DONSON:Slding in 2 the limelight

For over a decade, it has been known that yeast Sld2, Dpb11, GINS and Polε form the pre-loading complex (pre-LC), which is recruited to a CDC45-bound MCM2-7 complex by the Sld3/Sld7 heterodimer in a phospho-dependent manner. Whilst functional orthologs of Dbp11 (TOPBP1), Sld3 (TICRR) and Sld7 (MTBP) have been identified in metazoans, controversy has surrounded the identity of the Sld2 ortholog. It was originally proposed that the RECQ helicase, RECQL4, which is mutated in Rothmund-Thomson syndrome, represented the closest vertebrate ortholog of Sld2 due to a small region of sequence homology at its N-Terminus. However, there is no clear evidence that RECQL4 is required for CMG loading. Recently, new findings suggest that the functional ortholog of Sld2 is actually DONSON, a replication fork stability factor mutated in a range of neurodevelopmental disorders characterised by microcephaly, short stature and limb abnormalities. These studies show that DONSON forms a complex with TOPBP1, GINS and Polε analogous to the pre-LC in yeast, which is required to position the GINS complex on the MCM complex and initiate DNA replication. Taken together with previously published functions for DONSON, these observations indicate that DONSON plays two roles in regulating DNA replication, one in promoting replication initiation and one in stabilising the fork during elongation. Combined, these findings may help to uncover why DONSON mutations are associated with such a wide range of clinical deficits.</p

E3 ligases:a ubiquitous link between DNA repair, DNA replication and human disease

Maintenance of genome stability is of paramount importance for the survival of an organism. However, genomic integrity is constantly being challenged by various endogenous and exogenous processes that damage DNA. Therefore, cells are heavily reliant on DNA repair pathways that have evolved to deal with every type of genotoxic insult that threatens to compromise genome stability. Notably, inherited mutations in genes encoding proteins involved in these protective pathways trigger the onset of disease that is driven by chromosome instability e.g. neurodevelopmental abnormalities, neurodegeneration, premature ageing, immunodeficiency and cancer development. The ability of cells to regulate the recruitment of specific DNA repair proteins to sites of DNA damage is extremely complex but is primarily mediated by protein post-translational modifications (PTMs). Ubiquitylation is one such PTM, which controls genome stability by regulating protein localisation, protein turnover, protein-protein interactions and intra-cellular signalling. Over the past two decades, numerous ubiquitin (Ub) E3 ligases have been identified to play a crucial role not only in the initiation of DNA replication and DNA damage repair but also in the efficient termination of these processes. In this review, we discuss our current understanding of how different Ub E3 ligases (RNF168, TRAIP, HUWE1, TRIP12, FANCL, BRCA1, RFWD3) function to regulate DNA repair and replication and the pathological consequences arising from inheriting deleterious mutations that compromise the Ub-dependent DNA damage response.</p

Implementation frameworks for polypharmacy management within healthcare organisations: a scoping review.

Several guidelines support polypharmacy management in individual patients. More organisational-level focus is needed on the use of implementation frameworks. The aim of this scoping review was to characterise the peer-reviewed literature on implementation frameworks, focussing on barriers and facilitators to implementation at organisational level in the context of polypharmacy management. A scoping review protocol was devised, supporting retrieval of studies published in English, reporting from any sector of practice. Medline, International Pharmaceutical Abstracts, Cumulative Index of Nursing and Allied Health Literature and Business Source Complete were searched to January 2022 using Medical Subject Headings including: 'polypharmacy', 'deprescriptions', 'strategic planning' and 'organizational innovation'. A narrative approach to data synthesis was applied. Searching, data extraction and synthesis were undertaken independently by two reviewers. After screening 797 records, eight papers remained. Two were descriptive, outlining details of specific initiatives; six used qualitative methods to explore determinants for implementation, including barriers and enablers. Barriers at the organisation level included: poor organisational culture with a lack of sense of urgency and national plans, resource availability and communication issues including patient information and at transitions of care. Organisational facilitators included availability of government funding and regulatory environment promoting patient safety, a national emphasis on quality of care for older adults, co-ordinated national efforts and local evidence. Limited literature focusses on the use of implementation frameworks at organisational levels. This review highlights the need for further work on implementation frameworks in this context to help achieve effective organisational change

A qualitative exploration of key stakeholders’ views and perceptions in relation to organisational change for the implementation of polypharmacy management in Oman.

Polypharmacy contributes to patient non-adherence and increases medication harm. Barriers to implementation prevent desired outcomes when addressing inappropriate polypharmacy at organisational levels and there is a need for theory-based strategies for change management. The objective of this study was to explore the views and perceptions of key stakeholders in relation to organisational change for the development and implementation of a polypharmacy management healthcare strategy in Oman. Qualitative face to face interviews started in March 2022 with key stakeholders in Oman Ministry of Health (MOH) including leaders from practice of Medical, pharmacy and nursing as well as academic leaders from school of medicine, pharmacy and nursing. The interview schedule developed based on a scoping review, Kotter's first three steps of leading change and grounded in the consolidated Framework for Implementation Research (CIFR). Interviews were digitally recorded, transcribed, and analysed independently by at least two researchers using CFIR as a coding framework. Ethics approval was in place prior to data generation. Identified themes related to views and perceptions of key stakeholders in relation to the topic area. To date, ten interviews have been conducted with directors of medical (n=2), pharmacy (2) and nursing practice (1), academic healthcare leaders (3), a healthcare policy developer (1) and patient safety leader (1). Additional interviews are planned and will continue until data saturation. Emerging themes show that participants have views that polypharmacy is a burden on healthcare services and there is a need for organisational change in relation to polypharmacy management. Perceptions of reported organisational level barriers were; fragmentation of care, lack of systems for coordination among healthcare providers, absence of electronic link between the government and private sector, lack of sense of urgency among leaders regarding the polypharmacy and shortage of pharmacists. Facilitators were; the presence of well-developed electronic health system and leadership support. There is a need for for organisational change in relation to polypharmacy management in Oman. Further research is needed to obtain consensus of Omani stakeholders on the plan for a strategic framework for organisational change in relation to polypharmacy management

"Making Safety Happen" Through Probabilistic Risk Assessment at NASA

NASA is using Probabilistic Risk Assessment (PRA) as one of the tools in its Safety & Mission Assurance (S&MA) tool belt to identify and quantify risks associated with human spaceflight. This paper discusses some of the challenges and benefits associated with developing and using PRA for NASA human space programs. Some programs have entered operation prior to developing a PRA, while some have implemented PRA from the start of the program. It has been observed that the earlier a design change is made in the concept or design phase, the less impact it has on cost and schedule. Not finding risks until the operation phase yields much costlier design changes and major delays, which can result in discussions of just accepting the risk. Risk contributors identified by PRA are not just associated with hardware failures. They include but are not limited to crew fatality due to medical causes, the environment the vehicle and crew are exposed to, the software being used, and the reliability of the crew performing required actions. Some programs have entered operation prior to developing a PRA, and while PRA can still provide a benefit for operations and future design trades, the benefit of implementing PRA from the start of the program provides the added benefit of informing design and reducing risk early in program development. Currently, NASAs International Space Station (ISS) program is in its 20th year of on-orbit operations around the Earth and has several new programs in the design phase preparing to enter the operation phase all of which have active (or living) PRAs. These programs incorporate PRA as part of their Risk-Informed, Decision-Making (RIDM) process. For new NASA human spaceflight programs discussion begins with mission concept, establishing requirements, forming the PRA team, and continues through the design cycles into the operational phase. Several examples of PRA related applications and observed lessons are included

Constitutive phosphorylation of MDC1 physically links the MRE11–RAD50–NBS1 complex to damaged chromatin

The MRE11–RAD50–Nijmegen breakage syndrome 1 (NBS1 [MRN]) complex accumulates at sites of DNA double-strand breaks (DSBs) in microscopically discernible nuclear foci. Focus formation by the MRN complex is dependent on MDC1, a large nuclear protein that directly interacts with phosphorylated H2AX. In this study, we identified a region in MDC1 that is essential for the focal accumulation of the MRN complex at sites of DNA damage. This region contains multiple conserved acidic sequence motifs that are constitutively phosphorylated in vivo. We show that these motifs are efficiently phosphorylated by caseine kinase 2 (CK2) in vitro and directly interact with the N-terminal forkhead-associated domain of NBS1 in a phosphorylation-dependent manner. Mutation of these conserved motifs in MDC1 or depletion of CK2 by small interfering RNA disrupts the interaction between MDC1 and NBS1 and abrogates accumulation of the MRN complex at sites of DNA DSBs in vivo. Thus, our data reveal the mechanism by which MDC1 physically couples the MRN complex to damaged chromatin

Are they ‘worth their weight in gold’? Sport for older adults: benefits and barriers of their participation for sporting organisations

The ageing global population has led to an increased focus on health for older adults. However, older adults have not been a specific priority for some sporting organisations (SOs). Thus, there is an emerging opportunity for this age group to be considered within international sport policy. The aim of this study was to understand the benefits and barriers that SOs encounter when engaging older adults. Eight focus group interviews (n = 49) were held with representatives of Australian national sporting organisations (NSOs), and older adults who were either sport club or non-sport club members. The socioecological model domains, interpersonal, organisational and policy, were used as a framework for thematic analysis, and organisational capacity building concepts were utilised to explain the findings. Common perceived benefits included interpersonal benefits (intergenerational opportunities and role models) and organisational benefits (volunteering, financial contributions and maximised facility usage) for engaging older adults. Common perceived barriers included interpersonal barriers (competing priorities and perceived societal expectations), organisational barriers (lack of appropriate playing opportunities, lack of facility access and lack of club capacity) and policy barriers (strategic organisational focus on children and elite sport and risk management). Whilst participation in sport is not common for older adults, their involvement can be invaluable for sport clubs. It is not anticipated that any policy focus on older adults will significantly increase active participation for this age group. However, any increase in older adults’ sport participation either through actively playing, supporting family and friends and/or volunteering will contribute to the positive health of individuals, sport clubs and the community.Peer reviewedFinal Accepted Versio

Patient specific modeling of palpation-based prostate cancer diagnosis: effects of pelvic cavity anatomy and intrabladder pressure.

Computational modeling has become a successful tool for scientific advances including understanding the behavior of biological and biomedical systems as well as improving clinical practice. In most cases, only general models are used without taking into account patient-specific features. However, patient specificity has proven to be crucial in guiding clinical practice because of disastrous consequences that can arise should the model be inaccurate. This paper proposes a framework for the computational modeling applied to the example of the male pelvic cavity for the purpose of prostate cancer diagnostics using palpation. The effects of patient specific structural features on palpation response are studied in three selected patients with very different pathophysiological conditions whose pelvic cavities are reconstructed from MRI scans. In particular, the role of intrabladder pressure in the outcome of digital rectal examination is investigated with the objective of providing guidelines to practitioners to enhance the effectiveness of diagnosis. Furthermore, the presence of the pelvic bone in the model is assessed to determine the pathophysiological conditions in which it has to be modeled. The conclusions and suggestions of this work have potential use not only in clinical practice and also for biomechanical modeling where structural patient-specificity needs to be considered. © 2015 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd