"I Want to Grow Older With Dignity": Older LGBTQ+ Canadian Adults' Perceptions and Experiences of Aging.

The number of older LGBTQ+ adults is growing worldwide. Yet few studies outside of the United States have examined their experiences of aging. Drawing on the Health Equity Promotion Model and contextualized in Canada's unique socio-political history, our study used multiple, in-depth, qualitative interviews to examine 30 older Canadian LGBTQ+ adults' (aged 65-83) perceptions and experiences of growing older. Our descriptive thematic analysis identified three overarching categories: "Losses," "gains," and "needs." Losses referred to the changes in the participants' health, autonomy, and relationships that had occurred with age. Gains entailed positive later life changes, including increased wisdom, flexibility, and social connections. Finally, needs referred to those things that the participants deemed essential for aging well, namely, inclusive health care, meaningful activities, and supportive networks. We discuss the policy and practice implications of our findings for the fostering of health, well-being, and social inclusion amongst this often-marginalized population.

Wheelchair Skills Test in simulated versus community settings: a mixed-methods crossover study of experienced motorized mobility scooter users.

PURPOSE: The Wheelchair Skills Test (WST) is commonly conducted in a simulated setting. Although the WST can be done in the community setting, its usefulness in this setting has not been systematically evaluated. The purpose of this study was to compare the WST in the simulated versus community settings, and to explore participants' perceptions of performing in each environment. METHODS: For this mixed-methods study, we studied 20 motorized mobility scooter users who had used their devices for ≥ 3 months. Each participant completed the WST Version 4.3 twice in random order - once in a simulated setting and once in their community within a two-week period. Semi-structured interviews were conducted after completion of the WST in both environments. A self-report version of the WST (WST-Q) was also completed that measured perceived capacity, frequency of skill performance, and confidence. RESULTS: The mean (SD) total WST score in the simulated setting was 88.9% (8.6) and 92.7% (7.8) in the community setting. The two WST scores were moderately correlated (r = 0.306, p = 0.190). Community-setting WST scores were moderately correlated with WST-Q confidence scores. Simulated-setting scores were moderately correlated with WST-Q frequency scores. Although most participants preferred performing the WST in their communities due to convenience and familiarity, they perceived the simulated setting to be reflective of their community settings. CONCLUSION: Despite challenges, community-based testing may provide a better reflection of everyday performance for scooter users than testing in a simulated environment.

IMPLICATIONS FOR REHABILITATIONWheelchair Skills Test (WST) scores obtained from conducting the assessment in the community may be different from those obtained from conducting the assessment in a simulated setting.Since the WST conducted in the community likely provides different information from the WST conducted in the lab, clinicians should carefully consider which environment to access wheelchair skills in.In an urban, community setting, all WST skills were able to be found within a one block radius of participants' homes.

Integrating person-centred care and social justice: a model for practice with larger-bodied patients.

Person-centred care (PCC) has been touted as a promising paradigm for improving patients' experiences and outcomes, and the overall therapeutic environment for a range of health conditions, including obesity. While this approach represents an important shift away from a paternalistic and disease-focused paradigm, we argue that PCC must be explicitly informed by a social justice lens to achieve optimal conditions for health and well-being. We suggest that existing studies on PCC for obesity only go so far in achieving social justice goals as they operate within a biomedical model that by default pathologises excess weight and predetermines patients' goals as weight loss and/or management, regardless of patients' embodied experiences and desires. There remains a dearth of empirical research on what social justice-informed PCC looks like in practice with larger patients. This interview study fills a research gap by exploring the perspectives of 1) health practitioners (n=22) who take a critical, social justice-informed approach to weight and 2) larger patients (n=20) served by such practitioners. The research question that informed this paper was: What are the characteristics of social justice-informed PCC that play out in clinical interactions between healthcare practitioners and larger-bodied patients? We identified five themes, namely: 1) Integrating evidence-based practice with compassionate, narrative-based care; 2) Adopting a curious attitude about the patient's world; 3) Centring patients' own wisdom and expertise about their conditions; 4) Working within the constraints of the system to advocate for patients to receive equitable care; 5) Collaborating across professions and with community services to address the multifaceted nature of patient health. The findings illustrate that despite participants' diverse perspectives around weight and health, they shared a commitment to PCC by upholding patient self-determination and addressing weight stigma alongside other systemic factors that affect patient health outcomes.

Correlates of self-reported Wheelchair Skills Test Questionnaire scores of new users of mobility scooters: a cross-sectional study.

OBJECTIVES: To describe the subjective reported scooter-skill scores of new mobility scooter users and to identify significant correlations with other characteristics and measures. MATERIALS AND METHODS: This was a single-centre study using a cross-sectional design. Participants (N = 22) completed the Wheelchair Skills Test-Questionnaire (WST-Q) Version 4.3 for scooter users. It measures the users' perceived capacity (what the user can do), performance (what the user actually does), and confidence (or self-efficacy). Their scooter skills were also rated objectively with the Wheelchair Skills Test (WST). They completed standardised measures of cognition, hearing, vision, life space mobility, visual attention and task switching, and confidence negotiating the social environment using their scooters. RESULTS: Mean total WST-Q capacity scores were 83% and performance scores were 25%. WST-Q capacity scores had significant positive correlations with WST-Q performance (r = 0.321) and confidence scores (r = 0.787), WST capacity scores (r = 0.488), and confidence negotiating the social environment (WheelCon) (r = 0.463). WST-Q capacity scores were significantly negatively correlated with Trail Making B scores (r = -0.591) and age (r = -0.531). CONCLUSIONS: The correlations between WST-Q scores and other variables are similar to those found in other studies among users of scooters and other mobility devices. The gap between capacity and performance scores highlights the needs for additional skills training in this population of novice scooter users.IMPLICATIONS FOR REHABILITATIONIn implementing scooter training for new scooter users, attention should be paid to building community-based skills for navigating both the physical and the social environment.Scooter users' age and their driving capabilities need to be taken into account when developing and delivering the training.

Qualitative experiences of new motorised mobility scooter users relevant to their scooter skills: a secondary analysis.

OBJECTIVE: To explore the experiences of new motorised mobility scooter users from the perspectives of the assessment and training of scooter skills. DESIGN: Descriptive secondary analysis of qualitative data. SETTING: Community. PARTICIPANTS: 20 New users of motorised mobility scooters. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Directed qualitative analysis of up to four semi-structured interviews over the course of the first year of scooter use, to identify themes and sub-themes that could inform recommendations regarding assessment and training protocols. RESULTS: We identified two themes. The first related to potential new content. As one example of the sub-themes, there were many excerpts that dealt with the use of skills in various combinations and permutations that were used to carry out activities during everyday life and participate in society. These excerpts suggested the importance of training skills in combination to facilitate skill transfer (or generalizability). The second theme is related to enhancements of existing content. As one example of the sub-themes, there were several excerpts that dealt with scooter security. These excerpts led to the recommendation that removing and inserting the scooter key should be added to the assessment criteria for the "turns power on and off" skill of the Wheelchair Skills Test (WST) and its questionnaire version (WST-Q). CONCLUSIONS: The experiences of scooter users over the first year of receiving a scooter appear to be relevant to the assessment and training of scooter skills and suggest themes for further study. Clinical trial registration number: NCT02696213 IMPLICATIONS FOR REHABILITATIONThe experiences of new scooter users are highly relevant to the assessment and training of scooter skills.These experiences suggest both potential new content and enhancements of existing content to the Wheelchair Skills Program Manual.

'You're part of something bigger': interpersonal relationships and older Canadian men's body image.

OBJECTIVE: We examined older men's body image, with a focus on the role of interpersonal relationships in shaping their psychological adaptation to age-related body changes to appearance, function, and health. DESIGN: Qualitative narrative constructionist study. MAIN OUTCOME MEASURES: We conducted semi-structured interviews with 29 men aged 65-83. Data were analysed using thematic narrative analysis; we identified and interpreted patterns in and across the men's stories about their aging bodies. RESULTS: Narratives of purpose through meaningful engagement and belonging through connection permeated the men's accounts. Participants mitigated body-related changes and challenges through pleasurable physical, leisure, and community activities. They derived purpose from these activities as they kept them physically, cognitively, and socially engaged and thus relevant with advancing age, particularly post retirement. The men derived a sense of belonging through social connections. Relationships with family, friends, and community members shaped their capacity for meaningful engagement and associated psychological adjustment to age-related body changes. CONCLUSION: The findings point to the imperative need to consider how men negotiate their constantly changing, aging bodies within the context of interpersonal relationships, and highlight the role that later life belonging and purpose play in shaping how men experience their bodies as they grow older.

'It's not just to treat everybody the same': A social justice framework for caring for larger patients in healthcare practice.

Drawing on semi-structured interviews with larger bodied patients (n = 20) and their healthcare practitioners (n = 22) in Canada, this paper combines micro and macro approaches in outlining a social justice approach to caring for larger patients in healthcare practice. Theoretically, we draw upon structural competency and critical consciousness to address the question of how social justice is enacted, experienced, and understood in interactions between clinicians and larger patients. Our findings highlight four key themes that provide a framework for integrating social justice into healthcare practice: (1) an awareness of one's simultaneous experience of marginalisation and privilege in the clinical interaction; (2) navigating between additive and interactive understandings of intersectionality; (3) micro and macro approaches to change; and (4) straddling the line between equity and equality. The synergies in participants' perspectives across social identities suggests that the cultivation of social justice awareness potentially mitigates some blinders of privilege. Furthermore, practitioners' social justice orientation positively impacted patient experience, with most patients expressing appreciation for having their various histories of trauma and social challenges handled compassionately during appointments.

"There were no words": Older LGBTQ+ persons' experiences of finding and claiming their gender and sexual identities.

This article explores how older Canadian LGBTQ+ persons' gender and sexual identities evolved over time and were influenced by language, role models, and significant others. We draw on data from a qualitative interview study with 30 LGBTQ+ older adults. We analyze our data thematically, finding three overarching themes, namely: a) Lacking language and role models, b) Drawn and pushed out of the closet, and c) Current fluidities and future concerns. Our participants reported that, earlier in life, they had lacked language or positive frameworks with which to make sense of their identities. Upon finding language and role models, all but one eventually came out or transitioned, often after consulting trusted others, experimenting in secret, leading double lives, and/or finding same-sex love. Many were fearful that as they aged, they might once again lose their abilities to openly claim their gender and sexual identities. We discuss our findings in relation to queer theory and the LGBTQ+ aging literature.

"Dirty looks": A critical phenomenology of motorized mobility scooter use.

The use of motorized mobility scooters has become increasingly prevalent. Drawing on the critical-phenomenology and disability-studies literature, this study explored the embodied nature of scooter use among 20 new scooter users. The analysis revealed four themes: 1) Navigating the social environment and being (un)seen presented a paradox of how hypervisibility and invisibility can both exist; 2) Transitioning to scooter use revealed the affective component of becoming a scooter user despite the underlying desire to avoid unwanted attention; 3) Experiencing accessibility challenges en route and at destinations demonstrated that the inconsistency in accessibility along different routes unavoidably makes disability more visible; 4) Strategic and personalized use of devices for mobility illustrated how reliance on other mobility devices (e.g. canes and walkers) can be used as a strategy to circumvent the barriers and lessen the visibility of disability. The lifeworlds of "lived relation", "lived body", "lived space", and "lived things" encapsulated the multi-faceted experiences of new scooter users. The critical phenomenology of scooter use emphasized the need for creative strategies to address the physical and attitudinal barriers as well as scooter design-related concerns.

From invisible to extraordinary: Representations of older LGBTQ persons in Canadian print and online news media.

The purpose of this study was to examine how older LGTBQ adults were portrayed in mainstream Canadian newspapers and popular magazines. Our sample included stories that were published in English between July 1, 2016 and June 30, 2017 in three national newspapers, 13 provincial newspapers, one national online news website, and the five most widely-read popular magazines whose readerships included or catered to the mature market. Our content and thematic analyses of our sample of 190 stories resulted in three overarching findings: a) older LGBTQ adults were largely invisible; b) older LGBTQ persons were often depicted as victims of historical and ongoing discrimination and social exclusion; and c) older LGBTQ individuals were frequently portrayed as extraordinary role models and icons who demonstrated resilience and had paved the way for the younger generations. We discuss our findings in light of the extant research and theorizing concerning the role of the media in reflecting, reproducing, and/or challenging dominant social norms and ideologies, including heterosexism, homophobia, and age-based prejudice.

An examination of older men's body image: How men 65 years and older perceive, experience, and cope with their aging bodies.

We examined how older men perceived, experienced, and coped with age-related changes to their appearance, body function, and health. Data from semi-structured interviews with 28 men aged 65-83 living in a large urban Canadian city and diverse in ethnocultural background (European, East Asian, and South Asian) and sexual orientation (heterosexual and gay) were analyzed through a reflexive thematic analysis. Four overarching themes were constructed from the participants' accounts. Participants were ambivalent about their aging bodies; they were concerned about certain changes to their bodies, yet concurrently grateful for their retained health and body function. The men stressed the need to accept age-related body changes through pragmatism, awareness of challenging body-related cognitions and emotions without overidentification or suppression, and adjustments to expectations and activities. Participants engaged in upward and downward social comparisons to assess their aging bodies in relation to others and to their younger selves. Weight concerns were prominent. The men worried about their weight, with particular attention to their stomach, and were physically active and ate a healthy diet to manage their weight. This study contributes to body image theorizing by including older diverse men and can inform interventions aiming to enhance men's later life psychological adjustment.

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma.

The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates that MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p ≤ 0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification.

Clonality and evolutionary history of rhabdomyosarcoma.

To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS.

The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.

The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.

Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.

UNLABELLED: Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/RAS/PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma. SIGNIFICANCE: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention.

Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).

Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.

Massively parallel sequencing reveals an accumulation of de novo mutations and an activating mutation of LPAR1 in a patient with metastatic neuroblastoma.

Neuroblastoma is one of the most genomically heterogeneous childhood malignances studied to date, and the molecular events that occur during the course of the disease are not fully understood. Genomic studies in neuroblastoma have showed only a few recurrent mutations and a low somatic mutation burden. However, none of these studies has examined the mutations arising during the course of disease, nor have they systemically examined the expression of mutant genes. Here we performed genomic analyses on tumors taken during a 3.5 years disease course from a neuroblastoma patient (bone marrow biopsy at diagnosis, adrenal primary tumor taken at surgical resection, and a liver metastasis at autopsy). Whole genome sequencing of the index liver metastasis identified 44 non-synonymous somatic mutations in 42 genes (0.85 mutation/MB) and a large hemizygous deletion in the ATRX gene which has been recently reported in neuroblastoma. Of these 45 somatic alterations, 15 were also detected in the primary tumor and bone marrow biopsy, while the other 30 were unique to the index tumor, indicating accumulation of de novo mutations during therapy. Furthermore, transcriptome sequencing on the 3 tumors demonstrated only 3 out of the 15 commonly mutated genes (LPAR1, GATA2, and NUFIP1) had high level of expression of the mutant alleles, suggesting potential oncogenic driver roles of these mutated genes. Among them, the druggable G-protein coupled receptor LPAR1 was highly expressed in all tumors. Cells expressing the LPAR1 R163W mutant demonstrated a significantly increased motility through elevated Rho signaling, but had no effect on growth. Therefore, this study highlights the need for multiple biopsies and sequencing during progression of a cancer and combinatorial DNA and RNA sequencing approach for systematic identification of expressed driver mutations.

High-throughput molecular and histopathologic profiling of tumor tissue in a novel transplantable model of murine neuroblastoma: new tools for pediatric drug discovery.

Using two MYCN transgenic mouse strains, we established 10 transplantable neuroblastoma cell lines via serial orthotopic passage in the adrenal gland. Tissue arrays demonstrate that by histochemistry, vascularity, immunohistochemical staining for neuroblastoma markers, catecholamine analysis, and concurrent cDNA microarray analysis, there is a close correspondence between the transplantable lines and the spontaneous tumors. Several genes closely associated with the pathobiology and immune evasion of neuroblastoma, novel targets that warrant evaluation, and decreased expression of tumor suppressor genes are demonstrated. These studies describe a unique and generalizable approach to expand the utility of transgenic models of spontaneous tumor, providing new tools for preclinical investigation.

Regulation of lung endoderm progenitor cell behavior by miR302/367.

The temporal and spatial control of organ-specific endoderm progenitor development is poorly understood. miRNAs affect cell function by regulating programmatic changes in protein expression levels. We show that the miR302/367 cluster is a target of the transcription factor Gata6 in mouse lung endoderm and regulates multiple aspects of early lung endoderm progenitor development. miR302/367 is expressed at early stages of lung development, but its levels decline rapidly as development proceeds. Gain- and loss-of-function studies show that altering miR302/367 expression disrupts the balance of lung endoderm progenitor proliferation and differentiation, as well as apical-basal polarity. Increased miR302/367 expression results in the formation of an undifferentiated multi-layered lung endoderm, whereas loss of miR302/367 activity results in decreased proliferation and enhanced lung endoderm differentiation. miR302/367 coordinates the balance between proliferation and differentiation, in part, through direct regulation of Rbl2 and Cdkn1a, whereas apical-basal polarity is controlled by regulation of Tiam1 and Lis1. Thus, miR302/367 directs lung endoderm development by coordinating multiple aspects of progenitor cell behavior, including proliferation, differentiation and apical-basal polarity.