What Causes Premature Coronary Artery Disease?

PURPOSE OF REVIEW: This review provides an overview of genetic and non-genetic causes of premature coronary artery disease (pCAD). RECENT FINDINGS: pCAD refers to coronary artery disease (CAD) occurring before the age of 65 years in women and 55 years in men. Both genetic and non-genetic risk factors may contribute to the onset of pCAD. Recent advances in the genetic epidemiology of pCAD have revealed the importance of both monogenic and polygenic contributions to pCAD. Familial hypercholesterolemia (FH) is the most common monogenic disorder associated with atherosclerotic pCAD. However, clinical overreliance on monogenic genes can result in overlooked genetic causes of pCAD, especially polygenic contributions. Non-genetic factors, notably smoking and drug use, are also important contributors to pCAD. Cigarette smoking has been observed in 25.5% of pCAD patients relative to 12.2% of non-pCAD patients. Finally, myocardial infarction (MI) associated with spontaneous coronary artery dissection (SCAD) may result in similar clinical presentations as atherosclerotic pCAD. Recognizing the genetic and non-genetic causes underlying pCAD is important for appropriate prevention and treatment. Despite recent progress, pCAD remains incompletely understood, highlighting the need for both awareness and research.

The Ceiling Effects of EQ-5D-3L and 5L in General Population Health Surveys: A Systematic Review and Meta-analysis.

OBJECTIVES: This review aims to examine the ceiling effects of EQ-5D-3L (3L) and EQ-5D-5L (5L) in general adult populations and identify the factors influencing these effects. METHODS: We searched 8 databases for observational studies published in English from inception to 24 July 2023. Ceiling effects were calculated by dividing the number of participants reporting full health at dimension or profile level by the total sample size. Subgroup analysis and meta-regression using the metafor package in R software were performed. RESULTS: We identified 94 studies from 70 articles, including 4 543 647 adults across 37 countries. The global pooled proportion of individuals reporting full health ("11111") was 56% (95% CI 51%-62%) for 3L and 49% (95% CI 44%-54%) for 5L. The self-care dimension showed the highest ceiling effects (3L: 97%; 5L: 94%), whereas pain/discomfort had the lowest (3L: 69%; 5L: 60%). The ceiling effects in East/South-East Asia were higher than in Europe by 25% (95% CI 18%-32%) in 3L and 9% (95% CI -2%-20%) in 5L. Adjusting for mean age and proportion of males, significant regional differences persisted in the overall profile level of 3L, in all 3L dimensions (except for self-care), and 5L dimensions (except for pain/discomfort and anxiety/depression). CONCLUSIONS: This review highlights significant ceiling effects in the EQ-5D, especially in Asian populations. The 5L version exhibited fewer ceiling effects than the 3L, indicating its superiority for general population surveys. Further research is crucial to understand the disparities in self-reported health outcomes between Asians and other populations.

Using EQ-5D for Proxy Assessment of Health-Related Quality of Life in Residential Care Facilities: A Systematic Review of Feasibility and Psychometric Properties.

OBJECTIVES: The accurate assessment of Health-Related Quality of Life (HRQoL) in residents of residential care facilities (RCF) necessitates the use of proxy-reported instruments that possess robust psychometric properties. Generally, these instruments are modified versions of self-reported tools, with adjustments made to pronouns and instructions to better suit the respondent. Among such tools, the EQ-5D has emerged as a prominent instrument for evaluating HRQoL within RCF settings. This review aimed to synthesize evidence on psychometric properties of the proxy version of EQ-5D. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Residents in RCF. METHODS: An extensive search was conducted across 8 databases, covering articles from inception to May 29, 2023. We included a total of 20 articles reporting data that can be used to evaluate psychometric properties of this instrument in RCF. The quality appraisal employed the COSMIN Risk of Bias checklist, and data synthesis followed COSMIN methodology. RESULTS: Most of the included studies were conducted in Europe, with 75% using nursing staff as proxies. Missing data rates were 5% for EQ-5D and 26% for EQ VAS. Evidence of moderate certainty on construct validity of the EQ-5D index was inconsistent, although the EQ VAS showed sufficient construct validity supported by high certainty. EQ-5D index responsiveness evidence was limited, characterized by low certainty and inconsistency. Proxy-resident agreement ranged from poor to moderate, and improved with repeated administration for the "mobility" and "usual activities" dimensions. The lowest agreement was observed when staff served as proxies or the proxy-proxy perspective was adopted. CONCLUSIONS AND IMPLICATIONS: This review offers an overview of the psychometric properties of EQ-5D as a proxy HRQoL measure in RCF. The suboptimal evidence on psychometric properties of EQ-5D indicated the need for more validation studies and cautious use of the instrument in RCF.

Using the Matrixed Multiple Case Study approach to identify factors affecting the uptake of IPV screening programs following the use of implementation facilitation.

BACKGROUND: Intimate partner violence (IPV) is a prevalent social determinant of health. The US Preventive Services Task Force recommends routine IPV screening of women, but uptake remains variable. The Veterans Health Administration (VHA) initiated implementation facilitation (IF) to support integration of IPV screening programs into primary care clinics. An evaluation of IF efforts showed variability in IPV screening rates across sites. The follow-up study presented here used a Matrixed Multiple Case Study (MMCS) approach to examine the multilevel factors impacting IPV screening program implementation across sites with varying levels of implementation success. METHODS: This mixed methods study is part of a larger cluster randomized stepped wedge Hybrid-II program evaluation. In the larger trial, participating sites received 6 months of IF consisting of an external facilitator from VHA's Office of Women's Health working closely with an internal facilitator and key site personnel. Recognizing the heterogeneity in implementation outcomes across sites, the MMCS approach was used to enable interpretation of qualitative and quantitative data within and across sites to help contextualize the primary findings from the larger study. Qualitative data collection was guided by the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework and included interviews with key informants involved in IPV screening implementation at eight sites. Quantitative data on IPV screening uptake was derived from medical records and surveys completed by key personnel at the same eight sites to understand implementation facilitation activities. RESULTS: Fifteen factors influencing IPV screening implementation spanning all four i-PARIHS domains were identified and categorized into three distinct categories: (1) factors with enabling influence across all sites, (2) factors deemed important to implementation success, and (3) factors differentiating sites with high/medium versus low implementation success. CONCLUSIONS: Understanding the influencing factors across multi-level domains contributing to variable success of IPV screening implementation can inform the tailoring of IF efforts to promote spread and quality of screening. Implementation of IPV screening programs in primary care with IF should consider consistent engagement of internal facilitators with clinic staff involved in implementation, the resourcefulness of external facilitators, and appending resources to IPV screening tools to help key personnel address positive screens. TRIAL REGISTRATION: ClinicalTrials.gov NCT04106193. Registered on September 26, 2019.

Surrogate Adiposity Markers and Mortality.

Importance: Body mass index (BMI) is an easily obtained adiposity surrogate. However, there is variability in body composition and adipose tissue distribution between individuals with the same BMI, and there is controversy regarding the BMI associated with the lowest mortality risk. Objective: To evaluate which of BMI, fat mass index (FMI), and waist-to-hip (WHR) has the strongest and most consistent association with mortality. Design, Setting, and Participant: This cohort study used incident deaths from the UK Biobank (UKB; 2006-2022), which includes data from 22 clinical assessment centers across the United Kingdom. UKB British participants of British White ancestry (N = 387 672) were partitioned into a discovery cohort (n = 337 078) and validation cohort (n = 50 594), with the latter consisting of 25 297 deaths and 25 297 controls. The discovery cohort was used to derive genetically determined adiposity measures while the validation cohort was used for analyses. Exposure-outcome associations were analyzed through observational and mendelian randomization (MR) analyses. Exposures: BMI, FMI, and WHR. Main Outcomes and Measures: All-cause and cause-specific (cancer, cardiovascular disease [CVD], respiratory disease, or other causes) mortality. Results: There were 387 672 and 50 594 participants in our observational (mean [SD] age, 56.9 [8.0] years; 177 340 [45.9%] male, 210 332 [54.2%], female), and MR (mean [SD] age, 61.6 [6.2] years; 30 031 [59.3%] male, 20 563 [40.6%], female) analyses, respectively. Associations between measured BMI and FMI with all-cause mortality were J-shaped, whereas the association of WHR with all-cause mortality was linear using the hazard ratio (HR) scale (HR per SD increase of WHR, 1.41 [95% CI, 1.38-1.43]). Genetically determined WHR had a stronger association with all-cause mortality than BMI (odds ratio [OR] per SD increase of WHR, 1.51 [95% CI, 1.32-1.72]; OR per SD increase of BMI, 1.29 [95% CI, 1.20-1.38]; P for heterogeneity = .02). This association was stronger in male than female participants (OR, 1.89 [95% CI, 1.54-2.32]; P for heterogeneity = .01). Unlike BMI or FMI, the genetically determined WHR-all-cause mortality association was consistent irrespective of observed BMI. Conclusions and Relevance: In this cohort study, WHR had the strongest and most consistent association with mortality irrespective of BMI. Clinical recommendations should consider focusing on adiposity distribution compared with mass.

Frailty among older surgical patients and risk of hospital acquired adverse events: The South-Western Sydney frailty and nurse sensitive indicators study.

BACKGROUND: While advances in healthcare mean people are living longer, increasing frailty is a potential consequence of this. The relationship between frailty among older surgical patients and hospital acquired adverse events has not been extensively explored. We sought to describe the relationship between increasing frailty among older surgical patients and the risk of hospital acquired adverse events. METHODS: We included consecutive surgical admissions among patients aged 70 years or more across the SWSLHD between January 2010 and December 2020. This study used routinely collected ICD-10-AM data, obtained from the government maintained Admitted Patient Data Collection. The relationships between cumulative frailty deficit items and risk of hospital acquired adverse events were assessed using Poisson regression modelling. This study followed the RECORD/STROBE guidelines. RESULTS: During the study period, 44,721 (57% women) older adults were admitted, and 41% (25,306) were planned surgical admissions. The risk of all adverse events increased with increasing number of frailty deficit items, the highest deficit items group (4-12 deficit items) compared with the lowest deficit items group (0 or 1 deficit item): falls adjusted rate ratio (adj RR) = 15.3, (95% confidence interval (CI) 12.1, 19.42); pressure injury adj RR = 21.3 (95% CI 12.53, 36.16); delirium adj RR = 40.9 (95% CI 31.21, 53.55); pneumonia adj RR = 16.5 (95% CI 12.74, 21.27); thromboembolism adj RR = 17.3 (95% CI 4.4, 11.92); and hospital mortality adj RR = 6.2 (95% CI 5.18, 7.37). CONCLUSION: The increase in number of cumulative frailty deficit items among older surgical patients was associated with a higher risk of adverse hospital events. The link offers an opportunity to clinical nursing professionals in the surgical setting, to develop and implement targeted models of care and ensure the best outcomes for frail older adults and their families.

Psychometric Properties of Generic Preference-Weighted Measures for Children and Adolescents: A Systematic Review.

INTRODUCTION: Preference-weighted measures (PWMs)-also referred to as preference-based measures in the literature-of health status/health-related quality of life plays an essential role in estimating quality-adjusted life-years (QALY) for use in economic evaluations of healthcare products and interventions. However, as PWMs are first and foremost intended to accurately reflect respondent health status, they should ideally demonstrate good psychometric properties for the population in question. This study aimed to systematically review published evidence on the measurement properties of commonly used PWMs for children and adolescents. METHODS: Three electronic databases (PubMed, Medline, and PsycINFO) were searched for articles assessing the psychometric properties (content validity, construct validity-including convergent validity and known-group validity, test-retest reliability, and responsiveness) of the PWMs of interest (AQoL-6D, CHU9D, HUI2, HUI3, and EQ-5D-Y). The COsensus-based Standards for the selection of health Measurement INstruments methodology (COSMIN) guidelines were used to assess (a) the methodological quality of the studies included and (b) the psychometric performance of the instruments covered. Data were analysed overall as well as by population (country and disease group) and perspective (self-report or proxy-report). The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42021277296). RESULTS: In total, 53 articles were included in this systematic review. Health Utilities Index (HUI) was tested only in patient populations, CHU9D was most frequently tested in general population samples, while EQ-5D-Y was tested in both populations. Overall, there was high-quality evidence supporting sufficient construct validity for all instruments except AQoL-6D. Evidence supporting test-retest and responsiveness was scarce. There was high-quality evidence supporting sufficient responsiveness of HUI2 and HUI3, and inconsistent test-retest reliability of CHU9D and EQ-5D-Y. Evidence for content validity was minimal and therefore not extracted and synthesized for any PWMs. CONCLUSION: This review provides updated evidence on the measurement properties of existing generic PWMs for children and adolescents. High-quality evidence for all relevant psychometric properties and across a range of populations was not available for any of the instruments included, indicating that further work is needed in this direction. This study has identified some of the most noticeable evidence gaps for each of the individual measures. Users can use this information to guide their decision on the choice of PWM to administer.

Conformation specific antagonistic high affinity antibodies to the RON receptor kinase for imaging and therapy.

The RON receptor tyrosine kinase is an exceptionally interesting target in oncology and immunology. It is not only overexpressed in a wide variety of tumors but also has been shown to be expressed on myeloid cells associated with tumor infiltration, where it serves to dampen tumour immune responses and reduce the efficacy of anti-CTLA4 therapy. Potent and selective inhibitory antibodies to RON might therefore both inhibit tumor cell growth and stimulate immune rejection of tumors. We derived cloned and sequenced a new panel of exceptionally avid anti-RON antibodies with picomolar binding affinities that inhibit MSP-induced RON signaling and show remarkable potency in antibody dependent cellular cytotoxicity. Antibody specificity was validated by cloning the antibody genes and creating recombinant antibodies and by the use of RON knock out cell lines. When radiolabeled with 89-Zirconium, the new antibodies 3F8 and 10G1 allow effective immuno-positron emission tomography (immunoPET) imaging of RON-expressing tumors and recognize universally exposed RON epitopes at the cell surface. The 10G1 was further developed into a novel bispecific T cell engager with a 15 pM EC50 in cytotoxic T cell killing assays.

Cost-Effectiveness of Polygenic Risk Scores to Guide Statin Therapy for Cardiovascular Disease Prevention.

BACKGROUND: Atherosclerotic cardiovascular diseases (CVDs) are leading causes of death despite effective therapies and result in unnecessary morbidity and mortality throughout the world. We aimed to investigate the cost-effectiveness of polygenic risk scores (PRS) to guide statin therapy for Canadians with intermediate CVD risk and model its economic outlook. METHODS: This cost-utility analysis was conducted using UK Biobank prospective cohort study participants, with recruitment from 2006 to 2010, and at least 10 years of follow-up. We included nonrelated white British-descent participants (n=96 116) at intermediate CVD risk with no prior lipid lowering medication or statin-indicated conditions. A coronary artery disease PRS was used to inform decision to use statins. The effects of statin therapy with and without PRS, as well as CVD events were modelled to determine the incremental cost-effectiveness ratio from a Canadian public health care perspective. We discounted future costs and quality-adjusted life-years by 1.5% annually. RESULTS: The optimal economic strategy was when intermediate risk individuals with a PRS in the top 70% are eligible for statins while the lowest 1% are excluded. Base-case analysis at a genotyping cost of $70 produced an incremental cost-effectiveness ratio of $172 906 (143 685 USD) per quality-adjusted life-year. In the probabilistic sensitivity analysis, the intervention has approximately a 50% probability of being cost-effective at $179 100 (148 749 USD) per quality-adjusted life-year. At a $0 genotyping cost, representing individuals with existing genotyping information, PRS-guided strategies dominated standard care when 12% of the lowest PRS individuals were withheld from statins. With improved PRS predictive performance and lower genotyping costs, the incremental cost-effectiveness ratio demonstrates possible cost-effectiveness under thresholds of $150 000 and possibly $50 000 per quality-adjusted life-year. CONCLUSIONS: This study suggests that using PRS alongside existing guidelines might be cost-effective for CVD. Stronger predictiveness combined with decreased cost of PRS could further improve cost-effectiveness, providing an economic basis for its inclusion into clinical care.

Working out dads (WOD): a study protocol for a randomised controlled trial of a group-based peer support intervention for men experiencing mental health difficulties in early fatherhood.

BACKGROUND: Approximately one in ten men experience mental health difficulties during the early years of fatherhood, and these can have negative impacts on children and families. However, few evidence-based interventions targeting fathers' mental health are available. The aim of the trial is to evaluate the effectiveness and cost-effectiveness of Working Out Dads (WOD) - a facilitated peer support group intervention for fathers of young children, in reducing psychological distress and other mental health symptoms. METHODS: This trial will employ a parallel-arm randomised controlled trial (RCT) to evaluate the effectiveness and cost effectiveness of WOD peer support group intervention compared to usual care (a 30-min mental health and service focused phone consultation with a health professional). A total of 280 fathers of young children (aged 0-4 years) who are experiencing mental health difficulties and/or are at risk of poor mental health will be recruited. Randomisation and analyses will be at the level of the individual participant. The primary outcome is psychological distress symptoms, measured by the Kessler Psychological Distress Scale (K10) from baseline to 24 weeks post randomisation. A range of secondary outcomes will be assessed including suicidal ideation; mental health disorders, specific symptoms of depression, anxiety, and stress; social support, quality of life, health service use, and health care costs. Data will be collected at baseline, 10- and 24 weeks post-randomisation. DISCUSSION: This trial will examine the effectiveness of a novel group-based peer support intervention in reducing the psychological distress and other mental health symptoms of fathers compared to usual care. The economic and process evaluation will guide policy decision making along with informing the future implementation of WOD on a larger scale if effectiveness is demonstrated. TRIAL REGISTRATION: The current trial has been registered with ClinicalTrials.gov (Registration ID - NCT04813042 ). Date of Registration: March 22nd, 2021.

Effect of an mHealth self-help intervention on readmission after adult cardiac surgery: Protocol for a pilot randomized controlled trial.

AIM: To describe a protocol for the pilot phase of a trial designed to test the effect of an mHealth intervention on representation and readmission after adult cardiac surgery. DESIGN: A multisite, parallel group, pilot randomized controlled trial (ethics approval: HREC2020.331-RMH69278). METHODS: Adult patients scheduled to undergo elective cardiac surgery (coronary artery bypass grafting, valve surgery, or a combination of bypass grafting and valve surgery or aortic surgery) will be recruited from three metropolitan tertiary teaching hospitals. Patients allocated to the control group with receive usual care that is comprised of in-patient discharge education and local paper-based written discharge materials. Patients in the intervention group will be provided access to tailored 'GoShare' mHealth bundles preoperatively, in a week of hospital discharge and 30 days after surgery. The mHealth bundles are comprised of patient narrative videos, animations and links to reputable resources. Bundles can be accessed via a smartphone, tablet or computer. Bundles are evidence-based and designed to improve patient self-efficacy and self-management behaviours, and to empower people to have a more active role in their healthcare. Computer-generated permuted block randomization with an allocation ratio of 1:1 will be generated for each site. At the time of consent, and 30, 60 and 90 days after surgery quality of life and level of patient activation will be measured. In addition, rates of representation and readmission to hospital will be tracked and verified via data linkage 1 year after the date of surgery. DISCUSSION: Interventions using mHealth technologies have proven effectiveness for a range of cardiovascular conditions with limited testing in cardiac surgical populations. IMPACT: This study provides an opportunity to improve patient outcome and experience for adults undergoing cardiac surgery by empowering patients as end-users with strategies for self-help. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000082808.

Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories.

Rare variants are collectively numerous and may underlie a considerable proportion of complex disease risk. However, identifying genuine rare variant associations is challenging due to small effect sizes, presence of technical artefacts, and heterogeneity in population structure. We hypothesize that rare variant burden over a large number of genes can be combined into a predictive rare variant genetic risk score (RVGRS). We propose a method (RV-EXCALIBER) that leverages summary-level data from a large public exome sequencing database (gnomAD) as controls and robustly calibrates rare variant burden to account for the aforementioned biases. A calibrated RVGRS strongly associates with coronary artery disease (CAD) in European and South Asian populations by capturing the aggregate effect of rare variants through a polygenic model of inheritance. The RVGRS identifies 1.5% of the population with substantial risk of early CAD and confers risk even when adjusting for known Mendelian CAD genes, clinical risk factors, and a common variant genetic risk score.

"We're in the background": Facilitators and barriers to fathers' engagement and participation in a health intervention during the early parenting period.

ISSUES ADDRESSED: Little is known about the barriers and facilitators associated with engaging fathers in interventions targeting their physical and mental health. The current research therefore aimed to explore fathers' perceived barriers and facilitators to engagement and participation in a health intervention delivered during the early parenting period. METHODS: Eleven fathers of young children (0-4 years) were interviewed about their perceptions and experiences of facilitators and barriers to engaging and participating in an intervention (Working Out Dads) to target their mental and physical health. Interviews were recorded and transcribed. Transcripts were analysed using thematic analysis. RESULTS: Fathers identified a number of program-related and father-related facilitators and barriers which impacted their engagement and participation. Program-related facilitators included: accessibility of the program; father advocacy of the program; group fitness/exercise component; and having a father-specific program. Facilitating factors related to fathers included: making social connections; learning how to be a better dad/partner; and partner support and encouragement to attend. Program-related barriers included: travel; lack of awareness; and gender roles. While father-related barriers included: being time poor; sacrifices to family; and apprehension. CONCLUSIONS: The current findings identified many areas that facilitate, encourage and motivate men to participate in interventions which support their mental and physical health during the early parenting period. RELEVANCE: Generating evidence on barriers and facilitators to health interventions is important to improving the current intervention along with informing the development of engaging and targeted health interventions for fathers in early parenthood.

A Community-based Assessment of Skin Care, Allergies, and Eczema (CASCADE): an atopic dermatitis primary prevention study using emollients-protocol for a randomized controlled trial.

BACKGROUND: Atopic dermatitis (AD) is a common, chronic skin disorder often beginning in infancy. Skin barrier dysfunction early in life serves as a central event in the pathogenesis of AD. In infants at high risk of developing AD, preventative application of lipid-rich emollients may reduce the risk of developing AD. This study aims to measure the effectiveness of this intervention in a population not selected for risk via a pragmatic, randomized, physician-blinded trial in the primary care setting. METHODS: Infant-parent dyads are recruited from a primary care practice participating through one of four practice-based research networks in Oregon, Colorado, Wisconsin, and North Carolina. Eligible dyads are randomized to the intervention (daily use of lipid-rich emollient) or the control (no emollient) group (n = 625 infants in each) and are followed for 24 months. The primary outcome is the cumulative incidence of physician-diagnosed AD and secondary outcomes include caregiver-reported measures of AD and development of other atopic diseases. Data collection occurs via chart review and surveys, with no study visits required. Data will be analyzed utilizing intention-to-treat principles. DISCUSSION: AD is a common skin condition in infants that affects quality of life and is associated with the development of other atopic diseases. If a safe intervention, such as application of lipid-rich emollients, in the general population effectively decreases AD prevalence, this could alter the guidance given by providers regarding routine skin care of infants. Because of the pragmatic design, we anticipate that this trial will yield generalizable results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03409367. Registered on 11 February 2018.

A cross-sectional study exploring the relationship between burnout, absenteeism, and job performance among American nurses.

BACKGROUND: Studies suggest a high prevalence of burnout among nurses. The aim of this study was to evaluate the relationship between burnout among nurses and absenteeism and work performance. METHODS: A national sample of U.S. nurses was sent an anonymous, cross-sectional survey in 2016. The survey included items about demographics, fatigue, and validated instruments to measure burnout, absenteeism, and poor work performance in the last month. RESULTS: Of the 3098 nurses who received the survey, 812 (26.2%) responded. The mean age was 52.3 years (SD 12.5), nearly all were women (94.5%) and most were married (61.9%) and had a child (75.2%). Participating nurses had a mean of 25.7 (SD 13.9) years of experience working as nurse and most held a baccalaureate (38.2%) or masters of science (37.1%) degree in nursing. A quarter worked in the inpatient setting (25.5%) and the average hours worked per week was 41.3 (SD 14.1). Overall, 35.3% had symptoms of burnout, 30.7% had symptoms of depression, 8.3% had been absent 1 or more days in the last month due to personal health, and 43.8% had poor work performance in the last month. Nurses who had burnout were more likely to have been absent 1 or more days in the last month (OR 1.85, 95% CI 1.25-2.72) and have poor work performance (referent: high performer; medium performer, OR 2.68,95% CI 1.82-3.99; poor performer, OR 5.01, 95% CI 3.09-8.14). After adjusting for age, sex, relationship and parental status, highest academic degree, practice setting, burnout, depression, and satisfaction with work-life integration, nurses who were more fatigued (for each point worsening, OR 1.22, 95% CI 1.10-1.37) were more likely to have had absenteeism while those who worked more hours (for each additional hour OR 0.98, 95% CI 0.96-1.00) were less likely to have had absenteeism. Factors independently associated with poor work performance included burnout (OR 2.15, 95% CI 1.43-3.24) and fatigue (for each point of worsening, OR 1.22, 95% CI 1.12-1.33). CONCLUSIONS: These findings suggest burnout is prevalent among nurses and likely impacts work performance.

Therapeutic anti-cancer activity of antibodies targeting sulfhydryl bond constrained epitopes on unglycosylated RON receptor tyrosine kinase.

Recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) and its ligand, serum macrophage-stimulating protein (MSP), are well-established oncogenic drivers for tumorigenesis and metastasis. RON is often found to be alternatively spliced resulting in various isoforms that are constitutively active. RON is therefore an attractive target for cancer therapeutics, including small molecular inhibitors and monoclonal antibodies. While small molecule inhibitors of RON may inhibit other protein kinases including the highly similar MET kinase, monoclonal antibodies targeting RON are more specific, potentially inducing fewer side effects. Although anti-RON monoclonal antibody therapies have been developed and tested in clinical trials, they were met with limited success. Cancer cells have been associated with aberrant glycosylation mechanisms. Notably for RON, the loss of N-bisected glycosylation is a direct cause for tumorigenesis and poorer prognosis in cancer patients. Particularly in gastric cancer, aberrant RON glycosylation augments RON activation. Here, we present a novel panel of monoclonal antibodies which potentially widens the specific targeting of not only the glycosylated RON, but also unglycosylated and aberrantly glycosylated RON. Our antibodies can bind strongly to deglycosylated RON from tunicamycin treated cells, recognise RON in IHC/IF and possess superior therapeutic efficacy in RON expressing xenograft tumours. Our most potent antibody in xenograft assays, is directed to the RON alpha chain and targets a sulfhydryl bond constrained epitope that appears to be cryptic in the crystal structure. This establishes the paradigm that such constrained and cryptic epitopes represent good targets for therapeutic antibodies.

Assessing quality improvement capacity in primary care practices.

BACKGROUND: Healthy Hearts Northwest (H2N) is a study of external support strategies to build quality improvement (QI) capacity in primary care with a focus on cardiovascular risk factors: appropriate aspirin use, blood pressure control, and tobacco screening/cessation. METHODS: To guide practice facilitator support, experts in practice transformation identified seven domains of QI capacity and mapped items from a previously validated medical home assessment tool to them. A practice facilitator (PF) met with clinicians and staff in each practice to discuss each item on the Quality Improvement Capacity Assessment (QICA) resulting in a practice-level response to each item. We examined the association between the QICA total and sub-scale scores, practice characteristics, a measure of prior experience with managing practice change, and performance on clinical quality measures (CQMs) for the three cardiovascular risk factors. RESULTS: The QICA score was associated with prior experience managing change and moderately associated with two of the three CQMs: aspirin use (r = 0.16, p = 0.049) and blood pressure control (r = 0.18, p = 0.013). Rural practices and those with 2-5 clinicians had lower QICA scores.. CONCLUSIONS: The QICA is useful for assessing QI capacity within a practice and may serve as a guide for both facilitators and primary care practices in efforts to build this capacity and improve measures of clinical quality. TRIAL REGISTRATION: This trial is registered with www.clinicaltrials.gov Identifier# NCT02839382, retrospectively registered on July 21, 2016.

SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment.

BACKGROUND: SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). METHODS: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα- early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. RESULTS: As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc- [HR (95% CI) = 0.52 (0.34-0.78), p = 0.002]. Meanwhile, in ERα- patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto- [HR (95% CI) = 0.50 (0.34-0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc- or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28-27.03), p = 0.012], or SHON-Cyto- [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18-25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc- [HR (95% CI) = 0.41 (0.19-0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto- patients [HR (95% CI) = 4.63 (1.05-20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13-44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant. CONCLUSION: SHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.

Design features of a guideline implementation tool designed to increase awareness of a clinical practice guide to HIV rehabilitation: A qualitative process evaluation.

RATIONALE, AIMS, AND OBJECTIVES: A comprehensive electronic guide (e-module) describing an interprofessional, evidence-informed approach to HIV rehabilitation was developed as an education resource for rehabilitation professionals. We developed a guideline implementation tool, consisting of a 10-week, case-based education intervention delivered by email, that was perceived to increase rehabilitation professionals' (occupational therapists (OTs), physical therapists (PTs), and speech language pathologists (SLPs)) knowledge and confidence to apply best practices in HIV rehabilitation. This study aimed to increase understanding of how the design of the guideline implementation tool facilitated increased awareness of and access to the e-module among rehabilitation professionals. METHODS: We conducted a single group intervention study with rehabilitation professionals in Canada and the United Kingdom. Six case studies targeting HIV pathophysiology and associated conditions, an interprofessional approach to rehabilitation assessment and treatment, and psychosocial issues experienced by people living with HIV, were emailed to participants at 2-week intervals. Individual semi-structured interviews were conducted post-intervention. Interview transcripts were analysed using a descriptive qualitative approach. RESULTS: Twenty-six individuals (17 from Canada, and 9 from the UK; 16 PTs, 7 OTs, 3 SLPs) were interviewed. One main theme related to design features of the intervention that facilitated learning and access to the e-module emerged. Subthemes highlighted features of the case-based intervention, including technical feasibility, terminology, formatting and layout, hyperlinks, number and frequency of case studies, and diverse and realistic case scenarios relevant to the learner's practice, that participants described as facilitating access to information and learning. CONCLUSION: Electronically administered case studies were perceived as complementary knowledge tools that increased access to an evidence-informed guide to HIV rehabilitation. Findings provide guidance on using case studies as a guideline implementation tool to facilitate access to information and related resources to optimize learning.