Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.

Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine-tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.

SubcellulaRVis: a web-based tool to simplify and visualise subcellular compartment enrichment.

Cells contain intracellular compartments, including membrane-bound organelles and the nucleus, and are surrounded by a plasma membrane. Proteins are localised to one or more of these cellular compartments; the correct localisation of proteins is crucial for their correct processing and function. Moreover, proteins and the cellular processes they partake in are regulated by relocalisation in response to various cellular stimuli. High-throughput 'omics experiments result in a list of proteins or genes of interest; one way in which their functional role can be understood is through the knowledge of their subcellular localisation, as deduced through statistical enrichment for Gene Ontology Cellular Component (GOCC) annotations or similar. We have designed a bioinformatics tool, named SubcellulaRVis, that compellingly visualises the results of GOCC enrichment for quick interpretation of the localisation of a group of proteins (rather than single proteins). We demonstrate that SubcellulaRVis precisely describes the subcellular localisation of gene lists whose locations have been previously ascertained. SubcellulaRVis can be accessed via the web (http://phenome.manchester.ac.uk/subcellular/) or as a stand-alone app (https://github.com/JoWatson2011/subcellularvis). SubcellulaRVis will be useful for experimental biologists with limited bioinformatics expertise who want to analyse data related to protein (re)localisation and location-specific modules within the intracellular protein network.

The Implementation and Evaluation of an Innovative Clinical Immersion Experience for Undergraduate Nursing Students.

ABSTRACT: The demand for clinical placement sites for nursing students requires the development of alternative clinical settings. This study aimed to evaluate an innovative learning experience for nursing students at the World Scout Jamboree. Nineteen students and four faculty were assigned to base camp medical facilities, providing care for more than 45,000 campers. Student pre- and posttests reported significant increases in cultural awareness, communication skills, and clinical problem-solving ability; students rated interprofessional teamwork highly. Findings reveal promising direction for use of alternative clinical sites to fill the gap in clinical placements while offering unique learning experiences.

Using Multilayer Heterogeneous Networks to Infer Functions of Phosphorylated Sites.

Mass spectrometry-based quantitative phosphoproteomics has become an essential approach in the study of cellular processes such as signaling. Commonly used methods to analyze phosphoproteomics datasets depend on generic, gene-centric annotations such as Gene Ontology terms, which do not account for the function of a protein in a particular phosphorylation state. Analysis of phosphoproteomics data is hampered by a lack of phosphorylated site-specific annotations. We propose a method that combines shotgun phosphoproteomics data, protein-protein interactions, and functional annotations into a heterogeneous multilayer network. Phosphorylation sites are associated to potential functions using a random walk on the heterogeneous network (RWHN) algorithm. We validated our approach against a model of the MAPK/ERK pathway and functional annotations from PhosphoSitePlus and were able to associate differentially regulated sites on the same proteins to their previously described specific functions. We further tested the algorithm on three previously published datasets and were able to reproduce their experimentally validated conclusions and to associate phosphorylation sites with known functions based on their regulatory patterns. Our approach provides a refinement of commonly used analysis methods and accurately predicts context-specific functions for sites with similar phosphorylation profiles.

"It was one of those complicated cases": health practitioners' perspectives and practices of providing end-of-life care for people with profound intellectual and multiple disability.

BACKGROUND: Due to developments in health and social care, people with profound intellectual and multiple disability (PIMD) are living longer than ever before, meaning they are increasingly experiencing life-threatening health conditions requiring palliative care. Little is known about providing end-of-life care for people with PIMD. The aim of this study was to explore health practitioners' perspectives and practices relating to end-of-life decision-making and planning for people with PIMD. METHODS: Seven in-depth semi-structured interviews were conducted with health practitioners employed in a range of hospital and community services throughout Melbourne, Australia. Questions were designed to gather information about their experience, perceptions, and attitudes relating to people with PIMD during and at the end of their life. Each interview, ranging from 40 to 60 min in length, was audio recorded and transcribed. Inductive thematic analysis was used to analyse the data. RESULTS: Four main themes emerged: limited participation, bias, dignity, and quality of death. Health practitioners indicated that people with PIMD are frequently excluded from participating in decision-making related to end-of-life care. Participants discussed reasons for this exclusion including challenges with communication and cognition. Participants reported a need for additional support and guidance in providing care for people with PIMD at the end of life. Professional and family bias played a role in end-of-life decision-making for people with PIMD. Participants reported a disproportional focus by palliative care practitioners on physical as opposed to emotional and spiritual well-being for patients with PIMD at the end of life. Finally, participants reported that people with PIMD generally did not die in specialised palliative care settings, but in segregated supported living environments. CONCLUSIONS: Due to negative perceptions of a person with PIMD's decision-making capacity, people with PIMD are likely to be assessed as unable to express choice and preference regarding end-of-life care and are offered limited opportunity to be involved in their own end-of-life care. This research provides guidance for the development of training and professional development relating to people with PIMD at the end of life. It is hoped that this will increase the accessibility of end-of-life services for people with PIMD, ensuring that a respectful and dignified death can be a reality for all humankind regardless of disability.

Weighing up the risks and benefits of community gambling venues as recreational spaces for people with lifelong disability.

BACKGROUND: Community gambling venues (pubs and clubs) are commonly associated with leisure and recreational options in Australian communities. While these venues offer a range of activities and facilities, including social opportunities, sporting facilities, live entertainment, they also contain gambling products that are known to cause significant harm to individuals, their families and communities. Although researchers have explored how adults and children engage with these venues, there is limited understanding about the potential risks and benefits of these venues for people with lifelong disability. METHODS: Semi structured interviews were conducted with nineteen people aged 20-70 years with lifelong disability (includes in this context intellectual disability, autism spectrum disorder, ADHD, and learning disability), predominately intellectual disability. The interviews occurred in a large Australian city and explored interviewees' experiences and attitudes towards pubs and clubs. Using a range of visual prompts (if needed), participants were asked to describe their engagement in different activities offered within the venue. Interviews were audio-recorded and transcribed, with a thematic analysis used to identify themes across the group. RESULTS: Most participants attended venues with family, friends, and supporters, with a few attending on their own. Participants described socialising in the venue, going for reduced price meals, and attended for a range of activities including recreational activities, live entertainment and sport. Some participants also valued being a member of venues, and the interactions with staff members. While participants were cautious about the consumption of alcohol, most had gambled, particularly on electronic gambling machines (EGMs, pokies, or slots). Some participants stated that they had experienced problems with gambling. CONCLUSIONS: While many people with lifelong disability have positive experiences in pubs and clubs, some are vulnerable to the harms associated with risky products such as gambling within the venue. While it is important to acknowledge the positives associated with recreational facilities and encourage engagement in leisure activities for people with lifelong disability, further consideration is needed to ensure people are informed and protected from the harms associated with gambling and other products that are provided within these spaces.

Empowering junior doctors: a qualitative study of a QI programme in South West England.

AIM: To explore how the South-West Foundation Doctor Quality Improvement programme affected foundation year 1 (F1) doctors' attitudes and ability to implement change in healthcare. METHODS: Twenty-two qualitative interviews were carried out with two cohorts of doctors. The first F1 group before and after their participation in the QI programme; the second group comprised those who had completed the programme between 1 and 5 years earlier. Qualitative data were analysed using thematic analysis techniques. RESULTS : Prior to taking part in the QI programme, junior doctors' attitudes towards QI were mixed. Although there was agreement on the importance of QI in terms of patient safety, not all shared enthusiasm for engaging in QI, while some were sceptical that they could bring about any change. Following participation in the programme, attitudes towards QI and the ability to effect change were significantly transformed. Whether their projects were considered a success or not, all juniors reported that they valued the skills learnt and the overall experience they gained through carrying out QI projects. Participants reported feeling more empowered in their role as junior doctors, with several describing how they felt 'listened to' and able to 'have a voice', that they were beginning to see things 'at systems level' and learning to 'engage more critically' in their working environment. CONCLUSIONS : Junior doctors are ideally placed to engage in QI. Training in QI at the start of their medical careers may enable a new generation of doctors to acquire the skills necessary to improve patient safety and quality of care.

Supporting end of life decision making: Case studies of relational closeness in supported decision making for people with severe or profound intellectual disability.

BACKGROUND: The United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) promotes the use of supported decision making in lieu of substitute decision making. To date, there has been a lack of focus on supported decision making for people with severe or profound intellectual disability, including for end of life decisions. METHODS: Five people with severe or profound intellectual disability's experiences of supported decision making were examined. This article is particularly focused on one participant's experiences at the end of his life. RESULTS: All five case studies identified that supporters were most effective in providing decision-making support for participants when they were relationally close to the person and had knowledge of the person's life story, particularly in relation to events that demonstrated preference. CONCLUSIONS: Findings from this study provide new understandings of supported decision making for people with severe or profound intellectual disability and have particular relevance for supporting decision making at the end of life.

Nature-Based Design in Stroke Rehabilitation Environments: A Scoping Review.

OBJECTIVE: To identify, examine, and map the characteristics of knowledge of nature-based design in stroke rehabilitation facilities, examine how research in this field has been conducted and identify gaps in knowledge. BACKGROUND: Many stroke survivors have wide ranging impacts, resulting in long hospital stays to undertake rehabilitation. The physical environment can influence brain recovery; however, there is limited evidence to support the design of effective rehabilitation environments. Conversely, the health benefits available from connection with nature are well established. A nature-based design approach may have benefits and implications for the physical environment of inpatient stroke rehabilitation facilities; however, it is unclear what evidence exists in this field. METHOD: This scoping review followed the JBI methodological guidance for the conduct of scoping reviews, with systematic searches of six databases. RESULTS: Twenty-eight studies were included in the review. Aims and research methods varied widely. Investigations in 19 studies related to gardens and other designed outdoor nature-based environments. Other studies explored natural analogues, nature inside, inside/outside connections, and the natural environment. Findings from the studies were spread across the fields of design, use, exposure to, and engagement in nature-based environments. CONCLUSION: The characteristics of knowledge underpinning nature-based design in stroke rehabilitation environments are highly diverse, and significant gaps exist in the evidence base. A framework developed during this review for mapping knowledge on the intentions and impacts for spaces and services in this field assisted to identify these gaps and may be applied to other areas of healthcare design research.

Treating epidermal melasma with a 4% hydroquinone skin care system plus tretinoin cream 0.025%.

We sought to evaluate the efficacy and tolerability of treating melasma using a 4% hydroquinone skin care system, including a proprietary cleanser, toner, 4% hydroquinone, exfoliation enhancer, and sunscreen, plus tretinoin cream 0.025%. Together these products offer not only treatment of melasma but also a complete skin care regimen. Twenty participants with mild or moderate epidermal melasma with Fitzpatrick skin types III to VI were instructed to use the hydroquinone skin care system and tretinoin cream for 12 weeks. Melasma severity, melasma pigmentation intensity, and melasma area and severity index (MASI) score were significantly reduced from week 4 onward relative to baseline (P < or = .01). The proportion of participants who felt embarrassed or self-conscious about their skin very much or a lot declined from 80% (16/20) to 20% (4/20) between baseline and week 12. Similarly, the proportion of those who made very much or a lot of effort to hide their skin discoloration declined from 90% (18/20) to 37% (7/19). In total, 85% (17/20) of participants were satisfied with the overall effectiveness of the study treatment. Three participants had adverse events probably related to treatment (dryness, erythema, peeling, and stinging sensation). The 4% hydroquinone skin care system plus tretinoin cream 0.025% is effective and well-tolerated in the treatment of melasma.

Stretching beyond our perceived boundaries: The role of speech-language pathology in realising autonomy through supported decision-making.

PURPOSE: Based on a 2022 Speech Pathology Australia National Conference keynote address, the author explores the concept of autonomy and how it can be reconceptualised for people with profound intellectual and multiple disability through supported decision-making. METHOD: A collection of participatory action research studies with people with profound intellectual and multiple disability and their supporters are presented. Qualitative action research methodologies, including participatory observation, co-design workshops, and interviews, were used to explore supported decision-making for people with profound intellectual and multiple disability. RESULT: The insights have been used to co-design (with supporters) a definition and practice framework to enhance the autonomy of people with profound intellectual and multiple disability. CONCLUSION: Drawing on the construct of relational autonomy, readers are asked to reflect on their role as speech-language pathologists in enhancing autonomy of those they service, particularly people with profound intellectual and multiple disabilities. A definition of supported decision-making for people with profound intellectual and multiple disability along with a practice framework are offered. This body of work adds to a growing evidence base in supported decision-making, providing much needed practice guidance specifically relating to people with profound intellectual and multiple disability.

Investigating inequalities in men's health: a literature review.

As part of a project to review the delivery of healthcare services in Torbay and South Devon, England, the author undertook a literature review focusing on the specialty of men's health. Men have a shorter life expectancy than women and this discrepancy is particularly pronounced in areas of social deprivation such as those found in the coastal and rural communities of the author's locality. The concept of men's health is complex, and this literature review identified five main themes that can have a significant influence on the delivery of healthcare services for men: masculinity, ethnicity, mental health, relevance of place, and access to services. In this article, the author discusses these themes and considers approaches that could be used to improve the provision of men's healthcare.

Improving communication access in psychoeducational interventions for people with complex communication needs: a scoping review and stakeholder consultation.

PURPOSE: Psychoeducational interventions are commonly used to improve mental health among the general population; however, their application among people with complex communication needs is under explored. This scoping review aims to identify the psychoeducational interventions utilised with people with complex communication needs, any adaptations to improve communication access, and outcomes for this population. MATERIALS AND METHODS: The scoping review was conducted using the Arksey and O'Malley guidelines and included stakeholder consultations. A systematic search of the literature was conducted. Stakeholder consultations were conducted via semi-structured interviews with informants from three populations: people with complex communication needs, everyday communication partners and mental health workers. RESULTS: The search yielded 2112 articles. Twenty-four articles were retained for data extraction. Numerical analysis provided an overview of the existing literature. Thematic analysis highlighted the range of communication access strategies applied within psychoeducational interventions. Common aims and outcomes of interventions occurred across three interrelated themes: education, symptom reduction, and improved coping and wellbeing. Stakeholder consultations enabled contextualisation of literature. CONCLUSIONS: People with complex communication needs may benefit from psychoeducational interventions when effective, personalised communication access strategies are employed. Future research should include lived-experience perspectives to ensure the relevance of communication access strategies in mental health support.Implications for rehabilitationThis scoping review adds to the evidence base supporting equitable access to mental health support for people with complex communication needs.A range of specific strategies are presented for mental health workers to consider when working with people with complex communication needs.Positive behaviour support (PBS) practitioners must be equipped to address the psychoeducational and mental health support requirements of people with complex communication needs.

Exploring the communication needs and challenges of adults with autism spectrum disorders: Communication partners' perspectives.

Purpose: Individuals with autism spectrum disorders (ASD) and Complex Communication Needs (CCN) require additional support from communication partners in order to communicate effectively. This study aimed to address a current gap in the literature by exploring communication partners' perspectives of their role. Method: A qualitative multiple case study design was used. The sample consisted of four participants who represented a diverse range of relationships with adults with ASD and CCN. Individual, in-depth, semi-structured interviews were conducted. Interview transcripts were analysed using the Framework Method of thematic analysis. Result: Four key themes were identified: (1) respecting the individual (2) flexibility (3) reaching beyond the dyad and (4) underlying beliefs. Due to the diverse range of relationships represented in this study, each case provided a unique perspective and therefore the results of each individual case were contrasted within each theme. Conclusion: The findings of this study highlight the crucial role that communication partners play in enabling interactions with adults who have ASD and CCN. Additionally, these findings provide preliminary evidence to support an expansion of the existing framework of communicative competence for individuals with CCN. Future research should aim to expand on these findings in order to investigate their generalisability.

The impact of the United Nations Convention on the Rights of Persons with Disabilities (CRPD) on Victorian guardianship practice.

PURPOSE: Article 12 of the United Nations Convention on the Rights of Persons with Disabilities (CRPD) emphasises full and equal legal capacity of all citizens to participate in decisions. This paper examines whether the principles of Article 12, also reflected in other reform documents, were evident within 12 guardianship hearings conducted in Victoria, Australia from 2001 to 2016 involving adults with cognitive disability. The issues this study raises resonate loudly across the globe as multiple signatory nations to the CRPD grapple with the complexities of implementing Article 12. METHODS: Reports of VCAT decisions with written reasons of Guardianship List hearings from 2001 to 2016 were selected from the Australasian Legal Information Institute site and analysed thematically. RESULTS: Thematic analysis of proceedings revealed three consistent trends. Firstly, a presumption of incapacity based on disability excluded Proposed Represented Persons (PRP) from involvement in decision-making. Secondly, external perceptions of PRPs best interest were dominated by safeguarding concerns and conflict between supporters. Finally, in multiple cases, although a PRP's preference had been established, it was considered immaterial to the final decision. CONCLUSIONS: The paper concludes with a promising discussion of the new Guardianship and Administration Act 2019 (Vic), which came into force on 1 March 2020, and recommendations for guardianship practice both locally and internationally.IMPLICATIONS FOR REHABILITATIONLegal capacity should be recognised as inherent in all people, and therefore decision making incapacity should not be assumed based on a person's cognitive and/or communication disability;The supported decision making mechanisms, born from Article 12 of the CRPD, that facilitate acknowledgment, interpretation and acting upon a person's expression of will and preference need to be recognised and promoted within the context of Guardianship proceedings and by health professionals when assessing decision making capacity of people with cognitive disability;Significant knowledge and attitudinal changes are required within the Tribunal and incorporated into the practice of health professionals informing the Tribunal, in order to counter many conceptual underpinnings embedded within current guardianship legislation across the globe;Ascertaining the will and preference of the proposed represented person should be prioritised by Guardianship tribunal members' rather than the management of conflict between interested parties.

Education/Training Interventions to Improve Oral Health of Adults with Intellectual Disability.

People with intellectual disability have poorer oral health outcomes and experience greater difficulties accessing dental services than the rest of the community. Interdisciplinary educational programs for those involved in oral health decision making for people with intellectual disability aim to improve their oral health. This scoping review explored education/training interventions related to the oral health of adults with intellectual disability. Interventions targeted dental health and non-dental health professionals, adults with intellectual disability, and their paid and unpaid supporters. Six electronic databases were searched using PRISMA guidelines and the Crowes critical appraisal tool. The search strategy, plus the application of the inclusion and exclusion criteria, presented in the body of the manuscript, led to the selection of 20 papers for inclusion into this review. The quality of undergraduate tuition relating to disability was reported to be poor, but students and dental health professionals expressed interest in expanding their knowledge in this area. Disability-support workers and primary carers of people with intellectual disability reported improved knowledge and attitude, but the oral health status of the people they supported was not impacted. No research was found that explored the perspectives of non-dental health professionals. Oral health training/education contributes to systemic barriers in general health, wellbeing, and social inclusion of people with intellectual disability. Revision of disability-related programs in general dentistry courses and longitudinal impact research is needed.

Spatially resolved phosphoproteomics reveals fibroblast growth factor receptor recycling-driven regulation of autophagy and survival.

Receptor Tyrosine Kinase (RTK) endocytosis-dependent signalling drives cell proliferation and motility during development and adult homeostasis, but is dysregulated in diseases, including cancer. The recruitment of RTK signalling partners during endocytosis, specifically during recycling to the plasma membrane, is still unknown. Focusing on Fibroblast Growth Factor Receptor 2b (FGFR2b) recycling, we reveal FGFR signalling partners proximal to recycling endosomes by developing a Spatially Resolved Phosphoproteomics (SRP) approach based on APEX2-driven biotinylation followed by phosphorylated peptides enrichment. Combining this with traditional phosphoproteomics, bioinformatics, and targeted assays, we uncover that FGFR2b stimulated by its recycling ligand FGF10 activates mTOR-dependent signalling and ULK1 at the recycling endosomes, leading to autophagy suppression and cell survival. This adds to the growing importance of RTK recycling in orchestrating cell fate and suggests a therapeutically targetable vulnerability in ligand-responsive cancer cells. Integrating SRP with other systems biology approaches provides a powerful tool to spatially resolve cellular signalling.

Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.

Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cancer cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic to non-transformed cells but surprisingly not to cancer cells. Molecules underlying this cancer adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, is frequently up-regulated in melanoma, allowing melanoma cells to tolerate excess FA. DGAT1 over-expression alone transforms p53-mutant zebrafish melanocytes and co-operates with oncogenic BRAF or NRAS for more rapid melanoma formation. Antagonism of DGAT1 induces oxidative stress in melanoma cells, which adapt by up-regulating cellular reactive oxygen species defenses. We show that inhibiting both DGAT1 and superoxide dismutase 1 profoundly suppress tumor growth through eliciting intolerable oxidative stress.

Evaluation of a prescription strength 4% hydroquinone/10% L-ascorbic acid treatment system for normal to oily skin.

INTRODUCTION: A 4% hydroquinone/10% L-ascorbic acid treatment system aims to treat early signs of photodamage in normal to oily skin and help prevent further photodamage. The system also contains vitamin E, witch hazel, aloe barbadensis leaf juice, penetration-enhancing ingredients, micronized zinc oxide, and octinoxate. METHODS: Patients with minimal or mild facial photodamage and hyperpigmentation, and normal to oily facial skin, used the treatment system for 12 weeks. RESULTS: Of 34 females enrolled, 30 completed. Median scores for the overall integrated assessment of photodamage, overall intensity of pigmentation, fine lines and wrinkles, tactile roughness, and laxity were significantly improved at week 12 compared with baseline. Furthermore, ≥ 90 percent of patients considered their skin was smoother, softer, more evenly toned, and more radiant, and 100 percent were satisfied with the overall appearance of their skin. CONCLUSION: The treatment system can help to ameliorate early signs of photodamage in normal to oily skin.