Golgi-localized Ring Finger Protein 121 is necessary for MYCN-driven neuroblastoma tumorigenesis.

MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121WT) gene mutated to RNFM158R associated with heritable loss of tumorigenicity. While the RNF121WT protein localised predominantly to the cis-Golgi Complex, the RNF121M158R mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121WT expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121WT gene deletion reduced TH-MYCN tumorigenicity. The RNF121WT-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121WT transmembrane Helix 5. RNF121WT directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.

Barriers to healthcare access and experiences of stigma: Findings from a coproduced Long Covid case-finding study.

BACKGROUND AND AIM: Long Covid is often stigmatised, particularly in people who are disadvantaged within society. This may prevent them from seeking help and could lead to widening health inequalities. This coproduced study with a Community Advisory Board (CAB) of people with Long Covid aimed to understand healthcare and wider barriers and stigma experienced by people with probable Long Covid. METHODS: An active case finding approach was employed to find adults with probable, but not yet clinically diagnosed, Long Covid in two localities in London (Camden and Merton) and Derbyshire, England. Interviews explored the barriers to care and the stigma faced by participants and were analysed thematically. This study forms part of the STIMULATE-ICP Collaboration. FINDINGS: Twenty-three interviews were completed. Participants reported limited awareness of what Long Covid is and the available pathways to management. There was considerable self-doubt among participants, sometimes reinforced by interactions with healthcare professionals (HCPs). Participants questioned their deservedness in seeking healthcare support for their symptoms. Hesitancy to engage with healthcare services was motivated by fear of needing more investigation and concerns regarding judgement about the ability to carry out caregiving responsibilities. It was also motivated by the complexity of the clinical presentation and fear of all symptoms being attributed to poor mental health. Participants also reported trying to avoid overburdening the health system. These difficulties were compounded by experiences of stigma and discrimination. The emerging themes reaffirmed a framework of epistemic injustice in relation to Long Covid, where creating, interpreting and conveying knowledge has varied credibility based on the teller's identity characteristics and/or the level of their interpretive resources. CONCLUSION: We have codeveloped recommendations based on the findings. These include early signposting to services, dedicating protected time to listening to people with Long Covid, providing a holistic approach in care pathways, and working to mitigate stigma. Regardless of the diagnosis, people experiencing new symptoms must be encouraged to seek timely medical help. Clear public health messaging is needed among communities already disadvantaged by epistemic injustice to raise awareness of Long Covid, and to share stories that encourage seeking care and to illustrate the adverse effects of stigma. PATIENT OR PUBLIC CONTRIBUTION: This study was coproduced with a CAB made up of 23 members including HCPs, people with lived experience of Long Covid and other stakeholders.

"I Had to Know About It, I Had to Find It, I Had to Know How to Access it": Experiences of Access to Rehabilitation Services Among People Living with Long COVID.

Purpose: The aim of this qualitative study is to understand the need for, access to, and quality of rehabilitation services for people living with Long COVID. Little is known about the experiences of people living with Long COVID accessing rehabilitation services. Therefore, we explored health concerns leading people living with Long COVID to seek help to address functional concerns and their experiences with accessing and participating in rehabilitation. Method: Interpretive description guided exploration of participants' experiences with Long COVID rehabilitation in Alberta, Canada. Semi-structured interviews were completed with 56 participants recruited from: three publicly funded Long COVID clinics, a specialized private physiotherapy clinic, a telephone-based rehabilitation advice line, and a Workers' Compensation Board-funded Long COVID rehabilitation program. Recruitment through mass media coverage allowed us to include people who did not access rehabilitation services. Data analysis was informed by Braun and Clarke's reflexive thematic analysis. Results: Four themes were identified: (1) the burden of searching for guidance to address challenges with functioning and disability; (2) supportive relationships promote engagement in rehabilitation; (3) conditions for participation in safe rehabilitation; and (4) looking forward - provision of appropriate interventions at the right time. Conclusions: Our findings highlight the experiences of accessing rehabilitation services for people living with Long COVID. Results suggest approaches to Long COVID rehabilitation should be accessible, multi-disciplinary, flexible, and person-centred.

Objectif: étude qualitative pour comprendre les besoins en services de réadaptation des personnes qui vivent avec la COVID longue, l'accès à ces services et leur qualité. On sait peu de choses sur les expériences des personnes qui vivent avec la COVID longue et accèdent à des services de réadaptation. C'est pourquoi les auteurs ont exploré les inquiétudes qui incitent ces personnes à demander de l'aide pour répondre à leurs problèmes fonctionnels et les expériences qu'elles ont vécues en matière d'accès à la réadaptation et de participation aux services qui y sont associés. Méthodologie: exploration guidée de la description interprétative des expériences des participants qui suivent une réadaptation à cause de la COVID longue en Alberta, au Canada. Les chercheurs ont procédé à des entrevues semi-structurées auprès de 56 participants recrutés dans trois cliniques de COVID longue financées par le gouvernement, une clinique de physiothérapie spécialisée privée, une ligne téléphonique de conseils en réadaptation et un programme de réadaptation après la COVID longue remboursé par la commission des accidents de travail. Le recrutement dans les médias de masse a permis d'inclure des personnes qui n'avaient pas accédé aux services de réadaptation. L'examen des données reposait sur l'analyse thématique réflexive de Braun et Clarke. Résultats: les chercheurs ont relevé quatre thèmes : 1) le fardeau de la recherche de conseils pour répondre aux problèmes de fonctionnement et d'incapacité; 2) les relations de soutien qui favorisent la participation à la réadaptation; 3) les conditions nécessaires pour participer à une réadaptation sécuritaire et 4) pour l'avenir, la prestation d'interventions appropriées au bon moment. Conclusions: les constatations des auteurs font ressortir les expériences d'accès aux services de réadaptation chez les personnes qui vivent avec la COVID longue. Selon les résultats, les approches de réadaptation après la COVID longue devraient être accessibles, multidisciplinaires, flexibles et axées sur l'individu.

Episodic disability questionnaire (EDQ) measurement properties among adults living with HIV in Canada, Ireland, United Kingdom, and United States.

BACKGROUND: The Episodic Disability Questionnaire (EDQ) is a generic 35-item patient-reported outcome measure of presence, severity and episodic nature of disability. We assessed the measurement properties of the Episodic Disability Questionnaire (EDQ) with adults living with HIV. METHODS: We conducted a measurement study with adults living with HIV in eight clinical settings in Canada, Ireland, United Kingdom, and United States. We electronically administered the EDQ followed by three reference measures (World Health Organization Disability Assessment Schedule; Patient Health Questionnaire; Social Support Scale) and a demographic questionnaire. We administered the EDQ only 1 week later. We assessed the internal consistency reliability (Cronbach's alpha; > 0.7 acceptable), and test-retest reliability (Intra Class Correlation Coefficient; > 0.7 acceptable). We estimated required change in EDQ domain scores to be 95% certain that a change was not due to measurement error (Minimum Detectable Change (MDC95%)). We evaluated construct validity by assessing 36 primary hypotheses of relationships between EDQ scores and scores on the reference measures (> 75% hypotheses confirmed indicated validity). RESULTS: Three hundred fifty nine participants completed the questionnaires at time point 1, of which 321 (89%) completed the EDQ approximately 1 week later. Cronbach's alpha for internal consistency ranged from 0.84 (social domain) to 0.91 (day domain) for the EDQ severity scale, and 0.72 (uncertainty domain) to 0.88 (day domain) for the EDQ presence scale, and 0.87 (physical, cognitive, mental-emotional domains) to 0.89 (uncertainty domain) for the EDQ episodic scale. ICCs for test-retest reliability ranged from 0.79 (physical domain) to 0.88 (day domain) for the EDQ severity scale and from 0.71 (uncertainty domain) to 0.85 (day domain) for the EDQ presence scale. Highest precision was demonstrated in the severity scale for each domain (MDC95% range: 19-25 out of 100), followed by the presence (MDC95% range: 37-54) and episodic scales (MDC95% range:44-76). Twenty-nine of 36 (81%) construct validity hypotheses were confirmed. CONCLUSIONS: The EDQ possesses internal consistency reliability, construct validity, and test-retest reliability, with limited precision when administered electronically with adults living with HIV across in clinical settings in four countries. Given the measurement properties, the EDQ can be used for group level comparisons for research and program evaluation in adults living with HIV.

"None of us are lying": an interpretive description of the search for legitimacy and the journey to access quality health services by individuals living with Long COVID.

BACKGROUND: Understanding of Long COVID has advanced through patient-led initiatives. However, research about barriers to accessing Long COVID services is limited. This study aimed to better understand the need for, access to, and quality of, Long COVID services. We explored health needs and experiences of services, including ability of services to address needs. METHODS: Our study was informed by the Levesque et al.'s (2013) "conceptual framework of access to health care." We used Interpretive Description, a qualitative approach partly aimed at informing clinical decisions. We recruited participants across five settings. Participants engaged in one-time, semi-structured, virtual interviews. Interviews were transcribed verbatim. We used reflexive thematic analysis. Best practice to ensure methodological rigour was employed. RESULTS: Three key themes were generated from 56 interviews. The first theme illustrated the rollercoaster-like nature of participants' Long COVID symptoms and the resulting impact on function and health. The second theme highlighted participants' attempts to access Long COVID services. Guidance received from healthcare professionals and self-advocacy impacted initial access. When navigating Long COVID services within the broader system, participants encountered barriers to access around stigma; appointment logistics; testing and 'normal' results; and financial precarity and affordability of services. The third theme illuminated common factors participants liked and disliked about Long COVID services. We framed each sub-theme as the key lesson (stemming from all likes and dislikes) that, if acted upon, the health system can use to improve the quality of Long COVID services. This provides tangible ways to improve the system based directly on what we heard from participants. CONCLUSION: With Long COVID services continuously evolving, our findings can inform decision makers within the health system to better understand the lived experiences of Long COVID and tailor services and policies appropriately.

Research priorities in HIV, aging and rehabilitation: building on a framework with the Canada-International HIV and Rehabilitation Research Collaborative.

BACKGROUND: In 2016, the Canada-International HIV and Rehabilitation Research Collaborative established a framework of research priorities in HIV, aging and rehabilitation. Our aim was to review and identify any new emerging priorities from the perspectives of people living with HIV, clinicians, researchers, and representatives from community organizations. METHODS: We conducted a multi-stakeholder international consultation with people living with HIV, researchers, clinicians and representatives of community-based organizations. Stakeholders convened for a one-day Forum in Manchester, United Kingdom (UK) to discuss research priorities via a web-based questionnaire and facilitated discussions. We analyzed data using conventional content analytical techniques and mapped emerging priorities onto the foundational framework. RESULTS: Thirty-five stakeholders from the UK(n = 29), Canada(n = 5) and Ireland(n = 1) attended the Forum, representing persons living with HIV or representatives from community-based organizations(n = 12;34%), researchers or academics(n = 10;28%), service providers(n = 6;17%), clinicians(n = 4;11%); and trainees(n = 4;11%). Five priorities mapped onto the Framework of Research Priorities across three content areas: A-Episodic Health and Disability Aging with HIV (disability, frailty, social participation), B-Rehabilitation Interventions for Healthy Aging across the Lifespan (role, implementation and impact of digital and web-based rehabilitation interventions) and C-Outcome Measurement in HIV and Aging (digital and web-based rehabilitation health technology to measure physical activity). Stakeholders indicated methodological considerations for implementing digital and web-based rehabilitation interventions into research and practice and the importance of knowledge transfer and exchange among the broader community. CONCLUSION: Results highlight the sustained importance of the Framework of Research Priorities and provide further depth and areas of inquiry related to digital and web-based rehabilitation interventions and technology aging with HIV.

Long Covid active case finding study protocol: A co-produced community-based pilot within the STIMULATE-ICP study (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways).

BACKGROUND AND AIM: Long Covid is a significant public health concern with potentially negative implications for health inequalities. We know that those who are already socially disadvantaged in society are more exposed to COVID-19, experience the worst health outcomes and are more likely to suffer economically. We also know that these groups are more likely to experience stigma and have negative healthcare experiences even before the pandemic. However, little is known about disadvantaged groups' experiences of Long Covid, and preliminary evidence suggests they may be under-represented in those who access formal care. We will conduct a pilot study in a defined geographical area in London, United Kingdom to test the feasibility of a community-based approach of identifying Long Covid cases that have not been clinically diagnosed and have not been referred to Long Covid specialist services. We will explore the barriers to accessing recognition, care, and support, as well as experiences of stigma and perceived discrimination. METHODS: This protocol and study materials were co-produced with a Community Advisory Board (CAB) made up primarily of people living with Long Covid. Working with voluntary organisations, a study leaflet will be distributed in the local community to highlight Long Covid symptoms and invite those experiencing them to participate in the study if they are not formally diagnosed. Potential participants will be assessed according to the study's inclusion criteria and offered the opportunity to participate if they fit them. Awareness of Long Covid and associated symptoms, experiences of trying to access care, as well as stigma and discrimination will be explored through qualitative interviews with participants. Upon completion of the interviews, participants will be offered a referral to the local social prescribing team to receive support that is personalised to them potentially including, but not restricted to, liaising with their primary care provider and the regional Long Covid clinic.

Episodic Disability Questionnaire (EDQ) measurement properties among adults living with HIV in Canada, Ireland, United Kingdom, and United States.

Background: The Episodic Disability Questionnaire (EDQ) is a generic 35-item patient-reported outcome measure of presence, severity and episodic nature of disability. We assessed the measurement properties of the Episodic Disability Questionnaire (EDQ) with adults living with HIV. Methods: We conducted a measurement study with adults living with HIV in eight clinical settings in Canada, Ireland, United Kingdom, and United States. We electronically administered the EDQ followed by three reference measures (World Health Organization Disability Assessment Schedule; Patient Health Questionnaire; Social Support Scale) and a demographic questionnaire. We administered the EDQ only 1 week later. We assessed the internal consistency reliability (Cronbach's alpha; >0.7 acceptable), and test-retest reliability (Intra Class Correlation Coefficient; >0.7 acceptable). We estimated required change in EDQ domain scores to be 95% certain that a change was not due to measurement error (Minimum Detectable Change (MDC95%)). We evaluated construct validity by assessing 36 primary hypotheses of relationships between EDQ scores and scores on the reference measures (> 75% hypotheses confirmed indicated validity). Results: 359 participants completed the questionnaires at time point 1, of which 321 (89%) completed the EDQ approximately 1 week later. Cronbach's alpha for internal consistency ranged from 0.84 (social domain) to 0.91 (day domain) for the EDQ severity scale, and 0.72 (uncertainty domain) to 0.88 (day domain) for the EDQ presence scale, and 0.87 (physical, cognitive, mental-emotional domains) to 0.89 (uncertainty domain) for the EDQ episodic scale. ICCs for test-retest reliability ranged from 0.79 (physical domain) to 0.88 (day domain) for the EDQ severity scale and from 0.71 (uncertainty domain) to 0.85 (day domain) for the EDQ presence scale. Highest precision was demonstrated in the severity scale for each domain (MDC95% range: 19-25 out of 100), followed by the presence (MDC95% range: 37-54) and episodic scales (MDC95% range:44-76). Twenty-nine of 36 (81%) construct validity hypotheses were confirmed. Conclusions: The EDQ possesses internal consistency reliability, construct validity, and test-retest reliability, with limited precision when administered electronically with adults living with HIV across in clinical settings in four countries. Given the measurement properties, the EDQ can be used for group level comparisons for research and program evaluation in adults living with HIV.

Piloting an online telecoaching community-based exercise intervention with adults living with HIV: protocol for a mixed-methods implementation science study.

INTRODUCTION: Our aim is to evaluate the implementation of an online telecoaching community-based exercise (CBE) intervention with the goal of reducing disability and enhancing physical activity and health among adults living with HIV. METHODS AND ANALYSIS: We will conduct a prospective longitudinal mixed-methods two-phased intervention study to pilot the implementation of an online CBE intervention with ~30 adults (≥18 years) living with HIV who consider themselves safe to participate in exercise. In the intervention phase (0-6 months), participants will take part in an online CBE intervention involving thrice weekly exercise (aerobic, resistance, balance and flexibility), with supervised biweekly personal training sessions with a fitness instructor, YMCA membership providing access to online exercise classes, wireless physical activity monitor to track physical activity and monthly online educational sessions on topics related to HIV, physical activity and health. In the follow-up phase (6-12 months), participants will be encouraged to continue independent exercise thrice weekly. Quantitative assessment: Bimonthly, we will assess cardiopulmonary fitness, strength, weight, body composition and flexibility, followed by administering self-reported questionnaires to assess disability, contextual factor outcomes (mastery, engagement in care, stigma, social support), implementation factors (cost, feasibility, technology), health status and self-reported physical activity. We will conduct a segmented regression analyses to describe the change in level and trend between the intervention and follow-up phases. Qualitative assessment: We will conduct online interviews with a subsample of ~10 participants and 5 CBE stakeholders at baseline (month 0), postintervention (month 6) and end of follow-up (month 12) to explore experiences, impact and implementation factors for online CBE. Interviews will be audiorecorded and analysed using content analytical techniques. ETHICS AND DISSEMINATION: Protocol approved by the University of Toronto Research Ethics Board (Protocol # 40410). Knowledge translation will occur in the form of presentations and publications in open-access peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05006391.

Conceptualising the episodic nature of disability among adults living with Long COVID: a qualitative study.

INTRODUCTION: Our aim was to describe episodic nature of disability among adults living with Long COVID. METHODS: We conducted a community-engaged qualitative descriptive study involving online semistructured interviews and participant visual illustrations. We recruited participants via collaborator community organisations in Canada, Ireland, UK and USA.We recruited adults who self-identified as living with Long COVID with diversity in age, gender, race/ethnicity, sexual orientation and duration since initial COVID infection between December 2021 and May 2022. We used a semistructured interview guide to explore experiences of disability living with Long COVID, specifically health-related challenges and how they were experienced over time. We asked participants to draw their health trajectory and conducted a group-based content analysis. RESULTS: Among the 40 participants, the median age was 39 years (IQR: 32-49); majority were women (63%), white (73%), heterosexual (75%) and living with Long COVID for ≥1 year (83%). Participants described their disability experiences as episodic in nature, characterised by fluctuations in presence and severity of health-related challenges (disability) that may occur both within a day and over the long-term living with Long COVID. They described living with 'ups and downs', 'flare-ups' and 'peaks' followed by 'crashes', 'troughs' and 'valleys', likened to a 'yo-yo', 'rolling hills' and 'rollercoaster ride' with 'relapsing/remitting', 'waxing/waning', 'fluctuations' in health. Drawn illustrations demonstrated variety of trajectories across health dimensions, some more episodic than others. Uncertainty intersected with the episodic nature of disability, characterised as unpredictability of episodes, their length, severity and triggers, and process of long-term trajectory, which had implications on broader health. CONCLUSION: Among this sample of adults living with Long COVID, experiences of disability were described as episodic, characterised by fluctuating health challenges, which may be unpredictable in nature. Results can help to better understand experiences of disability among adults living with Long COVID to inform healthcare and rehabilitation.

Assessing the sensibility and utility of a short-form version of the HIV Disability Questionnaire in clinical practice settings in Canada, Ireland and the USA: a mixed methods study.

OBJECTIVES: The Short-Form HIV Disability Questionnaire (SF-HDQ) was developed to measure the presence, severity and episodic nature of health challenges across six domains. Our aim was to assess the sensibility, utility and implementation of the SF-HDQ in clinical practice. DESIGN: Mixed methods study design involving semistructured interviews and questionnaire administration. PARTICIPANTS: We recruited adults living with HIV and HIV clinicians in Canada, Ireland and the USA. METHODS: We electronically administered the SF-HDQ followed by a Sensibility Questionnaire (face and content validity, ease of usage, format) and conducted semistructured interviews to explore the utility and implementation of the SF-HDQ in clinical practice. The threshold for sensibility was a median score of >5/7 (adults living with HIV) and>4/7 (HIV clinicians) for ≥80% of items. Qualitative interview data were analysed using directed content analysis. RESULTS: Median sensibility scores were >5 (adults living with HIV; n=29) and >4 (HIV clinicians; n=16) for 18/19 (95%) items. Interview data indicated that the SF-HDQ represents the health-related challenges of living with HIV and other concurrent health conditions; captures the daily episodic nature of HIV; and is easy to use. Clinical utility included measuring health challenges and change over time, guiding referral to specialists and services, setting goals, facilitating communication and fostering a multidisciplinary approach to care. Considerations for implementation included flexible, person-centred approaches to administration, and communicating scores based on personal preferences. CONCLUSIONS: The SF-HDQ possesses sensibility and utility for use in clinical settings with adults living with HIV and HIV clinicians in three countries.

Prevalence, severity, and risk factors of disability among adults living with HIV accessing routine outpatient HIV care in London, United Kingdom (UK): A cross-sectional self-report study.

BACKGROUND: The study objectives were to measure disability prevalence and severity, and examine disability risk factors, among adults living with HIV in London, United Kingdom (UK). METHODS: Self-reported questionnaires were administered: World Health Organization Disability Assessment Schedule 2.0 (WHODAS), HIV Disability Questionnaire (HDQ), Equality Act disability definition (EADD), and demographic questionnaire. We calculated proportion (95% Confidence Interval; CI) of "severe" and "moderate" disability measured using EADD and WHODAS scores ≥2 respectively. We measured disability severity with HDQ domain severity scores. We used demographic questionnaire responses to assess risk factors of "severe" and "moderate" disability using logistic regression analysis, and HDQ severity domain scores using linear regression analysis. RESULTS: Of 201 participants, 176 (87.6%) identified as men, median age 47 years, and 194 (96.5%) virologically suppressed. Severe disability prevalence was 39.5% (n = 79/201), 95% CI [32.5%, 46.4%]. Moderate disability prevalence was 70.5% (n = 141/200), 95% CI [64.2%, 76.8%]. Uncertainty was the most severe HDQ disability domain. Late HIV diagnosis was a risk factor for severe disability [Odds Ratio (OR) 2.71; CI 1.25, 5.87]. Social determinants of health, economic inactivity [OR 2.79; CI 1.08, 7.21] and receiving benefits [OR 2.87; CI 1.05, 7.83], were risk factors for "severe" disability. Economic inactivity [OR 3.14; CI 1.00, 9.98] was a risk factor for "moderate" disability. Economic inactivity, receiving benefits, and having no fixed abode were risk factors (P≤0.05) for higher HDQ severity scores in physical, mental and emotional, difficulty with day-to-day activities, and challenges to social participation domains. Personal factors, identifying as a woman and being aged <50 years, were risk factors (P≤0.05) for higher HDQ severity scores in mental and emotional, uncertainty, and challenges with social participation domains. CONCLUSIONS: People living with well-controlled HIV in London UK experienced multi-dimensional and episodic disability. Results help to better understand the prevalence, severity, and risk factors of disability experienced by adults living with HIV, identify areas to target interventions, and optimise health and functioning.

Long COVID and episodic disability: advancing the conceptualisation, measurement and knowledge of episodic disability among people living with Long COVID - protocol for a mixed-methods study.

INTRODUCTION: As the prevalence of Long COVID increases, there is a critical need for a comprehensive assessment of disability. Our aims are to: (1) characterise disability experiences among people living with Long COVID in Canada, UK, USA and Ireland; and (2) develop a patient-reported outcome measure to assess the presence, severity and episodic nature of disability with Long COVID. METHODS AND ANALYSIS: In phase 1, we will conduct semistructured interviews with adults living with Long COVID to explore experiences of disability (dimensions, uncertainty, trajectories, influencing contextual factors) and establish an episodic disability (ED) framework in the context of Long COVID (n~10 each country). Using the conceptual framework, we will establish the Long COVID Episodic Disability Questionnaire (EDQ). In phase 2, we will examine the validity (construct, structural) and reliability (internal consistency, test-retest) of the EDQ for use in Long COVID. We will electronically administer the EDQ and four health status criterion measures with adults living with Long COVID, and readminister the EDQ 1 week later (n~170 each country). We will use Rasch analysis to refine the EDQ, and confirm structural and cross-cultural validity. We will calculate Cronbach's alphas (internal consistency reliability), and intraclass correlation coefficients (test-retest reliability), and examine correlations for hypotheses theorising relationships between EDQ and criterion measure scores (construct validity). Using phase 2 data, we will characterise the profile of disability using structural equation modelling techniques to examine relationships between dimensions of disability and the influence of intrinsic and extrinsic contextual factors. This research involves an academic-clinical-community partnership building on foundational work in ED measurement, Long COVID and rehabilitation. ETHICS AND DISSEMINATION: This study was approved by the University of Toronto Research Ethics Board. Knowledge translation will occur with community collaborators in the form of presentations and publications in open access peer-reviewed journals and presentations.

Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages.

A hallmark of Listeria (L.) monocytogenes pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for L. monocytogenes infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of L. monocytogenes and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious Listeria-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular L. monocytogenes from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar L. monocytogenes replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of L. monocytogenes in macrophages is not inevitably tied to bacterial persistence.

An Exploration of the Experiences of Physical Therapists Who Identify as LGBTQIA+: Navigating Sexual Orientation and Gender Identity in Clinical, Academic, and Professional Roles.

OBJECTIVE: The purpose of this study was to explore physical therapy through the stories of physical therapists who identify as lesbian, gay, bisexual, transgender, queer, intersex, asexual, and other related identities (LGBTQIA+) to consider how the profession enacts and constructs gender and sexual orientation. METHODS: Physical therapists with clinical, academic, and professional roles who identify as LGBTQIA+ were recruited from Australia, the United Kingdom, Canada, and the United States. In-depth data were collected via narrative interviews. An iterative group discourse analysis was used to examine key discourses underpinning interview narratives and how these relate to the physical therapy profession. RESULTS: Twenty-two physical therapists were interviewed. Participants had between 1.5 and 40 years of experience across various clinical areas and settings. Participants identified with varying sexual orientations and gender identities. Analysis identified discourses discussed under the following headings: (1) normativity, which related to hetero-normative assumptions about sexual orientation and cisnormative assumptions about gender identity and the intersectionality among sexual orientation, gender identity, and other forms of marginalization; (2) stress and labor, which explored the stress experienced by physical therapists who are LGBTQIA+ (due to fear of discrimination or actual discrimination) and additional emotional and other types of labor or work done in the workplace to hide aspects of their lives to feel safe, educate colleagues, and be a role model; and (3) professionalism, which related to the heterosexual/cisnormative (and other) "norms" that comprised participants' ideas of presenting as "professional" and positioning physical therapists who are LGBTQIA+ as "unprofessional." CONCLUSION: Findings suggest that cultural norms may need to be reconceptualized in physical therapy to promote inclusion and belonging of individuals who identify as LGBTQIA+. Approaches to upskill new and existing physical therapists may include elements such as individual and institutional reflexivity, learning and implementing appropriate terminology, displaying indicators of inclusivity, and cultural safety training. These elements may provide the first steps to promote inclusive and culturally safe environments for individuals who identify as LGBTQIA+ within the profession. IMPACT: This is the first known study to explore the lived experiences of those who identify as LGBTQIA+ in the physical therapy profession. The findings highlight how prevailing normative discourses in Western society are also present in physical therapy and impact those who identify as LGBTQIA+.

Disability and self-care living strategies among adults living with HIV during the COVID-19 pandemic.

BACKGROUND: Events associated with the COVID-19 pandemic, such as physical distancing, closure of community services, postponement of health appointments, and loss of employment can lead to social isolation, financial uncertainty, and interruption of antiretroviral adherence, resulting in additional health-related challenges (disability) experienced among adults living with chronic illness such as HIV. 'Living strategies' is a concept derived from the perspectives of people living with HIV, defined as behaviors, attitudes and beliefs adopted by people living with HIV to help deal with disability associated with HIV and multi-morbidity. Our aim was to describe disability among adults living with HIV and self-care living strategies used during the COVID-19 pandemic. METHODS: Adults living with HIV in Toronto, Ontario, Canada, including some with pre-pandemic HIV Disability Questionnaire (HDQ) data, completed a cross-sectional web-based survey between June-August 2020. The survey included the HDQ and questions about self-care living strategy use during the pandemic. We compared disability (HDQ) scores prior to versus during the pandemic using paired t-tests. We reported the proportion of participants who engaged in various living strategies at least 'a few times a week' or 'everyday' during the pandemic. RESULTS: Of the 63 respondents, 84% were men, median age 57 years, and 62% lived alone. During the pandemic the greatest disability severity was in the uncertainty [median 30; Interquartile range (IQR): 16, 43] and mental-emotional (25; IQR: 14, 41) domains. Among the 51 participants with pre-pandemic data, HDQ severity scores were significantly greater (worse) during the pandemic (vs prior) in all domains. Greatest change from prior to during the pandemic was in the mental-emotional domain for presence (17.7; p < 0.001), severity (11.4; p < 0.001), and episodic nature (9.3; p < 0.05) of disability. Most participants (> 60%) reported engaging a 'few times a week' or 'everyday' in self-care strategies associated with maintaining sense of control and adopting positive attitudes and beliefs. CONCLUSIONS: People living with HIV reported high levels of uncertainty and mental-emotional health challenges during the pandemic. Disability increased across all HDQ dimensions, with the greatest worsening in the mental-emotional health domain. Results provide an understanding of disability and self-care strategy use during the COVID-19 pandemic.