Neuronal non-CG methylation is an essential target for MeCP2 function.

DNA methylation is implicated in neuronal biology via the protein MeCP2, the mutation of which causes Rett syndrome. MeCP2 recruits the NCOR1/2 co-repressor complexes to methylated cytosine in the CG dinucleotide, but also to sites of non-CG methylation, which are abundant in neurons. To test the biological significance of the dual-binding specificity of MeCP2, we replaced its DNA binding domain with an orthologous domain from MBD2, which can only bind mCG motifs. Knockin mice expressing the domain-swap protein displayed severe Rett-syndrome-like phenotypes, indicating that normal brain function requires the interaction of MeCP2 with sites of non-CG methylation, specifically mCAC. The results support the notion that the delayed onset of Rett syndrome is due to the simultaneous post-natal accumulation of mCAC and its reader MeCP2. Intriguingly, genes dysregulated in both Mecp2 null and domain-swap mice are implicated in other neurological disorders, potentially highlighting targets of relevance to the Rett syndrome phenotype.

Development and validation of delirium prediction model for critically ill adults parameterized to ICU admission acuity.

BACKGROUND: Risk prediction models allow clinicians to forecast which individuals are at a higher risk for developing a particular outcome. We developed and internally validated a delirium prediction model for incident delirium parameterized to patient ICU admission acuity. METHODS: This retrospective, observational, fourteen medical-surgical ICU cohort study evaluated consecutive delirium-free adults surviving hospital stay with ICU length of stay (LOS) greater than or equal to 24 hours with both an admission APACHE II score and an admission type (e.g., elective post-surgery, emergency post-surgery, non-surgical) in whom delirium was assessed using the Intensive Care Delirium Screening Checklist (ICDSC). Risk factors included in the model were readily available in electric medical records. Least absolute shrinkage and selection operator logistic (LASSO) regression was used for model development. Discrimination was determined using area under the receiver operating characteristic curve (AUC). Internal validation was performed by cross-validation. Predictive performance was determined using measures of accuracy and clinical utility was assessed by decision-curve analysis. RESULTS: A total of 8,878 patients were included. Delirium incidence was 49.9% (n = 4,431). The delirium prediction model was parameterized to seven patient cohorts, admission type (3 cohorts) or mean quartile APACHE II score (4 cohorts). All parameterized cohort models were well calibrated. The AUC ranged from 0.67 to 0.78 (95% confidence intervals [CI] ranged from 0.63 to 0.79). Model accuracy varied across admission types; sensitivity ranged from 53.2% to 63.9% while specificity ranged from 69.0% to 74.6%. Across mean quartile APACHE II scores, sensitivity ranged from 58.2% to 59.7% while specificity ranged from 70.1% to 73.6%. The clinical utility of the parameterized cohort prediction model to predict and prevent incident delirium was greater than preventing incident delirium by treating all or none of the patients. CONCLUSIONS: Our results support external validation of a prediction model parameterized to patient ICU admission acuity to predict a patients' risk for ICU delirium. Classification of patients' risk for ICU delirium by admission acuity may allow for efficient initiation of prevention measures based on individual risk profiles.

Association between delirium in the intensive care unit and subsequent neuropsychiatric disorders.

BACKGROUND: Patients in the intensive care unit (ICU) are known to be at increased risk of developing delirium, but the risk of subsequent neuropsychiatric disorders is unclear. We therefore sought to examine the association between the presence of delirium in the ICU and incident neuropsychiatric disorders (including depressive, anxiety, trauma-and-stressor-related, and neurocognitive disorders) post-ICU stay among adult medical-surgical ICU patients. METHODS: Retrospective cohort study utilizing clinical and administrative data from both inpatient and outpatient healthcare visits to identify the ICU cohort and diagnostic information 5 years prior to and 1 year post-ICU stay. Patients ≥ 18 years of age admitted to one of 14 medical-surgical ICUs across Alberta, Canada, January 1, 2014-June 30, 2016, and survived to hospital discharge were included. The main outcome of interest was a new diagnosis of any neuropsychiatric disorder 1 year post-ICU stay. The exposure variable was delirium during the ICU stay identified through any positive delirium screen by the Intensive Care Unit Delirium Screening Checklist (ICDSC) during the ICU stay. RESULTS: Of 16,005 unique patients with at least one ICU admission, 4033 patients were included in the study of which 1792 (44%) experienced delirium during their ICU stay. The overall cumulative incidence of any neuropsychiatric disorder during the subsequent year was 19.7% for ICU patients. After adjusting for hospital characteristics using log-binomial regression, patients with delirium during the ICU stay had a risk ratio (RR) of 1.14 (95% confidence interval [CI] 0.98-1.33) of developing any neuropsychiatric disorder within 1 year post-ICU compared to those who did not experience delirium. Delirium was significantly associated with neurocognitive disorders (RR 1.59, 95% CI 1.08-2.35), but not depressive disorders (RR 1.16, 95% CI 0.92-1.45), anxiety (RR 1.16, 95% CI 0.92-1.47), and trauma-and-stressor-related (RR 0.82, 95% CI 0.53-1.28) disorders. CONCLUSIONS: The diagnosis of new onset of neurocognitive disorders is associated with ICU-acquired delirium. In this study, significant associations were not observed for depressive, anxiety, and trauma-and-stressor-related disorders.

Transfers from intensive care unit to hospital ward: a multicentre textual analysis of physician progress notes.

BACKGROUND: Little is known about documentation during transitions of patient care between clinical specialties. Therefore, we examined the focus, structure and purpose of physician progress notes for patients transferred from the intensive care unit (ICU) to hospital ward to identify opportunities to improve communication breaks. METHODS: This was a prospective cohort study in ten Canadian hospitals. We analyzed physician progress notes for consenting adult patients transferred from a medical-surgical ICU to hospital ward. The number, length, legibility and content of notes was counted and compared across care settings using mixed-effects linear regression models accounting for clustering within hospitals. Qualitative content analyses were conducted on a stratified random sample of 32 patients. RESULTS: A total of 447 patient medical records that included 7052 progress notes (mean 2.1 notes/patient/day 95% CI 1.9-2.3) were analyzed. Notes written by the ICU team were significantly longer than notes written by the ward team (mean lines of text 21 vs. 15, p < 0.001). There was a discrepancy between documentation of patient issues in the last ICU and first ward notes; mean agreement of patient issues was 42% [95% CI 31-53%]. Qualitative analyses identified eight themes related to focus (central point - e.g., problem list), structure (organization, - e.g., note-taking style), and purpose (intention - e.g., documentation of patient course) of the notes that varied across clinical specialties and physician seniority. CONCLUSIONS: Important gaps and variations in written documentation during transitions of patient care between ICU and hospital ward physicians are common, and include discrepancies in documentation of patient information.

Work Dissatisfaction and Sleep Problems among Canadians in the Latter Half of Life.

This study examined the relationship between work dissatisfaction and sleep problems among Canadian adults in the latter half of life, as well as how gender and social contact moderate this relationship. Data were obtained from the Canadian General Social Survey, Cycle 21 (2007), which sampled adults aged 45 and older in 2007. Analyses focused on individuals with employment as their main activity. Analyses show that work dissatisfaction positively predicts trouble sleeping. There are no significant gender differences in this relationship. Social contact with friends buffers this relationship, but social contact with family does not, and buffering does not vary significantly between men and women. This research contributes to knowledge on sleep problems by showing that work dissatisfaction is adversely associated with sleep problems among Canadians in the latter half of life, but social contact with friends can weaken this deleterious relationship.

Protocol to describe the analysis of text-based communication in medical records for patients discharged from intensive care to hospital ward.

INTRODUCTION: Effective communication during hospital transitions of patient care is fundamental to ensuring patient safety and continuity of quality care. This study will describe text-based communication included in patient medical records before, during and after patient transfer from the intensive care unit (ICU) to a hospital ward (n=10 days) by documenting (1) the structure and focus of physician progress notes within and between medical specialties, (2) the organisation of subjective and objective information, including the location and accessibility of patient data and whether/how this changes during the hospital stay and (3) missing, illegible and erroneous information. METHODS: This study is part of a larger mixed methods prospective observational study of ICU to hospital ward transfer practices in 10 ICUs across Canada. Medical records will be collected and photocopied for each consenting patient for a period of up to 10 consecutive days, including the final 2 days in the ICU, the day of transfer and the first 7 days on the ward (n=10 days). Textual analysis of medical record data will be completed by 2 independent reviewers to describe communication between stakeholders involved in ICU transfer. ETHICS AND DISSEMINATION: Research ethics board approval has been obtained at all study sites, including the coordinating study centre (which covers 4 Calgary-based sites; UofC REB 13-0021) and 6 additional study sites (UofA Pro00050646; UBC PHC Hi4-01667; Sunnybrook 336-2014; QCH 20140345-01H; Sherbrooke 14-172; Laval 2015-2171). Findings from this study will inform the development of an evidence-based tool that will be used to systematically analyse the series of notes in a patient's medical record.

The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome.

Rett syndrome is caused by mutations in the X-linked MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Mouse models mirror the human disorder and therefore allow investigation of phenotypes at a molecular level. We describe an Mecp2 allelic series representing the three most common missense Rett syndrome (RTT) mutations, including first reports of Mecp2[R133C] and Mecp2[T158M] knock-in mice, in addition to Mecp2[R306C] mutant mice. Together these three alleles comprise ∼25% of all RTT mutations in humans, but they vary significantly in average severity. This spectrum is mimicked in the mouse models; R133C being least severe, T158M most severe and R306C of intermediate severity. Both R133C and T158M mutations cause compound phenotypes at the molecular level, combining compromised DNA binding with reduced stability, the destabilizing effect of T158M being more severe. Our findings contradict the hypothesis that the R133C mutation exclusively abolishes binding to hydroxymethylated DNA, as interactions with DNA containing methyl-CG, methyl-CA and hydroxymethyl-CA are all reduced in vivo. We find that MeCP2[T158M] is significantly less stable than MeCP2[R133C], which may account for the divergent clinical impact of the mutations. Overall, this allelic series recapitulates human RTT severity, reveals compound molecular aetiologies and provides a valuable resource in the search for personalized therapeutic interventions.

Canadian†Stroke†Best†Practice†Recommendations: Hyperacute Stroke Care Guidelines, Update 2015.

The 2015 update of the Canadian Stroke Best Practice Recommendations Hyperacute Stroke Care guideline highlights key elements involved in the initial assessment, stabilization, and treatment of patients with transient ischemic attack (TIA), ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and acute venous sinus thrombosis. The most notable change in this 5th edition is the addition of new recommendations for the use of endovascular therapy for patients with acute ischemic stroke and proximal intracranial arterial occlusion. This includes an overview of the infrastructure and resources required for stroke centers that will provide endovascular therapy as well as regional structures needed to ensure that all patients with acute ischemic stroke that are eligible for endovascular therapy will be able to access this newly approved therapy; recommendations for hyperacute brain and enhanced vascular imaging using computed tomography angiography and computed tomography perfusion; patient selection criteria based on the five trials of endovascular therapy published in early 2015, and performance metric targets for important time-points involved in endovascular therapy, including computed tomography-to-groin puncture and computed tomography-to-reperfusion times. Other updates in this guideline include recommendations for improved time efficiencies for all aspects of hyperacute stroke care with a movement toward a new median target door-to-needle time of 30 min, with the 90th percentile being 60 min. A stronger emphasis is placed on increasing public awareness of stroke with the recent launch of the Heart and Stroke Foundation of Canada FAST signs of stroke campaign; reinforcing the public need to seek immediate medical attention by calling 911; further engagement of paramedics in the prehospital phase with prehospital notification to the receiving emergency department, as well as the stroke team, including neuroradiology; updates to the triage and same-day assessment of patients with transient ischemic attack; updates to blood pressure recommendations for the hyperacute phase of care for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The goal of these recommendations and supporting materials is to improve efficiencies and minimize the absolute time lapse between stroke symptom onset and reperfusion therapy, which in turn leads to better outcomes and potentially shorter recovery times.

The confidence of speech-language pathology students regarding communicating with people with aphasia.

BACKGROUND: Aphasia is an acquired language disorder that can present a significant barrier to patient involvement in healthcare decisions. Speech-language pathologists (SLPs) are viewed as experts in the field of communication. However, many SLP students do not receive practical training in techniques to communicate with people with aphasia (PWA) until they encounter PWA during clinical education placements. METHODS: This study investigated the confidence and knowledge of SLP students in communicating with PWA prior to clinical placements using a customised questionnaire. Confidence in communicating with people with aphasia was assessed using a 100-point visual analogue scale. Linear, and logistic, regressions were used to examine the association between confidence and age, as well as confidence and course type (graduate-entry masters or undergraduate), respectively. Knowledge of strategies to assist communication with PWA was examined by asking respondents to list specific strategies that could assist communication with PWA. RESULTS: SLP students were not confident with the prospect of communicating with PWA; reporting a median 29-points (inter-quartile range 17-47) on the visual analogue confidence scale. Only, four (8.2%) of respondents rated their confidence greater than 55 (out of 100). Regression analyses indicated no relationship existed between confidence and students' age (p = 0.31, r-squared = 0.02), or confidence and course type (p = 0.22, pseudo r-squared = 0.03). Students displayed limited knowledge about communication strategies. Thematic analysis of strategies revealed four overarching themes; Physical, Verbal Communication, Visual Information and Environmental Changes. While most students identified potential use of resources (such as images and written information), fewer students identified strategies to alter their verbal communication (such as reduced speech rate). CONCLUSIONS: SLP students who had received aphasia related theoretical coursework, but not commenced clinical placements with PWA, were not confident in their ability to communicate with PWA. Students may benefit from an educational intervention or curriculum modification to incorporate practical training in effective strategies to communicate with PWA, before they encounter PWA in clinical settings. Ensuring students have confidence and knowledge of potential communication strategies to assist communication with PWA may allow them to focus their learning experiences in more specific clinical domains, such as clinical reasoning, rather than building foundation interpersonal communication skills.

"Making a good time": the role of friendship in living successfully with aphasia.

Loss of friendship post-onset of aphasia is well documented, with reduced social network size and social isolation commonly reported. Because friendship has strong links to psychological well-being and health, increased knowledge about friendships of individuals with aphasia will have important clinical implications. This study aimed to explore the perspectives of 25 community dwelling individuals with chronic aphasia on the role of friendship in living successfully with aphasia. Thematic analysis of transcripts from semi-structured in-depth interviews revealed three over-arching themes relating to the role of friendship in participants' experience of life with aphasia: living with changes in friendships, good times together and support from friends, and the importance of stroke and aphasia friends. Overall, findings highlighted the valued role of friendship in living successfully with aphasia, while also providing evidence of how friendships change and evolve in both negative and positive ways following onset of aphasia. Clinicians are challenged to work creatively to address the role of friendship in life post-stroke in partnership with individuals with aphasia, their families, and friends.

The World Report on Disability as a blueprint for international, national, and local aphasia services.

This commentary aims to extend the debate of the lead article authors (Wylie, McAllister, Davidson, and Marshall, 2013) by translating the nine recommendations of the World Report on Disability into a plan of action for the aphasia community. Solutions for the advancement of aphasia science and services are presented at international (macro), national (meso), and local (micro) levels. Implications for speech-language pathologists and aphasia service delivery are discussed. An overarching call to action is the need for speech-language pathologists to support a strong and vibrant aphasia community at all levels, so that the voices of people with aphasia can be heard.

The first 3-months post-stroke: what facilitates successfully living with aphasia?

This study used a qualitative approach to describe the experience of the first 3 months post-stroke in order to identify factors which facilitate successfully living with aphasia. Fifteen participants completed semi-structured interviews and self-perceived ratings of how successfully he or she was living with aphasia. A number of themes were identified from the interviews, including: a need to do things in order to be actively engaged in rehabilitation; increase independence and have a purpose in life; the importance of social support; the value of rehabilitation; a need to adapt and make adjustments; and having a positive outlook. These results suggest that a range of service delivery models need to be considered during the early stages post-stroke in order to address individual needs and so that long-term outcomes of people with aphasia may be improved.

Living successfully with aphasia: a qualitative meta-analysis of the perspectives of individuals with aphasia, family members, and speech-language pathologists.

The concept of living successfully with aphasia has recently emerged as an alternative to more traditional "deficit" models in aphasiology, encouraging a focus on positive rather than negative outcomes. This research aimed to integrate findings from studies exploring the perspectives of three participant groups (individuals with aphasia, speech-language pathologists, and family members) about living successfully with aphasia. Qualitative meta-analysis of three studies conducted by the authors was used to integrate perspectives across the participant groups. Steps in the qualitative meta-analysis were based on those described in the process of "meta-ethnography" by Noblit and Hare (1988) . Analysis was an inductive process, in which data from each study were re-analysed and translated into each other in order to identify higher-level overarching themes that accounted for similarities and discrepancies across the original studies. A total of seven overarching themes related to living successfully with aphasia were identified. These were: participation, meaningful relationships, support, communication, positivity, independence and autonomy, and living successfully with aphasia as a journey over time. Findings indicate the need for a holistic, client-centred approach that considers communication in the broader context of an individual's daily life. The overarching themes may act as guides for areas of importance to be addressed in clinical practice, as well as in future research. By working in partnership with individuals with aphasia and their families, speech-language pathologists are challenged to continue to improve services and assist clients on their journey of living successfully with aphasia.

Living successfully with aphasia: family members share their views.

UNLABELLED: Language and lifestyle changes experienced following the onset of aphasia extend beyond the individual to impact family members of persons with aphasia. Research exploring the meaning of living successfully with aphasia has explored the perspectives of individuals with aphasia and speech-language pathologists. Family members' views of living successfully with aphasia may also contribute valuable insights into positive adaptive processes and factors that may influence clinical interventions and community-based services for individuals with aphasia and their families. PURPOSE: To explore, from the perspectives of family members of individuals with aphasia, the meaning of living successfully with aphasia. METHOD: Twenty-four family members (nominated by individuals with aphasia) participated in semistructured in-depth interviews about living successfully with aphasia. Interviews were transcribed verbatim and analyzed using interpretative phenomenological analysis to identify themes relating to the meaning of living successfully with aphasia. RESULTS: Seven themes were identified from analysis of family member participant transcripts: getting involved in life, support for the person with aphasia, communication, family members' own needs, putting life in perspective, focusing on and celebrating strengths and improvements, and experiences with services. CONCLUSION: Findings provide evidence to support previous research indicating that aphasia affects the whole family and not just an individual. The inclusion of family members as part of the rehabilitation team is indicated. Family members' needs and priorities must be considered in conceptualizing living successfully with aphasia to ensure family members are included in intervention programs.

Exploring speech-language pathologists' perspectives about living successfully with aphasia.

BACKGROUND: Exploring the concept of living successfully with aphasia challenges researchers and clinicians to identify positive rather than negative adaptive processes and factors that may inform clinical interventions and other community-based services for people with aphasia. Previous research on this topic has focused on the perspectives of individuals with aphasia, and identified a number of core components of living successfully with aphasia, including doing things, meaningful relationships, striving for a positive way of living, and communication. As service providers, speech-language pathologists may also contribute valuable insights regarding components of living successfully with aphasia and factors influencing individuals' abilities to achieve this goal. AIMS: This research aimed to explore speech-language pathologists' perspectives about the meaning of living successfully with aphasia, and factors they perceive to influence individuals' abilities to live successfully with aphasia. METHODS & PROCEDURES: Twenty-five speech-language pathologists from around Australia participated in semi-structured in-depth interviews on the topic of living successfully with aphasia. All interviews were transcribed verbatim and analysed using interpretative phenomenological analysis to identify themes of relevance. OUTCOMES & RESULTS: Through the analysis of speech-language pathologist participant transcripts, the following themes emerged as components of living successfully with aphasia: participation and community engagement; communication; meaningful relationships; autonomy or independence; acceptance and embracement of aphasia; self-esteem; happiness; and purpose or meaningfulness. A wide variety of factors were perceived to influence individuals' abilities to live successfully with aphasia. These included support, acceptance, and understanding; personal factors; and speech-language pathology services. CONCLUSIONS & IMPLICATIONS: Further research is required to extend findings by investigating how speech-language pathologists address identified themes in clinical practice. To improve service provision, continued reflection by speech-language pathologists on how services provided align with client's values and priorities is a necessity. A commitment by speech-language pathologists to work in partnership with people with aphasia and their families and friends to achieve successful living with aphasia is one way to translate this research into practice.

Flavor-evaluative conditioning is unaffected by contingency knowledge during training with color-flavor compounds.

In two experiments, participants inspected and drank a series of drinks, half of which contained sugarand half unpalatable Tween20 (tween). Each sugar and tween drink had a particular flavor and color. Following this training, the flavors of the sugar drinks were assigned higher hedonicevaluations than were those of thetween drinks, even though the participants did not reliably report which flavors had been present in the sugar and tween drinks during training. Moreover, the evaluative conditioning of the flavors was unaffected by whether or not the colors alone had been pretrained to predict the presence of sugar or tween in the drinks. In accord with Baeyens, Eelen, van den Bergh, and Crombez (1990), we conclude that flavor-evaluative conditioning is not mediated by contingency learning.