The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.

Large-scale human genetic data1-3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)4-6. VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization6,7. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.

The Development of the Attachment Defenses Questionnaire (ADQ-50): A Preliminary Examination of Reliability, Validity, and Factor Structure.

This paper marks the initial phase in the development of the Attachment Defenses Questionnaire (ADQ-50), a self-report tool crafted to assess defense mechanisms associated with attachment processes, catering to both clinical and research contexts. Anchored in the theoretical framework of attachment theory, the ADQ posits that an individual's internalized attachment style plays a influential role in predicting their defense mechanisms. The paper outlines the comprehensive development and refinement process of the ADQ-50. In Study 1 a preliminary 176-item version of the ADQ was examined. Data was collected online drawing from participants sourced from Prolific and undergraduate students (N = 1994). Study 2 further refined the ADQ, evaluating its initial convergent validity with a diverse participant pool (N = 726), including undergraduates, Prolific contributors, general practice medical patients, and individuals from social media. Exploratory factor analysis revealed a robust ten-factor structure, resulting in a 50-item scale aligning with theoretical expectations and demonstrating good psychometric properties. Findings, limitations, strengths and future research directions are discussed. We posit that the ADQ holds great potential to deepen our comprehension of defense mechanisms linked to attachment, with wide-ranging implications for clinical practices.

The Neurologist as an Agent of Exercise Rehabilitation in Multiple Sclerosis.

This review hypothesizes that the neurologist represents the linchpin of exercise behavior change within comprehensive multiple sclerosis (MS) care settings. This is based on a series of recent articles that developed actionable practice models for accomplishing such behavior change through the neurologist as the primary agent. This provides tangible, next steps for exercise promotion in MS.

"Kicking and Screaming" or "Gracefully Conceding": Creative Nonfiction Stories of Aging With Multiple Sclerosis.

Aging with multiple sclerosis (MS) is a complex phenomenon. Some individuals report physical and cognitive dysfunctions regarding these combined experiences, whereas others report perceived improvements in quality of life. Beyond this, little is known regarding how people make sense of, and come to embody, negative or positive experiences of MS. Thus, our objectives were to (a) explore how people made sense of aging with MS and (b) present this in an artful, engaging, transformative way. To achieve this, we conducted 40 semi-structured interviews with older adults who had MS, analyzed data using pluralistic narrative analyses, and presented results through two creative nonfictions. We detail our process of creating the nonfictions before presenting the different stories of aging with MS, namely "Kicking and Screaming" and "Gracefully Conceding." We then offer recommendations and implications for using these stories as knowledge translation devices, and further critique the limitations of these stories in practice.

"How Come You Sent Me the Canadian One?" Application and Uptake of the Canadian Physical Activity Guidelines for Adults With Multiple Sclerosis in the United States.

The uptake and benefits of the Canadian Physical Activity Guidelines for Adults with Multiple Sclerosis (PAGs) have been validated, but there is limited understanding regarding the knowledge, needs, and preferences of people with multiple sclerosis (MS) for implementing the PAGs outside of clinical research. The authors conducted online, semistructured interviews with 40 persons with MS from across the United States seeking information on awareness of and potential approaches for increasing the uptake of the PAGs. They identified first impressions and potential approaches for increasing the uptake of the PAGs through inductive, semantic thematic analysis. Participants perceived the PAGs as a good introduction for structured exercise but desired more information on how to meet the PAGs. Participants further believed that modifying the PAGs for inclusivity and applying a multifaceted approach for dissemination and implementation may increase uptake of exercise behavior. Physical activity research in MS should include both analyzing the effects of exercise and the unique challenges faced by persons with MS in putting the PAGs into practice.

Social cognitive theory as a guide for exercise engagement in persons with multiple sclerosis who use wheelchairs for mobility.

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the brain, optic nerves and spinal cord. Among persons with MS, 30% experience significant mobility impairment that requires use of a wheelchair for mobility. Exercise is an evidence-based second-line therapy that can improve mobility; however, little research has focused on individuals that use wheelchairs for mobility. Framed by social cognitive theory (SCT), we conducted a formative qualitative study examining exercise status and perceptions among 20 persons with MS who use wheelchairs for mobility. Using deductive, semantic thematic analysis, we coded for SCT variables (i.e. self-efficacy, knowledge, outcome expectations, barriers and facilitators) and identified participants as regular or inconsistent exercisers. In total, 12 participants were classified as regular exercisers and 8 inconsistent exercisers. Regular exercisers more frequently reported high self-efficacy, consistent exercise knowledge and numerous facilitators. All participants reported some positive outcome expectations and several barriers and facilitators. These findings can inform future intervention studies supporting exercise behavior change through SCT. Strategies such as increasing self-efficacy, imparting instructional materials, shaping realistic outcome expectations and providing tools directed toward overcoming barriers and identifying facilitators may work to support the exercise endeavor of persons with MS who use wheelchairs for mobility.

Necrotizing Soft Tissue Infections: Case Reports from the Patients Prospective.

All who have contributed in writing this chapter have been patients and parents that have experienced an horrific life event. The horrific disease named necrotising fasciitis has affected our lives for ever. All four stories have explained how easily an everyday infection can develop incredibly quickly into a life-threatening experience. Three stories are expressed from the worn hearts of being a mother, fighting for their child every step of the way. Knowing our children and how they react through pain and illness is felt in each word, sentence, paragraph and even between the lines. Dedicating our unmarkable love and devotion for the child we carried for 9 months. To see them suffer in illness is heart wrenching, but to experience this disease necrotising fasciitis is something else. We must live through every day watching them grow with their scars of debridement, and to support them through further operations, let alone mental scars. Parents show a strength of support like no other and we hope that their lives can be enhanced through the battle they have individually won let alone their family. Robert's story from a patient's perspective is quite different and you will read his courage throughout. We continue to raise awareness through education.

Evaluation of a Conceptual Model Regarding Exercise Promotion Through the Patient-Provider Interaction in Multiple Sclerosis: Health Care Provider Perspectives.

Nearly 80% of persons with multiple sclerosis (MS) do not engage in sufficient amounts of exercise for managing symptoms and improving quality of life. We have addressed this problem by developing a systematic line of qualitative research targeting the patient-provider interaction for promotion of exercise within comprehensive MS care. This research resulted in a conceptual model that guides health care providers in promoting exercise among persons with MS. The current study involves a final evaluation of the model based on semistructured interviews with 28 MS health care providers. Providers perceived that the model was a strong conceptualization of practice that reflected the MS illness course and supported exercise behavior change, but more steps were required to translate the model from concept into practice, including improved clarity of the model, and the development of practice models. The evaluation yielded a final conceptual model for exercise promotion in MS through the patient-provider interaction.

User involvement in regulation: A qualitative study of service user involvement in Care Quality Commission inspections of health and social care providers in England.

BACKGROUND: High profile failures of care in the NHS have raised concerns about regulatory systems for health-care professionals and organizations. In response, the Care Quality Commission (CQC), the regulator of health and social care in England overhauled its regulatory regime. It moved to inspections which made much greater use of expert knowledge, data and views from a range of stakeholders, including service users. OBJECTIVE: We explore the role of service users and citizens in health and social care regulation, including how CQC involved people in inspecting and rating health and social care providers. DESIGN: We analyse CQC reports and documents, and 61 interviews with CQC staff and representatives of groups of service users and citizens and voluntary sector organizations to explore the place of service user voice in regulatory processes. RESULTS: Care Quality Commission invited comments and facilitated the sharing of existing service user experiences and engaged with representatives of groups of service users and voluntary sector organizations. CQC involved service users in their inspections as "experts by experience." Information from service users informed both the inspection regime and individual inspections, but CQC was less focused on giving feedback to service users who contributed to these activities. DISCUSSION AND CONCLUSIONS: Service users can make an important contribution to regulation by sharing their experiences and having their voices heard, but their involvement was somewhat transactional, and largely on terms set by CQC. There may be scope for CQC to build more enduring relationships with service user groups and to engage them more effectively in the regulatory regime.

Promotion of Exercise in Multiple Sclerosis Through Health Care Providers.

Participation in exercise yields meaningful benefits among persons with multiple sclerosis (MS), yet this population engages in low rates of health-promoting physical activity. The disconnect between evidence of benefits and rates of participation requires consideration of new opportunities for changing this health behavior. The current article hypothesizes that the patient-provider interaction offers a fertile opportunity for promoting exercise behavior in MS.

Evaluation of a Conceptual Model to Guide Health Care Providers in Promoting Exercise Among Persons With Multiple Sclerosis.

Fewer than 20% of persons with multiple sclerosis (MS) engage in enough exercise to manage MS symptoms and improve function. To address this problem, the authors developed a conceptual model to promote exercise among persons with MS through the patient-provider interaction within health care settings. The current qualitative study evaluated and refined the conceptual model based on 32 semistructured interviews involving persons with MS. The data were subject to inductive, semantic thematic analysis. Participants highlighted that the conceptual model was a necessary addition to current MS care and noted multiple strengths regarding its design (e.g., structure) and content (e.g., patient-provider interaction). Furthermore participants noted areas of the conceptual model that could be improved (e.g., less focus on neurologists as exercise promoters). This comprehensive evaluation yielded a refined conceptual model for exercise promotion in MS through the patient-provider interaction.

The role of community engagement in the adoption of new agricultural biotechnologies by farmers: the case of the Africa harvest tissue-culture banana in Kenya.

BACKGROUND: The tissue culture banana (TCB) is a biotechnological agricultural innovation that has been adopted widely in commercial banana production. In 2003, Africa Harvest Biotech Foundation International (AH) initiated a TCB program that was explicitly developed for smallholder farmers in Kenya to help them adopt the TCB as a scalable agricultural business opportunity. At the heart of the challenge of encouraging more widespread adoption of the TCB is the question: what is the best way to introduce the TCB technology, and all its attendant practices and opportunities, to smallholder farmers. In essence, a challenge of community or stakeholder engagement (CE). RESULTS: In this paper, we report the results of a case study of the CE strategies employed by AH to introduce TCB agricultural practices to small-hold farmers in Kenya, and their impact on the uptake of the TCB, and on the nature of the relationship between AH and the relevant community of farmers and other stakeholders. We identified six specific features of CE in the AH TCB project that were critical to its effectiveness: (1) adopting an empirical, "evidence-based" approach; (2) building on existing social networks; (3) facilitating farmer-to-farmer engagement; (4) focusing engagement on farmer groups; (5) strengthening relationships of trust through collaborative experiential learning; and (6) helping farmers to "learn the marketing game". We discuss the implications of AH's "values-based" approach to engagement, and how these guiding values functioned as "design constraints" for the key features of their CE strategy. And we highlight the importance of attention to the human dimensions of complex partnerships as a key determinant of successful CE. CONCLUSION: Our findings suggest new ways of conceptualizing the relationship between CE and the design and delivery of new technologies for global health and global development.

Illness representations, coping, and illness outcomes in people with cancer: a systematic review and meta-analysis.

OBJECTIVE: Cancer is associated with negative health and emotional outcomes in those affected by it, suggesting the need to better understand the psychosocial determinants of illness outcomes and coping. The common sense model is the leading psychological model of self-regulation in the face of illness and assumes that subjective illness representations explain how people attempt to cope with illness. This systematic review and meta-analysis examines the associations of the common sense model's illness representation dimensions with health and coping outcomes in people with cancer. METHODS: A systematic literature search located 54 studies fulfilling the inclusion criteria, with 38 providing sufficient data for meta-analysis. A narrative review of the remaining studies was also conducted. RESULTS: Random-effects models revealed small to moderate effect sizes (Fisher Z) for the relations between illness representations and coping behaviors (in particular between control perceptions, problem-focused coping, and cognitive reappraisal) and moderate to large effect sizes between illness representations and illness outcomes (in particular between identity, consequences, emotional representations, and psychological distress). The narrative review of studies with insufficient data provided similar results. CONCLUSIONS: The results indicate how illness representations relate to illness outcomes in people with cancer. However, more high-quality studies are needed to examine causal effects of illness representations on coping and outcomes. High heterogeneity indicates potential moderators of the relationships between illness representations and health and coping outcomes, including diagnostic, prognostic, and treatment-related variables. This review can inform the design of interventions to improve coping strategies and mental health outcomes in people with cancer.

Collective Stories of Exercise: Making Sense of Gym Experiences With Disabled Peers.

Using a dialogical narrative approach, we explored how disabled people made sense of their gym experiences as part of a peer group. Interviews were conducted with 18 disabled people (10 men and 8 women, aged 23-60) who had experience exercising in the gym as part of a group. Data were rigorously analyzed using a dialogical narrative analysis. Within their peer group, participants crafted a collective story that they used to resist disablism in the gym. The dialogical components of the collective story functioned to (a) validate participants' experiences of oppression in the gym, (b) forge an unspoken understanding with peers, (c) craft a more affirmative identity, and (d) instill a sense of empowerment in participants so that they can tell their own story. This study extends knowledge in the field of exercise and disability by showing that despite the oppression disabled people experienced in the gym, they can create a collective story, which is useful for helping to promote and sustain exercise in this space.

Staying isolated indoors means that nobody sees me": ontological (in)security and living with significant appearance concerns before, during, and 'since' COVID-19.

PURPOSE: Though a worldwide period of uncertainty (COVID-19) has 'ended', there exists a legacy of maladaptive experiences among people with significant appearance concerns (SAC) that requires care and attention. METHODS: Using Giddens' concept of ontological security, we explored how people experienced their SAC before, during and "since" COVID-19. Qualitative surveys allowed us to capture diverse perspectives from individuals transnationally, analysed with deductive reflexive thematic analysis using ontological security as our theoretical foundation. RESULTS: Themes named "More Mirror(ed) Time" and "Locked Out, Shut Down, and Shut Out" gave a contextual grounding for the embodied experiences of this group through times of social restrictions, and the theme "Redefining Relevance" explored the continued legacy of COVID-19 - and continued global uncertainties such as economic hardship and warfare - that impact the wellbeing of people with SAC. CONCLUSIONS: People with SAC are still 'locked out' from essential healthcare support as those providing healthcare are overworked, under-resourced and rely on efficient interactive methods such as tele-health that may be triggers for people with SAC. Care providers may consider expanding appearance concerns verbiage, look to involve trusted others in the care-seeking process, and utilize modalities beyond digital health to support people with SAC.

Implementation of a clinical practice guideline for assessment and management of renal colic in the emergency department.

INTRODUCTION: Renal colic is a common emergency department (ED) presentation. Variations in assessment and management of suspected renal colic may have significant implications on patient and hospital outcomes. We developed a clinical practice guideline to standardize the assessment and management of renal colic in the ED. We subsequently compared outcomes before and after guideline implementation. METHODS: The guideline standardizes the analgesia regimen, urology consult criteria, imaging modality, patient education, and followup instructions. This is a single-center, observational cohort study of patients presenting to the ED with renal colic prospectively collected after guideline implementation (December 2018 to May 2019) compared to a control group retrospectively collected before guideline implementation (December 2017 to May 2018). A total of 528 patients (pre-guideline n=283, post-guideline n=245) were included. Statistical analysis was performed with SPSS using multivariate linear regression. RESULTS: ED length of stay (LOS) was significantly shorter after guideline implementation (pre-guideline 295.82±178.8 minutes vs. post-guideline 253.2±118.2 minutes, p=0.017). The number of computed tomography (CT) scans patients received was significantly less after guideline implementation (pre guideline 1.35±1.34 vs. post-guideline 1.00±0.68, p=0.034). Patients discharged for conservative management had a lower re-presentation rate in the post-guideline group (12.6%) than the pre-guideline group (17.2%); however, this did not reach statistical significance (p=0.18). CONCLUSIONS: Implementation of a clinical practice guideline for ureteric stones reduces the ED LOS and the total number of CT scan in patients who present with renal colic. Standardizing assessment and management of ureteric stones can potentially improve patient and hospital outcomes without compromising the quality of care.

Therapeutic reactivation of mutant p53 protein by quinazoline derivatives.

PURPOSE: The human tumour suppressor protein p53 is mutated in nearly half of human tumours and most mutant proteins have single amino acid changes. Several drugs including the quinazoline derivative 1 (CP-31398) have been reported to restore p53 activity in mutant cells. The side chain of 1 contains a styryl linkage that compromises its stability and we wished to explore the activity of analogues containing more stable side chains. METHODS: Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G(1)-phase cell cycle arrest and by western blotting to determine expression of p21(WAF1). DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out. RESULTS: Screening of analogues for potentiation of radiation-induced G(1)-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53(R248Q) mutation, demonstrated that the (2-benzofuranyl)-quinazoline derivative 5 was among the most active of the analogues. Compound 5 showed similar effects in several other p53 mutant human tumour cell lines but not in a p53 null cell line. 5 also potentiated p21(WAF1) expression induced by radiation. DNA binding affinity was measured and found to correlate with p53 reactivation activity. Plasma concentrations of 5 in mice were sufficient to suggest in vivo activity and a small induced tumour growth delay (7 days) of NZM4 melanoma xenografts was observed. CONCLUSION: Compound 5 restores p53-like function to a human tumour cells lines expressing a variety of mutant p53 proteins, thus providing a basis for the design of further new drugs.

Desired Resources for Changing Diet Among Persons With Multiple Sclerosis: Qualitative Inquiry Informing Future Dietary Interventions.

BACKGROUND: There are approximately 1 million adults in the United States with multiple sclerosis (MS). Persons with MS are interested in diet as a second-line therapy for improving MS symptoms and disease progression. Examination of desired resources regarding diet among persons with MS is necessary for supporting behavior change. METHODS: Twenty-five adults with MS completed 1-on-1, online semistructured interviews. An inductive, 6-phase, semantic thematic analysis was applied to identify themes associated with participant preferences for dietary behavior change. RESULTS: The research team crafted 4 key themes from the data that encompassed participants' desired resources for dietary behavior change. Theme 1, MS-specific evidence, involved the need for clear information about the impact of diet regimens or specific foods on MS. Theme 2, dietary guidelines, was related to guidelines provided by a reliable source such as a registered dietitian. Theme 3, behavioral supports, underscored the need for support for behavior change, including accountability, self-monitoring, motivation, habituation, and incremental changes. Theme 4, diet resources, highlighted tangible resources for supporting dietary change, including recipes, food lists, meal services, or games. CONCLUSIONS: This study provides a foundation for guiding dietary interventions for persons with MS that incorporates their needs and preferences and could improve their overall health. Such dietary change can be facilitated by theory-based behavioral interventions that incorporate behavior change techniques such as self-monitoring and goal setting for supporting behavior change.