Will “opt out” implementation save more lives; view of the South Asians’ in the UK

Organ transplantation is the gold standard treatment of choice for many patients with organ failure and has undoubtedly improved both the quality and longevity of life for the majority of patients. The success of human organ transplantation relies on the willingness of the public to donate their organs, either during their lifetime or after death. In the United Kingdom (UK), transplantation is limited by a shortage of donated organs, especially in the South Asian community. This leads to a disproportionate number of Asians waiting for transplants longer than the average waiting time, as often, most suitable matches are found between people of the same ethnic group. This disparity costs lives, and many who are waiting count down their days on the list and lead an agonizing life due to the scarcity of matching organ donors. This article is derived from a two phased study that sought to explore possible methods to increase the number of registered organ donors and cadaver organ retrieval in the South Asian community in the North West of England. A total of 907 participants completed the questionnaire and 10 semi structured interviews with individuals who declined to join the organ donor register were undertaken to understand the in-depth details of their negative attitude towards organ donation. This paper reflects on one of the focus areas of the study - the views of South Asians on the implementation of an opt-out system in the UK and to understand if the community will challenge or support such a donor recruitment method. This study was funded by the British Renal Society and supported by the Central Manchester Foundation Trust, University of Salford and National Health Service Blood and Transplant (NHSBT). Keywords: South Asian, Knowledge, Survey, Organ donation, Opt out, Opt in, Religio

Identifying information needs of patients with IgA Nephropathy, using an innovative social media stepped analytical approach

Introduction Increasingly people with kidney disease are using social media to search for medical information and to find peer-support. IgA nephropathy (IgAN) predominantly affects young adults, demographically the biggest users of social media. This paper presents an innovative analysis of social media interactions to identify unmet education and information needs of IgAN patients. Methods Following ethical approval for the study, the IgA Nephropathy Support UK Facebook group (https://www.facebook.com/groups/915274415226674) granted us permission to anonymously collect and analyse 1959 posts and comments from 498 group users. An initial patient focus group and quantitative word frequency analysis created an initial categorisation matrix which was iteratively refined following serial analyses of the social media database to generate a final categorisation matrix of needs. We examined narrative data relating to each identified category to define patient narratives relating to each area. Results A large number of information gaps and unanswered questions were identified relating to: diet, symptoms, diagnosis, treatment and patient co-morbidities. Additionally, patient-clinician communication and the presentation of information were drawn out as cross-cutting issues. These themes differed significantly from those identified from the traditional patient focus group highlighting the value of this novel method for interrogating social media data to understand unmet patient need. Conclusions Social media data is an untapped and valuable resource which can be used to better understand patient information gaps, leading to the generation of targeted materials to address unmet educational needs. This innovative approach could be replicated across other health conditions

Participating in CaMKIN : impact on patients

Introduction: Managing long-term health conditions is a global challenge, which has necessitated developing innovative ways to deliver patient centred care. Social media allow patients to access and share personal experiences and peer support, with potential to feed back into the patient-centred development and improvement of healthcare services. The Cheshire and Merseyside Kidney Information Network (CaMKIN) was established in 2019 as part of the Kidney Information Network (KIN), providing CKD patients 24-hour online access to information and support regarding their condition. Methods A novel digital method (Vasilica et al., 2021) of a dataset retrieved from a CaMKIN patient Facebook micro-community (1,119 posts and 5,266 comments), complemented by a survey (61 CaMKIN members). The digital methods steps involved a framework analysis to create themes and subthemes, directed analysis of data, familiarisation and sense making. Findings Analysis of data identified four major themes and an additional 13 subthemes of impact. Patients used the group to ‘improve understanding of their condition’ (theme 1) through sharing useful information, accessing information from lived experiences and organizing Q&A with health professionals. The micro-community formed a peer support network with both, in person and online peer to peer support. This support extended to ‘encouragement of self-management of health’ (theme 2), including managing diet and fitness. Group members created their own healthy choices weight loss accountability group, adopting a supportive ‘weight watchers’ style. They encouraged each other to take proactive steps in self-managing their health recommending people to contact renal team or ring emergency line where necessary. CaMKIN positively contributed to ‘improved health and wellbeing outcomes’ (theme 3), by providing a safe space to air frustrations, quell anxieties, and support each other’s mental health. This was important during the COVID_19 pandemic. CaMKIN provided patients a ‘safe environment, outside clinical settings’ (theme 4), to share and receive health information related to their kidney disease or treatment. Throughout the pandemic, the group discussed or clarified information (with professionals on the network), reducing demand on the local services through the self-organisation that occurred within the group. Survey results reinforced the Facebook dataset findings; most respondents benefited from access to health care information (86.9 %), which made them feel more informed about their condition (77.1%). Patients received valuable support from peers (75.4%). Almost half of respondents agreed that it reduced isolation and it contributed to management of mental health (48.8%). Conclusion This innovative micro-community helps CKD patients understand their condition better and improve health awareness through information sharing (peer and professionally developed) and peer support that contribute to increased self-management. Demonstrated through self-reported mechanisms, CaMKIN improved mental health and reduced social isolation. During the pandemic it offered patients a safe environment to develop understanding of the volatile situation to manage their health safely. The data provides insight into an untapped opportunity, recommendations include utilising the CAMKIN to further develop service provision and communication between hospitals and patients. Further research is required to roll out and evaluate embedding KIN into local service provision, and developing a patient network at a regional and national level

Intravital FRAP imaging using an E-cadherin-GFP mouse reveals disease- and drug-dependent dynamic regulation of cell-cell junctions in live tissue

E-cadherin-mediated cell-cell junctions play a prominent role in maintaining the epithelial architecture. The disruption or deregulation of these adhesions in cancer can lead to the collapse of tumor epithelia that precedes invasion and subsequent metastasis. Here we generated an E-cadherin-GFP mouse that enables intravital photobleaching and quantification of E-cadherin mobility in live tissue without affecting normal biology. We demonstrate the broad applications of this mouse by examining E-cadherin regulation in multiple tissues, including mammary, brain, liver, and kidney tissue, while specifically monitoring E-cadherin mobility during disease progression in the pancreas. We assess E-cadherin stability in native pancreatic tissue upon genetic manipulation involving Kras and p53 or in response to anti-invasive drug treatment and gain insights into the dynamic remodeling of E-cadherin during in situ cancer progression. FRAP in the E-cadherin-GFP mouse, therefore, promises to be a valuable tool to fundamentally expand our understanding of E-cadherin-mediated events in native microenvironments

MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.

BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer

Extending conceptual understanding : how interprofessional education influences affective domain development

Background: Interprofessional learning (IPL) can influence affective domain development of students, through teaching activities that facilitate learning with, from and about other professions. Current quantitative evidence offers limited explanation of how this learning is achieved within IPL programmes. This original paper tests a conceptual framework drawn from theories on IPL and affective domain development (attitudes, values and behaviours) to explain what works for whom, when and in what circumstances. Methods: The objectives of the study were twofold: to evaluate the impact of the IPL programme on the student’s attitudes and values, and identify behaviour changes in clinical practice towards interprofessional working. Using an action research approach, based in practice, an IPL programme was delivered over six weeks. Students from five professional disciplines: nursing, radiography, physiotherapy, social work, and podiatry (n=63) participated over the two action research cycles and in semi structured focus groups (n=37). Results: The recorded personal experiences of the IPL activities on the students were examined in relation to the: type of activity; impact on the affective domain of learning (attitude, value, or behaviour) and self-reported outcome on application to their practice. Modification in affective domain development was measured to identification or internalisation stage for 30 of the students. Self-reported outcomes on application to practice included direct impact on patient care, personal resilience building, improved communication and ability to challenge practice. Conclusion: This paper presents a conceptual framework not evident in current research, in regards to what IPL works for whom, in what circumstances and when. IPL Activities that address a personal reward or incentive and are delivered over 4 weeks, imitating ‘circles of care,’ that explore self-assessment, team building and reflection can lead to sustained change in values, attitudes and behaviours. Keywords: Action Research, Interprofessional Education, Interprofessional learning, Health and Social care, Collaboration

Researchers’ attitudes to the 3Rs - An upturned hierarchy?

Animal use in biomedical research is generally justified by its potential benefits to the health of humans, or other animals, or the environment. However, ethical acceptability also requires scientists to limit harm to animals in their research. Training in laboratory animal science (LAS) helps scientists to do this by promoting best practice and the 3Rs. This study evaluated scientists’ awareness and application of the 3Rs, and their approach to other ethical issues in animal research. It was based on an online survey of participants in LAS courses held in eight venues in four European countries: Portugal (Porto, Braga), Germany (Munich, Heidelberg), Switzerland (Basel, Lausanne, Zurich), and Denmark (Copenhagen). The survey questions were designed to assess general attitudes to animal use in biomedical research, Replacement alternatives, Reduction and Refinement conflicts, and harm-benefit analysis. The survey was conducted twice: immediately before the course (‘BC’, N = 310) and as a follow-up six months after the course (‘AC’, N = 127). While courses do appear to raise awareness of the 3Rs, they had no measurable effect on the existing low level of belief that animal experimentation can be fully replaced by non-animal methods. Most researchers acknowledged ethical issues with their work and reported that they discussed these with their peers. The level of an animal’s welfare, and especially the prevention of pain, was regarded as the most pressing ethical issue, and as more important than the number of animals used or the use of animals as such. Refinement was considered more feasible than Replacement, as well as more urgent, and was also favoured over Reduction. Respondents in the survey reversed the ‘hierarchy’ of the 3Rs proposed by their architects, Russell and Burch, prioritizing Refinement over Reduction, and Reduction over Replacement. This ordering may conflict with the expectations of the public and regulators.</div

Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma

BACKGROUND: Osteosarcoma is the most common type of primary bone tumor. The use of aggressive chemotherapy has drastically improved the prognosis of the patients with non-metastatic osteosarcomas, however the prognosis of the patients with metastasis is still very poor. Then, new and more effective treatments for curing osteosarcoma, such as immunotherapy are needed. Tumor-infiltrating lymphocytes (TIL) have been involved in the control of tumor development and already assessed with success for the treatment of several cancers including melanoma. While TIL represent a fascinating therapeutic approach in numerous malignant pathologies, there is few report concerning adult bone-associated tumors including osteosarcoma. METHODS: Human TIL were isolated and characterized (phenotype, lytic activity) from twenty-seven patients with bone-associated tumors (osteosarcoma, Ewing's sarcoma, giant cell tumor, chondrosarcoma, plasmocytoma and bone metastases). Similar experiments were performed using rat osteosarcoma model. RESULTS: While TIL with a main CD4(+ )profile were easily isolated from most of the tumor samples, only TIL extracted from osteosarcoma were cytotoxic against allogeneic tumor cells. In all cases, TIL lytic activity was significantly higher compared to autologous peripheral blood leukocytes. Similar data were observed in rat osteosarcoma model where TIL were characterized by a main CD4(+ )profile and high lytic activity against allogeneic and autologous tumor cells. Moreover, rat TIL expansion was not accompanied by refractoriness to further activation stimulus mainly by tumor antigens. CONCLUSION: These results demonstrated that TIL therapy could be a very efficient strategy for the treatment of adult osteosarcoma

A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts.

The small GTPase RhoA is involved in a variety of fundamental processes in normal tissue. Spatiotemporal control of RhoA is thought to govern mechanosensing, growth, and motility of cells, while its deregulation is associated with disease development. Here, we describe the generation of a RhoA-fluorescence resonance energy transfer (FRET) biosensor mouse and its utility for monitoring real-time activity of RhoA in a variety of native tissues in vivo. We assess changes in RhoA activity during mechanosensing of osteocytes within the bone and during neutrophil migration. We also demonstrate spatiotemporal order of RhoA activity within crypt cells of the small intestine and during different stages of mammary gestation. Subsequently, we reveal co-option of RhoA activity in both invasive breast and pancreatic cancers, and we assess drug targeting in these disease settings, illustrating the potential for utilizing this mouse to study RhoA activity in vivo in real time