Hydrogen isotope fractionation is controlled by CO2 in coccolithophore lipids.

Hydrogen isotope ratios (δ2H) represent an important natural tracer of metabolic processes, but quantitative models of processes controlling H-fractionation in aquatic photosynthetic organisms are lacking. Here, we elucidate the underlying physiological controls of 2H/1H fractionation in algal lipids by systematically manipulating temperature, light, and CO2(aq) in continuous cultures of the haptophyte Gephyrocapsa oceanica. We analyze the hydrogen isotope fractionation in alkenones (αalkenone), a class of acyl lipids specific to this species and other haptophyte algae. We find a strong decrease in the αalkenone with increasing CO2(aq) and confirm αalkenone correlates with temperature and light. Based on the known biosynthesis pathways, we develop a cellular model of the δ2H of algal acyl lipids to evaluate processes contributing to these controls on fractionation. Simulations show that longer residence times of NADPH in the chloroplast favor a greater exchange of NADPH with 2H-richer intracellular water, increasing αalkenone. Higher chloroplast CO2(aq) and temperature shorten NADPH residence time by enhancing the carbon fixation and lipid synthesis rates. The inverse correlation of αalkenone to CO2(aq) in our cultures suggests that carbon concentrating mechanisms (CCM) do not achieve a constant saturation of CO2 at the Rubisco site, but rather that chloroplast CO2 varies with external CO2(aq). The pervasive inverse correlation of αalkenone with CO2(aq) in the modern and preindustrial ocean also suggests that natural populations may not attain a constant saturation of Rubisco with the CCM. Rather than reconstructing growth water, αalkenone may be a powerful tool to elucidate the carbon limitation of photosynthesis.

Hic et Runx: new insights into T cell tissue residency.

Tissue-resident memory T cells (Trm), which typically do not enter the blood or lymphatic circulation at steady-state, are considered crucial for controlling pathogen entry at skin and mucosal barriers. Two recent studies (Fonseca et al. and Crowl et al.) shed light on the mechanisms of Trm cell differentiation.

Stem cell-derived cardiomyocyte heterogeneity confounds electrophysiological insights.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model for studying drug cardiotoxicity and patient-specific cardiovascular disease. The inherent electrophysiological heterogeneity of these cells limits the depth of insights that can be drawn from well-designed experiments. In this review, we provide our perspective on some sources and the consequences of iPSC-CM heterogeneity. We demonstrate the extent of heterogeneity in the literature and explain how such heterogeneity is exacerbated by patch-clamp experimental artifacts in the manual and automated set-up. Finally, we discuss how this heterogeneity, caused by both intrinsic and extrinsic factors, limits our ability to build digital twins of patient-derived cardiomyocytes.

Single-cell ionic current phenotyping elucidates non-canonical features and predictive potential of cardiomyocytes during automated drug experiments.

All new drugs must go through preclinical screening tests to determine their proarrhythmic potential. While these assays effectively filter out dangerous drugs, they are too conservative, often misclassifying safe compounds as proarrhythmic. In this study, we attempt to address this shortcoming with a novel, medium-throughput drug-screening approach: we use an automated patch-clamp system to acquire optimized voltage clamp (VC) and action potential (AP) data from human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) at several drug concentrations (baseline, 3×, 10× and 20× the effective free plasma concentrations). With our novel method, we show correlations between INa block and upstroke slowing after treatment with flecainide or quinine. Additionally, after quinine treatment, we identify significant reductions in current during voltage steps designed to isolate If and IKs. However, we do not detect any IKr block by either drug, and upon further investigation, do not see any IKr present in the iPSC-CMs when prepared for automated patch experiments (i.e. in suspension) - this is in contrast to similar experiments we have conducted with these cells using the manual patch setup. In this study, we: (1) present a proof-of-concept demonstration of a single-cell medium-throughput drug study, and (2) characterize the non-canonical electrophysiology of iPSC-CMs when prepared for experiments in a medium-throughput setting. KEY POINTS: Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model to study the proarrhythmic potential of drugs, but insights from these cells are often limited by the low throughput of manual patch-clamp. In this study, we use a medium-throughput automated patch-clamp system to acquire action potential (AP) and complex voltage clamp (VC) data from single iPSC-CMs at multiple drug concentrations. A correlation between AP upstroke and INa transients was identified and drug-induced changes in ionic currents found. We also characterize the substantially altered physiology of iPSC-CMs when patched in an automated system, suggesting the need to investigate differences between manual and automated patch experiments.

Optimization of a cardiomyocyte model illuminates role of increased INa,L in repolarization reserve.

Cardiac ion currents may compensate for each other when one is compromised by a congenital or drug-induced defect. Such redundancy contributes to a robust repolarization reserve that can prevent the development of lethal arrhythmias. Most efforts made to describe this phenomenon have quantified contributions by individual ion currents. However, it is important to understand the interplay between all major ion-channel conductances, as repolarization reserve is dependent on the balance between all ion currents in a cardiomyocyte. Here, a genetic algorithm was designed to derive profiles of nine ion-channel conductances that optimize repolarization reserve in a mathematical cardiomyocyte model. Repolarization reserve was quantified using a previously defined metric, repolarization reserve current, i.e., the minimum constant current to prevent normal action potential repolarization in a cell. The optimization improved repolarization reserve current up to 84% compared to baseline in a human adult ventricular myocyte model and increased resistance to arrhythmogenic insult. The optimized conductance profiles were not only characterized by increased repolarizing current conductances but also uncovered a previously unreported behavior by the late sodium current. Simulations demonstrated that upregulated late sodium increased action potential duration, without compromising repolarization reserve current. The finding was generalized to multiple models. Ultimately, this computational approach, in which multiple currents were studied simultaneously, illuminated mechanistic insights into how the metric's magnitude could be increased and allowed for the unexpected role of late sodium to be elucidated.NEW & NOTEWORTHY Genetic algorithms are typically used to fit models or extract desired parameters from data. Here, we use the tool to produce a ventricular cardiomyocyte model with increased repolarization reserve. Since arrhythmia mitigation is dependent on multiple cardiac ion-channel conductances, study using a comprehensive, unbiased, and systems-level approach is important. The use of this optimization strategy allowed us to find robust profiles that illuminated unexpected mechanistic determinants of key ion-channel conductances in repolarization reserve.

Single-cell ionic current phenotyping explains stem cell-derived cardiomyocyte action potential morphology.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising tool to study arrhythmia-related factors, but the variability of action potential (AP) recordings from these cells limits their use as an in vitro model. In this study, we use recently published brief (10 s), dynamic voltage-clamp (VC) data to provide mechanistic insights into the ionic currents contributing to AP heterogeneity; we call this approach rapid ionic current phenotyping (RICP). Features of this VC data were correlated to AP recordings from the same cells, and we used computational models to generate mechanistic insights into cellular heterogeneity. This analysis uncovered several interesting links between AP morphology and ionic current density: both L-type calcium and sodium currents contribute to upstroke velocity, rapid delayed rectifier K+ current is the main determinant of the maximal diastolic potential, and an outward current in the activation range of slow delayed rectifier K+ is the main determinant of AP duration. Our analysis also identified an outward current in several cells at 6 mV that is not reproduced by iPSC-CM mathematical models but contributes to determining AP duration. RICP can be used to explain how cell-to-cell variability in ionic currents gives rise to AP heterogeneity. Because of its brief duration (10 s) and ease of data interpretation, we recommend the use of RICP for single-cell patch-clamp experiments that include the acquisition of APs.NEW & NOTEWORTHY We present rapid ionic current phenotyping (RICP), a current quantification approach based on an optimized voltage-clamp protocol. The method captures a rich snapshot of the ionic current dynamics, providing quantitative information about multiple currents (e.g., ICa,L, IKr) in the same cell. The protocol helped to identify key ionic determinants of cellular action potential heterogeneity in iPSC-CMs. This included unexpected results, such as the critical role of IKr in establishing the maximum diastolic potential.

GJ Express: an improvement initiative to decrease sedation and anesthesia for gastrojejunostomy tube exchanges.

BACKGROUND: Overuse of sedation and anesthesia causes delays in gastrojejunostomy tube (GJ) exchanges, increased risk of complications, unnecessary use of resources, preventable hospital admissions, and an adverse impact on patient and family experience. Our hospital was over-utilizing sedation and anesthesia, and we aimed to decrease this use from 78% to 20% within two years. METHODS: An interdisciplinary quality improvement team comprehensively evaluated current processes for GJ tube exchanges through a retrospective chart review for baseline data with prospective time series analysis after improvement implementation. The primary outcome measure was the percentage of pediatric patients that utilized sedation or anesthesia for routine GJ tube exchanges. RESULTS: A statistical process control p-chart was used to calculate and show changes over time for patients (n = 45 patients average). The median percent of pediatric GJ tube exchanges performed with sedation or anesthesia decreased from 77.8% to 11.3%. Most patients (76%) were covered by Medicaid programs; with low reimbursement rates, decreased anesthesiologist billing revenue does not have a negative financial impact. CONCLUSIONS: An interprofessional improvement initiative that engaged patients and families, incorporated pediatric-specific staff services, and developed systematic weaning was associated with a significant decrease in the overuse of sedation and anesthesia for GJ tube exchanges. IMPACT: We believe that this work is highly relevant and impactful for medical centers caring for children who require gastrojejunostomy tubes, an increasingly common approach to management of children with feeding issues. There is very little literature available on the use of sedation or anesthesia for changing these tubes. While large children's medical centers in the USA usually do not utilize sedation or anesthesia, there are likely many serious outliers, especially when children receive care outside of a pediatric specific institution. This paper brings awareness to this serious issue and provides information about how we changed care to achieve higher patient safety and lower medical costs.

A Bayesian network approach incorporating imputation of missing data enables exploratory analysis of complex causal biological relationships.

Bayesian networks can be used to identify possible causal relationships between variables based on their conditional dependencies and independencies, which can be particularly useful in complex biological scenarios with many measured variables. Here we propose two improvements to an existing method for Bayesian network analysis, designed to increase the power to detect potential causal relationships between variables (including potentially a mixture of both discrete and continuous variables). Our first improvement relates to the treatment of missing data. When there is missing data, the standard approach is to remove every individual with any missing data before performing analysis. This can be wasteful and undesirable when there are many individuals with missing data, perhaps with only one or a few variables missing. This motivates the use of imputation. We present a new imputation method that uses a version of nearest neighbour imputation, whereby missing data from one individual is replaced with data from another individual, their nearest neighbour. For each individual with missing data, the subsets of variables to be used to select the nearest neighbour are chosen by sampling without replacement the complete data and estimating a best fit Bayesian network. We show that this approach leads to marked improvements in the recall and precision of directed edges in the final network identified, and we illustrate the approach through application to data from a recent study investigating the causal relationship between methylation and gene expression in early inflammatory arthritis patients. We also describe a second improvement in the form of a pseudo-Bayesian approach for upweighting certain network edges, which can be useful when there is prior evidence concerning their directions.

Comparing the Use of Crotaline-Polyvalent Immune Fab (Ovine) Versus Observation in Children.

OBJECTIVES: In the United States, studies are inconclusive regarding the indications for polyvalent antivenom administration for crotaline envenomation. We compared polyvalent antivenom administration versus observation used at 2 separate institutions. We hypothesized that deferring antivenom leads to increased hospital length of stay and surgical interventions. METHODS: Retrospective chart review of children who presented to Le Bonheur Children's Hospital (LBCH) in Memphis, Tennessee, and Monroe Carell Jr Children's Hospital at Vanderbilt (MCJCHV) in Nashville, Tennessee, from 2009 to 2021. Patient demographics, treatment utilization, bite location, and outcomes from both sites were statistically examined. RESULTS: A total of 183 patients met the inclusion criteria (123 at LBCH, 60 at MCJCHV). At LBCH, mean age was 9.2 years, 54% were male, and 79% of known snakes identified as copperheads. At MCJCHV, mean age was 8.9 years, 65% were male, and 88% of known snakes identified as copperheads. The most commonly envenomated areas for both sites were the foot (42%), hand (27%), and ankle (26%). Patients at LBCH were managed with antivenom only 25% of the time, whereas 75% were observed; 82% of MCJCHV patients were managed with antivenom (P < 0.001). There were no significant differences in length of stay (mean, 1.5 days at LBCH and 1.8 days at MCJCHV; P = 0.136) or surgical intervention (3.3% of LBCH encounters, 5.0% of MCJCHV encounters; P = 0.685). Secondary outcomes aside from coagulopathy and admission location (intensive care unit vs floor) were also not significant. CONCLUSIONS: The use of antivenom did not impact hospital length of stay or surgical interventions. Our results should be interpreted cautiously as our study reflects regional experiences with snake species in the Southeast United States and not North America as a whole. Other institutional differences in management and smaller n at MCJCHV may have contributed to different outcomes. Further study is needed to determine intermediate and long-term effects of deferring antivenom use.

Prevalence of adverse events in pronated intubated adult COVID-19 patients: A systematic review with meta-analysis.

AIM: To present the pooled estimated prevalence of adverse events in pronated intubated adult COVID-19 patients. DESIGN: A systematic review and meta-analysis. DATA SOURCES: This study used the Cochrane Library, CINAHL, Embase, LILACS, Livivo, PubMed, Scopus, and Web of Science databases as data sources. METHODS: The studies were meta-analysed using JAMOVI 1.6.15 software. A random-effects model was used to identify the global prevalence of adverse events, confidence intervals and the heterogeneity data. Risk of bias was assessed using the Joanna Briggs Institute tool, and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: Of the 7904 studies identified, 169 were included for full reading, and 10 were included in the review. The most prevalent adverse events were pressure injuries (59%), haemodynamic instability (23%), death (17%) and device loss or traction (9%). CONCLUSION: The most prevalent adverse events in mechanically ventilated pronated patients with COVID-19 are pressure injuries, presence of haemodynamic instability, death and device loss or traction. IMPLICATIONS FOR THE PATIENT CARE: The evidence identified in this review can help improve the quality and safety of patient care by helping to design care protocols to avoid the development of adverse events that can cause permanent sequelae in these patients. IMPACT: This systematic review addressed the adverse events related to prone position in intubated adult COVID-19 patients. We identified that the most prevalent adverse events in these patients were pressure injuries, haemodynamic instability, device loss or traction and death. The results of this review may influence the clinical practice of nurses who work in intensive care units and, consequently, the nursing care provided not only to COVID-19 patients but for all intubated patients due to other reasons in intensive care units. REPORTING METHOD: This systematic review adhered to the PRISMA reporting guideline. PATIENT OR PUBLIC CONTRIBUTION: As this is a systematic review, we analysed data from primary studies conducted by many researchers. Thus, there was no patient or public contribution in this review.

Evolutionary pressures of aerial insectivory reflected in anurognathid pterosaurs.

Across the evolution of powered flight, the ecological niche of aerial insectivore has been occupied by members of the three volant vertebrate clades-Aves and Chiroptera, and the first known volant vertebrates, pterosaurs. However, morphological and quantitative evidence to support pterosaurs exhibiting this ecology remains scant. Anurognathids are an unusual group of pterosaurs in which the skull exhibits the unique morphology of being mediolaterally expanded, so much so that their skulls may be wider than rostrocaudally long. Here, we conduct quantitative comparative cranial measurements and dental morphology in anurognathids against extant avian and chiropteran taxa, respectively, with ecologies and behaviors that are similar to predicted putative behaviors of anurognathids. Comparative analyses of both skull and dental morphology suggest anurognathid specimens in similar morphospaces as insectivorous crepuscular and nocturnal extant volant taxa. Our results support that this unique group of pterosaurs likely occupied a niche of mid-flight insectivorous capture in low-light conditions.

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.

AIMS: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. METHODS AND RESULTS: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models. Our in silico and in vitro studies demonstrate how seal-leak current depolarizes APs, substantially affecting their morphology, even with seal resistances (Rseal) above 1 GΩ. We show that compensation of this leak current is difficult due to challenges with obtaining accurate measures of Rseal during an experiment. Using simulation, we show that Rseal measures (i) change during an experiment, invalidating the use of pre-rupture values, and (ii) are polluted by the presence of transmembrane currents at every voltage. Finally, we posit that the background sodium current in baseline iPSC-CM models imitates the effects of seal-leak current and is increased to a level that masks the effects of seal-leak current on iPSC-CMs. CONCLUSION: Based on these findings, we make recommendations to improve iPSC-CM AP data acquisition, interpretation, and model-building. Taking these recommendations into account will improve our understanding of iPSC-CM physiology and the descriptive ability of models built from such data.

Relaxational dynamics of the T-number conversion of virus capsids.

We extend a recently proposed kinetic theory of virus capsid assembly based on Model A kinetics and study the dynamics of the interconversion of virus capsids of different sizes triggered by a quench, that is, by sudden changes in the solution conditions. The work is inspired by in vitro experiments on functionalized coat proteins of the plant virus cowpea chlorotic mottle virus, which undergo a reversible transition between two different shell sizes (T = 1 and T = 3) upon changing the acidity and salinity of the solution. We find that the relaxation dynamics are governed by two time scales that, in almost all cases, can be identified as two distinct processes. Initially, the monomers and one of the two types of capsids respond to the quench. Subsequently, the monomer concentration remains essentially constant, and the conversion between the two capsid species completes. In the intermediate stages, a long-lived metastable steady state may present itself, where the thermodynamically less stable species predominate. We conclude that a Model A based relaxational model can reasonably describe the early and intermediate stages of the conversion experiments. However, it fails to provide a good representation of the time evolution of the state of assembly of the coat proteins in the very late stages of equilibration when one of the two species disappears from the solution. It appears that explicitly incorporating the nucleation barriers to assembly and disassembly is crucial for an accurate description of the experimental findings, at least under conditions where these barriers are sufficiently large.

Behaviour change for type 2 diabetes: perspectives of general practitioners, primary care academics, and behaviour change experts on the use of the 5As framework.

BACKGROUND: The 5As framework is a recognized underpinning of behaviour change guidelines, teaching, and research in primary care. Supporting patients to improve their lifestyle behaviours, including diet and physical activity, is a common aspect of type 2 diabetes mellitus (T2DM) management. The 5As framework often informs behaviour change for patients with T2DM. OBJECTIVE: To explore the experience and perspectives of general practitioners (GPs) and primary care academics and behaviour change experts regarding using the 5As framework when caring for patients with T2DM to better understand how and why the 5As are effective in practice. METHODS: We recruited 20 practising GPs, primary care academics, and behaviour change experts for an individual semistructured interview and analysed the data using a realist evaluation approach. RESULTS: There were diverse accounts of how GPs use the 5As in practice and few of the participants could name each "A." The 5As were commonly regarded as a framework best suited to beginners and although GPs expressed they followed the broad direction of the 5As, they did not consciously follow the framework in an instructive manner. Elements that could enhance the 5As included more emphasis on motivational interviewing, changing how "Ask" is included in the consultation, and increased person-centredness. CONCLUSION: Although it is a ubiquitous framework in primary care, the 5As are understood in diverse ways and applied variably in practice. There is room to enhance how the 5As support behaviour change consultations to optimize outcomes in primary care.

General practitioners (GPs) are usually involved in helping patients with diabetes to improve their diet, physical activity, and other lifestyle behaviours. The 5As are a framework designed to be used to structure behaviour change conversations­5As stand for Ask, Assess, Advise, Assist, and Arrange. We interviewed 20 people who were either GPs or experts in behaviour change. They had different ways of explaining the intent and usage of the 5As but consistently saw them as a framework for new practitioners. No one used the 5As consciously in their consultations with patients. The participants had multiple suggestions for how the 5As could be enhanced to support better care for patients living with diabetes. These included: more focus on motivational interviewing techniques, changing the number or order of the 5As steps, more focus on teamwork as well as the individual cultural needs of the patients. This work can inform further research on how patients can be better supported by GPs through evidence-based behaviour change care.

Causes, Predictors, and Timing of Early Neurological Deterioration and Symptomatic Intracranial Hemorrhage After Administration of IV tPA.

BACKGROUND: Acute ischemic stroke (AIS) is a major contributor toward healthcare-associated costs and services. Symptomatic intracranial hemorrhage (sICH) and early neurologic decline (END), defined as a National Health Institute Stroke Scale score decline of ≥ 4 within 24 h (with or without sICH), remain major concerns when administering intravenous tissue plasminogen activator (IV tPA) despite improved functional neurologic outcomes with its use. Given these risks, current guidelines recommend comprehensive stroke care (most often in an intensive care unit setting) for 24 h posttreatment. However, a number of patients may remain stable after IV tPA and thus not require such intensive resources. We sought to determine causes of END, along with timing and predictors of both sICH and END, to identify patients at lower risk of neurological deterioration and those suitable for earlier transition to a lower level of care. METHODS: This present study analyzed patients with AIS that presented within 4.5 h of being last seen well and received IV tPA. Baseline demographic, clinical, and radiographic findings were collected. Outcomes included END from any cause, parenchymal hemorrhage (PH1 or PH2), sICH, and mortality at 90 days. RESULTS: A total of 1238 patients with AIS without acute treatment of large vessel occlusion received IV tPA. 9.4% (116) had presence of any degree of ICH on noncontrast computed tomography head and 7.4% (91) experienced associated END. 2.7% (33) of patients experienced sICH, while 6.7% (83) experienced asymptomatic ICH. Of the patients with END, 63.7% did not have ICH. Predictive factors at presentation for END included an older age (72.6 ± 16.1 vs. 69.1 ± 14.8, p = 0.03), history of tobacco use (odds ratio [OR] 2.1 [1.1-4.3], p = 0.04), and hyperlipidemia (OR 1.7 [1.1-2.8], p = 0.02), along with the presence of an untreated large vessel occlusion (OR 2.1 [1.4-3.1], p = 0.02). Most END occurred within a mean time of 242 ± 251 min (4 ± 4 h). Because of the small proportion of patients suffering from sICH (33), predictors could not be determined; however, for patients with any ICH, predictive factors included an older age (74.6 ± 12.4 vs. 68.8 ± 15.1, p = 0.001), higher baseline National Health Institute Stroke Scale score (14.6 ± 7.3 vs. 10.8 ± 7.9, p = 0.002), and higher baseline glucose levels (155.1 ± 87.5 vs. 140.4 ± 70.5, p = 0.04). CONCLUSIONS: In this study, only a small proportion suffered from either sICH and/or END, typically within 12 h of tPA administration. These findings may support earlier deescalation of higher acuity monitoring in clinically stable post-IV tPA patients without large vessel occlusion.

Distributional Lattices as a Model for Discovering Syntactic Categories in Child-Directed Speech.

Distribution information plays an important role in word categorization. In this paper, we present a novel distributional model, distributional lattices to discover syntactic categories in child directed speech. A distributional lattice is a hierarchy formed by closed sets of words that are distributionally similar. Such a hierarchy is potentially useful for capturing syntactic categories by clustering words with associate patterns they occur in. In order to empirically support the suggestion that the distributional lattice is effective at categorizing words, we present a distributional lattice analysis of the Brent corpus of child-directed speech. The results show that distributional lattices are able to yield extremely accurate syntactic categories.

Obesity management in primary care: systematic review exploring the influence of therapeutic alliance.

PURPOSE: To identify the influence of the therapeutic alliance on the effectiveness of obesity interventions delivered in primary care. METHOD: Systematic review of randomized controlled trials of primary care interventions for adult patients living with obesity. Comprehensive search strategy using the terms 'obesity', 'primary care' and 'intervention' of seven databases from 1 January 1998 to March 2018. Primary outcome was difference in weight loss in interventions where a therapeutic alliance was present. RESULTS: From 10 636 studies, 11 (3955 patients) were eligible. Only one study had interventions that reported all aspects of therapeutic alliance, including bond, goals and tasks. Meta-analysis was not included due to high statistical heterogeneity and low numbers of trials; as per our protocol, we proceeded to narrative synthesis. Some interventions included the regular primary care practitioner in management; very few included collaborative goal setting and most used prescriptive protocols to direct care. CONCLUSIONS: We were surprised that so few trials reported the inclusion of elements of the therapeutic alliance when relational aspects of primary care are critical for effectiveness. Interventions could be developed to maximize therapeutic relationships and research reports should describe interventions comprehensively. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42018091338 in PROSPERO (International prospective register of systematic reviews).

Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.

BACKGROUND: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era. OBJECTIVES: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies. METHODS: Whole-genome methylation and transcriptional data from isolated CD4+ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources. RESULTS: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4+ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4+ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally. CONCLUSIONS: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.

Dressings for the central venous catheter to prevent infection in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis.

PURPOSE: To identify the most effective dressing for covering long-term central venous catheter exit site to prevent catheter-related infections and skin irritation in patients undergoing hematopoietic stem cell transplantation. METHODS: Systematic Review. The search was performed in the following electronic databases: CINAHL, Cochrane Library CENTRAL, EMBASE, LILACS, PubMed, Scopus, and Web of Science. Google Scholar was used for the gray literature search. RESULTS: Seven studies were included which tested different arrangements of dressings: sterilized gauze and adhesive tape with a transparent polyurethane film (n = 2), transparent polyurethane film with a different replacement interval frequency (n = 2), transparent polyurethane film with and without chlorhexidine released continuously by the dressing at the site of intravascular catheter insertion (n = 2), and dressings vs. no dressings (n = 1). The meta-analysis for catheter-related infection prevention showed no difference between type of dressing (RR 1.76, [95% CI 0.82; 3.75], I2 0%) and for the replacement frequency at different intervals (RR 1.04, [95% CI 0.67; 1.61], I2 0%). The meta-analysis for skin irritation evaluated the transparent polyurethane film replacement frequency and indicated that a longer dressing replacement interval (10 to 15 days) reduces the risk of developing this outcome (RR 0.71, 0.52; 0.96, 95% CI, I2 24%). CONCLUSIONS: Regarding the type of the dressing, there is no evidence indicating the best dressing. Although there is no evidence available for the ideal replacement frequency, the risk to develop skin irritation is reduced in longer dressing replacements intervals.

Views of Patients With Heart Failure on Their Value-Based Self-care Decisions: A Qualitative Study.

BACKGROUND: Self-care adherence remains low in patients with heart failure (HF); little is known about the influence of patients' values on self-care decisions and behaviors. OBJECTIVES: The aim of this study was to explore how participants living with HF perceive their values and how those values are reportedly expressed in self-care decision making. METHODS: The Interpretative Phenomenological Analysis approach was used. Semistructured interviews were conducted with 12 patients 60 years or older; with New York Heart Association class II and III HF; and able to speak, read, and understand English. Participants recruited via convenience sampling (January-December 2016) from 2 urban sites in Western Canada. RESULTS: Values were reported to pivotally influence HF self-care decisions and behaviors. Overarching themes addressed aspects of values and decision making: notably, directness and complexity. Two main types of values, functional and emotional values, were involved in both adherent and nonadherent decisions. Values were often in flux, with the pursuit of these values being frequently in conflict with physical ability and changing over time. CONCLUSION: Two types of values serve influence self-care decisions and adherence. As HF and its self-care prevent patients from pursuing their prioritized values, patients are often nonadherent. Thus, patients with HF should be supported to find alternative ways to enact their values.