Midkine Attenuates Aß Fibril Assembly and AmyloidPlaque Formation.

Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with Aß since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates Aß assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both Aß40 and Aß42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdkgene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and aggregated proteome in these mouse models indicates significant accumulation of Aß and Aß-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimer's disease.

Universal energy-accuracy tradeoffs in nonequilibrium cellular sensing.

We combine stochastic thermodynamics, large deviation theory, and information theory to derive fundamental limits on the accuracy with which single cell receptors can estimate external concentrations. As expected, if the estimation is performed by an ideal observer of the entire trajectory of receptor states, then no energy consuming nonequilibrium receptor that can be divided into bound and unbound states can outperform an equilibrium two-state receptor. However, when the estimation is performed by a simple observer that measures the fraction of time the receptor is bound, we derive a fundamental limit on the accuracy of general nonequilibrium receptors as a function of energy consumption. We further derive and exploit explicit formulas to numerically estimate a Pareto-optimal tradeoff between accuracy and energy. We find this tradeoff can be achieved by nonuniform ring receptors with a number of states that necessarily increases with energy. Our results yield a thermodynamic uncertainty relation for the time a physical system spends in a pool of states and generalize the classic Berg-Purcell limit [H. C. Berg and E. M. Purcell, Biophys. J. 20, 193 (1977)0006-349510.1016/S0006-3495(77)85544-6] on cellular sensing along multiple dimensions.

Being kind in unkind spaces: a qualitative examination of how medical educators and first year medical students perceive empathy training.

Introduction: It has become de rigueur for healthcare systems to tout their ability to provide compassionate medical care that addresses the emotional as well as physical needs of patients. Not surprisingly, then, there is considerable pressure on medical schools to train their students to be empathic. Existing literature on empathy training in medicine tends to focus on how to build emotional intelligence in individual trainees, largely ignoring the sociocultural factors that contribute to or thwart empathy development in medical school. Additionally, research tends to examine student perspectives, with little attention given to medical educators and their viewpoints. Methods: In this paper, we adopt an "emotion practice" framework and utilize an inductive descriptive study design to qualitatively consider how first year medical students (N = 23) and their instructors (N = 9) perceive empathy training at a site we call Midtown Medical School. Results and discussion: We find that both groups have an understanding of empathic capital but differ in their beliefs about the utility and legitimacy of this capital. Both educators and students also recognize the limitations of standardized empathy curriculum but do not agree on the implications of such rote learning. Finally, students and instructors alike find the hidden curriculum of medical school to be antithetical to empathy development, concurring that it is difficult to cultivate empathy in spaces where biomedical coursework is prioritized over social-emotional learning. In short, both groups find it difficult to be kind in an unkind place.

Synaptic balancing: A biologically plausible local learning rule that provably increases neural network noise robustness without sacrificing task performance.

We introduce a novel, biologically plausible local learning rule that provably increases the robustness of neural dynamics to noise in nonlinear recurrent neural networks with homogeneous nonlinearities. Our learning rule achieves higher noise robustness without sacrificing performance on the task and without requiring any knowledge of the particular task. The plasticity dynamics-an integrable dynamical system operating on the weights of the network-maintains a multiplicity of conserved quantities, most notably the network's entire temporal map of input to output trajectories. The outcome of our learning rule is a synaptic balancing between the incoming and outgoing synapses of every neuron. This synaptic balancing rule is consistent with many known aspects of experimentally observed heterosynaptic plasticity, and moreover makes new experimentally testable predictions relating plasticity at the incoming and outgoing synapses of individual neurons. Overall, this work provides a novel, practical local learning rule that exactly preserves overall network function and, in doing so, provides new conceptual bridges between the disparate worlds of the neurobiology of heterosynaptic plasticity, the engineering of regularized noise-robust networks, and the mathematics of integrable Lax dynamical systems.

Exploiting breakdown in nonhost effector-target interactions to boost host disease resistance.

Plants are resistant to most microbial species due to nonhost resistance (NHR), providing broad-spectrum and durable immunity. However, the molecular components contributing to NHR are poorly characterised. We address the question of whether failure of pathogen effectors to manipulate nonhost plants plays a critical role in NHR. RxLR (Arg-any amino acid-Leu-Arg) effectors from two oomycete pathogens, Phytophthora infestans and Hyaloperonospora arabidopsidis, enhanced pathogen infection when expressed in host plants (Nicotiana benthamiana and Arabidopsis, respectively) but the same effectors performed poorly in distantly related nonhost pathosystems. Putative target proteins in the host plant potato were identified for 64 P. infestans RxLR effectors using yeast 2-hybrid (Y2H) screens. Candidate orthologues of these target proteins in the distantly related non-host plant Arabidopsis were identified and screened using matrix Y2H for interaction with RxLR effectors from both P. infestans and H. arabidopsidis. Few P. infestans effector-target protein interactions were conserved from potato to candidate Arabidopsis target orthologues (cAtOrths). However, there was an enrichment of H. arabidopsidis RxLR effectors interacting with cAtOrths. We expressed the cAtOrth AtPUB33, which unlike its potato orthologue did not interact with P. infestans effector PiSFI3, in potato and Nicotiana benthamiana. Expression of AtPUB33 significantly reduced P. infestans colonization in both host plants. Our results provide evidence that failure of pathogen effectors to interact with and/or correctly manipulate target proteins in distantly related non-host plants contributes to NHR. Moreover, exploiting this breakdown in effector-nonhost target interaction, transferring effector target orthologues from non-host to host plants is a strategy to reduce disease.

A high-resolution single-molecule sequencing-based Arabidopsis transcriptome using novel methods of Iso-seq analysis.

BACKGROUND: Accurate and comprehensive annotation of transcript sequences is essential for transcript quantification and differential gene and transcript expression analysis. Single-molecule long-read sequencing technologies provide improved integrity of transcript structures including alternative splicing, and transcription start and polyadenylation sites. However, accuracy is significantly affected by sequencing errors, mRNA degradation, or incomplete cDNA synthesis. RESULTS: We present a new and comprehensive Arabidopsis thaliana Reference Transcript Dataset 3 (AtRTD3). AtRTD3 contains over 169,000 transcripts-twice that of the best current Arabidopsis transcriptome and including over 1500 novel genes. Seventy-eight percent of transcripts are from Iso-seq with accurately defined splice junctions and transcription start and end sites. We develop novel methods to determine splice junctions and transcription start and end sites accurately. Mismatch profiles around splice junctions provide a powerful feature to distinguish correct splice junctions and remove false splice junctions. Stratified approaches identify high-confidence transcription start and end sites and remove fragmentary transcripts due to degradation. AtRTD3 is a major improvement over existing transcriptomes as demonstrated by analysis of an Arabidopsis cold response RNA-seq time-series. AtRTD3 provides higher resolution of transcript expression profiling and identifies cold-induced differential transcription start and polyadenylation site usage. CONCLUSIONS: AtRTD3 is the most comprehensive Arabidopsis transcriptome currently. It improves the precision of differential gene and transcript expression, differential alternative splicing, and transcription start/end site usage analysis from RNA-seq data. The novel methods for identifying accurate splice junctions and transcription start/end sites are widely applicable and will improve single-molecule sequencing analysis from any species.

Exploring the relationship between the usability of a goal-oriented mobile health application and non-usage attrition in patients with multimorbidity: A blended data analysis approach.

BACKGROUND: Mobile health applications are increasingly used to support the delivery of health care services to a variety of patients. Based on data obtained from a pragmatic trial of the electronic Patient Reported Outcome (ePRO) app designed to support goal-oriented care primary care, this study aims to (1) examine how patient-reported usability changed over the one-year intervention period, and (2) explore participant attrition rate of the electronic Patient Reported Outcome app over one year study period. METHODS: We performed a secondary analysis of 44 older adults with complex chronic needs enrolled in the electronic Patient Reported Outcome-digital health intervention. App usage and attrition were measured using device-generated usage logs; usability was measured using the patient-reported post-study system usability questionnaire collected at 3, 6, 9, and 12 months. Research memos were used to interpret potential contextual contributing factors to patients' overall usage and usability score pattern. A data triangulation method of both quantitative and qualitative data was used to analyze and interpret study findings. RESULTS: While there was gradual attrition in the use of the ePRO app, patients' usability scores remained consistent throughout the study period. Qualitative memos suggested patients' encounters with technical difficulties and relationship dynamics with primary providers influenced patients' adherence to the ePRO app. CONCLUSION: This study highlights that the patient-provider relationship is a key determining factor that influences complex patients' continued engagement with a Mobile health app. The finding calls attention to the measurement of usability of a Mobile health app, its impact on attrition, and contributing factors that influence patients' attrition. Trial registration: Clinicaltrials.gov Identified NCT02917954.

Exploring the perspectives of primary care providers on use of the electronic Patient Reported Outcomes tool to support goal-oriented care: a qualitative study.

BACKGROUND: Digital health technologies can support primary care delivery, but clinical uptake in primary care is limited. This study explores enablers and barriers experienced by primary care providers when adopting new digital health technologies, using the example of the electronic Patient Reported Outcome (ePRO) tool; a mobile application and web portal designed to support goal-oriented care. To better understand implementation drivers and barriers primary care providers' usage behaviours are compared to their perspectives on ePRO utility and fit to support care for patients with complex care needs. METHODS: This qualitative sub-analysis was part of a larger trial evaluating the use of the ePRO tool in primary care. Qualitative interviews were conducted with providers at the midpoint (i.e. 4.5-6 months after ePRO implementation) and end-point (i.e. 9-12 months after ePRO implementation) of the trial. Interviews explored providers' experiences and perceptions of integrating the tool within their clinical practice. Interview data were analyzed using a hybrid thematic analysis and guided by the Technology Acceptance Model. Data from thirteen providers from three distinct primary care sites were included in the presented study. RESULTS: Three core themes were identified: (1) Perceived usefulness: perceptions of the tool's alignment with providers' typical approach to care, impact and value and fit with existing workflows influenced providers' intention to use the tool and usage behaviour; (2) Behavioural intention: providers had a high or low behavioural intention, and for some, it changed over time; and (3) Improving usage behaviour: enabling external factors and enhancing the tool's perceived ease of use may improve usage behaviour. CONCLUSIONS: Multiple refinements/iterations of the ePRO tool (e.g. enhancing the tool's alignment with provider workflows and functions) may be needed to enhance providers' usage behaviour, perceived usefulness and behavioural intention. Enabling external factors, such as organizational and IT support, are also necessary to increase providers' usage behaviour. Lessons from this study advance knowledge of technology implementation in primary care. TRIAL REGISTRATION: Clinicaltrials.gov Identified NCT02917954. Registered September 2016, https://www.clinicaltrials.gov/ct2/show/study/NCT02917954.

Assessing the Implementation and Effectiveness of the Electronic Patient-Reported Outcome Tool for Older Adults With Complex Care Needs: Mixed Methods Study.

BACKGROUND: Goal-oriented care is being adopted to deliver person-centered primary care to older adults with multimorbidity and complex care needs. Although this model holds promise, its implementation remains a challenge. Digital health solutions may enable processes to improve adoption; however, they require evaluation to determine feasibility and impact. OBJECTIVE: This study aims to evaluate the implementation and effectiveness of the electronic Patient-Reported Outcome (ePRO) mobile app and portal system, designed to enable goal-oriented care delivery in interprofessional primary care practices. The research questions driving this study are as follows: Does ePRO improve quality of life and self-management in older adults with complex needs? What mechanisms are likely driving observed outcomes? METHODS: A multimethod, pragmatic randomized controlled trial using a stepped-wedge design and ethnographic case studies was conducted over a 15-month period in 6 comprehensive primary care practices across Ontario with a target enrollment of 176 patients. The 6 practices were randomized into either early (3-month control period; 12-month intervention) or late (6-month control period; 9-month intervention) groups. The primary outcome measure of interest was the Assessment of Quality of Life-4D (AQoL-4D). Data were collected at baseline and at 3 monthly intervals for the duration of the trial. Ethnographic data included observations and interviews with patients and providers at the midpoint and end of the intervention. Outcome data were analyzed using linear models conducted at the individual level, accounting for cluster effects at the practice level, and ethnographic data were analyzed using qualitative description and framework analysis methods. RESULTS: Recruitment challenges resulted in fewer sites and participants than expected; of the 176 target, only 142 (80.6%) patients were identified as eligible to participate because of lower-than-expected provider participation and fewer-than-expected patients willing to participate or perceived as ready to engage in goal-setting. Of the 142 patients approached, 45 (32%) participated. Patients set a variety of goals related to self-management, mental health, social health, and overall well-being. Owing to underpowering, the impact of ePRO on quality of life could not be definitively assessed; however, the intervention group, ePRO plus usual care (mean 15.28, SD 18.60) demonstrated a nonsignificant decrease in quality of life (t24=-1.20; P=.24) when compared with usual care only (mean 21.76, SD 2.17). The ethnographic data reveal a complex implementation process in which the meaningfulness (or coherence) of the technology to individuals' lives and work acted as a key driver of adoption and tool appraisal. CONCLUSIONS: This trial experienced many unexpected and significant implementation challenges related to recruitment and engagement. Future studies could be improved through better alignment of the research methods and intervention to the complex and diverse clinical settings, dynamic goal-oriented care process, and readiness of provider and patient participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02917954; https://clinicaltrials.gov/ct2/show/NCT02917954.

Defining Familial Interactions and Networks: An Exploratory Qualitative Study on Family Networks and Surrogate Decision-Making.

To characterize patient preferences for medical surrogate decision-makers in the ICU to capture the complexity of decision-making preferences and highlight potential conflicts between patients' preferences and clinicians' surrogate decision-maker identification in usual clinical practice. DESIGN: Prospective qualitative cross-sectional study. SETTING: Two ICUs in a quaternary referral center in the eastern United States. PATIENTS: Convenience sample of patients admitted to the ICU and their family members. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Twenty-six patient-family-clinician units were interviewed. Men were three times more likely than women to have a legally appointed decision-maker that matched their preferred decision-maker as expressed in the interview. Patients who were married or in a long-term relationship were the most consistent group of respondents, with 94% of them selecting their spouse or partner as the preferred decision-maker. The most common reasons for selecting a surrogate decision-maker were intangible themes such as feeling "known" by that person rather than having prior discussions about specific wishes or advance directives. CONCLUSIONS: Asking about a patient's familial network and qualities they value in a surrogate decision-maker may aid ICU teams in honoring patients' wishes for surrogate decision-making. This may be an important supplement to accepted legal hierarchies for proxy decision-makers and advance directive documents. Further studies with larger sample sizes could be used to shed light on the nuances of familial and relationship networks of a more diverse population of respondents.

The direct and indirect effects of clinical empathy on well-being among pre-medical students: a structural equation model approach.

BACKGROUND: Empathy is a well-established facet of clinical competency that research suggests is associated with enhanced medical student well-being. Since little is known about empathy and well-being before students enter medical school-during pre-medical education-the main goal of this study is to test a conceptual model of how clinical empathy is related to two indicators of well-being, depression, and burnout among pre-medical students. The theoretical model hypothesizes that three dimensions of clinical empathy-Perspective-Taking, Compassionate Care, and Standing in Patients' Shoes- will be directly and negatively related to depression, as well as indirectly through its inverse relationship with three facets of burnout, Emotional Exhaustion, Poor Academic Efficacy, and Cynicism. METHODS: Using survey data from a sample of 132 pre-medical students at an American Midwestern university, this study employs structural equation modeling (SEM) to test the theoretical model of the relationships between empathy, burnout, and depression among pre-medical students. We identify the direct effects of the three dimensions of the Jefferson Scale of Physician Empathy (JSE-S) on depression (CES-D), as well as the indirect effects of clinical empathy on depression through the three dimensions of the Maslach Burnout Inventory (MBI-S). RESULTS: SEM analyses show that while none of the three dimensions of the JSE-S are directly related to depression, clinical empathy does significantly affect depression indirectly through burnout. Specifically, as predicted, we find that Perspective-Taking decreases Emotional Exhaustion, but, contrary to expectations, Compassionate Care increases it. And, the positive relationship between Compassionate Care and Emotional Exhaustion is particularly strong. In turn, Perspective-Taking and Compassionate Care are associated with depression in opposite directions and to different degrees. CONCLUSIONS: Findings suggest that clinical empathy as measured by the JSE-S produces both positive and negative effects on personal well-being. We conclude that further conceptual clarity of clinical empathy is needed to better discern how the different dimensions impact different indicators of well-being. Given that pre-medical education is a crucial time for emotional socialization, the challenge for medical education will be fostering the positive, cognitive aspects of clinical empathy while simultaneously mitigating the adverse effects of affective empathy on medical student well-being.

A chromosome-level Amaranthus cruentus genome assembly highlights gene family evolution and biosynthetic gene clusters that may underpin the nutritional value of this traditional crop.

Traditional crops have historically provided accessible and affordable nutrition to millions of rural dwellers but have been neglected, with most modern agricultural systems over-reliant on a small number of internationally traded crops. Traditional crops are typically well-adapted to local agro-ecological conditions and many are nutrient-dense. They can play a vital role in local food systems through enhanced nutrition (particularly where diets are dominated by starch crops), food security and livelihoods for smallholder farmers, and a climate-resilient and biodiverse agriculture. Using short-read, long-read and phased sequencing technologies, we generated a high-quality chromosome-level genome assembly for Amaranthus cruentus, an under-researched crop with micronutrient- and protein-rich leaves and gluten-free seed, but lacking improved varieties, with respect to productivity and quality traits. The 370.9 Mb genome demonstrates a shared whole genome duplication with a related species, Amaranthus hypochondriacus. Comparative genome analysis indicates chromosomal loss and fusion events following genome duplication that are common to both species, as well as fission of chromosome 2 in A. cruentus alone, giving rise to a haploid chromosome number of 17 (versus 16 in A. hypochondriacus). Genomic features potentially underlying the nutritional value of this crop include two A. cruentus-specific genes with a likely role in phytic acid synthesis (an anti-nutrient), expansion of ion transporter gene families, and identification of biosynthetic gene clusters conserved within the amaranth lineage. The A. cruentus genome assembly will underpin much-needed research and global breeding efforts to develop improved varieties for economically viable cultivation and realization of the benefits to global nutrition security and agrobiodiversity.

Vitamin D upregulates the macrophage complement receptor immunoglobulin in innate immunity to microbial pathogens.

Vitamin D deficiency remains a global concern. This 'sunshine' vitamin is converted through a multistep process to active 1,25-dihydroxyvitamin D3 (1,25D), the final step of which can occur in macrophages. Here we demonstrate a role for vitamin D in innate immunity. The expression of the complement receptor immunoglobulin (CRIg), which plays an important role in innate immunity, is upregulated by 1,25D in human macrophages. Monocytes cultured in 1,25D differentiated into macrophages displaying increased CRIg mRNA, protein and cell surface expression but not in classical complement receptors, CR3 and CR4. This was associated with increases in phagocytosis of complement opsonised Staphylococcus aureus and Candida albicans. Treating macrophages with 1,25D for 24 h also increases CRIg expression. While treating macrophages with 25-hydroxyvitamin D3 does not increase CRIg expression, added together with the toll like receptor 2 agonist, triacylated lipopeptide, Pam3CSK4, which promotes the conversion of 25-hydroxyvitamin D3 to 1,25D, leads to an increase in CRIg expression and increases in CYP27B1 mRNA. These findings suggest that macrophages harbour a vitamin D-primed innate defence mechanism, involving CRIg.

Effectiveness of an eHealth self-management tool for older adults with multimorbidity (KeepWell): protocol for a hybrid effectiveness-implementation randomised controlled trial.

INTRODUCTION: In response to the burden of chronic disease among older adults, different chronic disease self-management tools have been created to optimise disease management. However, these seldom consider all aspects of disease management are not usually developed specifically for seniors or created for sustained use and are primarily focused on a single disease. We created an eHealth self-management application called 'KeepWell' that supports seniors with complex care needs in their homes. It incorporates the care for two or more chronic conditions from among the most prevalent high-burden chronic diseases. METHODS AND ANALYSIS: We will evaluate the effectiveness, cost and uptake of KeepWell in a 6-month, pragmatic, hybrid effectiveness-implementation randomised controlled trial. Older adults age ≥65 years with one or more chronic conditions who are English speaking are able to consent and have access to a computer or tablet device, internet and an email address will be eligible. All consenting participants will be randomly assigned to KeepWell or control. The allocation sequence will be determined using a random number generator.Primary outcome is perceived self-efficacy at 6 months. Secondary outcomes include quality of life, health background/status, lifestyle (nutrition, physical activity, caffeine, alcohol, smoking and bladder health), social engagement and connections, eHealth literacy; all collected via a Health Risk Questionnaire embedded within KeepWell (intervention) or a survey platform (control). Implementation outcomes will include reach, effectiveness, adoption, fidelity, implementation cost and sustainability. ETHICS AND DISSEMINATION: Ethics approval has been received from the North York General Hospital Research and Ethics Board. The study is funded by the Canadian Institutes of Health Research and the Ontario Ministry of Health. We will work with our team to develop a dissemination strategy which will include publications, presentations, plain language summaries and an end-of-grant meeting. TRIAL REGISTRATION NUMBER: NCT04437238.

Building a Digital Bridge to Support Patient-Centered Care Transitions From Hospital to Home for Older Adults With Complex Care Needs: Protocol for a Co-Design, Implementation, and Evaluation Study.

BACKGROUND: Older adults with multimorbidity and complex care needs (CCN) are among those most likely to experience frequent care transitions between settings, particularly from hospital to home. Transition periods mark vulnerable moments in care for individuals with CCN. Poor communication and incomplete information transfer between clinicians and organizations involved in the transition from hospital to home can impede access to needed support and resources. Establishing digitally supported communication that enables person-centered care and supported self-management may offer significant advantages as we support older adults with CCN transitioning from hospital to home. OBJECTIVE: This protocol outlines the plan for the development, implementation, and evaluation of a Digital Bridge co-designed to support person-centered health care transitions for older adults with CCN. The Digital Bridge builds on the foundation of two validated technologies: Care Connector, designed to improve interprofessional communication in hospital, and the electronic Patient-Reported Outcomes (ePRO) tool, designed to support goal-oriented care planning and self-management in primary care settings. This project poses three overarching research questions that focus on adapting the technology to local contexts, evaluating the impact of the Digital Bridge in relation to the quadruple aim, and exploring the potential to scale and spread the technology. METHODS: The study includes two phases: workflow co-design (phase 1), followed by implementation and evaluation (phase 2). Phase 1 will include iterative co-design working groups with patients, caregivers, hospital providers, and primary care providers to develop a transition workflow that will leverage the use of Care Connector and ePRO to support communication through the transition process. Phase 2 will include implementation and evaluation of the Digital Bridge within two hospital systems in Ontario in acute and rehab settings (600 patients: 300 baseline and 300 implementation). The primary outcome measure for this study is the Care Transitions Measure-3 to assess transition quality. An embedded ethnography will be included to capture context and process data to inform the implementation assessment and development of a scale and spread strategy. An Integrated Knowledge Translation approach is taken to inform the study. An advisory group will be established to provide insight and feedback regarding the project design and implementation, leading the development of the project knowledge translation strategy and associated outputs. RESULTS: This project is underway and expected to be complete by Spring 2024. CONCLUSIONS: Given the real-world implementation of Digital Bridge, practice changes in the research sites and variable adherence to the implementation protocols are likely. Capturing and understanding these considerations through a mixed-methods approach will help identify the range of factors that may influence study results. Should a favorable evaluation suggest wide adoption of the proposed intervention, this project could lead to positive impact at patient, clinician, organizational, and health system levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04287192; https://clinicaltrials.gov/ct2/show/NCT04287192. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/20220.

Downy Mildew effector HaRxL21 interacts with the transcriptional repressor TOPLESS to promote pathogen susceptibility.

Hyaloperonospora arabidopsidis (Hpa) is an oomycete pathogen causing Arabidopsis downy mildew. Effector proteins secreted from the pathogen into the plant play key roles in promoting infection by suppressing plant immunity and manipulating the host to the pathogen's advantage. One class of oomycete effectors share a conserved 'RxLR' motif critical for their translocation into the host cell. Here we characterize the interaction between an RxLR effector, HaRxL21 (RxL21), and the Arabidopsis transcriptional co-repressor Topless (TPL). We establish that RxL21 and TPL interact via an EAR motif at the C-terminus of the effector, mimicking the host plant mechanism for recruiting TPL to sites of transcriptional repression. We show that this motif, and hence interaction with TPL, is necessary for the virulence function of the effector. Furthermore, we provide evidence that RxL21 uses the interaction with TPL, and its close relative TPL-related 1, to repress plant immunity and enhance host susceptibility to both biotrophic and necrotrophic pathogens.

The impact of Clinical Nurse Specialists on the decision making process in cancer multidisciplinary team meetings: A qualitative study.

PURPOSE: There are well-documented barriers to nurse participation in cancer multidisciplinary team (MDT) meetings. This paper aims to identify the approaches used by Clinical Nurse Specialists (CNSs) in this setting to contribute during discussion, and to consider the impact of these approaches on the decision making process. In doing so it aims to highlight ways that CNSs can increase their influence, and enhance multidisciplinary engagement. METHODS: This study is based on analysis of observation data from 122 MDT meetings in gynaecology, haematology and skin cancer MDTs. Field notes were reviewed, identifying 58 cases where CNSs contributed to MDT discussion. Audio recordings of the relevant sections were then transcribed and analysed thematically. RESULTS: Five approaches were used by CNSs to contribute in MDT meetings: sharing information, asking questions, providing practical suggestions, framing and using humour. These approaches influenced three key intermediary processes identified during the analysis ('successful contributions'): prompting discussion, influencing a treatment plan and facilitating teamwork. CNSs contributed successfully in cases where medical factors (such as relapsed disease or complex comorbidities) or non-medical factors (such as strong patient preference), had the potential to impact on the ability of teams to deliver treatment. CONCLUSIONS: CNSs have an important role in cancer MDT meetings. By focusing on a subset of cases where CNSs contributed during MDT discussion, this study has provided an insight into approaches that can be adopted by CNSs to increase their influence on the decision making process, enabling teams to capitalise on their knowledge and expertise in MDT meetings.

The Crucible simulation: Behavioral simulation improves clinical leadership skills and understanding of complex health policy change.

BACKGROUND: The Health and Social Care Act 2012 represents the most complex National Health Service reforms in history. High-quality clinical leadership is important for successful implementation of health service reform. However, little is known about the effectiveness of current leadership training. PURPOSE: This study describes the use of a behavioral simulation to improve the knowledge and leadership of a cohort of medical doctors expected to take leadership roles in the National Health Service. METHODOLOGY: A day-long behavioral simulation (The Crucible) was developed and run based on a fictitious but realistic health economy. Participants completed pre- and postsimulation questionnaires generating qualitative and quantitative data. Leadership skills, knowledge, and behavior change processes described by the "theory of planned behavior" were self-assessed pre- and postsimulation. RESULTS: Sixty-nine medical doctors attended. Participants deemed the simulation immersive and relevant. Significant improvements were shown in perceived knowledge, capability, attitudes, subjective norms, intentions, and leadership competency following the program. Nearly one third of participants reported that they had implemented knowledge and skills from the simulation into practice within 4 weeks. CONCLUSIONS: This study systematically demonstrates the effectiveness of behavioral simulation for clinical management training and understanding of health policy reform. Potential future uses and strategies for analysis are discussed. PRACTICE IMPLICATIONS: High-quality care requires understanding of health systems and strong leadership. Policymakers should consider the use of behavioral simulation to improve understanding of health service reform and development of leadership skills in clinicians, who readily adopt skills from simulation into everyday practice.

Collaborative learning: Application of the mentorship model for adult nursing students in the acute placement setting.

Traditionally mentorship of pre-registration student nurses in clinical practice has followed a 1:1 model. Students are allocated a named mentor for the duration of the placement and they are responsible for supporting and assessing the learner. Many studies have identified problems with this approach to mentorship, including lack of time to facilitate learning on a 1:1 basis. In response to some of these challenges, a collaborative model of mentorship is being adopted both internationally and nationally. This involves placing a range of 1st, 2nd and 3rd year students on placement together, with students being allocated specific patients to care for collaboratively, under supervision. This model has already become established in Amsterdam, as an effective approach to mentorship (Lobo et al., 2014). In addition collaborative learning in practice has also been introduced in Ireland, Australia and the United States of America. This paper discusses the implementation of a collaborative model of learning by a district hospital and higher education institute (HEI) in the South West of England, commencing with a preliminary study in one placement area. Following success of this project this model is being implemented in other placement areas within the Trust.

Partial maintenance of organ-specific epigenetic marks during plant asexual reproduction leads to heritable phenotypic variation.

Plants differ from animals in their capability to easily regenerate fertile adult individuals from terminally differentiated cells. This unique developmental plasticity is commonly observed in nature, where many species can reproduce asexually through the ectopic initiation of organogenic or embryogenic developmental programs. While organ-specific epigenetic marks are not passed on during sexual reproduction, the fate of epigenetic marks during asexual reproduction and the implications for clonal progeny remain unclear. Here we report that organ-specific epigenetic imprints in Arabidopsis thaliana can be partially maintained during asexual propagation from somatic cells in which a zygotic program is artificially induced. The altered marks are inherited even over multiple rounds of sexual reproduction, becoming fixed in hybrids and resulting in heritable molecular and physiological phenotypes that depend on the identity of the founder tissue. Consequently, clonal plants display distinct interactions with beneficial and pathogenic microorganisms. Our results demonstrate how novel phenotypic variation in plants can be unlocked through altered inheritance of epigenetic marks upon asexual propagation.