A systematic review of the barriers and facilitators impacting patient enrolment in clinical trials for lung cancer.

PURPOSE: Clinical research trials are needed to enhance the medical care and treatment for lung cancer, which remains the leading cause of cancer-related deaths worldwide. While clinical trials allow for the development of novel therapies to treat cancer, the recruitment of lung cancer patients to trials is low. This review aimed to identify and synthesise the available literature concerning barriers and facilitators affecting lung cancer patients' decisions to enrol in clinical trials to guide future cancer research efforts. METHODS: Four databases were systematically searched: Academic Search Complete, CINHAL, PubMed, and PsycINFO in August 2023. A supplemental grey literature search was also conducted alongside this. Articles were quality appraised using CASP and JMI checklists, and results were narratively synthesised. RESULTS: Eighteen articles of varied design met the inclusion criteria, and results were mapped onto the Capability, Opportunity, and Motivation Behaviour (COM-B) Model to help structure and conceptualise review findings. Evidence suggests that the decision to enrol in a trial is multifaceted and informed by: when and how study information is presented, travel and trial eligibility, and altruistic hopes and fears. CONCLUSIONS: There is need to address the many different concerns that lung cancer patients have about participating in a clinical trial through the supply of accessible and timely trial information, and via the reduction of travel, expansion of study eligibility criteria, and recognition of a person's altruistic wishes, hopes, fears, and family-oriented concerns. Future research should aim to work alongside lung cancer patients, clinicians, and other stakeholders to increase research accessibility.

Understanding the lived-experience and support-needs of people living with antimicrobial resistance in the UK through interpretative phenomenological analysis.

In the UK nearly 54,000 infections were caused by serious resistant bacteria in 2022 but there is a lack of evidence regarding the long-term impact on patients' lives nor what support they need. This research aimed to answer the question: "What are the key elements of experience and support needs of people living with AMR in the UK?". In-depth semi-structured interviews were undertaken with nine people who had been living with resistant infections or colonisation for 12-months or longer. Interpretive Phenomenological Analysis was used to study the accounts and illustrate individuals' experiences and support-needs. Participants experienced marginalisation and isolation but also empowerment; described across three major themes: (1) I live in fear and stigma: The long-term impact of AMR; (2) I am battling on my own: A journey toward self-advocacy; and (3) I like to share my story: The role of AMR communities. All participants perceived a lack of knowledge, information, and support from clinicians; difficulties accessing reliable and understandable information; and lack of understanding from family and friends. Charities and online groups provided support with coping with their situation and improving mental health and wellbeing. Understandable and relatable information regarding the science of AMR, transmission, prevention, and living with AMR needs to be provided by clinicians and healthcare services around the time of diagnosis to readily available after diagnosis.

Dispersal of PRC1 condensates disrupts polycomb chromatin domains and loops.

Polycomb repressive complex 1 (PRC1) strongly influences 3D genome organization, mediating local chromatin compaction and clustering of target loci. Several PRC1 subunits have the capacity to form biomolecular condensates through liquid-liquid phase separation in vitro and when tagged and over-expressed in cells. Here, we use 1,6-hexanediol, which can disrupt liquid-like condensates, to examine the role of endogenous PRC1 biomolecular condensates on local and chromosome-wide clustering of PRC1-bound loci. Using imaging and chromatin immunoprecipitation, we show that PRC1-mediated chromatin compaction and clustering of targeted genomic loci-at different length scales-can be reversibly disrupted by the addition and subsequent removal of 1,6-hexanediol to mouse embryonic stem cells. Decompaction and dispersal of polycomb domains and clusters cannot be solely attributable to reduced PRC1 occupancy detected by chromatin immunoprecipitation following 1,6-hexanediol treatment as the addition of 2,5-hexanediol has similar effects on binding despite this alcohol not perturbing PRC1-mediated 3D clustering, at least at the sub-megabase and megabase scales. These results suggest that weak hydrophobic interactions between PRC1 molecules may have a role in polycomb-mediated genome organization.

How multiple threats to safety affects quality of life for picky eating adults: A new explanatory model.

Picky eating describes a pattern of eating characterised by a narrow dietary range with rejection of both novel and familiar foods. Research has suggested that picky eating in adulthood is associated with several negative psychosocial outcomes including impaired quality of life. This research aimed to build and test a model explaining the relationship between picky eating and quality of life. 230 participants were recruited via online support forums for picky eating, and an undergraduate research participation scheme. Participants completed self-report measures of picky eating, sensory sensitivity, disgust, anxiety, fear of negative evaluation and eating related quality of life. Regression analysis indicated that picky eating, disgust sensitivity, anxiety, and fear of negative evaluation were all associated with impaired eating-related quality of life. A theoretical model was then devised which aimed to explain the interactions between these factors, and Path Analysis indicated that this model was a good fit for the data. This Safety in Picky Eating and Quality of life (SPEQ) model suggests that threat perception and the drive for safety underlies the relationship between picky eating and impaired quality of life. The SPEQ model provides a preliminary basis for understanding how picky eating impacts quality of life in adulthood.

A Mixed-Methods Evaluation of "The Quest," A Health and Well-Being Intervention for British-Based Black, Asian and Minority Ethnic Gay and Bisexual Men.

This article provides an evaluation of a health and well-being workshop-based intervention, "The Quest" for gay and bisexual men from British Black Asian and Minority Ethnic (BAME) communities. A quantitative component assessed reported and intended sexual risk, drugs and alcohol use alongside measures of psychological well-being with pre and post-program data collected from 26 men. Fourteen men participated in focus groups that discussed experiences of the intervention. Significant improvements were found on measures of internalized homophobia, self-esteem and self-efficacy but not for health behaviors including safer sex or substance use. Qualitative feedback was generally positive especially around enhanced psychological well-being, identity integration, and enhanced self-awareness. There were some concerns over group size and whether non-BAME gay men were appropriate as facilitators. Theoretically informed, culturally competent interventions can demonstrate significant potential in enhancing the well-being of BAME gay and bisexual men but follow-up data are needed to show longer-term benefits.

Cohesin is required for long-range enhancer action at the Shh locus.

The regulatory landscapes of developmental genes in mammals can be complex, with enhancers spread over many hundreds of kilobases. It has been suggested that three-dimensional genome organization, particularly topologically associating domains formed by cohesin-mediated loop extrusion, is important for enhancers to act over such large genomic distances. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment, here we show that cohesin, but not CTCF, is required for activation of the target gene Shh by distant enhancers in mouse embryonic stem cells. Cohesin is not required for activation directly at the promoter or by an enhancer located closer to the Shh gene. Our findings support the hypothesis that chromatin compaction via cohesin-mediated loop extrusion allows for genes to be activated by enhancers that are located many hundreds of kilobases away in the linear genome and suggests that cohesin is dispensable for enhancers located more proximally.

Living in the shadow of Lynch Syndrome: British women's accounts.

In this paper we explore accounts of eight British women living with Lynch Syndrome: a hereditary syndrome that increases the risk of developing bowel and gynecological cancers. We collected data via semi-structured interviews and analyzed them using Interpretative Phenomenological Analysis. Two themes, 'It's Up to Us': The Lynch Patient Experience; and 'The Biggest Challenge': The Lynch Parent Experience, illustrate the experiential burden and emotional labor of living with Lynch Syndrome. We theorize our analysis through Corbin and Strauss's concept of 'Health Work', and Hochschild's concept of 'Emotion Work'. Recommendations for clinical care and familial support are discussed.

The lived experience of parenting a child with sensory sensitivity and picky eating.

"Picky eating" is a common behaviour seen in childhood in both clinical and nonclinical populations. Sensory processing difficulties have been repeatedly associated with food refusal and picky eating behaviours. The aim of this study was to explore the lived experiences of parents/caregivers who have a child displaying both sensory processing differences and picky eating behaviours utilising Interpretative Phenomenological Analysis (IPA). Participants were recruited from social media support groups for parents of picky eating children. Pre-selection criteria utilised an adapted short sensory profile questionnaire to ensure the children displayed probable/definite taste-smell, audio-visual and tactile sensory sensitivities. Twelve participants fulfilling the required criteria were interviewed face to face utilising a semi-structured interview schedule. Interviews were transcribed and analysed following IPA guidelines and three common themes are presented here: Battling for control of the sensory environment, Living with stigma and, disapproval, and Staying positive and moving forward. The findings show the very considerable day-to-day challenges of parenting a child with sensory issues with food, including a lack of support and criticism from others. It was apparent that the parents in our study gradually adopted a positive and accepting attitude to their child's eating. This acceptance allowed them to have positive interactions around food with their child such as cooking and playing with food, suggesting that experiential activities serve an important purpose in this population. Further research should examine whether parental interventions based on acceptance of child eating behaviour, and commitment to gradual positive food interactions would be the best strategy to support parents and children.

The experience of living with mesothelioma: A meta-ethnographic review and synthesis of the qualitative literature.

OBJECTIVE: Mesothelioma is a life limiting cancer caused by previous exposure to asbestos. Due to the continued use of asbestos products internationally, the condition presents an increasing risk to global health with case numbers peaking in industrially developed nations. With the cancer reducing patient well-being, this study aimed to synthesizes the qualitative findings of studies exploring the experiences of patients living with mesothelioma to generate new conceptual insights and guide therapeutic care. METHOD: Thirteen databases were systematically searched: Academic Search Premier, BioMed Central, British Nursing Database, CINAHL Plus, Cochrane Library, Europe PubMed Central, MEDLINE, PsycARTICLES, PsycINFO, Science Direct, Scopus, Social Care Online, and Web of Science, between August and September 2020. Included articles were subject to quality appraisal using CASP checklists, and their respective findings analyzed using a metaethnographic form of qualitative data synthesis. RESULTS: Twenty-two articles met the inclusion criteria, and the data synthesis produced three themes: (1) "complex trauma"; (2) "psycho-behavioral coping strategies"; and (3) "external sources of support." Combined, these themes form a novel conceptual framework and awareness of the patient experience that presents the lived trauma of disease alongside a patients coping processes and support pathways. CONCLUSION: Robust therapeutic support is needed to address the psychosocial and existential burden shouldered by people with mesothelioma. Therapies that promote sentiments of acceptance, hope, and benefit finding are proposed alongside initiatives that foster patient empowerment and meaning, and further promote patient choice in deciding end-of-life care. Recommendations for future research are also made. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Acceptance, grief and adaptation amongst caregivers of partners with acquired brain injury: an interpretative phenomenological enquiry.

PURPOSE: Families provide vital support to relatives with brain injury yet shoulder significant stress and anxiety with little help threatening family cohesion and rehabilitative outcomes. This paper analyses the accounts of people caring for a long-term partner with brain injury to identify coping mechanisms and support systems that enhanced well-being. Materials and method: This study used semi-structured interviews with eight participants and interpretative phenomenological analysis. RESULTS: Three themes are reported-"moving through denial toward acceptance"; "confronting and managing ambiguous loss"; and "becoming an expert carer". Theme one describes participants' struggles to accept the longevity of brain injury and use of strenuous care practices to deny or fight disability; this proved counterproductive and was later remedied by individuals embracing change and making adaptations. Theme two reports how participants split their partners' identities -before and after brain injury- to help grieve for the marital relationships they lost. Theme three looks at participants' development of self-reliant attitudes to caregiving due to perceived limited state help, while embracing peer support that enhanced information and emotion-based coping. CONCLUSIONS: Findings support therapeutic practices that help family members confront the permanence of brain injury, and target feelings of complex and unresolved grief. Future research proposals are discussed.IMPLICATIONS FOR REHABILITATION:Caregivers typically provide considerable rehabilitative support to spouses living with Acquired Brain Injury to manage the physical and psychosocial burdens of long-term disability.Therapeutic interventions should reconcile notions of hope and acceptance in order to help carers confront the permanence of brain injury and develop sustainable care practices.We recommend that interventions address feelings of unresolved grief and ambiguous loss and develop tailored support for caregivers which targets pertinent psychological concerns.

Disturbance at the dinner table: Exploring mothers' experiences of mealtimes when caring for their son or daughter with anorexia nervosa.

This study examined mothers' (n = 9) mealtime experiences when caring for their son or daughter with anorexia nervosa through semi-structured interviews. Interpretative Phenomenological Analysis identified three themes: (1) managing mealtime combat through accommodation and acceptance; (2) feeling isolated, inauthentic and ill-equipped and (3) a need for understanding and to be understood. The overarching concepts of 'combat' and 'distortion' also underpin the analysis, uniquely outlining how mothers come to understand this daily situation. Mealtime-related interventions need to be developed which prioritise promoting skills and confidence in managing mealtimes and helping carers to address the emotional challenges of these occasions.

MUC4 is not expressed in cell lines used for live cell imaging.

Background: The ability to visualise specific mammalian gene loci in living cells is important for understanding the dynamic processes linked to transcription. However, some of the tools used to target mammalian genes for live cell imaging, such as dCas9, have been reported to themselves impede processes linked to transcription. The MUC4 gene is a popular target for live cell imaging studies due to the repetitive nature of sequences within some exons of this gene. Methods: We set out to compare the impact of dCas9 and TALE-based imaging tools on MUC4 expression, including in human cell lines previously reported as expressing MUC4. Results: We were unable to detect MUC4 mRNA in these cell lines. Moreover, analysis of publicly available data for histone modifications associated with transcription, and data for transcription itself, indicate that neither MUC4, nor any of the mucin gene family are significantly expressed in the cell lines where dCas9 targeting has been reported to repress MUC4 and MUC1 expression, or in the cell lines where dCas13 has been used to report MUC4 RNA detection in live cells. Conclusions: Methods for visualising specific gene loci and gene transcripts in live human cells are very challenging. Our data suggest that care should be given to the choice of the most appropriate cell lines for these analyses and that orthogonal methods of assaying gene expression be carefully compared.

Linking the FTO obesity rs1421085 variant circuitry to cellular, metabolic, and organismal phenotypes in vivo.

Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates Irx3 and Irx5 gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.

Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5.

Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.

Evaluating approaches to designing effective Co-Created hand-hygiene interventions for children in India, Sierra Leone and the UK.

Effective and culturally appropriate hand-hygiene education is essential to promote health-related practices to control and prevent diseases such as Diarrhoea, Ebola and COVID-19. In this paper we outline and evaluate the Co-Creation processes underpinning a handwashing intervention for young children (A Germ's Journey) developed and delivered in India, Sierra Leone and the UK, and consider the implications surrounding Imperialist/Colonial discourse and the White Saviour Complex. The paper focuses both on the ways Co-Creation was conceptualised by our collaborators in all three countries and the catalysts and challenges encountered. Qualitative data have been drawn from in-depth interviews with five key stakeholders, focus group data from 37 teachers in Sierra Leone and responses to open-ended questionnaires completed by teachers in India (N = 66) and UK (N = 63). Data were analysed using thematic analysis and three themes, each with three constituent subthemes are presented. In the theme 'Representations of and Unique Approaches to Co-Creation' we explore the ways in which Co-Creation was constructed in relation to teamwork, innovative practice and more continuous models of evaluation. In 'Advantages of Co-Creation' we consider issues around shared ownership, improved outcomes and more meaningful insights alongside the mitigation of risks and short-circuiting of problems. In 'Challenges of Co-Creation' we discuss issues around timing and organisation, attracting and working with appropriate partners and understanding the importance of local context with inherent social, economic and structural barriers, especially in low-and-middle-income countries. We consider how theoretical elements of Co-Creation can inform effective international public health interventions; crucial during a global pandemic in which handwashing is the most effective method to control the transmission of COVID-19. Finally we reflect on some of the methodological challenges of our own work and in managing the potentially conflicting goals of the ethical and participatory values of Co-Creation with pragmatic considerations about ensuring an effective final 'product'.

A central role for canonical PRC1 in shaping the 3D nuclear landscape.

Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses, we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demonstrate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci disrupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are separable events. These findings provide important insights into the function of PRC1, while highlighting the complexity of this regulatory system.

DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency.

The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in two small molecule inhibitors (2i) results in redistribution of polycomb (H3K27me3) away from its target loci. Here, we demonstrate that 3D genome organization is also altered in 2i, with chromatin decompaction at polycomb target loci and a loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground state, we are able to restore to ESC in 2i the H3K27me3 distribution, as well as polycomb-mediated 3D genome organization that is characteristic of primed ESCs grown in serum. However, these cells retain the functional characteristics of 2i ground-state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organization but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.

Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation.

Enhancers can regulate the promoters of their target genes over very large genomic distances. It is widely assumed that mechanisms of enhancer action involve the reorganization of three-dimensional chromatin architecture, but this is poorly understood. The predominant model involves physical enhancer-promoter interaction by looping out the intervening chromatin. However, studying the enhancer-driven activation of the Sonic hedgehog gene (Shh), we have identified a change in chromosome conformation that is incompatible with this simple looping model. Using super-resolution 3D-FISH and chromosome conformation capture, we observe a decreased spatial proximity between Shh and its enhancers during the differentiation of embryonic stem cells to neural progenitors. We show that this can be recapitulated by synthetic enhancer activation, is impeded by chromatin-bound proteins located between the enhancer and the promoter, and appears to involve the catalytic activity of poly (ADP-ribose) polymerase. Our data suggest that models of enhancer-promoter communication need to encompass chromatin conformations other than looping.

Developmentally regulated Shh expression is robust to TAD perturbations.

Topologically associating domains (TADs) have been proposed to both guide and constrain enhancer activity. Shh is located within a TAD known to contain all its enhancers. To investigate the importance of chromatin conformation and TAD integrity on developmental gene regulation, we have manipulated the Shh TAD - creating internal deletions, deleting CTCF sites, and deleting and inverting sequences at TAD boundaries. Chromosome conformation capture and fluorescence in situ hybridisation assays were used to investigate the changes in chromatin conformation that result from these manipulations. Our data suggest that these substantial alterations in TAD structure have no readily detectable effect on Shh expression patterns or levels of Shh expression during development - except where enhancers are deleted - and result in no detectable phenotypes. Only in the case of a larger deletion at one TAD boundary could ectopic influence of the Shh limb enhancer be detected on a gene (Mnx1) in the neighbouring TAD. Our data suggests that, contrary to expectations, the developmental regulation of Shh expression is remarkably robust to TAD perturbations.