Genome-wide methylome stability and parental effects in the worldwide distributed Lombardy poplar.

BACKGROUND: Despite the increasing number of epigenomic studies in plants, little is known about the forces that shape the methylome in long-lived woody perennials. The Lombardy poplar offers an ideal opportunity to investigate the impact of the individual environmental history of trees on the methylome. RESULTS: We present the results of three interconnected experiments on Lombardy poplar. In the first experiment, we investigated methylome variability during a growing season and across vegetatively reproduced generations. We found that ramets collected over Europe and raised in common conditions have stable methylomes in symmetrical CG-contexts. In contrast, seasonal dynamics occurred in methylation patterns in CHH context. In the second experiment, we investigated whether methylome patterns of plants grown in a non-parental environment correlate with the parental climate. We did not observe a biological relevant pattern that significantly correlates with the parental climate. Finally, we investigated whether the parental environment has persistent carry-over effects on the vegetative offspring's phenotype. We combined new bud set observations of three consecutive growing seasons with former published bud set data. Using a linear mixed effects analysis, we found a statistically significant but weak short-term, parental carry-over effect on the timing of bud set. However, this effect was negligible compared to the direct effects of the offspring environment. CONCLUSIONS: Genome-wide cytosine methylation patterns in symmetrical CG-context are stable in Lombardy poplar and appear to be mainly the result of random processes. In this widespread poplar clone, methylation patterns in CG-context can be used as biomarkers to infer a common ancestor and thus to investigate the recent environmental history of a specific Lombardy poplar. The Lombardy poplar shows high phenotypic plasticity in a novel environment which enabled this clonal tree to adapt and survive all over the temperate regions of the world.

Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.

OBJECTIVE: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN: We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1ß and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION: Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1ß-targeting therapies upstream of IL-23.

Developing a Social Determinants of Learning™ Framework: A Case Study.

AIM: The aim of the study was to propose a framework, social determinants of learning™ (SDOL™), an actionable model to address learning disparities and expand learning opportunities to support nursing student diversity, equity, and inclusion. BACKGROUND: There is significant growth in the racial and ethnic diversity across students at all levels of higher education, mirroring the growing diversity of the US population. Yet, lower rates of persistence and higher attrition rates among these student groups continue. METHOD: The authors established six socially imposed forces, causative domains, as foundational to the SDOL framework. Key attributes of each domain were identified through a literature search. A case study illustrates an initial study of interventions targeting specific domains of the framework aimed toward student success. CONCLUSION: Equitable education for all has far-reaching implications across nursing education and higher education in general. Further development and testing of the SDOL framework will support the goal of equitable education for all.

Developing and validating a questionnaire for mortality follow-back studies on end-of-life care and decision-making in a resource-poor Caribbean country.

BACKGROUND: Palliative and end-of-life care development is hindered by a lack of information about the circumstances surrounding dying in developing and resource-poor countries. Our aims were to develop and obtain face and content validity for a self-administered questionnaire on end-of-life care provision and medical decision-making for use in population-based surveys. METHODS: Modelled on validated questionnaires from research in developed countries, our questionnaire was adapted to the cultural sensitivity and medico-legal context of Trinidad and Tobago. Two sets of semi-structured face-to-face cognitive interviews were done with a sample of physicians, sampling was purposive. Phase 1 assessed interpretation of the questions, terminology and content of the questionnaire. Phase 2 was tested on a heterogeneous group of physicians to identify and fix problematic questions or recurring issues. Adjustments were made incrementally and re-tested in successive interviews. RESULTS: Eighteen physicians were interviewed nationwide. Adaptations to questionnaires used in developed countries included: addition of a definition of palliative care, change of sensitive words like expedited to influenced, adjustments to question formulations, follow-up questions and answer options on medications used were added, the sequence, title and layout were changed and instructions for completion were included at the beginning of the questionnaire. CONCLUSION: A new instrument for assessing and documenting end-of-life care and circumstances of dying in a small, resource-poor Caribbean country was developed and validated, and can be readily used as a mortality follow-back instrument. Our methods and procedures of development can be applied as a guide for similar studies in other small developing countries.

TIGER Team: Rapid Response at the University of Missouri.

By the end of the 20th century, health care organizations worldwide were recognizing the benefits of a quick response when patients were experiencing a clinical decline and the difficulty in achieving that goal. The University of Missouri STAT Nurse program, developed in 1989, was an early innovation to deliver the "right care" at the "right time" every time. Over the years, the STAT Nurse program evolved and became the core component of a Rapid Response System. Today Rapid Response at University of Missouri Health Care is called the Targeted Interventional Group Emergency Response Team, also known as the TIGER Team after the much beloved University mascot.

Preregistration nursing students' experiences of a palliative care course in a resource-poor setting.

BACKGROUND: Palliative care education for non-specialist health professionals is an important strategy for widening access to palliative care. AIM: To describe Cameroonian nursing students' experiences and perceptions of the strengths and weaknesses of a palliative care course, with a view to refining the course. METHODS: Three focus groups were conducted with 23 students, and data were analysed thematically using the framework approach. RESULTS: The students reported connecting with their past personal and professional experiences in the care of patients with palliative care needs during the course. The main course strength reported was its use of a variety of interactive educational strategies, such as role plays, group discussions and case studies. The course's main reported weakness was the lack of supervised clinical practice in palliative care. CONCLUSION: The use of a variety of interactive educational strategies-including supervised clinical practice-is considered by nursing students as vital to enhancing learning in palliative care education. However, the lack of supervised palliative care clinical practice opportunities is a challenge in Cameroon.

Loss of BMPR2 leads to high bone mass due to increased osteoblast activity.

Imbalances in the ratio of bone morphogenetic protein (BMP) versus activin and TGFß signaling are increasingly associated with human diseases yet the mechanisms mediating this relationship remain unclear. The type 2 receptors ACVR2A and ACVR2B bind BMPs and activins but the type 2 receptor BMPR2 only binds BMPs, suggesting that type 2 receptor utilization might play a role in mediating the interaction of these pathways. We tested this hypothesis in the mouse skeleton, where bone mass is reciprocally regulated by BMP signaling and activin and TGFß signaling. We found that deleting Bmpr2 in mouse skeletal progenitor cells (Bmpr2-cKO mice) selectively impaired activin signaling but had no effect on BMP signaling, resulting in an increased bone formation rate and high bone mass. Additionally, activin sequestration had no effect on bone mass in Bmpr2-cKO mice but increased bone mass in wild-type mice. Our findings suggest a novel model whereby BMPR2 availability alleviates receptor-level competition between BMPs and activins and where utilization of ACVR2A and ACVR2B by BMPs comes at the expense of activins. As BMP and activin pathway modulation are of current therapeutic interest, our findings provide important mechanistic insight into the relationship between these pathways in human health.

Avoiding hospital admission in COPD: impact of a specialist nursing team.

Chronic obstructive pulmonary disease (COPD) is a common, preventable and incurable disease. The costs of caring for patients with COPD is estimated to be more than £800 million a year for acute hospital admissions alone ( Department of Health, 2012 ). The hospital-at-home model is increasingly being adopted for COPD patients following British Thoracic Society (BTS) guidelines for the delivery of hospital admission-avoidance schemes ( BTS, 2007 ). The aim of this case-note review was to evaluate the safety and effectiveness of a specialist nurse-led acute respiratory assessment service working with COPD patients in the community. The review recorded patient flow through the service and documented assessments and treatments. It was able to document potential benefits and cost savings.

Unmet care needs in people living with advanced cancer: a systematic review.

PURPOSE: The support needs of cancer patients vary according to the phase of their cancer journey. Recent developments in healthcare are such that the advanced cancer phase is increasingly experienced as a chronic illness phase, with consequent changes in patient support needs. Understanding these needs, and identifying areas of unmet need, can enable us to develop services that are more adequate to the task of supporting this population. METHODS: We conducted a systematic search of four electronic databases to identify studies examining the unmet needs of people living with advanced cancer. Relevant data were extracted and synthesised; meta-analyses were conducted to obtain pooled estimates for prevalence of needs. RESULTS: We identified 23 studies (4 qualitative) for inclusion. Unmet needs were identified across a broad range of domains, with greatest prevalence in informational (30-55 %), psychological (18-42 %), physical (17-48 %), and functional (17-37 %) domains. There was considerable heterogeneity amongst studies in terms of methods of assessment, coding and reporting of needs, respondent characteristics, and appraised study quality. CONCLUSIONS: Heterogeneity made it difficult to compare across studies and inflated confidence intervals for pooled estimates of prevalence-we need standardised and comprehensive approaches to assessment and reporting of unmet needs to further our understanding. Nonetheless, the review identified prominent needs across a range of (interacting) experiential domains. Moreover, by focussing on unmet needs for support, we were able to extrapolate potential implications for service development.

A qualitative evaluation of the impact of a palliative care course on preregistration nursing students' practice in Cameroon.

BACKGROUND: Current evidence suggests that palliative care education can improve preregistration nursing students' competencies in palliative care. However, it is not known whether these competencies are translated into students' practice in the care of patients who are approaching the end of life. This paper seeks to contribute to the palliative care evidence base by examining how nursing students in receipt of education report transfer of learning to practice, and what the barriers and facilitators may be, in a resource-poor country. METHODS: We utilised focus groups and individual critical incident interviews to explore nursing students' palliative care learning transfer. Three focus groups, consisting of 23 participants and 10 individual critical incident interviews were conducted with preregistration nursing student who had attended a palliative care course in Cameroon and had experience caring for a patient approaching the end of life. Data was analysed thematically, using the framework approach. RESULTS: The results suggest that nursing students in receipt of palliative care education can transfer their learning to practice. Students reported recognizing patients with palliative care needs, providing patients with physical, psychosocial and spiritual support and communicating patient information to the wider care team. They did however perceive some barriers to this transfer which were either related to themselves, qualified nurses, the practice setting or family caregivers and patients. CONCLUSION: The findings from this study suggest that nursing student in receipt of palliative care education can use their learning in practice to provide care to patients and their families approaching the end of life. Nevertheless, these findings need to be treated with some caution given the self-reported nature of the data. Demonstrating the link between preregistration palliative care education and patient care is vital to ensuring that newly acquired knowledge and skills are translated and embedded into clinical practice. This study also has implications for advocating for palliative care policies and adequately preparing clinical placement sites for students' learning and transfer of learning.

The psychological impact of undergoing genetic-risk profiling in men with a family history of prostate cancer.

BACKGROUND: The ability to identify men at genetically high-risk of prostate cancer (PrCa) would enable screening to be targeted at those most in need. This study explored the psychological impact (in terms of general and PrCa-specific worry and risk perceptions) on men with a family history of PrCa, undergoing prostate screening and genetic-risk profiling, within a research study. METHODS: A prospective exploratory approach was adopted, incorporating a sequential mixed-method design. Questionnaires were completed at two time points to measure the impact of undergoing screening and genetic-risk profiling. In-depth interviews were completed in a subgroup after all study procedures were completed and analysed using a framework approach. RESULTS: Ninety-five men completed both questionnaires, and 26 were interviewed. No measurable psychological distress was detectable in the group as a whole. The interview findings fell into two categories: 'feeling at risk' and 'living with risk'. The feeling of being at risk of PrCa is a part of men's lives, shaped by assumptions and information gathered over many years. Men used this information to communicate about PrCa risk to their peers. Men overestimate their risk of PrCa and have an innate assumption that they will develop PrCa. The interviews revealed that men experienced acute anxiety when waiting for screening results. CONCLUSIONS: Personalised genetic-risk assessments do not prevent men from overestimating their risk of PrCa. Screening anxiety is common, and timeframes for receiving results should be kept to a minimum. Methods of risk communication in men at risk of PrCa should be the subject of future research.

BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing.

Adult bones have a notable regenerative capacity. Over 40 years ago, an intrinsic activity capable of initiating this reparative response was found to reside within bone itself, and the term bone morphogenetic protein (BMP) was coined to describe the molecules responsible for it. A family of BMP proteins was subsequently identified, but no individual BMP has been shown to be the initiator of the endogenous bone repair response. Here we demonstrate that BMP2 is a necessary component of the signaling cascade that governs fracture repair. Mice lacking the ability to produce BMP2 in their limb bones have spontaneous fractures that do not resolve with time. In fact, in bones lacking BMP2, the earliest steps of fracture healing seem to be blocked. Although other osteogenic stimuli are still present in the limb skeleton of BMP2-deficient mice, they cannot compensate for the absence of BMP2. Collectively, our results identify BMP2 as an endogenous mediator necessary for fracture repair.

Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor.

Interference with DNA damage checkpoints has been demonstrated preclinically to be a highly effective means of increasing the cytotoxicity of a number of DNA-damaging cancer therapies. Cell cycle arrest at these checkpoints protects injured cells from apoptotic cell death until DNA damage can be repaired. In the absence of functioning DNA damage checkpoints, cells with damaged DNA may proceed into premature mitosis followed by cell death. A key protein kinase involved in activating and maintaining the S and G2/M checkpoints is Chk1. Pharmacological inhibition of Chk1 in the absence of p53 functionality leads to abrogation of DNA damage checkpoints and has been shown preclinically to enhance the activity of many standard of care chemotherapeutic agents. LY2603618 is a potent and selective small molecule inhibitor of Chk1 protein kinase activity in vitro (IC(50) = 7 nM) and the first selective Chk1 inhibitor to enter clinical cancer trials. Treatment of cells with LY2603618 produced a cellular phenotype similar to that reported for depletion of Chk1 by RNAi. Inhibition of intracellular Chk1 by LY2603618 results in impaired DNA synthesis, elevated H2A.X phosphorylation indicative of DNA damage and premature entry into mitosis. When HeLa cells were exposed to doxorubicin to induce a G2/M checkpoint arrest, subsequent treatment with LY2603618 released the checkpoint, resulting in cells entering into metaphase with poorly condensed chromosomes. Consistent with abrogation of the Chk1 and p53-dependent G2/M checkpoint, mutant TP53 HT-29 colon cancer cells were more sensitive to gemcitabine when also treated with LY2603618, while wild-type TP53 HCT116 cells were not sensitized by LY2603618 to gemcitabine. Treatment of Calu-6 human mutant TP53 lung cancer cell xenografts with gemcitabine resulted in a stimulation of Chk1 kinase activity that was inhibited by co-administration of LY2603618. By all criteria, LY2603618 is a highly effective inhibitor of multiple aspects of Chk1 biology.

The effect of drought stress on heterozygosity-fitness correlations in pedunculate oak (Quercus robur).

BACKGROUND AND AIMS: The interaction between forest fragmentation and predicted climate change may pose a serious threat to tree populations. In small and spatially isolated forest fragments, increased homozygosity may directly affect individual tree fitness through the expression of deleterious alleles. Climate change-induced drought stress may exacerbate these detrimental genetic consequences of forest fragmentation, as the fitness response to low levels of individual heterozygosity is generally thought to be stronger under environmental stress than under optimal conditions. METHODS: To test this hypothesis, a greenhouse experiment was performed in which various transpiration and growth traits of 6-month-old seedlings of Quercus robur differing in multilocus heterozygosity (MLH) were recorded for 3 months under a well-watered and a drought stress treatment. Heterozygosity-fitness correlations (HFC) were examined by correlating the recorded traits of individual seedlings to their MLH and by studying their response to drought stress. KEY RESULTS: Weak, but significant, effects of MLH on several fitness traits were obtained, which were stronger for transpiration variables than for the recorded growth traits. High atmospheric stress (measured as vapour pressure deficit) influenced the strength of the HFCs of the transpiration variables, whereas only a limited effect of the irrigation treatment on the HFCs was observed. CONCLUSIONS: Under ongoing climate change, increased atmospheric stress in the future may strengthen the negative fitness responses of trees to low MLH. This indicates the necessity to maximize individual multilocus heterozygosity in forest tree breeding programmes.

High levels of effective long-distance dispersal may blur ecotypic divergence in a rare terrestrial orchid.

BACKGROUND: Gene flow and adaptive divergence are key aspects of metapopulation dynamics and ecological speciation. Long-distance dispersal is hard to detect and few studies estimate dispersal in combination with adaptive divergence. The aim of this study was to investigate effective long-distance dispersal and adaptive divergence in the fen orchid (Liparis loeselii (L.) Rich.). We used amplified fragment length polymorphism (AFLP)-based assignment tests to quantify effective long-distance dispersal at two different regions in Northwest Europe. In addition, genomic divergence between fen orchid populations occupying two distinguishable habitats, wet dune slacks and alkaline fens, was investigated by a genome scan approach at different spatial scales (continental, landscape and regional) and based on 451 AFLP loci. RESULTS: We expected that different habitats would contribute to strong divergence and restricted gene flow resulting in isolation-by-adaptation. Instead, we found remarkably high levels of effective long-distance seed dispersal and low levels of adaptive divergence. At least 15% of the assigned individuals likely originated from among-population dispersal events with dispersal distances up to 220 km. Six (1.3%) 'outlier' loci, potentially reflecting local adaptation to habitat-type, were identified with high statistical support. Of these, only one (0.22%) was a replicated outlier in multiple independent dune-fen population comparisons and thus possibly reflecting truly parallel divergence. Signals of adaptation in response to habitat type were most evident at the scale of individual populations. CONCLUSIONS: The findings of this study suggest that the homogenizing effect of effective long-distance seed dispersal may overwhelm divergent selection associated to habitat type in fen orchids in Northwest Europe.

A modified systematic review of research evidence about education for pre-registration nurses in palliative care.

BACKGROUND: We undertook a modified systematic review of research regarding educational approaches to and effectiveness of pre-registration palliative care nursing, to inform the development of a short course in palliative care for pre-registration nursing students in Cameroon. The aim of this review was to examine educational approaches applied to pre-registration palliative care nursing education and their effectiveness, and to discuss implications for the development of palliative care curricula in resource-poor countries. METHOD: A modified systematic review of research on palliative care educational interventions, conducted with pre-registration student nurses was undertaken. Relevant literature was gathered from CINAHL, EMBASE, MEDLINE and PsychINFO databases for the period 2000-2013. Inclusion was limited to studies of educational interventions evaluating the effectiveness and outcomes of palliative and end of life care education with pre-registration student nurses. RESULTS: 17 studies were found, all of which were conducted in resource-rich countries: United States of America, Canada, Australia, and United Kingdom. Palliative care nursing education at pre-registration level is either delivered as a discrete course within the curriculum or palliative care content is embedded into other nursing specialty courses throughout the wider curriculum. Palliative care education is delivered to students at a variety of stages in their nursing program, using a mix of both didactic and experiential educational strategies. Course facilitators span palliative care specialists, educators who have attended 'train-the-trainer' courses in palliative care, and nurses with hospice experience. Education is underpinned by transformative and experiential learning theories and reported as effective in improving students' attitudes towards care of the dying. CONCLUSION: The educational strategies identified in this review may be applicable to resource-poor countries. However, there are challenges in transferability because of the lack of availability of specialist palliative care practitioners who can serve as educators, specialist palliative care units/institutions for experiential learning, funds to design and use high fidelity simulations, and palliative care textbooks and other educational materials. There is thus a need for innovative educational strategies that can bridge these barriers in resource-poor countries. There is also a need for further research into how palliative care education impacts on pre-registration student nurses' knowledge and practice.

Care for community-dwelling frail older people: a practice nurse perspective.

AIMS AND OBJECTIVES: To evaluate care programmes for community-dwelling frail older people from a practice nurse perspective and gain a deeper understanding of their role within the programmes. BACKGROUND: In response to the increasing frail population, three regions in the Netherlands implemented care programmes, in which a proactive approach is used to identify frail older people in the community and provide them with the appropriate care and support. DESIGN: A constructivist grounded theory approach. METHODS: A formative process evaluation was performed, in which study participants were practice nurses (n = 23) focusing on the identification of and care for frail older people in primary care settings. Based on the principles of grounded theory, data were collected via semi-structured interviews and focus groups and analysed. RESULTS: The practice nurses explain that 'building a trusting relationship' with the older person and 'making connections' between older people, family and other professionals are key elements of good care in the programmes. 'Targeting the wrong audience' and 'providing good care' reflect the doubts and feelings of insecurity the practice nurses have about the screening and selection procedures and their own role and expertise in the programme. CONCLUSION: According to the experiences of practice nurses, a trusting relationship with the older people is necessary to provide good care. Practice nurses feel they should receive more support and education to conquer issues concerning social problems in frail older people. Moreover, practice nurses considered the screening and selection procedures to be unsuccessful in identifying frail older people who do need care. RELEVANCE TO CLINICAL PRACTICE: A trusting relationship should be given high priority in the care for community-dwelling frail older people. To improve the care programmes, screening and selection procedures need adjustments. Practice nurses should receive more support in dealing with older people with psychosocial problems.