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Abstract Background The expansion of GGC repeats (typically exceeding 60 repeats) in the 5’ untranslated region (UTR) of the NOTCH2NLC gene (N2C) is linked to N2C-related repeat expansion disorders (NREDs), such as neuronal intranuclear inclusion disease (NIID), frontotemporal dementia (FTD), essential tremor (ET), and Parkinson’s disease (PD). These disorders share common clinical manifestations, including parkinsonism, dementia, seizures, and muscle weakness. Intermediate repeat sizes ranging from 40 to 60 GGC repeats, particularly those with AGC-encoded serine insertions, have been reported to be associated with PD; however, the functional implications of these intermediate repeats with serine insertion remain unexplored. Methods Here, we utilized cellular models harbouring different sizes of N2C variant 2 (N2C2) GGC repeat expansion and CRISPR-Cas9 engineered transgenic mouse models carrying N2C2 GGC intermediate repeats with and without serine insertion to elucidate the underlying pathophysiology associated with N2C intermediate repeat with serine insertion in NREDs. Results Our findings revealed that the N2C2 GGC intermediate repeat with serine insertion (32G13S) led to mitochondrial dysfunction and cell death in vitro. The neurotoxicity was influenced by the length of the repeat and was exacerbated by the presence of the serine insertion. In 12-month-old transgenic mice, 32G13S intensified intranuclear aggregation and exhibited early PD-like characteristics, including the formation of α-synuclein fibers in the midbrain and the loss of tyrosine hydroxylase (TH)-positive neurons in both the cortex and striatum. Additionally, 32G13S induced neuronal hyperexcitability and caused locomotor behavioural impairments. Transcriptomic analysis of the mouse cortex indicated dysregulation in calcium signaling and MAPK signaling pathways, both of which are critical for mitochondrial function. Notably, genes associated with myelin sheath components, including MBP and MOG, were dysregulated in the 32G13S mouse. Further investigations using immunostaining and transmission electron microscopy revealed that the N2C intermediate repeat with serine induced mitochondrial dysfunction-related hypermyelination in the cortex. Conclusions Our in vitro and in vivo investigations provide the first evidence that the N2C-GGC intermediate repeat with serine promotes intranuclear aggregation of N2C, leading to mitochondrial dysfunction-associated hypermyelination and neuronal hyperexcitability. These changes contribute to motor deficits in early PD-like neurodegeneration in NREDs.

Treatment with anti–PD-1 and anti-PD-L1 therapies has shown durable clinical benefit in non–small cell lung cancer (NSCLC). However, patients with NSCLC with epidermal growth factor receptor (EGFR) mutations do not respond as well to treatment as patients without an EGFR mutation. We show that EGFR-mutated NSCLC expressed higher levels of CD73 compared with EGFR WT tumors and that CD73 expression was regulated by EGFR signaling. EGFR-mutated cell lines were significantly more resistant to T cell killing compared with WT cell lines through suppression of T cell proliferation and function. In a xenograft mouse model of EGFR-mutated NSCLC, neither anti–PD-L1 nor anti-CD73 antibody alone inhibited tumor growth compared with the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth, increased the number of tumor-infiltrating CD8+ T cells, and enhanced IFN-γ and TNF-α production of these T cells. Consistently, there were increases in gene expression that corresponded to inflammation and T cell function in tumors treated with the combination of anti–PD-L1 and anti-CD73. Together, these results further support the combination of anti-CD73 and anti–PD-L1 therapies in treating EGFR-mutated NSCLC, while suggesting that increased T cell activity may play a role in response to therapy.

Purpose: While research is beginning to reveal the potential of dialogue in sparking critical reflection (critically reflective ways of seeing), additional research is needed to guide the teaching of critical reflection toward enabling critically reflective practice (critically reflective ways of seeing and doing). An experimental study was conducted to investigate the impact of dialogic learning on critically reflective practice, compared to discussion-based learning. The dialogic intervention integrated the theory of Mikhail Bakhtin with the theory of critical reflection and critical disability studies., Method: In interprofessional groups of 4, medical, occupational therapy, and speech-language pathology students were randomly assigned to a learning condition that used a reflective discussion or critically reflective dialogue about a pediatric patient case. All participants were then randomly assigned a clinical report for a novel pediatric patient and asked to write a hypothetical clinical letter to the child's school. Hierarchical logistic regression models were constructed to estimate the probabilities of sentences and letters being critically reflective., Results: The probability of sentences being critically reflective was significantly higher for the dialogue condition (0.26, 95% CI [0.2, 0.33]), compared to the discussion condition (0.11, 95% CI [0.07, 0.15]). Likewise, the probability of letters being critically reflective was significantly higher for the dialogue condition (0.26, 95% CI [0.15, 0.4]), compared to the discussion condition (0.04, 95% CI [0.01, 0.16]). In both conditions, the probability of a letter being critically reflective was positively associated with the proportion of critically reflective sentences., Conclusions: The results demonstrate dialogic learning prepared students to enact critically reflective practice when writing mock clinical letters. Students who participated in a dialogue engaged in a collaborative process of critical reflection and subsequently applied that way of seeing in the individual act of writing a letter. This study highlights how Bakhtin's theory of dialogue can advance critical pedagogy., (Copyright © 2022 by the Association of American Medical Colleges.)

Purpose: Networking is essential to leadership effectiveness in the business context. Yet little is known about leadership networking within the academic health science context. If we are going to train academic leaders, we must first understand the relational, network-based activities of their work. The purpose of this study was to explore how academic health science leaders engage in networking activities in the academic health science context., Method: A constructivist grounded theory approach guided our study. The authors interviewed 24 academic health science leaders who were enrolled in the New and Evolving Academic Leadership program at the University of Toronto and used social network mapping as an elicitation method. Interviews, which were conducted between September 2014 and June 2015, explored participants' networks and networking activities. Constant comparative analysis was used to analyze the interviews, with attention paid to identifying key networking activities., Results: Academic health science leaders were found to engage in 4 types of networking activities: role bound, project based, goal/vision informed, and opportunity driven. These 4 types were influenced by participants' conception of their role and their perceived leadership work context, which in turn influenced their sense of agency., Conclusions: The networking activities identified in this study of academic health science leaders resonate with effective networking activities found in other fields. The findings highlight that these activities can be facilitated by focusing on leaders' perceptions about role and work context. Leadership development should thus attend to these perceptions to encourage effective networking skills.

As a field, health professions education (HPE) has begun to answer calls to draw on social sciences and humanities (SS&H) knowledge and approaches for curricular content, design, and pedagogy. Two commonly used SS&H concepts in HPE are critical reflection and critical reflexivity. But these are often conflated, misunderstood, and misapplied. Improved clarity of these concepts may positively affect both the education and practice of health professionals. Thus, the authors seek to clarify the origins of each, identify the similarities and differences between them, and delineate the types of teaching and assessment methods that fit with critical reflection and/or critical reflexivity. Common to both concepts is an ultimate goal of social improvement. Key differences include the material emphasis of critical reflection and the discursive emphasis of critical reflexivity. These similarities and differences result in some different and some similar teaching and assessment approaches, which are highlighted through examples. The authors stress that all scientific and social scientific concepts and methods imported into HPE must be subject to continued scrutiny both from within their originating disciplines and in HPE. This continued questioning is core to the ongoing development of the HPE field and also to health professionals' thinking and practice.

Medical education research faces increasing pressure to demonstrate impact and utility. These pressures arise amidst a climate of accountability and within a culture of outcome measurement. Conventional metrics for assessing research impact such as citation analysis have been adopted in medical education, despite researchers' assertion that these quantitative measures insufficiently reflect the value of their work. Every knowledge community has its own definitions of what counts as knowledge, how that knowledge should be produced, and how the quality of that knowledge production should be evaluated. Definitions of impact and knowledge shape and constrain researchers' foci and endeavors. Therefore, metrics that meaningfully evaluate the knowledge outputs of researchers need to be defined within each field. It is time for medical education research, as a field, to examine how to measure research impact and carefully consider the broader implications these measures may have. The authors discuss developments in research metrics more broadly, then critically examine impact metrics currently used in the medical education field and propose alternatives to more meaningfully track and represent impact in medical education research. Grey metrics and narrative impact stories to more fully capture the richness and nuanced nature of impact in medical education research are introduced. The authors advocate for a continual examination of how impact is defined, eschewing unquestioned use of conventional metrics. A new conversation is needed, as well as a research agenda to help medical education conceptualize and study metrics more appropriate for the field.

Purpose: Health professions education and practice have seen renewed calls to restore compassion to care. However, because of the ways evidence-based practice (EBP) has been implemented in health care, wherein research-based knowledge is privileged, the dominance of EBP may silence clinician and patient experience-based knowledge needed for compassionate care. This study explored what happens when the discourses of compassionate care and EBP interact in practice., Method: Chronic pain management in Canada was selected as the context for the study. Data collection involved compiling an archive of 458 chronic pain texts, including gray literature from 2009-2015 (non-peer-reviewed sources, e.g., guidelines), patient blog posts from 2013-2015, and transcripts of study interviews with 9 clinicians and postgraduate trainees from local pain clinics from 2015-2016. The archive was analyzed using an interpretive qualitative approach informed by critical discourse analysis., Results: Four manifestations of the discourse of compassionate care were identified: curing the pain itself, returning to function, alleviating suffering, and validating the patient experience. These discourses produced particular subject positions, activities, practices, and privileged forms of knowledge. They operated in response, partnership, apology, and resistance, respectively, to the dominant discourse of EBP. These relationships were mediated by other prevalent discourses in the system: patient safety, patient-centered care, professional liability, interprofessional collaboration, and efficiency., Conclusions: Medical education efforts to foster compassion in health professionals and systems need to acknowledge the complex web of discourses-which carry with them their own expectations, material effects, and roles-and support people in navigating this web.