptive learners need to have adaptive educators, teaching, learning, and institutional culture to support challenge and grow Master Adaptive Learners.

Epithelial ovarian cancer (EOC) is most frequently diagnosed at an advanced stage, and is characterized by its high recurrence rate and almost-universal acquisition of chemoresistance. Metastasis of EOC is driven by heterogenous spheroids that passively disseminate throughout the peritoneal cavity, promoting tumor spread and recurrence. We previously identified a sub-population of highly motile and invasive “Leader cells” (LCs) that express the basal epithelial protein KRT14 as an absolute determinant of invasive potential. We demonstrated KRT14 knockout in EOC cells does not impact viability or proliferation, however completely ablates their ability to invade through Matrigel in 2D and 3D format in vitro. Although a role for LCs in mesothelial clearance and invasion has been established, these mechanisms remain poorly understood. Here we show a critical role for KRT14+ LCs in immunosuppression and tumor-immune privilege in vivo. In the ID8 syngeneic EOC mouse model, tumor-specific LC (KRT14) loss (LCKO) impaired ovarian intrabursal primary tumor engraftment and subsequent metastatic spread. Immune phenotyping by flow cytometry revealed that mice bearing LCKO tumors displayed decreased proportions of immunosuppressive tumor-adjacent Tregs and M2 macrophages, and improved CD8+ T-cell/Treg ratios. Conversely, forced LC-overexpression (LCOE) in EOC tumors accelerated metastasis, and promoted tumor-immune evasion via upregulated secretion of suppressive chemokines including CCL22 and CCL5. In addition to their critical role in migration and invasion, the current study provides in vivo evidence that leader cells are mediators of immune suppression in ovarian cancer. This work supports the basis that defining novel strategies to target LCs to promote anti-tumor immunity and limit metastatic progression may be a useful strategy for improved epithelial ovarian cancer therapy. Citation Format: Amy L. Wilson, Brittany R. Doran, Bashirah Basri, Laura R. Moffitt, Magdalena Plebanski, Andrew N. Stephens, Maree Bilandzic. Leader cells mediate tumor engraftment and promote immunosuppression to drive ovarian cancer progression in vivo [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B040.

Background Leader cells are a subset of cancer cells that coordinate the complex cell-cell and cell-matrix interactions required for ovarian cancer migration, invasion, tumour deposition and are negatively associated with progression-free survival and response to therapy. Emerging evidence suggests leader cells may be enriched in response to chemotherapy, underlying disease recurrence following treatment. Methods CRISPR was used to insert a bicistronic T2A-GFP cassette under the native KRT14 (leader cell) promoter. 2D and 3D drug screens were completed in the presence of chemotherapies used in ovarian cancer management. Leader cell; proliferative (Ki67); and apoptotic status (Cleaved Caspase 3) were defined by live cell imaging and flow cytometry. Quantitative real-time PCR defined “stemness” profiles. Proliferation was assessed on the xCELLigence real time cell analyser. Statistical Analysis was performed using unpaired non-parametric t-tests or one-way ANOVA and Tukey’s multiple comparison post hoc. Results Leader cells represent a transcriptionally plastic subpopulation of ovarian cancer cells that arise independently of cell division or DNA replication, and exhibit a “stemness” profile that does not correlate with epithelial-to-mesenchymal transition. Chemotherapeutics increased apoptosis-resistant leader cells in vitro, who retained motility and expressed known chemo-resistance markers including ALDH1, Twist and CD44v6. Functional impairment of leader cells restored chemosensitivity, with leader cell-deficient lines failing to recover following chemotherapeutic intervention. Conclusions Our data demonstrate that ovarian cancer leader cells are resistant to a diverse array of chemotherapeutic agents, and are likely to play a critical role in the recurrence of chemo-resistant disease as drivers of poor treatment outcomes.

The purpose of this study was to compare the effectiveness and qualitative experience of learning gross anatomy of the pelvis and perineum (P/P) and musculoskeletal system (MSK) via cadaveric dissection to learning these same anatomical regions using the Anatomage table. The Anatomage table is an anatomical visualization system that projects male and female gross anatomical structures from human cadavers onto a life-sized touchscreen table. A crossover design was implemented. Four volunteer dissection groups, consisting of four students each, were randomly assigned to dissect P/P on the Anatomage table and MSK (upper and lower limb) not on the cadaver lab or vice versa. Participating students completed surveys before and after each lab, formative quizzes following each lab, and summative final practical exams on both the Anatomage table and in the cadaver lab. Results indicated that when studying on the Anatomage table, students were more excited before and after labs and perceived a greater degree of learning. The groups did not demonstrate a significant difference in P/P knowledge based on quiz results; however, the Anatomage group had a significantly higher mean score on quizzes in MSK anatomy. Finally, the practical exam results suggest that for some anatomical regions, students may perform similarly regardless of the modality on which they were instructed.

Illness scripts describe the mental model used by experienced clinicians to store and recall condition-specific knowledge when making clinical decisions. Studies demonstrate that novice clinicians struggle to develop and apply strong illness scripts. We developed the Integrated Illness Script and Mechanism of Disease (IIS-MOD) map framework to address this challenge.

Simple Summary The role of immunity in the development and progression of epithelial ovarian cancer (EOC) is well established. Poor T-cell infiltration is associated with mortality in EOC patients, and recent evidence has suggested that the enzyme DPP4 plays a role in this process. The aim of our study was to evaluate the potential of the clinically-approved DPP4-inhibitor sitagliptin to improve immune responses in mice with EOC. We showed that sitagliptin improved CD8+ T-cell responses in an EOC mouse model, consequently reducing metastatic burden and prolonging survival. These data provide a rationale for the use of DPP4-inhibitors as a second-line treatment for EOC. Abstract Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival.

The treatment of ovarian cancer has not significantly changed in decades and it remains one of the most lethal malignancies in women. The serine protease dipeptidyl peptidase 4 (DPP4) plays key roles in metabolism and immunity, and its expression has been associated with either pro- or anti-tumour effects in multiple tumour types. In this study, we provide the first evidence that DPP4 expression and enzyme activity are uncoupled under hypoxic conditions in ovarian cancer cells. Whilst we identified strong up-regulation of DPP4 mRNA expression under hypoxic growth, the specific activity of secreted DPP4 was paradoxically decreased. Further investigation revealed matrix metalloproteinases (MMP)-dependent inactivation and proteolytic shedding of DPP4 from the cell surface, mediated by at least MMP10 and MMP13. This is the first report of uncoupled DPP4 expression and activity in ovarian cancer cells, and suggests a previously unrecognized, cell- and tissue-type-dependent mechanism for the regulation of DPP4 in solid tumours. Further studies are necessary to identify the functional consequences of DPP4 processing and its potential prognostic or therapeutic value.

Purpose: Problem-based learning (PBL) is an instructional method widely used by medical educators that promotes an environment in which students effectively learn the foundational knowledge and ski...

Background/objectives: Major depression has a negative impact on quality of life, increasing the risk of premature death. It imposes social and economic costs on individuals, families and society. Mental illness is now the leading cause globally of disability/lost quality life and premature mortality. Finding cost-effective treatments for depression is a public health priority. We report an economic evaluation of a dietary intervention for treating major depression. Methods: This economic evaluation drew on the HELFIMED RCT, a 3-month group-based Mediterranean-style diet (MedDiet) intervention (including cooking workshops), against a social group-program for people with major depression. We conducted (i) a cost-utility analysis, utility scores measured at baseline, 3-months and 6-months using the AQoL8D, modelled to 2 years (base case); (ii) a cost-effectiveness analysis, differential cost/case of depression resolved (to normal/mild) measured by the DASS. Differential program costs were calculated from resources use costed in AUD2017. QALYs were discounted at 3.5%pa. Results: Best estimate differential cost/QALY gain per person, MedDiet relative to social group was AUD2775. Probabilistic sensitivity analysis, varying costs, utility gain, model period found 95% likelihood cost/QALY less than AUD20,000. Estimated cost per additional case of depression resolved, MedDiet group relative to social group was AUD2,225. Conclusions: A MedDiet group-program for treating major depression was highly cost-effective relative to a social group-program, measured in terms of cost/QALY gain and cost per case of major depression resolved. Supporting access by persons with major depression to group-based dietary programs should be a policy priority. A change to funding will be needed to realise the potential benefits. Refereed/Peer-reviewed

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

Introduction LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. Methods This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD. Primary endpoints were the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA). Other motor and non-motor data were also assessed. The Mann-Whitney U Test was utilized to compare LRRK2 G2019S carriers with PD (LRRK2+) with non-carrier PD controls who were matched for age, gender, education, and PD duration. Survival analyses and log rank tests were utilized to compare interval from onset of PD to development of motor and non-motor complications. Results We screened 251 subjects and 231 completed the study, of whom 9 were LRRK2+, including 7 AJ subjects. 22.73% of AJ subjects with a family history of PD (FH) and 12.96% of AJ subjects without a FH were LRRK2+. There were no significant differences between the 9 LRRK2+ subjects and 19 matched PD controls in MDS-UPDRS, MoCA, or other motor and non-motor endpoints. Conclusion Prevalence of the LRRK2 G2019S mutation in AJ and non-AJ subjects in our study population in Cleveland, Ohio was comparable to other clinical studies. There were no significant motor or non-motor differences between LRRK2+ PD and matched PD controls.

The Negative Binomial Distribution (NBD) is a model that describes consumer purchase frequency over time. This paper tests the applicability of this model to a novel context: physical activity behaviours (using data obtained from Australia, the United States, and Singapore). The fit of the NBD to the data demonstrates that physical activity behaviour is consistent with other consumer behaviour patterns. Within a one-week period, the majority of people are either non- or light-engagers of the different intensities of leisure-time physical activity. Yet, people are not 'active' or 'inactive', rather, degree of engagement varies. Infrequency of reported levels and variety of physical activities might be due to health promotion having a strong focus on rational persuasion and less focus on mass communication that builds mental availability. Our contribution broadens the applicability of the NBD showing it can be helpful for those seeking to promote health behaviours, not just purchases. Refereed/Peer-reviewed

Dear Editor We thank Gordon et al. (2020) for their thoughtful comments on our paper and read with great interest the McManus et al. (2020) article describing the MedDifs study of UK medical school...

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, caused by the degeneration of the dopaminergic neurons in the substantia nigra. Mutations in PARK7 (DJ-1) result in early onset autosomal recessive PD, and oxidative modification of DJ-1 has been reported to regulate the protective activity of DJ-1 in vitro. Glutathionylation is a prevalent redox modification of proteins resulting from the disulfide adduction of the glutathione moiety to a reactive cysteine-SH, and glutathionylation of specific proteins has been implicated in regulation of cell viability. Glutaredoxin 1 (Grx1) is the principal deglutathionylating enzyme within cells, and it has been reported to mediate protection of dopaminergic neurons in Caenorhabditis elegans; however many of the functional downstream targets of Grx1 in vivo remain unknown. Previously, DJ-1 protein content was shown to decrease concomitantly with diminution of Grx1 protein content in cell culture of model neurons (SH-SY5Y and Neuro-2A lines). In the current study we aimed to investigate the regulation of DJ-1 by Grx1 in vivo and characterize its glutathionylation in vitro. Here, with Grx(-/-) mice we provide show that Grx1 regulates protein levels of DJ-1 in vivo. Furthermore, with model neuronal cells (SH-SY5Y) we observed decreased DJ-1 protein content in response to treatment with known glutathionylating agents, and with isolated DJ-1 we identified two distinct sites of glutathionylation. Finally, we found that overexpression of DJ-1 in the dopaminergic neurons partly compensates for the loss of the Grx1 homologue in a C. elegans in vivo model of PD. Therefore, our results reveal a novel redox modification of DJ-1 and suggest a novel regulatory mechanism for DJ-1 content in vivo.

The assumption in the literature that the transition to tertiary studies occurs within the first year has not been tested. This study investigates the timing of the transition by comparing the experiences of domestic students from rural (n = 7) and urban (n = 8) secondary schools, using an ecological framework. Semi-structured interviews of students' experiences revealed that the timing of the transition period can extend beyond the initial transition year, particularly for urban students who experience less immediate changes to social networks. Research and support for students in transition needs to consider more than just the first year of studies to increase student satisfaction, reduce attrition rates and improve educational outcomes. Refereed/Peer-reviewed

Ovarian cancer is the most lethal gynecological malignancy and treatment options have not improved in decades. Whilst ovarian tumors have an immune-mediated component, emerging immunotherapies (e.g. anti-PD-1, anti-PD-L1) have failed to achieve robust clinical response for ovarian cancer patients. There is an urgent need to develop new therapeutic strategies to improve survival rates in women, particularly those with recurrent, chemoresistant disease. In an ongoing study we are investigating the repurposing of sitagliptin, an anti-diabetes drug, as a novel immunomodulatory therapy in ovarian cancer. Ovarian tumors were generated in C57BL/6 wild-type mice by intrabursal implantation of ID8 murine ovarian cancer cells. Following the formation of primary tumors (~2 weeks), mice received a daily oral dose of sitagliptin (50mg/kg) until ethical endpoint. Anti-tumor immune responses were examined by flow cytometry and immunohistochemical staining according to tumor stage. Mice were assessed for overall survival compared to paclitaxel chemotherapy as standard-of-care. Daily sitagliptin treatment increased circulating Teff:Treg cell ratios in the blood, peritoneal fluid and tumor tissue at an early stage, and this was sustained throughout disease. Sitagliptin also enhanced T effector cell activation and proliferation, indicating that increased Teff:Treg ratios were a positive indicator of the anti-tumor immune response. Treatment with sitagliptin alone increased median survival time by 27% compared to both untreated controls and paclitaxel as standard-of-care, suggesting a beneficial effect mediated by anti-tumor immune responses. Of particular interest, sitagliptin treatment specifically increased the percentage of CXCR3+ T effector cells in the peritoneal cavity. Recent data has suggested that CXCR3+ T cells are functionally required for immune checkpoint inhibitors to exert efficacy. Thus, we hypothesize that sitagliptin may enhance the efficacy of immune checkpoint inhibitor therapies in ovarian cancers. Our ongoing studies are investigating the combination of sitagliptin with anti-PD-1 and anti-PD-L1 antibodies, as a rational approach to improving their efficacy in ovarian cancers. These studies will identify a clinically relevant and directly translatable approach to improve prognosis for ovarian cancer patients. Citation Format: Laura R. Moffitt, Amy L. Wilson, Bashirah Basri, Kirsty L. Wilson, Magdalena Plebanski, Andrew N. Stephens. Synergistic action of sitagliptin and checkpoint inhibition for ovarian cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5547.

Ovarian cancers are the most lethal gynecologic malignancy, with high levels of relapse and acquired chemoresistance. Immunity clearly plays a role in ovarian tumor growth, but the inability to accurately correlate progression with stage-specific changes in immunity—both over time and in response to therapy—has hampered our understanding of antitumor immune responses. There is a clear need for improved methods to accurately model and monitor ovarian cancer progression and study its interplay with immunity in vivo. We have generated and characterized an ovarian cancer mouse model allowing noninvasive, real-time tumor imaging with stage-specific tracking of progression over time. Using CRISPR, we integrated the near infra-red phytochrome iRFP720 into the ROSA26 locus of ID8 mouse ovarian cancer cells, and intrabursally implanted these into syngeneic C57BL/6 mice. Noninvasive fluorescence imaging was correlated with post-mortem tumor deposition, and immune populations were assessed at each stage to link immune status with disease progression. Finally, we tested whether this model could be used to monitor therapeutic responses in vivo in real time. Fluorescence imaging accurately identified four distinct stages of cancer progression; (i) primary tumor establishment and growth over 3 weeks; (ii) initial dissemination; (iii) development and expansion of multiple metastases; and (iv) end-stage accumulation of peritoneal ascites. These observations were validated post-mortem. Weight and circumference increase, the standard parameters for tumor burden, did not occur until extensive disease dissemination (week 8), demonstrating their inadequacy for early tumor monitoring. There were no significant differences in immune populations between wild-type and iRFP+ tumor-bearing mice by flow cytometry, indicating iRFP expression by itself does not alter immune profiles. Tumor progression, by contrast, was clearly correlated with decreased frequencies of T-helper 1 (Th1) cells, increased Th2 cells, and a stage-specific decrease in Teff:Treg cell ratios in the peritoneal cavity. Treatment with paclitaxel reduced the tumor volume detected by fluorescence, with tumor recurrence over time. Moreover, paclitaxel depleted peritoneal CD8+ Teff cells, dendritic cells and Th1 cells. Our data demonstrate the effective use of noninvasive fluorescence imaging to discretely stage and quantify ovarian tumor progression, and to correlate therapeutic responses in real time. Moreover, the model mimics the progression of human disease, despite lacking genetic equivalence to human ovarian cancer, and hence has utility for the stage-specific analysis of immune-mediated function. Citation Format: Amy L. Wilson, Kirsty L. Wilson, Maree Bilandzic, Laura R. Moffitt, Magdalena Plebanski, Andrew N. Stephens. Noninvasive tumor tracking and characterization of stage-specific immunity in a syngeneic mouse model of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B69.

Ovarian cancers (OCs) are the most lethal gynaecological malignancy, with high levels of relapse and acquired chemo-resistance. Whilst the tumour&ndash, immune nexus controls both cancer progression and regression, the lack of an appropriate system to accurately model tumour stage and immune status has hampered the validation of clinically relevant immunotherapies and therapeutic vaccines to date. To address this need, we stably integrated the near-infrared phytochrome iRFP720 at the ROSA26 genomic locus of ID8 mouse OC cells. Intrabursal ovarian implantation into C57BL/6 mice, followed by regular, non-invasive fluorescence imaging, permitted the direct visualization of tumour mass and distribution over the course of progression. Four distinct phases of tumour growth and dissemination were detectable over time that closely mimicked clinical OC progression. Progression-related changes in immune cells also paralleled typical immune profiles observed in human OCs. Specifically, we observed changes in both the CD8+ T cell effector (Teff):regulatory (Treg) ratio, as well as the dendritic cell (DC)-to-myeloid derived suppressor cell (MDSC) ratio over time across multiple immune cell compartments and in peritoneal ascites. Importantly, iRFP720 expression had no detectible influence over immune profiles. This new model permits non-invasive, longitudinal tumour monitoring whilst preserving host&ndash, tumour immune interactions, and allows for the pre-clinical assessment of immune profiles throughout disease progression as well as the direct visualization of therapeutic responses. This simple fluorescence-based approach provides a useful new tool for the validation of novel immuno-therapeutics against OC.

Background Abnormally sustained immune reactions drive B-cell proliferation in some cases of marginal zone lymphoma but the CD4+ T-cell subsets, which are likely to contribute to the B-cell responses in the tumour microenvironment, are not well characterised and neither has the spatial distribution of the different subsets in involved lymph nodes been investigated. Methods Employing a workflow of multiplex semi-automated immunohistochemistry combined with image processing we investigated association between infiltrating T-cells and proliferating lymphoma B-cells. Results Both total numbers of activating follicular helper (Tfh) cells (defined by high expression of PD1) and suppressive regulatory (Treg) T-cells (defined by FOXP3+ expression) and the Tfh:Treg ratio, assessed over relatively large areas of tissue, varied among cases of marginal zone lymphoma. We determined spatial distribution and demonstrated that PD1hi cells showed significantly more clustering than did FOXP3+. To investigate the association of infiltrating T-cells with lymphoma B-cells we employed Pearson correlation and Morisita-Horn index, statistical measures of interaction. We demonstrated that PD1hi cells were associated with proliferating B-cells and confirmed this by nearest neighbour analysis. Conclusions The unexpected architectural complexity of T-cell infiltration in marginal zone lymphoma, revealed in this study, further supports a key role for Tfh cells in driving proliferation of lymphoma B-cells. We demonstrate the feasibility of digital analysis of spatial architecture of T-cells within marginal zone lymphoma and future studies will be needed to determine the clinical importance of these observations.

It is critical for health professionals to continue to learn and this must be supported by health professions education (HPE). Adaptive expert clinicians are not only expert in their work but have the additional capacity to learn and improve in their practices. The authors review a selective aspect of learning to become an adaptive expert: the capacity to optimally balance routine approaches that maximize efficiency with innovative ones where energy and resources are used to customize actions for novel or difficult situations. Optimal transfer of learning, and hence the design of instruction, differs depending on whether the goal is efficient or innovative practice. However, the task is necessarily further complicated when the aspiration is an adaptive expert practitioner who can fluidly balance innovation with efficiency as the situation requires. Using HPE examples at both the individual and organizational level, the authors explore the instructional implications of learning to shift from efficient to innovative expert functioning, and back. They argue that the efficiency-innovation tension is likely to endure deep into the future and therefore warrants important consideration in HPE.

This paper describes the patterns discovered in fruit and vegetable buying behaviour in the United States and India. Using claimed buying data obtained from online questionnaires, it compares the patterns against those found extensively in consumer goods categories across the world. This study analyses consumer loyalty with Double Jeopardy, consumer sharing with Duplication of Purchase and brand user profiles with Mean Absolute Deviations. The results show the buying behaviour patterns of Double Jeopardy, Duplication of Purchase and that brand user profiles exist within the fruit and vegetable categories. The implications of these findings are: (1) that the size of fruit and vegetable brands are largely determined by how many people buy them and not how loyal those consumers are; (2) fruit and vegetable brands share consumers with one another; and (3) fruit and vegetable brands are not purchased by unique segments of the population. Therefore, in order to increase the number of people buying fruit and vegetable brands, marketers should focus on increasing their mental and physical availability (i.e. the same strategies used for consumer goods brands). Refereed/Peer-reviewed

Background: People with serious mental illness (SMI) have a 25–30 year lower life expectancy than the general population due largely to cardiovascular disease (CVD). Mediterranean diet can reduce CVD risk and repeat events by 30–70%. We conducted a pilot feasibility study (HELFIMED) with people who have SMI residing within a Community Rehabilitation Centre in South Australia, aimed at improving participants’ diets according to Mediterranean diet principles. Methods: During a 3-month intervention, participants were provided with nutrition education, food hampers, and twice-weekly cooking workshops and guided shopping trips. This report presents the results of a mixed method evaluation of the programme using thorough in-depth interviews with participants and support staff (n = 20), contextualized by changes in dietary biomarkers and CVD risk factors. Results: The framework thematic analysis revealed evidence of improvements in participants’ knowledge of and intake of the key elements of a Mediterranean-style diet (fruit and vegetables, olive oil, fish, legumes), reduction in poor nutrition habits (soft drinks, energy drinks, take away meals) and development of independent living skills—culinary skills such as food preparation and cooking based on simple recipes,food shopping and budgeting, healthy meal planning and social interaction. These changes were supported by dietary biomarkers, and were associated with reduced CVD risk factors. Conclusions: A Mediterranean diet-based pilot study achieved positive change in dietary behaviours associated with CVD risk for participants with SMI. This supports a need to include dietary education and cooking skills into rehabilitation programmes for people with SMI. Refereed/Peer-reviewed

The Case Western Reserve University School of Medicine medical education curriculum includes a series of supplemental online pharmacology modules (“PharmWeb”) that run concurrently with the standard curriculum to introduce first-year students to fundamental principles of pharmacology. Although this voluntary online pharmacology curriculum correlated with higher test scores during the formal, required portion of pharmacology learning in the curriculum, the utilization among medical students of the PharmWeb resource was low. We hypothesized that improving the design and accessibility of the online curriculum using commercial design principles could promote adoption of this voluntary curriculum. The modules were redesigned with a cleaner interface, and convenience of access to each module was enhanced by adding links to relevant modules within required, formative weekly pharmacology multiple choice questions. We report here an increased use of this optional online introduction to pharmacological principles and increased satisfaction in learning pharmacology that correlates with the design intervention.

Obesity is a major burden on healthcare systems. Simple, cost effective interventions that encourage healthier behaviours are required. The present study evaluated the efficacy of a salience nudge for promoting a change in milk selection from full-cream to low-fat (lower calorie) in the kitchen of a university-based research institute that provided full-cream and low-fat milk free of charge. Milk selection was recorded for 12 weeks (baseline). A sign with the message “Pick me! I am low calorie” was then placed on the low-fat milk and consumption was recorded for a further 12 weeks. During baseline, selection of low-fat milk was greater than selection of full-cream milk (p = 0.001) with no significant milk-type × time interaction (p = 0.12). During the intervention period overall milk selection was not different from baseline (p = 0.22), with low-fat milk consumption remaining greater than full-cream milk selection (p &lt, 0.001) and no significant milk-type × time interaction (p = 0.41). However, sub-analysis of the first two weeks of the intervention period indicated an increase in selection of both milk types (p = 0.03), but with a greater increase in low-fat milk selection (p = 0.01, milk-type × time interaction). However, milk selection then returned towards baseline during the rest of the intervention period. Thus, in the present setting, salience nudging promoted a transient increase in low-fat milk consumption, but also increased selection of full-cream milk, indicating that nudging was not effective in promoting healthier milk choices.

Problem-based learning (PBL) presents unique challenges to longitudinal disciplines such as pharmacology. A curricular supplement (PharmWeb) was created to increase pharmacology knowledge, increase surface learning/recognition memory, and increase deeper learning/production memory. First-year medical students (162) were presented 14 brief, optional, self-paced, weekly online learning modules. Usage was assessed by module views and quiz completions. Learning gains were assessed via multiple-choice question (MCQ) pre-/post-tests and existing curriculum assessments (National Board of Medical Examiners [NBME] MCQ customized assessment and an essay examination). Most students (92 %) visited PharmWeb; users demonstrated significant learning gains (t(32) = 6.12, p

Purpose For the vast majority of ovarian cancer patients, optimal surgical debulking remains a key prognostic factor associated with improved survival. A standardized, biomarker-based test, to preoperatively discriminate benign from malignant disease and inform appropriate patient triage, is highly desirable. However, no fit-for-purpose biomarkers have yet been identified. Experimental design We conducted a pilot study consisting of 40 patient urine samples (20 from each group), using label-free quantitative (LFQ) mass spectrometry, to identify potential biomarker candidates in urine from individual ovarian cancer patients. To validate these changes, we used parallel reaction monitoring (PRM) to investigate their abundance in an independent validation cohort (n = 20) of patient urine samples. Results LFQ analyses identified 4394 proteins (17 027 peptides) in a discovery set of 20 urine samples. Twenty-three proteins were significantly elevated in the malignant patient group compared to patients with benign disease. Several proteins, including LYPD1, LYVE1, PTMA, and SCGB1A1 were confirmed to be enriched in the urine of ovarian cancer patients using PRM. We also identified the established ovarian cancer biomarkers WFDC2 (HE4) and mesothelin (MSLN), validating our approach. Conclusions and clinical relevance This is the first application of a LFQ-PRM workflow to identify and validate ovarian cancer-specific biomarkers in patient urine samples.

Background/Aims: Poor diets are an independent risk factor for depression while healthy diets are protective. Traditional Mediterranean diets (MedDiet) are associated with reduced cardiovascular disease risk which overlaps with depression. We investigated whether MedDiet can improve mental health. Methods: A total of 163 adults aged 18-65 with self-reported depression participated in a randomised controlled trial (RCT) providing nutrition education and fortnightly food hampers and cooking workshops for 3 months with 6 months follow-up. The control group attended fortnightly social groups. Participants completed mental health, quality of life (QoL) and dietary questionnaires. Data were analysed using linear mixed modelling and Pearson correlations. Results: In comparison to the control group at 3 months the treatment group had a higher MedDiet score (t = 4.27, p < 0.001), consumed more vegetables (t = 3.95, p < 0.001), fruit (t = 2.11, p = 0.037), nuts (t = 2.43, p = 0.016), wholegrains (t = 2.39, p = 0.018) and legumes (t = 2.45, p = 0.016), greater diversity of vegetables (t = 3.46, p = 0.001) and fruit (t = 2.08, p = 0.040) and less unhealthy snacks (t = -2.20, p = 0.030) and red meat/chicken (t = -2.25, p = 0.026). The treatment group had reduced depression scores (t = -2.02, p = 0.045), and higher mental health QoL scores (t = 2.17, p = 0.032). Reduced depression scores were correlated with increased MedDiet (r = -0.275, p = 0.006), consumption of nuts (r = -0.251, p = 0.011), legumes (r = -0.233, p = 0.018), and greater diversity of vegetables (r = -0.284, p = 0.004). Similar correlations were seen with other mental health and QoL improvements, particularly for legumes and diversity of vegetables and fruit. All changes were sustained at 6 months. Conclusions: This is one of the first RCTs to show a benefit of diet for mental health.

Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic neurons. Although the etiology of PD remains incompletely understood, oxidative stress has been implicated as an important contributor in the development of PD. Oxidative stress can lead to oxidation and functional perturbation of proteins critical to neuronal survival. Glutaredoxin 1 (Grx1) is an evolutionally conserved antioxidant enzyme that repairs protein oxidation by reversing the oxidative modification of cysteine known as S-glutathionylation. We aimed to explore the regulatory role of Grx1 in PD. We first examined the levels of Grx1 in postmortem midbrain samples from PD patients, and observed that Grx1 content is decreased in PD, specifically within the dopaminergic neurons. We subsequently investigated the potential role of Grx1 deficiency in PD pathogenesis by examining the consequences of loss of the Caenorhabditis elegans Grx1 homolog in well-established worm models of familial PD caused by overexpression of pathogenic human LRRK2 mutants G2019S or R1441C. We found that loss of the Grx1 homolog led to significant exacerbation of the neurodegenerative phenotype in C. elegans overexpressing the human LRRK2 mutants. Re-expression in the dopaminergic neurons of the active, but not a catalytically inactive form of the Grx1 homolog rescued the exacerbated phenotype. Loss of the Grx1 homolog also exacerbated the neurodegenerative phenotype in other C. elegans models, including overexpression of human α-synuclein and overexpression of tyrosine hydroxylase (a model of sporadic PD). Therefore, our results reveal a novel neuroprotective role of glutaredoxin against dopaminergic neurodegeneration in models of familial and sporadic PD.

Background: Modern diets, characterised by excess consumption of processed foods, are accompanied by an epidemic of chronic diseases. Cardiovascular disease and depression carry a large burden of disease and often occur together. Poor dietary patterns have been identified as an independent risk factor for depression while healthy diets with minimally processed food are protective. Traditional Mediterranean diets have been shown to reduce risk of cardiovascular disease; however there is a need for clinical trials in people with depression. This paper reports the study protocol of a Mediterranean-style diet intervention conducted in adults with self-reported depression. Methods/design: HELFIMED is a parallel 6-month randomised controlled trial investigating whether dietary patterns can be improved in people with depressive symptoms and whether healthier diet combined with fish oil supplementation can improve mental and cardiometabolic health and quality of life. Adults aged 18-65 years with self-reported depressive symptoms over the previous two months (N = 163) were block-randomised on age and gender between May 2014 and June 2015 to receive nutrition education, food hampers, fortnightly cooking workshops based on Mediterranean-style dietary principles for 3 months and fish oil supplementation for 6 months, or to attend fortnightly social groups (control group) for 3 months. All participants completed mental health (DASS and PANAS), quality of life, dietary and shopping and budgeting questionnaires and provided anthropometric measurements, blood and urine samples at baseline, 3 and 6 months. Additionally the treatment group attended focus groups at 3 and 6 months. Primary and secondary outcomes will be analysed using linear mixed modelling and correlations will investigate associations between improved health outcomes and subjective/objective measures of improved diet/nutritional status. Discussion: This study will contribute causal evidence to prior observational and longitudinal studies that have shown associations between Mediterranean diet and mental health. The results will inform public health and clinical strategies for treatment of depression and comorbid cardiometabolic risk factors.Trial registration: Australian New Zealand Clinical Trials Register (ACTRN12614000438651). Trial registration date: 23rd April 2014. Refereed/Peer-reviewed

Cardiovascular disease (CVD) is higher in people with mental illness and is associated with a 30 year higher mortality rate in this population. Erythrocyte docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA) (omega-3 index) ≤ 4% is a marker for increased mortality risk from CVD while >8% is protective. Omega-3 polyunsaturated fatty acids are also important for brain function and may ameliorate symptoms of mental illness. We investigated the erythrocyte omega-3 index in people with mental illness. One hundred and thirty adults aged 18-65 years (32.6% male) with schizophrenia (n=14) and depression (n=116) provided blood samples and completed physiological assessments and questionnaires. Both populations had risk factors for metabolic syndrome and CVD. The average omega-3 index was 3.95% (SD=1.06), compared to an estimated 5% in the Australian population. These data indicate an unfavourable omega-3 profile in people with mental illness that could contribute to higher CVD risk. Refereed/Peer-reviewed

High rates of overweight, obesity and chronic disease are partly attributable to an increased prevalence of poor dietary choices, which are in part due to the modern environment being conducive to the development of habitual unhealthy food and beverage choices. Nudging aims to influence habitual behaviors by altering the presentation of options to consumers. This systematic literature review investigated nudging interventions, as attributed by the original authors, and their effectiveness for influencing healthier choices. Eight bibliographic databases from the disciplines of psychology, business and health were searched. Included studies were available in the English language and as full-text peer reviewed publication. Studies used nudging or choice architecture interventions that influenced adult food and beverage choices. The number of papers reporting nudging interventions (as attributed by the authors) was low, with only thirteen articles included in the review (comprising 26 primary studies). All studies fall into 'salience'; and 'priming' - type nudging interventions, which were tested across different adult populations and settings - including laboratories, canteens, cafeterias and restaurants. According to the NHMRC levels of evidence (NHMRC, 2007) only two interventions were of a high level of evidence, and the majority of articles received average or poor quality ratings, as per the Scottish Intercollegiate Guidelines. Combined 'salience' and 'priming' nudges showed consistent positive influence on healthier food and beverage choices. This review had limited ability to determine effectiveness of nudging due to various populations and settings tested and the use and reporting of incomparable outcome measures. This is the first review to synthesize nudging interventions, finding minimal uptake of nudging in the academic literature, and mixed effectiveness of nudging for influencing healthier food and beverage choices. This review is registered with PROSPERO - CRD42013005056. Refereed/Peer-reviewed

Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.

All health care professionals are affected in some way, shape, or form by the continual changes in health care education, delivery, and regulation. As multiple states have now moved forward to implement diagnostic medical sonography licensure, sonographers should be aware of the process by which this occurs as well as the potential outcome of state-by-state licensure. This article will attempt to describe the process of occupational licensure as well as provide an overview of recent legislative activities at the state and federal levels.

Sonography of the breast has become invaluable in the characterization of breast lesions identified on mammography or at physical examination. The ability of sonographers and sonologists to employ critical thinking skills when imaging breast lesions is an important aspect to correctly diagnose and follow breast pathology. The purpose of this article is to delineate this process and provide examples of each sonographic categorization that these masses might present with. With careful attention to what can and should be documented with every breast lesion found by sonography, consistency to clinical and surgical treatment may increase.