Inhibition of Aurora B kinase (AURKB) enhances the effectiveness of 5-fluorouracil chemotherapy against colorectal cancer cells.

BACKGROUND: 5-Fluorouracil (5-FU) remains a core component of systemic therapy for colorectal cancer (CRC). However, response rates remain low, and development of therapy resistance is a primary issue. Combinatorial strategies employing a second agent to augment the therapeutic effect of chemotherapy is predicted to reduce the incidence of treatment resistance and increase the durability of response to therapy. METHODS: Here, we employed quantitative proteomics approaches to identify novel druggable proteins and molecular pathways that are deregulated in response to 5-FU, which might serve as targets to improve sensitivity to chemotherapy. Drug combinations were evaluated using 2D and 3D CRC cell line models and an ex vivo culture model of a patient-derived tumour. RESULTS: Quantitative proteomics identified upregulation of the mitosis-associated protein Aurora B (AURKB), within a network of upregulated proteins, in response to a 24 h 5-FU treatment. In CRC cell lines, AURKB inhibition with the dihydrogen phosphate prodrug AZD1152, markedly improved the potency of 5-FU in 2D and 3D in vitro CRC models. Sequential treatment with 5-FU then AZD1152 also enhanced the response of a patient-derived CRC cells to 5-FU in ex vivo cultures. CONCLUSIONS: AURKB inhibition may be a rational approach to augment the effectiveness of 5-FU chemotherapy in CRC.

hSSB1 (NABP2/OBFC2B) modulates the DNA damage and androgen-induced transcriptional response in prostate cancer.

BACKGROUND: Activation and regulation of androgen receptor (AR) signaling and the DNA damage response impact the prostate cancer (PCa) treatment modalities of androgen deprivation therapy (ADT) and radiotherapy. Here, we have evaluated a role for human single-strand binding protein 1 (hSSB1/NABP2) in modulation of the cellular response to androgens and ionizing radiation (IR). hSSB1 has defined roles in transcription and maintenance of genome stability, yet little is known about this protein in PCa. METHODS: We correlated hSSB1 with measures of genomic instability across available PCa cases from The Cancer Genome Atlas (TCGA). Microarray and subsequent pathway and transcription factor enrichment analysis were performed on LNCaP and DU145 prostate cancer cells. RESULTS: Our data demonstrate that hSSB1 expression in PCa correlates with measures of genomic instability including multigene signatures and genomic scars that are reflective of defects in the repair of DNA double-strand breaks via homologous recombination. In response to IR-induced DNA damage, we demonstrate that hSSB1 regulates cellular pathways that control cell cycle progression and the associated checkpoints. In keeping with a role for hSSB1 in transcription, our analysis revealed that hSSB1 negatively modulates p53 and RNA polymerase II transcription in PCa. Of relevance to PCa pathology, our findings highlight a transcriptional role for hSSB1 in regulating the androgen response. We identified that AR function is predicted to be impacted by hSSB1 depletion, whereby this protein is required to modulate AR gene activity in PCa. CONCLUSIONS: Our findings point to a key role for hSSB1 in mediating the cellular response to androgen and DNA damage via modulation of transcription. Exploiting hSSB1 in PCa might yield benefits as a strategy to ensure a durable response to ADT and/or radiotherapy and improved patient outcomes.

Concordance of Diagnosis of Autism Spectrum Disorder Made by Pediatricians vs a Multidisciplinary Specialist Team.

Importance: Wait times for autism spectrum disorder (ASD) diagnosis are lengthy because of inadequate supply of specialist teams. General pediatricians may be able to diagnose some cases of ASD, thereby reducing wait times. Objective: To determine the accuracy of ASD diagnostic assessments conducted by general pediatricians compared with a multidisciplinary team (MDT). Design, Setting, and Participants: This prospective diagnostic study was conducted in and a specialist assessment center in Toronto, Ontario, Canada, and Ontario general pediatrician practices from June 2016 to March 2020. Children were younger than 5.5 years, referred with a developmental concern, and without an existing ASD diagnosis. Data analysis was performed from October 2021 to February 2022. Exposures: The pediatrician and MDT each conducted blinded assessments and recorded a decision as to whether the child had ASD. Main Outcomes and Measures: Main outcomes included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A logistic regression was performed to identify factors associated with accurate pediatrician assessment for children with or without an ASD diagnosis. Results: Seventeen pediatricians (12 women [71%]) participated in the study and referred 106 children (79 boys [75%]; mean [SD] age, 41.9 [13.3] months). Sixty participants (57%) were from minoritized racial and ethnic groups (eg, Black, Asian, Hispanic, Middle Eastern, and multiracial). Seventy-two participants (68%) received a diagnosis of ASD by the MDT. Sensitivity and specificity of the pediatrician assessments compared with MDT were 0.75 (95% CI, 0.67-0.83) and 0.79 (95% CI, 0.62-0.91), respectively. The PPV of the pediatrician assessments was 0.89 (95% CI, 0.80-0.94) (ie, 89% agreement with the MDT), and NPV was 0.60 (95% CI, 0.49-0.70) (ie, 60% agreement with the MDT). Higher pediatrician certainty (odds ratio [OR], 3.33; 95% CI, 1.71-7.34; P = .001) was associated with increased diagnostic accuracy for children with ASD. Lower accuracy was seen for children with higher Visual Reception subscale developmental skills (OR, 0.93; 95% CI, 0.89-0.97; P = .001), speaking abilities (OR, 0.17; 95% CI, 0.03-0.67; P = .03), and White race (OR, 0.32; 95% CI, 0.10-0.97; P = .04). Age, gender, and Autism Diagnostic Observation Schedule, 2nd Edition composite scores were not significantly associated with the accuracy of assessments. All 7 children with a sibling with ASD received an accurate diagnosis; otherwise, no significant factors were identified for accuracy in children without ASD. Conclusions and Relevance: This study of concordance of autism assessment between pediatricians and an expert MDT in young children found high accuracy when general pediatricians felt confident and lower accuracy when ruling out ASD. These findings suggest that children with co-occurring delays may be potential candidates for community assessment.

Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer.

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3high EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.

Being there: A scoping review of grief support training in medical education.

INTRODUCTION: Medical education experts argue that grief support training for physicians would improve physician and patient and family wellness, and should therefore be mandatory. However, there is little evidence about the range of curricula interventions or the impact of grief training. The aim of this scoping review was to describe the current landscape of grief training worldwide in medical school, postgraduate residency and continuing professional development in the disciplines of pediatrics, family medicine and psychiatry. METHODS: Using Arksey and O'Malley's scoping review principles, MEDLINE, EMBASE, ERIC, PsychInfo and Web of Science were searched by a librarian. Two levels of screening took place: a title and abstract review for articles that fit a predefined criteria and a full-text review of articles that met those criteria. Three investigators reviewed the articles and extracted data for analysis. To supplement the search, we also scanned the reference lists of included studies for possible inclusion. RESULTS: Thirty-seven articles published between 1979 and 2019 were analyzed. Most articles described short voluntary grief training workshops. At all training levels, the majority of these workshops focused on transmitting knowledge about the ethical and legal dimensions of death, dying and bereavement in medicine. The grief trainings described were characterized by the use of diverse pedagogical tools, including lectures, debriefing sessions, reflective writing exercises and simulation/role-play. DISCUSSION: Grief training was associated with increased self-assessed knowledge and expertise; however, few of the studies analyzed the impact of grief training on physician and patient and family wellness. Our synthesis of the literature indicates key gaps exist, specifically regarding the limited emphasis on improving physicians' communication skills around death and dying and the limited use of interactive and self-reflexive learning tools. Most trainings also had an overly narrow focus on bereavement grief, rather than a more broadly defined definition of loss.

Family physicians and health advocacy: Is it really a difficult fit?

OBJECTIVE: To examine whether family medicine residents and faculty members appreciate the full spectrum of health advocacy as described in articles published in Canadian Family Physician in 2016 and to identify the perceived challenges and enablers of advocating across the entire spectrum. DESIGN: Analysis of a subset of data from a qualitative study using semistructured interviews and focus groups. SETTING: University of Toronto in Ontario. PARTICIPANTS: A total of 9 family medicine faculty members and 6 family medicine residents. METHODS: A subset of transcripts from a 2015 qualitative study that explored family medicine and psychiatry residents' and faculty members' understanding of the CanMEDS-Family Medicine health advocate role were reviewed, guided by interpretive descriptive methodology. MAIN FINDINGS: Results indicated that family medicine physicians and residents were able to identify the full spectrum of advocacy described in the Canadian Family Physician articles and that they valued the role. Further, there was widespread agreement that being a health advocate was linked with their identities as health professionals. The time it takes to be a health advocate was seen as a barrier to being effective in the role, and the work was seen as extremely challenging owing to system constraints. Participants also described a gap in training relating to advocacy at the system level as a challenge. CONCLUSION: Team-based care was seen as one of the most important enablers for becoming involved in the full spectrum of advocacy, as was time for personal reflection.

Being there: protocol for a scoping review of the medical education literature on grief support training for medical professionals.

INTRODUCTION: Medical trainees and professionals do not perceive that they are adequately taught the skills to address issues of grief with their patients. Atypical grief responses can prolong suffering, interrupt normal activities and lead to increased morbidity and mortality. Grief training can help physicians cope with feelings about and responses to suffering, loss and death in a way that improves both physician and patient/family wellness. This scoping review will describe the current landscape of grief training worldwide in medical school and residency and in continuing professional development in the disciplines of paediatrics, family medicine and psychiatry. The ultimate goal is to help physicians support patients experiencing grief. METHODS AND ANALYSIS: The study design has been adapted from Arksey and O'Malley's review methodology. We will work with an information specialist who will run searches in six multidisciplinary databases. To supplement the search, we will scan the reference lists of included studies. Two levels of screening will take place: a title and abstract review for articles that fit predefined criteria and a full-text review of articles that meet those criteria. To be included in the review, articles must report on grief training for medical residents and professionals in the fields of paediatrics, family medicine and psychiatry. Two investigators will review each article and extract data. ETHICS AND DISSEMINATION: Research ethics approval is not required for this review. We plan to share the findings through national and international medical education conferences and to publish the results in a peer-reviewed academic journal. We have the support of several directors of medical education at our institution who are interested in the growing focus on humanism in medical education as a way of decreasing burnout among medical students, residents and faculty.

Thought Spot: Embedding Usability Testing into the Development Cycle.

Usability testing is a vital component in the development of any digital innovation. Thought Spot, a mental health and wellness mobile application designed for and by transition-aged youth, underwent three distinct phases of usability testing (lab testing, field testing and heuristic evaluations). Testing highlighted that participants generally had a positive experience with the platform. Although some app functions were initially difficult for users, positive trends in learnability were observed. The key lesson learned from this process is the need for iterative testing timelines, concurrent with app development.

Understanding health advocacy in family medicine and psychiatry curricula and practice: A qualitative study.

BACKGROUND: We explored understanding and experiences of health advocacy among psychiatry and family medicine residents and faculty and the implications for clinical care and teaching through the lens of relationship-centred care. METHODS: This qualitative study was conducted in the psychiatry and family medicine departments at a large urban university. We interviewed 19 faculty members and conducted two focus groups with 18 residents. Semi-structured questions explored the relational meaning of health advocacy, how residents and faculty learned about the role and ethical considerations involved in incorporating advocacy work into clinical practice within a relationship-centred care framework. RESULTS: Four themes emerged from the interviews and focus groups: 1) health advocacy as an extension of the relationship to self; 2) health advocacy and professional boundaries in the physician-patient relationship; 3) health advocacy within a team-based approach; and 4) health advocacy and the physician-community/organization relationship. Participants described implications for practice of the challenges of health advocacy, including perceived institutional risks, professional boundaries and the appropriation of patient voice. CONCLUSIONS: Our study provides insights into the relational complexities of the health advocate role in residency curriculum and clinical practice. All participants described health advocacy as a broad spectrum of actions that are guided by relationships among patients, health care professionals and communities. Our analysis revealed that some challenges that participants identified with a health advocacy role could be addressed by anchoring the role within a specific theoretical framework. This would better enable us to create a culture of advocacy in the training and development of physicians.

The Optimization of an eHealth Solution (Thought Spot) with Transition-Aged Youth in Postsecondary Settings: Participatory Design Research.

BACKGROUND: Seventy percent of lifetime cases of mental illness emerge before the age of 24 years, but many youth are unable to access the support and services they require in a timely and appropriate way. With most youth using the internet, electronic health (eHealth) interventions are promising tools for reaching this population. Through participatory design research (PDR) engagement methods, Thought Spot, a Web- and mobile-based platform, was redeveloped to facilitate access to mental health services by transition-aged youth (aged 16-29 years) in postsecondary settings. OBJECTIVE: The aim of this study was to describe the process of engaging with postsecondary students through the PDR approaches, with the ultimate goal of optimizing the Thought Spot platform. METHODS: Consistent with the PDR approaches, five student-led workshops, attended by 41 individuals, were facilitated to obtain feedback regarding the platform's usability and functionality and its potential value in a postsecondary setting. Various creative engagement activities were delivered to gather experiences and opinions, including semistructured focus groups, questionnaires, personas, journey mapping, and a world café. Innovative technological features and refinements were also brainstormed during the workshops. RESULTS: By using PDR methods of engagement, participants knew that their ideas and recommendations would be applied. There was also an overall sense of respect and care integrated into each group, which facilitated an exchange of ideas and suggestions. CONCLUSIONS: The process of engaging with students to redesign the Thought Spot platform through PDR has been effective. Findings from these workshops will significantly inform new technological features within the app to enable positive help-seeking behaviors among students. These behaviors will be further explored in the second phase that involves a randomized controlled trial.

A Web- and Mobile-Based Map of Mental Health Resources for Postsecondary Students (Thought Spot): Protocol for an Economic Evaluation.

BACKGROUND: Youth demonstrate a low propensity to seek help for mental health issues and exhibit low use of health services despite the high prevalence of mental health challenges in this population. Research has found that delivering interventions via the internet and mobile devices is an effective way to reach youth. Thought Spot, a Web- and mobile-based map, was developed to help transition-aged youth in postsecondary settings overcome barriers to help-seeking, thereby reducing the economic burden associated with untreated mental health issues. OBJECTIVE: This paper presents the protocol for an economic evaluation that will be conducted in conjunction with a randomized controlled trial (RCT) to evaluate the effectiveness and cost of Thought Spot compared with usual care in terms of self-efficacy for mental health help-seeking among postsecondary students. METHODS: A partially blinded RCT will be conducted to assess the impact of Thought Spot on the self-efficacy of students for mental health help-seeking. Students from 3 postsecondary institutions in Ontario, Canada will be randomly allocated to 1 of 2 intervention groups (resource pamphlet or Thought Spot) for 6 months. The economic evaluation will focus on the perspective of postsecondary institutions or other organizations interested in using Thought Spot. Costs and resources for operating and maintaining the platform will be reported and compared with the costs and resource needs associated with usual care. The primary outcome will be change in help-seeking intentions, measured using the General Help-Seeking Questionnaire. The cost-effectiveness of the intervention will be determined by calculating the incremental cost-effectiveness ratio, which will then be compared with willingness to pay. RESULTS: The RCT is scheduled to begin in February 2018 and will run for 6 months, after which the economic evaluation will be completed. CONCLUSIONS: We expect to demonstrate that Thought Spot is a cost-effective way to improve help-seeking intentions and encourage help-seeking behavior among postsecondary students. The findings of this study will help inform postsecondary institutions when they are allocating resources for mental health initiatives. TRIAL REGISTRATION: ClinicalTrials.gov NCT03412461; https://clinicaltrials.gov/ct2/show/NCT03412461 (Archived at WebCite at http://www.webcitation.org/6xy5lWpnZ).

Collaborating with Families: Exploring Family Member and Health Care Provider Perspectives on Engaging Families Within Medical Education.

OBJECTIVE: With 40 to 65% of mental health patients being cared for by family members, nearly 500,000 Canadians are serving as caregivers. Yet family members are often excluded from daily clinical interactions and the development of mental health continuing medical education (CME). This qualitative study aimed to understand how best to involve families in mental health CME and how to advance their meaningful and equitable engagement in such initiatives. METHODS: Semi-structured interviews were conducted with two samples: mental health care providers (n = 8) and family members of individuals diagnosed with a co-occurring addiction and mental health problems (n = 12) to explore barriers, facilitators, and strategies for family engagement. RESULTS: Several themes related to the perception of expertise emerged from the interviews, including the tension between the validity of knowledge based on education/credentials and knowledge based on lived experience, as well as expressions of "voice." Participants also identified barriers to, and ethical considerations related to, family engagement, including stigma and confidentiality, and recommended strategies and supports to meaningfully include the family perspective within mental health CME. CONCLUSIONS: Aligning with the movement to improve collaboration between mental health professionals and service users requires developing relationships with family members. Identifying strategies to involve families in the development of CME is crucial to initiating and maintaining family engagement.

Gender bias in hospital leadership: a qualitative study on the experiences of women CEOs.

Purpose The purpose of this paper is to examine the experiences of gender bias among women hospital CEOs and explore to what these female leaders attribute their success within a male-dominated hospital executive leadership milieu. Design/methodology/approach This qualitative study involved 12 women hospital CEOs from across Ontario, Canada. Purposeful sampling techniques and in-depth qualitative interview methods were used to facilitate discussion around experiences of gender and leadership. Findings Responses fell into two groups: the first group represented the statement "Gender inequality is alive and well". The second group reflected the statement "Gender inequity is not significant, did not happen to me, and things are better now". This group contained a sub-group with no consciousness of systemic discrimination and that claimed having no gendered experiences in their leadership journey. The first group described gender issues in various contexts, from the individual to the systemic. The second group was ambivalent about gender as a factor impacting leadership trajectories. Originality/value Representations of women's leadership have become detached from feminism, with major consequences for women. This study reveals how difficult it is for some women CEOs to identify gender bias. The subtle everyday norms and practices within the workplace make it difficult to name and explain gender bias explicitly and may explain the challenges in understanding how it might affect a woman's career path.

Thought Spot: Co-Creating Mental Health Solutions with Post-Secondary Students.

It is difficult for the nearly 20% of Canadian 15- to 24-year olds reporting symptoms to seek the help they need within the current mental health system. Web-based and mobile health interventions are promising tools for reaching this group; having the capacity to reduce access-to-service barriers and engage youth in promoting their mental well-being. A three-phased, iterative, co-creation developmental approach was used to develop Thought Spot, a platform to better enable post-secondary students to seek mental health support. Co-creation activities included student development teams, hosting a hackathon, conducting focus groups and evidence-based workshops and student advisory groups. Evaluation results highlighted the need for greater role clarity and strategies for sustainable engagement in the co-creation process. Lessons learned are informing the project optimization phase and will be utilized to inform the design and implementation of an RCT, assessing impact on help seeking behaviour.

Enhancing Self-Efficacy for Help-Seeking Among Transition-Aged Youth in Postsecondary Settings With Mental Health and/or Substance Use Concerns, Using Crowd-Sourced Online and Mobile Technologies: The Thought Spot Protocol.

BACKGROUND: Seventy percent of lifetime cases of mental illness emerge prior to age 24. While early detection and intervention can address approximately 70% of child and youth cases of mental health concerns, the majority of youth with mental health concerns do not receive the services they need. OBJECTIVE: The objective of this paper is to describe the protocol for optimizing and evaluating Thought Spot, a Web- and mobile-based platform cocreated with end users that is designed to improve the ability of students to access mental health and substance use services. METHODS: This project will be conducted in 2 distinct phases, which will aim to (1) optimize the existing Thought Spot electronic health/mobile health intervention through youth engagement, and (2) evaluate the impact of Thought Spot on self-efficacy for mental health help-seeking and health literacy among university and college students. Phase 1 will utilize participatory action research and participatory design research to cocreate and coproduce solutions with members of our target audience. Phase 2 will consist of a randomized controlled trial to test the hypothesis that the Thought Spot intervention will show improvements in intentions for, and self-efficacy in, help-seeking for mental health concerns. RESULTS: We anticipate that enhancements will include (1) user analytics and feedback mechanisms, (2) peer mentorship and/or coaching functionality, (3) crowd-sourcing and data hygiene, and (4) integration of evidence-based consumer health and research information. CONCLUSIONS: This protocol outlines the important next steps in understanding the impact of the Thought Spot platform on the behavior of postsecondary, transition-aged youth students when they seek information and services related to mental health and substance use.