Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition.

Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells.

Ductal Carcinoma in Situ: Molecular Changes Accompanying Disease Progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal carcinoma (IDC), whereby if left untreated, approximately 12% of patients develop invasive disease. The current standard of care is surgical removal of the lesion, to prevent potential progression, and radiotherapy to reduce risk of recurrence. There is substantial overtreatment of DCIS patients, considering not all DCIS lesions progress to invasive disease. Hence, there is a critical imperative to better predict which DCIS lesions are destined for poor outcome and which are not, allowing for tailored treatment. Active surveillance is currently being trialed as an alternative management practice, but this approach relies on accurately identifying cases that are at low risk of progression to invasive disease. Two DCIS-specific genomic profiling assays that attempt to distinguish low and high-risk patients have emerged, but imperfections in risk stratification coupled with a high price tag warrant the continued search for more robust and accessible prognostic biomarkers. This search has largely turned researchers toward the tumor microenvironment. Recent evidence suggests that a spectrum of cell types within the DCIS microenvironment are genetically and phenotypically altered compared to normal tissue and play critical roles in disease progression. Uncovering the molecular mechanisms contributing to DCIS progression has provided optimism for the search for well-validated prognostic biomarkers that can accurately predict the risk for a patient developing IDC. The discovery of such markers would modernize DCIS management and allow tailored treatment plans. This review will summarize the current literature regarding DCIS diagnosis, treatment, and pathology.

Progress towards enhanced access and use of technology during the COVID-19 pandemic: A need to be mindful of the continued digital divide for many rural and northern communities.

The COVID-19 pandemic produced unprecedented adoption and deployment of technology in rural and northern areas; however, this expansion widened the digital divide for many. Evidence shows that older adults' use of technology has increased. Coupled with an increasing number of available technologies to enhance healthcare delivery, social engagement, meaningful activities, and support to carers, we are at a crossroads for change. Emerging strategies used by organizations to promote technology and support efforts to bridge and close the digital divide are discussed. In a post-pandemic society, policy-makers can play a critical role to ensure that improvements, efficiency gains, and lessons learned are fully leveraged to reap the benefits of technology use by older adults, care partners, and the healthcare system. Recommendations are given for policy-makers to capitalize on this opportunity to narrow the digital divide for those in rural and northern communities.

Levelling the playing field through the London Network of the UK clinical trials accelerator platform.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

Designer Benzodiazepines Gidazepam and Desalkygidazepam (Bromonordiazepam): What Do We Know?

Designer benzodiazepines are one of the primary new psychoactive substance (NPS) threats around the world, being found in large numbers in postmortem, driving under the influence of drugs and drug-facilitated sexual assault cases. Even though when compared to many other NPS types, such as opioids and cathinones, there are relatively few designer benzodiazepines being monitored. Recently, a new NPS benzodiazepine has been reported in Europe, the USA and Canada, desalkygidazepam, also known as bromonordiazepam. This substance is a metabolite of the prodrug gidazepam, a drug licensed for use in Ukraine and Russia under the name Gidazepam IC®. In the paper, we review what is currently known about the use, pharmacology and analytical detection of gidazepam, its metabolite desalkygidazepam and their other possible metabolites.

A systematic review to identify and collate factors influencing patient journeys through clinical trials.

Patient-centred trial design and delivery; improves recruitment and retention; increases participant satisfaction; encourages participation by a more representative cohort; and allows researchers to better meet participants' needs. Research in this area mostly focusses on narrow facets of trial participation. We aimed to systematically identify the breadth of patient-centred factors influencing participation and engagement in trials, and collate them into a framework. Through this we hoped to assist researchers to identify factors that could improve patient-centred trial design and delivery. Robust qualitative and mixed methods systematic reviews are becoming increasingly common in health research. The protocol for this review was prospectively registered on PROSPERO, CRD42020184886. We used the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research Type) framework as a standardised systematic search strategy tool. 3 databases were searched as well as references checking, and thematic synthesis was conducted. Screening agreement was performed and code and theme checking were conducted by 2 independent researchers. Data were drawn from 285 peer-reviewed articles. 300 discrete factors were identified, and sorted into 13 themes and subthemes. The full catalogue of factors is included in the Supplementary Material. A summary framework is included in the body of the article. This paper focusses on outlining common ground that themes share, highlighting critical features, and exploring interesting points from the data. Through this, we hope researchers from multiple specialities may be better able to meet patients' needs, protect patients' psychosocial wellbeing, and optimise trial recruitment and retention, with direct positive impact on research time and cost efficiency.

Understanding triage assessment of acuity by emergency nurses at initial adult patient presentation: A qualitative systematic review.

BACKGROUND: Nurses make complex triage decisions within emergency departments, which significantly affect patient outcomes. Understanding how nurses make these decisions and why they deviate from triage algorithms facilitates interventions that work with their decision-making processes, increasing acceptability and effectiveness. AIMS: This qualitative systematic review aimed to understand decision-making processes emergency nurses use to make acuity decisions during triage assessment at initial patient presentation. METHODOLOGY: Medline, CINAHL and Academic Search Complete were systematically searched to 15th December 2022. Data were analysed using thematic synthesis. Established themes were reviewed with GRADE-CERQual to evaluate certainty of evidence. RESULTS: 28 studies were included in the review. Data analysis uncovered three superordinate themes of holistic reasoning, situational awareness, and informed decision-making. The findings show nurses value holistic assessments over algorithms and rely on knowledge and experience. They also assess the wider situation in the emergency department. CONCLUSIONS: This review presents new perspectives on nurses' decision-making processes about patient's acuity. Nurses holistically gather information about patients before translating that information into acuity scores. These actions are informed by their knowledge and experience; however, the wider situation also impacts their decisions. In turn, the nurses use interpretations of patients' acuity to control the wider situation.

Going the Extra Mile: Why Clinical Research in Cystic Fibrosis Must Include Children.

This is an exciting time for research and novel drug development in cystic fibrosis. However, rarely has the adage, "Children are not just little adults" been more relevant. This article is divided into two main sections. In the first, we explore why it is important to involve children in research. We discuss the potential benefits of understanding a disease and its treatment in children, and we highlight that children have the same legal and ethical right to evidence-based therapy as adults. Additionally, we discuss why extrapolation from adults may be inappropriate, for example, medication pharmacokinetics may be different in children, and there may be unpredictable adverse effects. In the second part, we discuss how to involve children and their families in research. We outline the importance and the complexities of selecting appropriate outcome measures, and we discuss the role co-design may have in improving the involvement of children. We highlight the importance of appropriate staffing and resourcing, and we outline some of the common challenges and possible solutions, including practical tips on obtaining consent/assent in children and adolescents. We conclude that it is unethical to simply rely on extrapolation from adult studies because research in young children is challenging and that research should be seen as a normal part of the paediatric therapeutic journey.

Development of an International Tool for Students to Record and Reflect on Patient Safety Learning Experiences.

BACKGROUND: Underpinning all nursing education is the development of safe practitioners who provide quality care. Learning in practice settings is important, but student experiences vary. PURPOSE: This study aimed to systematically develop a robust multilingual, multiprofessional data collection tool, which prompts students to describe and reflect on patient safety experiences. APPROACH: Core to a 3-year, 5-country, European project was development of the SLIPPS (Sharing Learning from Practice for Patient Safety) Learning Event Recording Tool (SLERT). Tool construction drew on literature, theory, multinational and multidisciplinary experience, and involved pretesting and translation. Piloting included assessing usability and an initial exploration of impact via student interviews. OUTCOMES: The final SLERT (provided for readers) is freely available in 5 languages and has face validity for nursing across 5 countries. Student reports (n = 368) were collected using the tool. CONCLUSIONS: The tool functions well in assisting student learning and for collecting data. Interviews indicated the tool promoted individual learning and has potential for wider clinical teams.

Rehabilitation and transition in military veterans after limb-loss.

PURPOSE: This study aims to explore the physical, psychological and social wellbeing of veterans who have experienced limb-loss and to ascertain the factors that contribute to the ability of veterans to maintain their independence at various stages in their lives. METHODS: Sixty two life-story interviews were conducted with 32 veterans (aged between 40 and 95) who had experienced limb-loss either during or after military service. RESULTS: Three overarching superordinate themes and related sub-themes were generated from a detailed Framework Analysis "Barriers to transition" describes issues related to employment, legal support and compensation, stigma and loss of identity. "Disparity of care" highlights the issues related to military and civilian care and prosthetics service user experience. The final superordinate theme, "Enduring challenge of limb loss," considers stoicism, dealing with pain, mobility, physical isolation and social networks. CONCLUSIONS: The outcomes offer an opportunity to shape future health and social care policy around the requirements of veterans who have experienced limb-loss by understanding the complexity, and ascertaining the factors that contribute to, maintaining long-term independence.Implication for RehabilitationThe outcomes offer an opportunity to shape future health and social care policy around the requirements of veterans who have experienced limb-loss by understanding the complexity, and ascertaining the factors that contribute to rehabilitation and maintaining long-term independence.

Housing Needs of Ageing Veterans Who Have Experienced Limb Loss.

Military veterans can experience limb loss as a direct result of conflict, an accident, illness or injury. Whatever the cause, there is a need to recognise the long-term consequences and challenges of limb loss on maintaining independence in one's home. This study aimed to examine the housing needs of veterans experiencing limb loss, and the impact of limb loss on housing needs and home adaptations of ageing military veterans. Thirty-two military veterans (aged 43-95) participated in this study and up to three life-story interviews were carried out with each participant. Two themes were generated: availability of support and changing housing needs. It is evident from the findings that military veterans are unique in various ways, specifically due to military culture, geographical relocation and the additional support that is available to the Armed Forces Community. This must be considered in long-term support to maintain independence in the home.

Critical Incident Techniques and Reflection in Nursing and Health Professions Education: Systematic Narrative Review.

BACKGROUND: The terms critical incident technique and reflection are widely used but often not fully explained, resulting in ambiguity. PURPOSE: The aims of this review were to map and describe existing approaches to recording or using critical incidents and reflection in nursing and health professions literature over the last decade; identify challenges, facilitating factors, strengths, and weaknesses; and discuss relevance for nursing education. METHODS: A systematic narrative review was undertaken. MEDLINE and the Cumulative Index to Nursing and Allied Health Literature were searched using MeSH terms, returning 223 articles (2006-2017). After exclusions, 41 were reviewed. RESULTS: Articles were categorized into 3 areas: descriptions of the development of an original tool or model, critical incidents or reflection on events used as a learning tool, and personal reflections on critical incidents. CONCLUSIONS: Benefits have been identified in all areas. More attention is needed to the pedagogy of reflection and the role of educators in reflection.

Using photo-elicitation to explore the lived experience of informal caregivers of individuals living with dementia.

OBJECTIVES: This study aims to explore the subjective lived experience of informal caregivers supporting an individual with dementia. DESIGN: This study uses the interpretive phenomenological approach utilizing the method of photo-elicitation and in-depth semi-structured interviews. METHODS: Six individuals were given a disposable camera to capture photographs which they felt illustrated their own lived experiences of being a caregiver of an individual living with dementia. Photographs were printed and used to form discussion within an in-depth semi-structured interview. The photographs provided an innovative way of capturing the lived experiences of formal dementia caregivers and allowed the interview data to be grounded in their daily living, centring around their own lived experiences. RESULTS: Three themes emerged from data analysis: 'conceptualising the role of informal caregiver', 'support for the informal caregiver', and 'the caregivers own needs'. CONCLUSIONS: Findings demonstrated the complexity of the relationship between the caregiver and the person living with dementia, and the shift in this relationship specifically due to the role of carer, with notable differences between spousal caregivers and adult-child caregivers. The importance of social, emotional, and practical support for caregivers was highlighted, as well as significance of the caregiver's individual needs. Statement of contribution What is already known on this subject? Informal caregivers of individuals living with dementia cover much of the associated health care costs. Informal caregiving of individuals living with dementia can lead to negative health outcomes of the carer. Health outcomes of informal caregivers living with dementia are grounded in culture and are influenced by multiple factors. What does this study add? The complexity of the transition from family member to informal caregiver has both a physical and emotional impact on caregivers. The transition, and experiences of informal caregiving, is dependent on the relationship to the individual living with dementia. Caregiver support and recognizing the caregiver's individual needs were imperative to caregiver well-being.

The Implementation of an Innovative Hydration Monitoring App in Care Home Settings: A Qualitative Study.

BACKGROUND: In response to marked concern regarding inadequate fluid intake recording in care homes, an innovative mobile hydration app was collaboratively developed. "Hydr8" aimed to facilitate accurate recording and communication of residents' fluid intake and ultimately increase care quality and patient safety. OBJECTIVE: The aim of this study was to examine the implementation of Hydr8 in a sample of care homes in one area in England. METHODS: The principles of Realist Evaluation and Action research were drawn upon throughout the study. Overall, 5 care homes participated in this study, 3 interview-only sites and 2 case-study sites, where interviews and observations were conducted at 3 time-points. Furthermore, 28 staff members participated, including care staff, management, a registered nurse, and administrative staff. RESULTS: Findings suggest that Hydr8 benefits practice, enhancing the understanding of hydration and person-centered care and improving staff communication. However, technical glitches hindered the seamless embedding of Hydr8 into everyday practice, and enthusiasm for long-term use was dependent on the resolution of issues. In addition, Hydr8 heightened perceptions of personal accountability, and while managers viewed this as positive, some staff members were apprehensive. However, individuals were enthusiastic about the long-term use and potential of Hydr8. CONCLUSIONS: Utilizing the findings of this study to further develop and adapt Hydr8 indicates the long-term use of Hydr8 as promising. Although perceptions of Hydr8 were primarily positive, setbacks in its implementation and use created difficulties in normalizing the solution into everyday practice. This study highlights the need for education related to hydration practice and a change of infrastructure in care home settings to implement technical solutions and changes to care.

Health professionals' attitudes to patients' use of wearable technology.

OBJECTIVE: Wearable technologies for health monitoring are becoming increasingly mainstream. However, there is currently limited evidence exploring use from the perspective of healthcare professionals. This study aimed to explore health professionals' attitudes toward their patients' use of wearable technologies. METHODS: A convenience sample of health professionals was recruited to participate in this study. Qualitative semi-structured interviews were carried out either face-to-face, via Skype or telephone. Interviews were recorded using a Dictaphone, transcribed verbatim and analysed using thematic analysis. RESULTS: Four themes emerged from the qualitative findings: 'opportunities for wearable technology', 'usability and understanding', 'privacy and surveillance' and 'cost'. CONCLUSIONS: The findings portray health professionals' ambivalence to the use of wearable technology, and it was apparent that whilst the participants considered the technology as being beneficial to patients, they still had concerns for its use.

The hidden impact of home adaptations: Using a wearable camera to explore lived experiences and taken-for-granted behaviours.

Most adults over 65 years old live in mainstream housing in the United Kingdom, yet these can often be unsuitable for an individual's needs. With increased understanding of the relationship between housing, and health and well-being, the importance of modifying the home to suit individuals is recognised as being paramount. However, it is often difficult to monitor the ways in which home adaptations and equipment are used in the home. This study used innovative wearable technology to explore everyday, lived experiences of using home adaptations and equipment. Six older adults who had received a major home adaptation in the last 24 months took part in this study. Each participant used a wearable camera for one day and participated in a semi-structured interview while watching the images back as a 'slideshow'. Using this novel approach, three themes were generated from the data: acquiring adaptations and equipment, adapting routine and changing behaviour, and inconsistent and unintended uses. The findings of this study open up the complexity of the lived experience of using home adaptations and equipment. Experiences from access to long-term outcomes are personal, and individuals modify and use the adaptations in various ways to suit their own needs. The wearable camera allowed additional insight into lived experience that would otherwise not have been captured without its use, as the photographs acted as a way of stimulating conversation and highlighting taken-for-granted behaviours not often consciously considered by the individuals.

Utilisation of the principles of the Armed Forces Covenant in NHS Trusts and Clinical Commissioning Groups across England: a freedom of information investigation.

OBJECTIVES: To determine the extent to which National Health Service (NHS) service providers appoint a named Armed Forces veteran lead or champion, and to explore the commissioning of veteran-specific services by Clinical Commissioning Groups. DESIGN: A convergent mixed method design was used to improve understanding obtained from the information provided by respondents on their practice. The study comprised two parts: phase 1 involved NHS Trusts, and phase 2 involved Clinical Commissioning Groups. SETTING: All NHS Trusts and Clinical Commissioning Groups in England were contacted using a freedom of information request. PARTICIPANTS: All NHS trusts and Clinical Commissioning Groups across England. INTERVENTIONS: Initially, existing national websites were searched to gather information within the public domain. An audit was carried out, using the Freedom of Information Act (FOIA) 2000 to gather further information. PRIMARY AND SECONDARY OUTCOME MEASURES: The FOIA 2000 applies to UK Government departments and public authorities, including NHS Trusts in England, Wales and Northern Ireland. RESULTS: Responses from the freedom of information requests illustrate inconsistencies in relation to adopting the principles of the Armed Forces Covenant. The inconsistencies extend to the practice of appointing an Armed Forces Veteran Lead or an Armed Forces Veteran Champion. There is also evidence to suggest a lack of commitment to and understanding of policy guidance in relation to Clinical Commissioning Group responsibility for commissioning veteran-specific services. CONCLUSIONS: Findings from this study support the case for making improvements to, and improving the consistency of, commissioning practices for veterans.

"What? That's for Old People, that." Home Adaptations, Ageing and Stigmatisation: A Qualitative Inquiry.

Older people, even those living with long-term conditions or poor mobility, can be supported to live well at home, through adapting their home to meet changing need. Installing home adaptations, from grab rails to walk in shower rooms, is cost effective, may prevent falls, reduce social isolation and improve self confidence. Despite austerity cuts to public spending, the UK government increased home adaptations' funding. However, not much is known about older people's experiences and understanding of acquiring and living with home adaptations and uptake of home adaptations could be improved. Using wearable camera and face to face interview data, this qualitative study explored a diverse group of older people's retrospective experiences (n = 30). Focus group discussions were also carried out with a wide range of professionals involved in the provision of home adaptations (n = 39). Findings suggest people may delay having adaptations, because of perceived stigmatising associations with decline and vulnerability. As delaying the installation of home adaptations until crisis point is known to reduce their effectiveness, such associations need to be challenged.

The use of a wearable camera to explore daily functioning of older adults living with persistent pain: Methodological reflections and recommendations.

BACKGROUND: Persistent pain is prevalent within the ageing population and impacts daily functioning. Measuring daily functioning using conventional measures is problematic and novel technologies offer an alternative way of observing these behaviours. METHODS: This study aimed to consider the use of a wearable camera as a method of exploring a range of day-to-day patterns of functioning of older adults living with persistent pain. This study followed a mixed methods design. A purposive sample of 13 older adults (65±) with persistent pain (pain >3 months) took part in this study. Two younger adults (<65) with persistent pain and two older adults with no pain also participated. Individuals used a wearable camera (Microsoft SenseCam) for seven days. RESULTS: The wearable camera recorded the frequency of body position, movement, and activities of daily living. The wearable camera also presented contextual data of location, social interactions, use of assistive devices, and behavioural adaptations and was used to inform other methods of data collection. CONCLUSIONS: The wearable camera allowed insight into patterns and experiences of daily functioning that would not have otherwise been captured. However, not all aspects of functioning were recorded using the wearable camera, including the relationship between functioning and persistent pain.