Impact on stakeholders of a cultural adaptation of a social and emotional well-being intervention in an Aboriginal community.

PURPOSE: Australian Indigenous people conceptualise health broadly as situated within a social and emotional well-being (SEWB) framework. A consultation process with an Aboriginal community revealed that the fundamental principles of the population wide, community-based Act-Belong-Commit mental health promotion Campaign were consistent with Aboriginal people's understanding of SEWB and that a cultural adaptation of the Campaign would be welcomed in the community. The purpose of this paper is to present key stakeholders' feedback on the Campaign adaptation. METHODOLOGY: Two years after implementation of the Campaign, individual in-depth interviews were conducted with a purposeful sample of n = 18 Indigenous and non-Indigenous stakeholders to identify ongoing issues in the community and assess their reactions to the Campaign implementation and perceptions of the effects of the Campaign on the community. RESULTS: The two primary factors influencing stakeholder acceptance of the Campaign in the community were (i) the nature of the consultation process that clearly acknowledged that it was for the community to decide whether or not to adopt the Campaign and (ii) the ability of the Aboriginal Project Manager to gain the trust of the community, bring stakeholders together and illustrate the Act-Belong-Commit principles in her actions in the community. Stakeholders reported observing social and emotional well-being benefits for individuals, their families and the whole community. CONCLUSION: Overall, the results suggest that the Act-Belong-Commit mental health promotion Campaign can be successfully culturally adapted as a community-based, social and emotional well-being Campaign in Aboriginal and Torres Strait communities. SO WHAT?: The Act-Belong-Commit cultural adaptation in Roebourne provides an evidence-based best practice model for the development of culturally appropriate mental health promotion campaigns in Indigenous communities around Australia.

Deepening leadership identity development.

After decrying the lack of attention paid to identity, equity, and power in leadership education, this article delineates key concepts such as identity, identity development, and leader/leadership identity development. It explores areas of concordance and distinction across leader and leadership identity development models and suggests increasing convergence across these bodies of scholarship and adding criticality for deeper leadership identity development.

Exploring the utility, limitations, and possibilities of the leadership identity development (LID) model.

The article summarizes a conversation with early career scholars who utilize the LID theory and model in their scholarship and practice. Authors offer thoughts as to which aspects of leader and leadership identity development remain most useful to leadership education and development, as well as ways this body of scholarship might also be incomplete and insufficient. They reflect on how leader and leadership identity development theorizing is related to identity, equity, and power. The article concludes with ideas about how the scholarship and practice of leadership identity development may evolve in the future for deeper leadership identity development.

Discovery of a Novel DCAF1 Ligand Using a Drug-Target Interaction Prediction Model: Generalizing Machine Learning to New Drug Targets.

DCAF1 functions as a substrate recruitment subunit for the RING-type CRL4DCAF1 and the HECT family EDVPDCAF1 E3 ubiquitin ligases. The WDR domain of DCAF1 serves as a binding platform for substrate proteins and is also targeted by HIV and SIV lentiviral adaptors to induce the ubiquitination and proteasomal degradation of antiviral host factors. It is therefore attractive both as a potential therapeutic target for the development of chemical inhibitors and as an E3 ligase that could be recruited by novel PROTACs for targeted protein degradation. In this study, we used a proteome-scale drug-target interaction prediction model, MatchMaker, combined with cheminformatics filtering and docking to identify ligands for the DCAF1 WDR domain. Biophysical screening and X-ray crystallographic studies of the predicted binders confirmed a selective ligand occupying the central cavity of the WDR domain. This study shows that artificial intelligence-enabled virtual screening methods can successfully be applied in the absence of previously known ligands.

C-L Case Conference: The Case of a 34-Year-Old Male Veteran with Suicidal Ideation in the Context of Alcohol Intoxication.

We describe the case of a 34-year-old male veteran who presents to the emergency department with suicidal ideation while intoxicated on alcohol. From his progression from intoxication through sobriety, this case details changes in his suicide risk during the sobering process. Consultation-liaison psychiatrists present guidance for this clinical scenario based on their experiences and a review of the available literature. The following important concepts for managing suicide risk among patients with alcohol intoxication are considered: evaluating for medical risk, timing the suicide risk assessment, anticipating withdrawal, diagnosing other disorders, and achieving a safe disposition.

Leadership identity development.

This article examines various applications of the leadership identity development (LID) grounded theory and model and explores the process used to apply LID to the construction of collegiate student leadership development experiences. Featured programs include those that use LID as a design element of the program, but do not explicitly teach it; those that explicitly teach the content of the LID theory and model in leadership programs and curricula; and those that use LID at the institutional level to inform university-wide leadership programming. The article concludes with critiques and considerations for leadership educators interested in applying LID in their leadership education and development programs.

In pursuit of inter-specialty consensus on excited delirium syndrome: a scoping literature review.

Excited delirium syndrome (ExDS) is a controversial and disputed diagnosis involving altered mentation, agitation, and, frequently, substance abuse. Recently, it has become a common pre-hospital diagnosis, serving as justification for use of force, restraint, and/or medication administration. To conduct a scoping review across three databases to describe the most frequently reported diagnostic criteria for ExDS, as well as to explore its use as a diagnosis for deaths of individuals in the custody of law enforcement. In 2021, three literature databases were searched: Ovid Medline, PsycInfo, and Scopus. Studies were included if they were peer-reviewed, English articles describing (1) ExDS symptoms, (2) substance intoxication with at least 2 ExDS symptoms present, or (3) centering on deaths occurring in the custody of law enforcement and attributed to ExDS. Key study data were extracted and the current literature was described qualitatively. Analysis took place between March and December 2021. A total of 97 studies were identified through initial abstract and secondary full-text review, with noted discrepancies in the definition of ExDS itself. After review, differences in ExDS diagnosis among organizations were explored, along with subsequent clinical impact, particularly in the pre-hospital setting. Resulting impact on patients, particularly those of minoritized ethnic and racial groups, was also noted. Prone aggressive restraint, in particular, is noted as an established risk factor for fatalities in ExDS cases. At this time, ExDS should not be utilized as a diagnosis; major medical organizations have an urgent responsibility to convene to formalize consensus-based diagnostic criteria or to propose alternate management guidelines for agitated and altered persons.

Indigenous Cultural Identity of Research Authors Standard: research and reconciliation with Indigenous Peoples in rural health journals.

The Indigenous Cultural Identity of Research Authors Standard (ICIRAS) is based on a gap in research publishing practice where Indigenous peoples' identity is not systematically and rigorously recognised in rural health research publications. There are widespread reforms, in different research areas, to counter the reputation of scientific research as a vehicle of racism and discrimination. Reflecting on these broader movements, the editorial teams of three rural health journals - Rural and Remote Health, the Australian Journal of Rural Health, and the Canadian Journal of Rural Medicine - adopted a policy of 'Nothing about Indigenous Peoples, without Indigenous Peoples'. This meant changing practices so that Indigenous Peoples' identity could be embedded in authorship credentials - such as in the byline. An environmental scan of literature about the inclusion of Indigenous Peoples in research revealed many ways in which editorial boards of journals could improve their process to signal to readers that Indigenous voices are included in rural health research publication governance. Improving the health and wellbeing of Indigenous peoples worldwide requires high-quality research evidence. This quality benchmark needs to explicitly signal the inclusion of Indigenous authors. The ICIRAS is a call to action for research journals and institutions to rigorously improve research governance and leadership to amplify the cultural identity of Indigenous peoples in rural health research.

Sex Differences in the Brain Transcriptome Related to Alcohol Effects and Alcohol Use Disorder.

There is compelling evidence that sex and gender have crucial roles in excessive alcohol (ethanol) consumption. Here, we review some of the data from the perspective of brain transcriptional differences between males and females, focusing on rodent animal models. A key emerging transcriptional feature is the role of neuroimmune processes. Microglia are the resident neuroimmune cells in the brain and exhibit substantial functional differences between males and females. Selective breeding for binge ethanol consumption and the impacts of chronic ethanol consumption and withdrawal from chronic ethanol exposure all demonstrate sex-dependent neuroimmune signatures. A focus is on resolving sex-dependent differences in transcriptional responses to ethanol at the neurocircuitry level. Sex-dependent transcriptional differences are found in the extended amygdala and the nucleus accumbens. Telescoping of ethanol consumption is found in some, but not all, studies to be more prevalent in females. Recent transcriptional studies suggest that some sex differences may be due to female-dependent remodeling of the primary cilium. An interesting theme appears to be developing: at least from the animal model perspective, even when males and females are phenotypically similar, they differ significantly at the level of the transcriptome.

Responding to the Psychological Needs of Health-Care Workers During the COVID-19 Pandemic: Case Study from the Medical College of Wisconsin.

With the advent of the novel coronavirus (COVID-19) pandemic, health-care workers have been faced with an inordinately high level of trauma as frontline providers. The Medical College of Wisconsin (MCW) partnered with affiliate hospitals and community partners to mobilize a matrix of available support and interventions to deliver psychological services to reach all levels of health-care providers in timely, accessible formats. While virtual peer support groups were the most utilized resource among the support group options, other opportunities also provided unique benefits to learners whose education had been disrupted by the pandemic. Mental health must be prioritized for health-care workers in the event of future public health crises. Lessons learned from this pandemic indicate that it is critical to involve learners early on in the process in order to meet their educational needs and to increase access to evidence-based care.

Hidden costs and commitments: Leadership, social class, and experiential learning.

As leadership can be developed and practiced in multiple on- and off-campus contexts, this chapter offers ways to make experiential opportunities more accessible to poor and working-class students. Aiding students in leveraging leadership learning experiences they already have through family and community roles are explored.

Proteomics of REPLICANT perfusate detects changes in the metastatic lymph node microenvironment.

In breast cancer (BC), detecting low volumes of axillary lymph node (ALN) metastasis pre-operatively is difficult and novel biomarkers are needed. We recently showed that patient-derived ALNs can be sustained ex-vivo using normothermic perfusion. We now compare reactive (tumour-free; n = 5) and macrometastatic (containing tumour deposits >2 mm; n = 4) ALNs by combining whole section multiplex immunofluorescence with TMT-labelled LC-MS/MS of the circulating perfusate. Macrometastases contained significantly fewer B cells and T cells (CD4+/CD8+/regulatory) than reactive nodes (p = 0.02). Similarly, pathway analysis of the perfusate proteome (119/1453 proteins significantly differentially expressed) showed that immune function was diminished in macrometastases in favour of 'extracellular matrix degradation'; only 'neutrophil degranulation' was preserved. Qualitative comparison of the perfusate proteome to that of node-positive pancreatic and prostatic adenocarcinoma also highlighted 'neutrophil degranulation' as a contributing factor to nodal metastasis. Thus, metastasis-induced changes in the REPLICANT perfusate proteome are detectable, and could facilitate biomarker discovery.

Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype.

The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.

Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study.

Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain viable after 24 h of ex vivo perfusion: haematoxylin and eosin-stained histological appearance and proliferation (by Ki67 immunohistochemistry) did not change significantly over time for any perfused ALN compared with a control from time-point zero. Furthermore, targeted gene expression analysis (NanoString PanCancer IO360 panel) showed that only 21/750 genes were differentially expressed between control and perfused ALNs (|log2 FC| > 1 and q < 0.1): none were involved in apoptosis and metabolism, but rather all 21 genes were involved in immune function and angiogenesis. During perfusion, tissue acid-base balance remained stable. Interestingly, the flow rate increased (p < 0.001) in cancer-replaced (i.e. metastasis occupied more than 90% of the surface area on multiple levels) compared to cancer-free nodes (i.e. nodes with no metastasis on multiple sections). CXCL11 transcripts were significantly more abundant in cancer-replaced nodes, while CXCL12 transcripts were significantly more abundant in cancer-free nodes. These cytokines were also detected in the circulating perfusate. Monoclonal antibodies (nivolumab and trastuzumab) were administered into a further three ALNs to confirm perfusion efficacy. These drugs saturated the nodes; nivolumab even induced cancer cell death. Normothermic ALN perfusion is not only feasible but sustains the tumour microenvironment ex vivo for scientific investigation. This model could facilitate the identification of actionable immuno-oncology targets. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer.

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αß T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αß TCRs. However, whereas in most cases TCRαß repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αß T cells.

Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer.

Lymphatic vasculature is crucial for metastasis in triple-negative breast cancer (TNBC); however, cellular and molecular drivers controlling lymphovascular metastasis are poorly understood. We define a macrophage-dependent signaling cascade that facilitates metastasis through lymphovascular remodeling. TNBC cells instigate mRNA changes in macrophages, resulting in ß4 integrin-dependent adhesion to the lymphovasculature. ß4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-ß1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-ß1 drives ß4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-ß1 signaling in this context. ß4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-ß signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between ß4 integrin and TGF-ß1.

Arguments for the Adoption of a Nystagmus Care Pathway.

Pathological nystagmus is a spontaneous oscillation of the eyes. It is a complex problem with many subtypes and causes ranging from the acute neurological emergency to chronic visual disorders. There is considerable variability in clinical management and patient experience across the UK. The Nystagmus Care Pathway (NCP) is a proposal to provide an evidence-based, consistent minimum standard of care across all eye services for patients with nystagmus. The NCP coordinates expertise from the various team members with a staged approach: 1) pathway entry; 2) nystagmus identification; 3) finding underlying causes/associations; 4) managing causes/associations; 5) managing the nystagmus and its effects; 6) support for patients and families; 7) pathway exit. Orthoptists are ideally placed to coordinate the NCP as they are trained in ocular motility and visual assessment. They are accustomed to providing continuity of care, multidisciplinary working and via the British and Irish Orthoptic Society (BIOS), they can provide consistency of care across the UK. Key performance indicators are proposed.

A review of the benefits and limitations of a primary care-embedded psychiatric consultation service in a medically underserved setting.

A significant percentage of patients with psychiatric disorders are exclusively seen for health-care services by primary care physicians. To address the mental health needs of such patients, collaborative models of care were developed including the embedded psychiatry consult model which places a consultant psychiatrist on-site to assist the primary care physician to recognize psychiatric disorders, prescribe psychiatric medication, and develop management strategies. Outcome studies have produced ambiguous and inconsistent findings regarding the impact of this model. This review examines a primary care-embedded psychiatric consultation service in place for nine years in a family medicine residency program. Psychiatric consultants, family physicians, and residents actively involved in the service participated in structured interviews designed to identify the clinical and educational value of the service. The benefits and limitations identified were then categorized into physician, consultant, patient, and systems factors. Among the challenges identified were inconsistent patient appointment-keeping, ambiguity about appropriate referrals, consultant scope-of-practice parameters, and delayed follow-up with consultation recommendations. Improved psychiatric education for primary care physicians also appeared to shift referrals toward more complex patients. The benefits identified included the availability of psychiatric services to underserved and disenfranchised patients, increased primary care physician comfort with medication management, and improved interprofessional communication and education. The integration of the service into the clinic fostered the development of a more psychologically minded practice. While highly valued by respondents, potential benefits of the service were limited by residency-specific factors including consultant availability and the high ratio of primary care physicians to consultants.