SLX4IP Antagonizes Promiscuous BLM Activity during ALT Maintenance.

Cancer cells acquire unlimited proliferative capacity by either re-expressing telomerase or inducing alternative lengthening of telomeres (ALT), which relies on telomere recombination. Here, we show that ALT recombination requires coordinate regulation of the SMX and BTR complexes to ensure the appropriate balance of resolution and dissolution activities at recombining telomeres. Critical to this control is SLX4IP, which accumulates at ALT telomeres and interacts with SLX4, XPF, and BLM. Loss of SLX4IP increases ALT-related phenotypes, which is incompatible with cell growth following concomitant loss of SLX4. Inactivation of BLM is sufficient to rescue telomere aggregation and the synthetic growth defect in this context, suggesting that SLX4IP favors SMX-dependent resolution by antagonizing promiscuous BLM activity during ALT recombination. Finally, we show that SLX4IP is inactivated in a subset of ALT-positive osteosarcomas. Collectively, our findings uncover an SLX4IP-dependent regulatory mechanism critical for telomere maintenance in ALT cancer cells.

Telehealth interventions for transition to self-management in adolescents with allergic conditions: A systematic review.

Telehealth is an emerging approach that uses technology to provide healthcare remotely. Recent publications have outlined the importance of supporting the transition to self-management of adolescents with allergic conditions. However, no synthesis of the evidence base on the use and impact of telehealth interventions for this purpose has been conducted to date. This review achieves these aims, in addition to exploring the language use surrounding these interventions, and their implementation. Four databases were searched systematically. References were independently screened by two reviewers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was undertaken. Eighteen articles were included, reporting on 15 telehealth interventions. A total of 86% targeted adolescents with asthma. Mobile applications were the most common telehealth modality used, followed by video-conferencing, web-based, virtual reality and artificial intelligence. Five intervention content categories were identified; educational, monitoring, behavioural, psychosocial and healthcare navigational. Peer and/or healthcare professional interaction, gamification and tailoring may increase engagement. The studies showed positive effects of the interventions or no difference from active controls, in self-management outcomes such as knowledge, health outcomes such as quality-of-life, and economic outcomes such as healthcare utilization. The most common implementation outcomes reported were acceptability, appropriateness, feasibility and fidelity.

Community Group-Based Physical Activity Programs for Immigrant Older Adults: A Systematic Realist Review.

Physical activity program interventions often lack sensitivity to the needs of older immigrant adults. The objective of this systematic realist review is to explain how, why, for whom, and under which circumstances community group-based physical activity programs work for immigrant older adults. The initial program theory was developed using prior research, team expertise, social cognitive theory, and knowledge user consultations. The program theory was tested and refined via a systematic review of the literature. Database searches were conducted in MEDLINE, EMBASE, CINAHL, Scopus, Cochrane Library, Sports Medicine and Education Index, and SPORTDiscus. A total of 22 sources of evidence met inclusion criteria and included intervention studies, systematic reviews, and a discussion paper. Intervention studies were appraised using the Mixed Methods Appraisal Tool. The final program theory constituted eight context-mechanism-outcome configurations that highlight the importance of facilitator characteristics, access to safe spaces, group dynamics, and social support. A limitation was the small number and variable quality of included evidence. Physical activity programs that target immigrant older adults must strengthen physical and psychological safety and maximize opportunities for role modeling and socialization. This research was supported by the Alberta Health Services Seniors Health Strategic Clinical Network and is registered in PROSPERO (ID#258179).

Knowledge translation strategies used for sustainability of an evidence-based intervention in child health: a multimethod qualitative study.

BACKGROUND: Sustainability of evidence-based interventions (EBIs) is suboptimal in healthcare. Evidence on how knowledge translation (KT) strategies are used for the sustainability of EBIs in practice is lacking. This study examined what and how KT strategies were used to facilitate the sustainability of Alberta Family Integrated Care (FICare)™, a psychoeducational model of care scaled and spread across 14 neonatal intensive care units, in Alberta, Canada. METHODS: First, we conducted an environmental scan of relevant documents to determine the use of KT strategies to support the sustainability of Alberta FICare™. Second, we conducted semi-structured interviews with decision makers and operational leaders to explore what and how KT strategies were used for the sustainability of Alberta FICare™, as well as barriers and facilitators to using the KT strategies for sustainability. We used the Expert Recommendations for Implementation Change (ERIC) taxonomy to code the strategies. Lastly, we facilitated consultation meetings with the Alberta FICare™ leads to share and gain insights and clarification on our findings. RESULTS: We identified nine KT strategies to facilitate the sustainability of Alberta FICare™: Conduct ongoing training; Identify and prepare local champions; Research co-production; Remind clinicians; Audit and provide feedback; Change record systems; Promote adaptability; Access new funding; and Involve patients/consumers and family members. A significant barrier to the sustainability of Alberta FICare™ was a lack of clarity on who was responsible for the ongoing maintenance of the intervention. A key facilitator to sustainability of Alberta FICare was its alignment with the Maternal, Newborn, Child & Youth Strategic Clinical Network (MNCY SCN) priorities. Co-production between researchers and health system partners in the design, implementation, and scale and spread of Alberta FICare™ was critical to sustainability. CONCLUSION: This research highlights the importance of clearly articulating who is responsible for continued championing for the sustainability of EBIs. Additionally, our research demonstrates that the adaptation of interventions must be considered from the onset of implementation so interventions can be tailored to align with contextual barriers for sustainability. Clear guidance is needed to continually support researchers and health system leaders in co-producing strategies that facilitate the long-term sustainability of effective EBIs in practice.

SDE2 is an essential gene required for ribosome biogenesis and the regulation of alternative splicing.

RNA provides the framework for the assembly of some of the most intricate macromolecular complexes within the cell, including the spliceosome and the mature ribosome. The assembly of these complexes relies on the coordinated association of RNA with hundreds of trans-acting protein factors. While some of these trans-acting factors are RNA-binding proteins (RBPs), others are adaptor proteins, and others still, function as both. Defects in the assembly of these complexes results in a number of human pathologies including neurodegeneration and cancer. Here, we demonstrate that Silencing Defective 2 (SDE2) is both an RNA binding protein and also a trans-acting adaptor protein that functions to regulate RNA splicing and ribosome biogenesis. SDE2 depletion leads to widespread changes in alternative splicing, defects in ribosome biogenesis and ultimately complete loss of cell viability. Our data highlight SDE2 as a previously uncharacterized essential gene required for the assembly and maturation of the complexes that carry out two of the most fundamental processes in mammalian cells.

Definitions of health and social care standards used internationally: A narrative review.

Setting standards is a quality improvement mechanism and an important means for shaping the provision of health and social care services. Standards comprise statements describing a process or outcome of care. Setting standards is a global practice. It would be useful to have an understanding of the underpinning definitions of standards used internationally. Therefore, the aim of this review was to examine definitions of health and social care standards used internationally and identify similarities and differences. A targeted grey literature search of standard-setting bodies' websites and related health legislation was conducted to retrieve explicit definitions of standards. Of 15 standard-setting bodies that were searched, 12 definitions of standards were narratively synthesised. Terms that appeared in two or more of the definitions were extracted. Counts and percentages were calculated for these terms to determine magnitude of use. The commonalities among definitions included 'quality' (n = 6, 50%), 'statements' (n = 5, 42%), 'performance' (n = 5, 42%), and 'measureable' (n = 4, 33%). The less commonly used terms were 'processes' (n = 3, 25%), 'set' (n = 3, 25%), 'evidence based' (n = 2, 17%), 'outcome' (n = 2, 17%), 'safe' (n = 2, 17%), and 'guidance' (n = 2, 17%). Explicit definitions of standards were not retrieved from health legislation documents. Standard-setting bodies develop standards in the context of the health systems in which they are implemented; some are aspirational levels of quality, while others are minimum levels of quality. Researchers, standards developers and policy makers should be cognisant of this when comparing standards between countries.

Surviving Telomere Attrition with the MiDAS Touch.

Cancer cells maintain telomere lengths through telomerase activity or by alternative lengthening of telomeres (ALT). Using an engineered model system, a recent study by Min et al. reveals that the combination of BLM-mediated DNA resection and telomere clustering, a characteristic of ALT telomeres, catalyzes RAD52-dependent mitotic DNA synthesis (MiDAS) specifically at telomeres to drive ALT activity.

RAD54 promotes alternative lengthening of telomeres by mediating branch migration.

Cancer cells can activate the alternative lengthening of telomeres (ALT) pathway to promote replicative immortality. The ALT pathway promotes telomere elongation through a homologous recombination pathway known as break-induced replication (BIR), which is often engaged to repair single-ended double-stranded breaks (DSBs). Single-ended DSBs are resected to promote strand invasion and facilitate the formation of a local displacement loop (D-loop), which can trigger DNA synthesis, and ultimately promote telomere elongation. However, the exact proteins involved in the maturation, migration, and resolution of D-loops at ALT telomeres are unclear. In vitro, the DNA translocase RAD54 both binds D-loops and promotes branch migration suggesting that RAD54 may function to promote ALT activity. Here, we demonstrate that RAD54 is enriched at ALT telomeres and promotes telomeric DNA synthesis through its ATPase-dependent branch migration activity. Loss of RAD54 leads to the formation of unresolved recombination intermediates at telomeres that form ultra-fine anaphase bridges in mitosis. These data demonstrate an important role for RAD54 in promoting ALT-mediated telomere synthesis.

A transposon-mediated reciprocal translocation promotes environmental adaptation but compromises domesticability of wild soybeans.

Large structural variations frequently occur in higher plants; however, the impact of such variations on plant diversification, adaptation and domestication remains elusive. Here, we mapped and characterised a reciprocal chromosomal translocation in soybeans and assessed its effects on diversification and adaptation of wild (Glycine soja) and semiwild (Glycine gracilis) soybeans, and domestication of cultivated soybean (Glycine max), by tracing the distribution of the translocation in the USDA Soybean Germplasm Collection and population genetics analysis. We demonstrate that the translocation occurred through CACTA transposon-mediated chromosomal breakage in wild soybean c. 0.34 Ma and is responsible for semisterility in translocation heterozygotes and reduces their reproductive fitness. The translocation has differentiated Continental (i.e. China and Russia) populations from Maritime (i.e. Korea and Japan) populations of G. soja and predominately adapted to cold and dry climates. Further analysis revealed that the divergence of G. max from G. soja predates the translocation event and that G. gracilis is an evolutionary intermediate between G. soja and G. max. Our results highlight the effects of a chromosome rearrangement on the processes leading to plant divergence and adaptation, and provides evidence that suggests G. gracilis, rather than G. soja, as the ancestor of cultivated soybean.

Contextual factors and mechanisms that influence sustainability: a realist evaluation of two scaled, multi-component interventions.

BACKGROUND: In 2012, Alberta Health Services created Strategic Clinical NetworksTM (SCNs) to develop and implement evidence-informed, clinician-led and team-delivered health system improvement in Alberta, Canada. SCNs have had several provincial successes in improving health outcomes. Little research has been done on the sustainability of these evidence-based implementation efforts. METHODS: We conducted a qualitative realist evaluation using a case study approach to identify and explain the contextual factors and mechanisms perceived to influence the sustainability of two provincial SCN evidence-based interventions, a delirium intervention for Critical Care and an Appropriate Use of Antipsychotics (AUA) intervention for Senior's Health. The context (C) + mechanism (M) = outcome (O) configurations (CMOcs) heuristic guided our research. RESULTS: We conducted thirty realist interviews in two cases and found four important strategies that facilitated sustainability: Learning collaboratives, audit & feedback, the informal leadership role, and patient stories. These strategies triggered certain mechanisms such as sense-making, understanding value and impact of the intervention, empowerment, and motivation that increased the likelihood of sustainability. For example, informal leaders were often hands-on and influential to front-line staff. Learning collaboratives broke down professional and organizational silos and encouraged collective sharing and learning, motivating participants to continue with the intervention. Continual audit-feedback interventions motivated participants to want to perform and improve on a long-term basis, increasing the likelihood of sustainability of the two multi-component interventions. Patient stories demonstrated the interventions' impact on patient outcomes, motivating staff to want to continue doing the intervention, and increasing the likelihood of its sustainability. CONCLUSIONS: This research contributes to the field of implementation science, providing evidence on key strategies for sustainability and the underlying causal mechanisms of these strategies that increases the likelihood of sustainability. Identifying causal mechanisms provides evidence on the processes by which implementation strategies operate and lead to sustainability. Future work is needed to evaluate the impact of informal leadership, learning collaboratives, audit-feedback, and patient stories as strategies for sustainability, to generate better guidance on planning sustainable improvements with long term impact.

Preparing Nursing Contexts for Evidence-Based Practice Implementation: Where Should We Go From Here?

BACKGROUND: Context is important to the adoption and sustainability of evidence-based practices (EBPs). Currently, most published implementation efforts address context in relation to one specific EBP or a bundle of related EBPs. Since EBP and implementation are ongoing and dynamic, more discussion is needed on preparing nursing contexts to be more conducive to implementation generally. AIM: To discuss the need to create contexts that are more adaptable to ongoing change due to the dynamic nature of EBPs and the ever-changing healthcare environment. METHODS: This paper builds on a collection of our previous work, as nursing implementation scientists representing the Canadian and American healthcare contexts, and a literature review of the implementation science, knowledge translation, and sustainability literatures from 2006 to 2019. RESULTS: We argue for a different way of thinking about the influence of context and implementation of EBPs. We contend that nursing contexts must be prepared to be more flexible and conducive to ongoing EBP implementation more generally. Contexts that embrace, facilitate, and have the capacity for change may be more likely to effectively de-implement ineffective interventions or implement and sustain new EBPs. We outline future directions to build a program of research on preparing the soil for implementation of EBPs, including building capacity among nurses, supporting organizations to embrace change, co-producing research evidence, and contributing to implementation science. LINKING EVIDENCE TO ACTION: Supporting contexts to adopt and sustain evidence in nursing practice is essential for bridging the evidence to practice gap and improving outcomes for patients, clinicians, and the health system. Moving forward, we need to develop a better understanding of how to create contexts that embrace change prior to the implementation of EBPs in order sustain improvements to patient and health system outcomes.

Understanding Determinants of Sustainability Through a Realist Investigation of a Large-Scale Quality Improvement Initiative (Lean): A Refined Program Theory.

BACKGROUND: Implementation science research seeks to understand ways to best ensure uptake of research-based initiatives to health care; however, there is little research done on how to sustain such efforts. Sustainability is the degree to which an initiative continues to be used in practice after efforts of implementation have ended. Sustainability research is a growing field of implementation science that needs further research to understand how to predict and measure the long-term use of effective initiatives to improve health care. The question of what influences the sustainability of research-based initiatives to improve health care remains unknown. PURPOSE: The purpose of this article was to present a refined program theory on the contextual factors and mechanisms that influence the sustainability of one large-scale quality management initiative (Lean) in pediatric health care. DESIGN: We conducted a multiphase realist investigation to explain under what contexts, for whom, how, and why Lean efforts are sustained or not sustained in pediatric health care through the generation of an explanatory program theory. METHODS: This article presents the theoretical triangulation of our multiphase realist investigation, resulting in a refined program theory. We integrated the initial program theories (IPTs) from each research phase to form a refined program theory. It involved going back and forth from the initial IPT to the findings from each phase and our middle-range theories and examining the most substantiated IPTs on the contextual factors and mechanisms that influenced the sustainability of Lean efforts. FINDINGS: The refined program theory depicts the complex nature to sustaining Lean efforts and that sustainability as a small, often unrepresentative portion of something much larger or more complex that cannot yet be seen or understood. The approach and nature of implementation is critical to shaping contexts for sustainability. Outcomes from implementation become facilitating or hindering contexts for sustainability. Customization to context is an important contextual factor for sustainability. Sense making, value congruency, and staff engagement are critical aspects from early implementation that enable or hinder processes of sustainment. Such mechanisms can trigger staff empowerment that can lead to a greater likelihood of sustainability. CONCLUSIONS: These findings have important implications for sustainability research, in understanding the determinants of sustainability of research-based initiatives in health care. CLINICAL RELEVANCE: It is important to understand and explain determinants of sustainability through theory-driven evaluative research in order to assist key stakeholders in sustaining the effective research-based initiatives made to improve healthcare services, patient care, and outcomes.

Future Directions for Early Childhood Prevention of Mental Disorders: A Road Map to Mental Health, Earlier.

Mental disorders are the predominant chronic diseases of youth, with substantial life span morbidity and mortality. A wealth of evidence demonstrates that the neurodevelopmental roots of common mental health problems are present in early childhood. Unfortunately, this has not been translated to systematic strategies for improving population-level mental health at this most malleable neurodevelopmental period. We lay out a translational Mental Health, Earlier road map as a key future direction for prevention of mental disorder. This paradigm shift aims to reduce population attributable risk of mental disorder emanating from early life, by preventing, attenuating, or delaying onset/course of chronic psychopathology via the promotion of self-regulation in early childhood within large-scale health care delivery systems. The Earlier Pillar rests on a "science of when to worry" that (a) optimizes clinical assessment methods for characterizing probabilistic clinical risk beginning in infancy via deliberate incorporation of neurodevelopmental heterogeneity, and (b) universal primary-care-based screening targeting patterns of dysregulated irritability as a robust transdiagnostic marker of vulnerability to life span mental health problems. The core of the Healthier Pillar is provision of low-intensity selective intervention promoting self-regulation for young children with developmentally atypical patterns of irritability within an implementation science framework in pediatric primary care to ensure highest population impact and sustainability. These Mental Health, Earlier strategies hold much promise for transforming clinical outlooks and ensuring young children's mental health and well-being in a manner that reverberates throughout the life span.

A realist evaluation to identify contexts and mechanisms that enabled and hindered implementation and had an effect on sustainability of a lean intervention in pediatric healthcare.

BACKGROUND: In 2012, the Saskatchewan Ministry for Health mandated a system-wide Lean transformation. Research has been conducted on the implementation processes of this system-wide Lean implementation. However, no research has been done on the sustainability of these Lean efforts. We conducted a realist evaluation on the sustainability of Lean in pediatric healthcare. We used the context (C) + mechanism (M) = outcome (O) configurations (CMOcs) heuristic to explain under what contexts, for whom, how and why Lean efforts are sustained or not sustained in pediatric healthcare. METHODS: We employed a case study research design. Guided by a realist evaluation framework, we conducted qualitative realist interviews with various stakeholder groups across four pediatric hospital units 'cases' at one acute hospital. Interview data was analyzed using an integrated approach of CMOc categorization coding, CMOc connecting and pattern matching. RESULTS: We conducted thirty-two interviews across the four cases. Five CMOcs emerged from our realist interview data. These configurations illustrated a 'ripple-effect' from implementation outcomes to contexts for sustainability. Sense-making and staff engagement were prominent mechanisms to the sustainment of Lean efforts. Failure to trigger these mechanisms resulted in resistance. The implementation approach used influenced mechanisms and outcomes for sustainability, more so than Lean itself. Specifically, the language, messaging and training approaches used triggered mechanisms of innovation fatigue, poor 'sense-making' and a lack of engagement for frontline staff. The mandated, top-down, externally led nature of implementation and lack of customization to context served as potential pitfalls. Overall, there was variation between leadership and frontline staff's perceptions on how embedded Lean was in their contexts, and the degree to which participants supported Lean sustainability. CONCLUSIONS: This research illuminates important contextual factors and mechanisms to the process of Lean sustainment that can be applicable to those implementing systems changes. Future work is needed to continue to develop the science on the sustainability of interventions for healthcare improvement.

CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase.

The proper coordination between DNA replication and mitosis during cell-cycle progression is crucial for genomic stability. During G2 and mitosis, Set8 catalyzes monomethylation of histone H4 on lysine 20 (H4K20me1), which promotes chromatin compaction. Set8 levels decline in S phase, but why and how this occurs is unclear. Here, we show that Set8 is targeted for proteolysis in S phase and in response to DNA damage by the E3 ubiquitin ligase, CRL4(Cdt2). Set8 ubiquitylation occurs on chromatin and is coupled to DNA replication via a specific degron in Set8 that binds PCNA. Inactivation of CRL4(Cdt2) leads to Set8 stabilization and aberrant H4K20me1 accumulation in replicating cells. Transient S phase expression of a Set8 mutant lacking the degron promotes premature H4K20me1 accumulation and chromatin compaction, and triggers a checkpoint-mediated G2 arrest. Thus, CRL4(Cdt2)-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis.

TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA.

Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the re-accumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity.

The potential for nurses to contribute to and lead improvement science in health care.

AIM: A discussion of how nurses can contribute to and lead improvement science activities in health care. BACKGROUND: Quality failures in health care have led to the urgent need for healthcare quality improvement. However, commonly quality improvement interventions proceed to practice implementation without rigorous methods or sufficient empirical evidence. This lack of evidence for quality improvement has led to the development of improvement science, which embodies quality improvement research and quality improvement practice. This paper discusses how the discipline of nursing and the nursing profession possesses many strengths that enable nurses to lead and to play an integral role in improvement science activities. However, we also discuss that there are insufficiencies in nursing education that require attention for nurses to truly contribute to and lead improvement science in health care. DESIGN: Discussion paper. DATA SOURCES: This paper builds on a collection of our previous work, a 12-month scoping review (March 2013-March 2014), baseline study on a quality improvement management system (Lean), interviews with nurses on quality improvement implementation and supporting literature. IMPLICATIONS FOR NURSING: This paper highlights how nurses have the philosophical, theoretical, political and ethical positioning to contribute to and lead improvement science activities. However up to now, the potential for nurses to lead improvement science activities has not been fully used. CONCLUSION: We suggest that one starting point is to include improvement science in nursing education curricula. Specifically, there needs to be increased focus on the nursing roles and skills needed to contribute to and lead healthcare improvement science activities.

Vaccinia virus F1L protein promotes virulence by inhibiting inflammasome activation.

Host innate immune responses to DNA viruses involve members of the nucleotide-binding domain, leucine-rich repeat and pyrin domain containing protein (NLRP) family, which form "inflammasomes" that activate caspase-1, resulting in proteolytic activation of cytokines interleukin (IL)-1ß and IL-18. We hypothesized that DNA viruses would target inflammasomes to overcome host defense. A Vaccinia virus (VACV) B-cell CLL/lymphoma 2 (Bcl-2) homolog, F1L, was demonstrated to bind and inhibit the NLR family member NLRP1 in vitro. Moreover, infection of macrophages in culture with virus lacking F1L (ΔF1L) caused increased caspase-1 activation and IL-1ß secretion compared with wild-type virus. Virulence of ΔF1L virus was attenuated in vivo, causing altered febrile responses, increased proteolytic processing of caspase-1, and more rapid inflammation in lungs of infected mice without affecting cell death or virus replication. Furthermore, we found that a hexapeptide from F1L is necessary and sufficient for inhibiting the NLRP1 inflammasome in vitro, thus identifying a peptidyl motif required for binding and inhibiting NLRP1. The functional importance of this NLRP1-binding motif was further confirmed by studies of recombinant ΔF1L viruses reconstituted either with the wild-type F1L or a F1L mutant that fails to bind NLRP1. Cellular infection with wild-type F1L reconstituted virus-suppressed IL-1ß production, whereas mutant F1L did not. In contrast, both wild-type and mutant versions of F1L equally suppressed apoptosis. In vivo, the NLR nonbinding F1L mutant virus exhibited an attenuated phenotype similar to ΔF1L virus, thus confirming the importance of F1L interactions with NLRP1 for viral pathogenicity in mice. Altogether, these findings reveal a unique viral mechanism for evading host innate immune responses.

ATR: a master conductor of cellular responses to DNA replication stress.

The integrity of the genome is constantly challenged by intrinsic and extrinsic genotoxic stresses that damage DNA. The cellular responses to DNA damage are orchestrated by DNA damage signaling pathways, also known as DNA damage checkpoints. These signaling pathways play crucial roles in detecting DNA damage, regulating DNA repair and coordinating DNA repair with other cellular processes. In vertebrates, the ATM- and Rad3-related (ATR) kinase plays a key role in the response to a broad spectrum of DNA damage and DNA replication stress. Here, we will discuss the recent findings on how ATR is activated by DNA damage and how it protects the genome against interference with DNA replication.

Sustainability of enhanced recovery after surgery programmes in gastrointestinal surgery: A scoping review.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) is an evidence-based intervention that is well-recognised across multiple surgical specialties as having potential to lead to improved patient and hospital outcomes. Little is known about sustainability of ERAS programmes. AIMS: This review aimed to describe available evidence evaluating sustainability of ERAS programmes in gastrointestinal surgery to understand: (a) how sustainability has been defined; (b) examine determinants of sustainability; (c) identify strategies used to facilitate sustainability; (d) identify adaptations to support sustainability; and (e) examine outcomes measured as indicators of sustainability of ERAS programmes. METHODS: This scoping review was conducted following the Joanna Briggs Institute's methodology. Research databases (PubMed, Embase, CINHAL) and the grey literature were searched (inception to September 2022) for studies reporting sustainability of ERAS programmes in gastrointestinal surgery. Included articles reported an aspect of sustainability (i.e., definition, determinants, strategies, adaptations, outcomes and ongoing use) at ≥2 years following initial implementation. Aspects of sustainability were categorised according to relevant frameworks to facilitate synthesis. RESULTS: The search strategy yielded 1852 records; first round screening excluded 1749, leaving 103 articles for full text review. Overall, 22 studies were included in this review. Sustainability was poorly conceptualised and inconsistently reported across included studies. Provision of adequate resources was the most frequently identified enabler to sustainability (n/N = 9/12, 75%); however, relatively few studies (n = 4) provided a robust report of determinants, with no study reporting determinants of sustainability and strategies and adaptations to support sustainability alongside patient and service delivery outcomes. CONCLUSION: Improved reporting, particularly of strategies and adaptations to support sustainability is needed. Refinement of ERAS reporting guidelines should be made to facilitate this, and future implementation studies should plan to document and report changes in context and corresponding programme changes to help researchers and clinicians sustain ERAS programmes locally.