Physical literacy, health and interactive aging: a position paper.

Physical literacy (PL), a concept commonly associated with the early years, physical education, and youth sport development, can become a meaningful determinant of health and longevity for the adult and older adult population. A review of 55 recent publications from 2018 to 2023 that encompassed physical literacy conceptual frameworks, assessments, and intervention-based studies was undertaken through an heuristic inspired by the philosophy which gave birth to PL. With particular interest in how PL has evolved in response to the needs of an aging population, this position paper tracks a key shift in focus from the individual to the relational context. It references positive interaction and social participation in recent models as significant features of an across-the-lifespan PL perspective.The concluding position is that fostering joyful inter-action be at the heart of PL promotion, resource development and assessment practices, especially in the case of an aging population.

Salsa Rhythms and Soul Connections.

The rhythmic interplay of accent, tempo, and musical mood is expressed in the bodily postures, gestures, and expressions of attuned responsiveness in Salsa Dura, a genre of salsa music from the 1970s featuring improvisational dance solos. These dancers embrace the feelings and flows of soloing musicians going off and breaking free from any predictable form and structure. We inquire into how world-class salsa dancers and educators feel themselves moved by such intricate rhythms to experience soul connections. Video recordings and interviews yield insight into the call and response dynamics of this essentially tactful practice of alterity.

Health service improvement using positive patient feedback: Systematic scoping review.

BACKGROUND: Healthcare services regularly receive patient feedback, most of which is positive. Empirical studies suggest that health services can use positive feedback to create patient benefit. Our aim was to map all available empirical evidence for how positive patient feedback creates change in healthcare settings. METHODS: Empirical studies in English were systematically identified through database searches (ACM Digital Library, AMED, ASSIA, CINAHL, MEDLINE and PsycINFO), forwards and backwards citation, and expert consultation. We summarise the characteristics of included studies and the feedback they consider, present a thematic synthesis of qualitative findings, and provide narrative summaries of quantitative findings. RESULTS: 68 papers were included, describing research conducted across six continents, with qualitative (n = 51), quantitative (n = 10), and mixed (n = 7) methods. Only two studies were interventional. The most common settings were hospitals (n = 27) and community healthcare (n = 19). The most common recipients were nurses (n = 29). Most outcomes described were desirable. These were categorised as (a) short-term emotional change for healthcare workers (including feeling motivated and improved psychological wellbeing); (b) work-home interactional change for healthcare workers (such as improved home-life relationships); (c) work-related change for healthcare workers (such as improved performance and staff retention). Some undesirable outcomes were described, including envy when not receiving positive feedback. The impact of feedback may be moderated by characteristics of particular healthcare roles, such as night shift workers having less interaction time with patients. Some factors moderating the change created by feedback are modifiable. CONCLUSION: Further interventional research is required to assess the effectiveness and cost-effectiveness of receiving positive feedback in creating specific forms of change such as increases in staff retention. Healthcare managers may wish to use positive feedback more regularly, and to address barriers to staff receiving feedback.

Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles.

Poor understanding of intracellular delivery and targeting hinders development of nucleic acid-based therapeutics transported by nanoparticles. Utilizing a siRNA-targeting and small molecule profiling approach with advanced imaging and machine learning biological insights is generated into the mechanism of lipid nanoparticle (MC3-LNP) delivery of mRNA. This workflow is termed Advanced Cellular and Endocytic profiling for Intracellular Delivery (ACE-ID). A cell-based imaging assay and perturbation of 178 targets relevant to intracellular trafficking is used to identify corresponding effects on functional mRNA delivery. Targets improving delivery are analyzed by extracting data-rich phenotypic fingerprints from images using advanced image analysis algorithms. Machine learning is used to determine key features correlating with enhanced delivery, identifying fluid-phase endocytosis as a productive cellular entry route. With this new knowledge, MC3-LNP is re-engineered to target macropinocytosis, and this significantly improves mRNA delivery in vitro and in vivo. The ACE-ID approach can be broadly applicable for optimizing nanomedicine-based intracellular delivery systems and has the potential to accelerate the development of delivery systems for nucleic acid-based therapeutics.

Loss of Cyclin C or CDK8 provides ATR inhibitor resistance by suppressing transcription-associated replication stress.

The protein kinase ATR plays pivotal roles in DNA repair, cell cycle checkpoint engagement and DNA replication. Consequently, ATR inhibitors (ATRi) are in clinical development for the treatment of cancers, including tumours harbouring mutations in the related kinase ATM. However, it still remains unclear which functions and pathways dominate long-term ATRi efficacy, and how these vary between clinically relevant genetic backgrounds. Elucidating common and genetic-background specific mechanisms of ATRi efficacy could therefore assist in patient stratification and pre-empting drug resistance. Here, we use CRISPR-Cas9 genome-wide screening in ATM-deficient and proficient mouse embryonic stem cells to interrogate cell fitness following treatment with the ATRi, ceralasertib. We identify factors that enhance or suppress ATRi efficacy, with a subset of these requiring intact ATM signalling. Strikingly, two of the strongest resistance-gene hits in both ATM-proficient and ATM-deficient cells encode Cyclin C and CDK8: members of the CDK8 kinase module for the RNA polymerase II mediator complex. We show that Cyclin C/CDK8 loss reduces S-phase DNA:RNA hybrid formation, transcription-replication stress, and ultimately micronuclei formation induced by ATRi. Overall, our work identifies novel biomarkers of ATRi efficacy in ATM-proficient and ATM-deficient cells, and highlights transcription-associated replication stress as a predominant driver of ATRi-induced cell death.

Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.

Radiotherapy is an effective anticancer treatment, but combinations with targeted agents that maximize efficacy while sparing normal tissue are needed. Here, we assess the radiopotentiation profiles of DNA damage response inhibitors (DDRi) olaparib (PARP1/2), ceralasertib (ATR), adavosertib (WEE1), AZD0156 (ATM), and KU-60648 (DNA-PK). We performed a radiotherapy combination screen and assessed how drug concentration and cellular DDR deficiencies influence the radiopotentiation ability of DDRi. We pre-selected six lung cancer cell lines with different genetic/signaling aberrations (including mutations in TP53 and ATM) and assessed multiple concentrations of DDRi in combination with a fixed radiotherapy dose by clonogenic assay. The effective concentration of DDRi in radiotherapy combinations is lower than that required for single-agent efficacy. This has the potential to be exploited further in the context of DDR deficiencies to increase therapeutic index and we demonstrate that low concentrations of AZD0156 preferentially sensitized p53-deficient cells. Moreover, testing multiple concentrations of DDRi in radiotherapy combinations indicated that olaparib, ceralasertib, and adavosertib have a desirable safety profile showing moderate increases in radiotherapy dose enhancement with increasing inhibitor concentration. Small increases in concentration of AZD0156 and particularly KU-60648, however, result in steep increases in dose enhancement. Radiopotentiation profiling can inform on effective drug doses required for radiosensitization in relation to biomarkers, providing an opportunity to increase therapeutic index. Moreover, multiple concentration testing demonstrates a relationship between drug concentration and radiotherapy effect that provides valuable insights that, with future in vivo validation, can guide dose-escalation strategies in clinical trials.

Management of Allogeneic Stem Cell Transplantation for High-Risk AML following SARS-CoV-2 Associated Pancytopenia with Marked Bone Marrow Biopsy Alterations.

The present study describes a patient aged 70 with very high-risk AML who successfully received a nonmyeloablative matched unrelated donor allograft shortly following SARS-CoV-2 infection, which manifested with mild cough, interstitial abnormalities on chest CT, and pancytopenia with profound bone marrow biopsy histological alterations. In parallel, our study provides bone marrow biopsy data in a series of contemporary patients with serious haematological diseases who had a bone marrow biopsy performed within two weeks of PCR confirmation of SARS-CoV-2 infection. This study is notable because there are no published data describing the bone marrow biopsy changes observed in patients with haematological malignancies and SARS-CoV-2 infection. Finally, it is suggested that nonmyeloablative hematopoietic stem cell transplantation for very high-risk haematological malignancies can be successfully performed following recovery from SARS-CoV-2 infection.

Becoming InterActive for Life: Mobilizing Relational Knowledge for Physical Educators.

The overarching purpose of the InterActive for Life (IA4L) project is to mobilize relational knowledge of partnered movement practices for physical education practitioners. Through a participatory, motion-sensing phenomenological methodology, relational knowledge gleaned from world class experts in salsa dance, equestrian arts, push hands Tai Chi and acroyoga, and analyzed through the Function2Flow conceptual model, was shared with Physical Education Teacher Education (PETE) students. They, in turn, made sense of the ways these experts cultivate relational connections through a process of designing interactive games suitable for physical education curricula. The kinetic, kinesthetic, affective and energetic dynamics of these games were then shared through professional development workshops, mentoring, and open-access resources. Each phase of the IA4L project invites us to depart from the predominance of individualistic ways of conceiving and teaching movement and instead explore what it means to be attuned to the pulse of life as we break away from tendencies to objectify movement as something our bodies do or that is done to them. Consideration is given to the ways in which meaningful relational connections are formed in and through movement and how this learning prioritizes the InterActive Functions, Forms, Feelings and Flows of moving purposefully, playfully and expressively with others. In so doing, what this research offers is an understanding of how knowledge of an essentially motion-sensitive kind, which can breathe life into physical education curricula, can be actively and interactively mobilized.

Autoimmune Cytopenias Developing Late Post Alemtuzumab-Based Allogeneic Stem Cell Transplantation: Presentation of Short Case Series from a Transplant Center.

Stem cell transplantation remains the curative option for many patients with hematological malignancies. The long-term effects of these treatments on the patients and their immune systems have been extensively investigated, but there remains a paucity of data regarding autoimmune manifestations post-transplant, although these effects are well recognized.Herein we present the clinical picture and therapeutic approach in three patients (cases 1-3), with varied presentations of autoimmune disease post-transplant. Case 1 exhibited autoimmune hemolytic anemia and other autoimmune manifestations (serositis, thyroiditis), that were probably linked to graft versus relapsed leukemia effect. Cases 2 and 3 had pure red white cell aplasia and pure red cell aplasia, respectively, which were associated with hyperglobulinemia and a clonal T cell expansion.

First case of near haploid philadelphia negative B-Cell acute lymphoblastic leukaemia relapsing as acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation.

Herein we present a female patient aged 61 with Philadelphia negative acute lymphoblastic leukaemia demonstrating near haploid karyotype and abnormal TP53 expression at diagnosis, who relapsed with lineage switch as Acute Monocytic Leukemia post allogeneic stem cell transplantation. Molecular analysis established that both neoplasms were derived from the same founder clone. The leukemic lineage switch phenomenon has recently re-attracted interest as mechanism of leukemic evasion post treatment with chimeric antigen receptor T-cells but there is paucity of data on its presence post allograft or following novel antibody treatments such as Inotuzumab Ozogamicin or Blinatumomab. Our proposition for cancer research is that near haploidy in ALL could be linked to leukemic stem cell plasticity evading stem cell transplantation and other immunotherapy approaches.

Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells.

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.

Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.

Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcription factors but subsequently converge on the same naive endpoint, showing surprising flexibility in mechanisms underlying identity transitions and suggesting that naive pluripotency is a multidimensional attractor state. These route differences are reconciled by precise expression of Oct4 as a unifying, essential, and sufficient feature. We propose that fine-tuned regulation of this "transition factor" underpins multidimensional access to naive pluripotency, offering a conceptual framework for understanding cell identity transitions.

OA38†From service delivery to community enablement: a public health approach to palliative care.

: Milford Care Centre is the only hospice in Ireland to make a strategic decision to embrace a public health approach to palliative care, through the development, implementation and evaluation of the Compassionate Communities Project. This presentation seeks to examine why Milford made the decision to move toward a community enablement model, describes the development and implementation of the Compassionate Communities Project to date, presents key findings from recent evaluations and highlights our plans for the future. The presentation uses a reflective, story telling approach to meet it's aims, coupled with data and statistics gathered from the evaluations, and includes a new short film 'Tell Me' developed by recent Computer Science graduates for the Project to use to engage with communities during Café Conversations. The presentation will highlight the relevance of Health Promoting Palliative Care theory to the development of a three-tier model of programme activity, examine the challenges in implementing such an approach and will discuss the impact of upstream intervention to downstream service provision using case studies.

OA39†Digging a hole planting a seed water it and watch it start to grow, grow, grow.

BACKGROUND: Milford Care Centre's Compassionate Communities Project uses a seed grant scheme to engage with communities around illness, dying, death and bereavement. The scheme, now in it's 3(rd) cycle strives to inspire and support the work of local groups, organisations and individuals who wish to mark in some tangible way their response to the universal realities of death, dying, loss and care as lived and experienced by those living within their communities. A key requirement for the receipt of a grant is that the level of funding must be matched either in cash or in kind. AIM: This presentation will report on the projects supported, describing the short and medium term impact they have had on the local community. METHOD: A short film will showcase the projects. Qualitative interviews were conducted with all grant recipients to determine the impact of the seed grant at a community level. RESULTS: Seed grants were used in a variety of ways, for example: Supporting a community group to develop a reflection space Supporting a youth project to explore what death, dying, loss and care means to service users through the creative arts. Supporting a library to develop a bereavement information 'resource'. Supporting local groups to run a community event aimed at increasing awareness and knowledge about 'healthy' ways of coping with loss and grief. Supporting those seeking practical ways of providing support to other living with illness and loss. CONCLUSIONS: The seed grant scheme offers a low cost, high impact approach to working with communities.

OA41†How can we support people living with death, dying, loss and care using animation? social workers reflect on the compassionate communities 'let's talk' films.

BACKGROUND: Milford Care Centre's Compassionate Communities Project has developed a series of animated films - The 'Let's Talk' Series. These films are used by the project to encourage people to have think about having difficult conversations about illness and death. The films are available on the project website, via You Tube and are shown during Café Conversations as part of the Compassionate Communities Project. More recently, members of the Specialist Palliative Care Social Work department have been using the films during their direct work with patients and their families. AIM: This presentation aims to introduce participants to the Let's Talk film series and describe the learning from social workers who have used the films at home, and in the inpatient unit, with patients, their partners and their children. METHOD: Social workers were interviewed, sharing their experience and reflection on using the animated films as a practice tool. RESULTS: A number of case studies will be presented to describe the use and impact of the films in practice. CONCLUSION: The films are a very useful addition to the social work toolbox. Guidelines for their use in practice will be presented.

Promoting vitality in health and physical education.

Vitality draws together the interests of health and physical education. Already these fields of education have come together, with health, fitness, wellness, and active and healthy living as shared curricular concepts. Vitality furthers these conjunctions by having us rethink prevailing views of the body of knowledge in health and physical education. More than a concept, vitality is promoted phenomenologically in terms of the essential movements of the body. It is explicated as vitality affects, specifically identifiable motions and developmental patterns of movement that provide curricular structure for teaching health and physical education. The promotional implications of this analysis relate to enlivening the baseline criteria currently used in health and physical education assessments; revitalizing the curricular concepts of body awareness, space, time, and relationships on which provincial programs are based; and expanding the reach of these programs to mental, emotional, spiritual, and, particularly, environmental health.