Hyponatremia in Stable Patients with Advanced Heart Failure: Association to Hemodynamics and Outcome.

INTRODUCTION: Hyponatremia is associated with worse outcomes in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). However, it is unclear whether the worse prognosis is driven by hemodynamic derangement and how this potentially could be associated with hyponatremia. METHODS: The study included 502 patients with HFrEF evaluated for advanced HF therapies, who underwent a right heart catheterization (RHC). Hyponatremia was defined as p-Na ≤136 mmol/L. The risk of all-cause mortality and a composite endpoint including mortality, left ventricular assist device (LVAD) implantation, implantation of total artificial heart (TAH), or heart transplantation (HTx) was evaluated using Cox regression analyses and Kaplan-Meier models. RESULTS: Included patients were predominantly men 79% and had a median age of 54 years (IQR: 43-62). A third (165) of the patients had hyponatremia. In both univariate and multivariate regression analyses, p-Na was associated with increased central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery pressure (mPAP) but not with cardiac index. Hyponatremia was significantly associated with the combined endpoint (HR: 1.36 [95% CI, 1.07-1.74]; p = 0.01), but not all-cause mortality in adjusted Cox models. CONCLUSION: In stable HFrEF patients evaluated for advanced HF therapies, lower p-Na was associated with more deranged invasive hemodynamic measurements. Hyponatremia remained significantly associated with the combined endpoint but not all-cause mortality in adjusted Cox models. The study suggests that the increased mortality associated with hyponatremia in HFrEF patients could partly be driven by hemodynamic derangement.

Novel subgroups in acute respiratory failure based on the trajectories of three endotheliopathy biomarkers: A cohort study.

Baseline levels of endotheliopathy are associated with worse respiratory outcomes and mortality in undifferentiated acute respiratory failure (ARF), but knowledge is lacking on the development of endotheliopathy over time in ARF. We, therefore, aimed to evaluate the prognostic significance of trajectories of endotheliopathy during the first days of ARF. We performed a secondary, exploratory analysis of a single-center prospective cohort including 459 patients requiring mechanical ventilation. Based on Days 1-3 Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), we divided patients into subgroups using latent class mixed modeling and correlated subgroups with clinical outcomes using Cox regression. Based on Syndecan-1 and sTM, respectively, we identified two subgroups. Based on PECAM-1, we identified three subgroups. Subgroups based on Syndecan-1 and sTM were identifiable from the baseline levels, but subgroups based on PECAM-1 were not. Patients with persistently high levels of both sTM and PECAM-1 were liberated from mechanical ventilation more slowly (Group high vs. Group low, sTM: hazard ratio [HR]: 0.66, 95% confidence interval [CI]: 0.50-0.88, p = .01, PECAM-1: HR: 0.59, 95% CI: 0.37-0.93, p = .02) and had higher 30-day mortality (sTM: HR: 1.90, 95% CI: 1.20-3.01, p = .01, PECAM-1: HR: 4.25, 95% CI: 1.99-9.07, p < .01). In ARF requiring mechanical ventilation, patients in subgroups with persistently high levels of sTM and PECAM-1 had lower rates of liberation from mechanical ventilation and higher 30-day mortality. However, patients with persistently high levels of sTM were identifiable based on the baseline level, and only the trajectory of PECAM-1 added information to that of the baseline level.

Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in families? A population-based study of 2 million Swedes.

Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979-2001, and identified their diagnoses during 1997-2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6-20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0-42.2; full siblings, aOR = 2.8, 95% CI = 2.6-3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2-1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3-1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

Topological Dynamics of Micelles Formed by Geometrically Varied Surfactants.

The molecular architecture of sugar-based surfactants strongly affects their self-assembled structure, i.e., the type of micelles they form, which in turn controls both the dynamics and rheological properties of the system. Here, we report the segmental and mesoscopic structure and dynamics of a series of C16 maltosides with differences in the anomeric configuration and degree of tail unsaturation. Neutron spin-echo measurements showed that the segmental dynamics can be modeled as a one-dimensional array of segments where the dynamics increase with inefficient monomer packing. The network dynamics as characterized by dynamic light scattering show different relaxation modes that can be associated with the micelle structure. Hindered dynamics are observed for arrested networks of worm-like micelles, connected to their shear-thinning rheology, while nonentangled diffusing rods relate to Newtonian rheological behavior. While the design of novel surfactants with controlled properties poses a challenge for synthetic chemistry, we demonstrate how simple variations in the monomer structure can significantly influence the behavior of surfactants.

Endotheliopathy is associated with slower liberation from mechanical ventilation: a cohort study.

BACKGROUND: Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ failure, but its role in acute respiratory failure is not yet determined. We investigated if endotheliopathy biomarkers at ICU admission are associated with illness severity and clinical outcomes in patients with acute respiratory failure requiring mechanical ventilation. METHODS: We conducted a prospective single-center cohort study including 459 mechanically ventilated adults at ICU admission. Plasma levels of three endotheliopathy biomarkers were measured at ICU admission: Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). The primary outcome was the rate of liberation from mechanical ventilation, which is presented together with the rate of the competing risk of death while still on mechanical ventilation. Secondary outcomes were PaO2/FiO2-ratios on admission and on last measurement in patients dying within five days, and 30-day all-cause mortality. The primary outcome and 30-day all-cause mortality were analyzed using Cox regression, controlled for gender, age, chronic obstructive pulmonary disease, septic shock, heart failure, PaO2/FiO2-ratio at admission, respiratory infection, acute kidney injury, and bilirubin. PaO2/FiO2-ratios were analyzed using linear regression, controlled for age, chronic obstructive pulmonary disease, respiratory infection, and shock. RESULTS: Patients with high sTM were liberated from mechanical ventilation at a lower rate (adjusted hazard ratio (HR) 0.71, for an increase from the 25th to the 75th percentile, 95% confidence interval (CI) 0.54-0.93, p = 0.01). Patients with high PECAM-1 were liberated from mechanical ventilation at a lower rate, but only during the first 5 days (adjusted HR 0.72, for an increase from the 25th to the 75th percentile, 95% CI 0.58-0.9, p < 0.01). High levels of Syndecan-1 and PECAM-1 were associated with a higher rate of death while still on mechanical ventilation. sTM and PECAM-1 were negatively associated with PaO2/FiO2-ratio at ICU admission and no biomarker was associated with last measured PaO2/FiO2-ratio. High levels of all biomarkers were associated with higher 30-day all-cause mortality. CONCLUSION: In acute respiratory failure, endotheliopathy biomarkers are associated with lower rates of liberation from mechanical ventilation, hypoxemia at ICU admission, and 30-day all-cause mortality.

Effect of the Anomeric Configuration on the Micellization of Hexadecylmaltoside Surfactants.

The self-assembly of the two anomeric forms of n-hexadecyl-d-maltopyranoside (denoted α-C16G2 and ß-C16G2) has been studied in dilute aqueous solution by means of surface tension measurements, scattering methods (dynamic light scattering, static light scattering, and small-angle X-ray and neutron scattering), and cryo-transmission electron microscopy at different surfactant concentrations and temperatures. Surface tension measurements demonstrate differences in the surfactant adsorption at the air-water interface, where α-C16G2 shows a lower CMC than ß-C16G2. Similarly, micelle morphology was found to profoundly depend on anomerism. ß-C16G2 preferentially forms very elongated micelles with large persistence lengths, whereas α-C16G2 assembles into smaller micelles for which the structure varies with concentration and temperature. The differences between the two surfactant anomers in terms of self-assembly can be attributed to the interaction between neighboring headgroups. Specifically, ß-C16G2 allows for a closer packing in the palisade layer, hence reducing the micelle curvature and promoting the formation of more elongated micelles. Strong intermolecular headgroup interactions may also account for the observed rigidity of the micelles.

Liquid crystal phantom for validation of microscopic diffusion anisotropy measurements on clinical MRI systems.

PURPOSE: To develop a phantom for validating MRI pulse sequences and data processing methods to quantify microscopic diffusion anisotropy in the human brain. METHODS: Using a liquid crystal consisting of water, detergent, and hydrocarbon, we designed a 0.5-L spherical phantom showing the theoretically highest possible degree of microscopic anisotropy. Data were acquired on the Connectome scanner using echo-planar imaging signal readout and diffusion encoding with axisymmetric b-tensors of varying magnitude, anisotropy, and orientation. The mean diffusivity, fractional anisotropy (FA), and microscopic FA (µFA) parameters were estimated. RESULTS: The phantom was observed to have values of mean diffusivity similar to brain tissue, and relaxation times compatible with echo-planar imaging echo times on the order of 100 ms. The estimated values of µFA were at the theoretical maximum of 1.0, whereas the values of FA spanned the interval from 0.0 to 0.8 as a result of varying orientational order of the anisotropic domains within each voxel. CONCLUSIONS: The proposed phantom can be manufactured by mixing three widely available chemicals in volumes comparable to a human head. The acquired data are in excellent agreement with theoretical predictions, showing that the phantom is ideal for validating methods for measuring microscopic diffusion anisotropy on clinical MRI systems. Magn Reson Med 79:1817-1828, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel.

Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the ß-subunit KCNE1 form the cardiac IKs channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as IKs channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pKa value, to preserve their negative charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogs with a positively charged head group inhibit IKs channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.

Socio-economic position, multimorbidity, and health care utilization among Danish left ventricular assist device patients.

AIMS: Increasing numbers of patients with advanced heart failure and significant comorbidity and social barriers are considered for left ventricular assist devices (LVADs). We sought to examine health care utilization post-LVAD implantation, including the influence of individual-level socio-economic position and multimorbidity. METHODS AND RESULTS: We conducted a Danish nationwide cohort study linking individual-level data from clinical LVAD databases, the Scandiatransplant Database, and Danish national medical and administrative registries. Socio-economic position included cohabitation status, educational level, and employment status. Multimorbidity was defined as two or more chronic conditions from at least two chronic disease groups. Health care utilization (hospital activity, general practice activity, and redeemed medical prescriptions) within 2 years post-discharge after LVAD implantation was evaluated using descriptive statistics at 0.5 year intervals. We identified 119 patients discharged alive with first-time LVAD implanted between 2006 and 2018. The median age of the patients was 56.1 years, and 88.2% were male. Patients were followed until heart transplantation, LVAD explantation, death, 31 December 2018, or for 2 years. The median follow-up was 0.8 years. The highest median use of health care services was observed 0-0.5 years post-LVAD discharge compared with the subsequent follow-up intervals: 0.5-1, 1-1.5, and 1.5-2 years, respectively. The median (interquartile range) number of hospitalizations was 10 (7-14), bed days 14 (9-28), outpatient visits 8 (5-12), telephone contacts with a general practitioner 4 (2-8), and total redeemed medical prescriptions 26 (19-37) within 0-0.5 years post-LVAD discharge compared with the median utilization within the consecutive follow-up periods [e.g. within 0.5-1 year: hospitalizations 5 (3-8), bed days 8 (4-14), outpatient visits 5 (3-8), telephone contacts 2 (0-5), and redeemed medical prescriptions 24 (18-30)]. The median use of health care services was stable from 0.5 years onwards. The median number of hospitalizations and bed days was slightly higher in patients living alone with a low educational level or low employment status within 0-0.5 years post-LVAD implantation. Finally, the median number of in-hospital days and redeemed prescriptions was higher among patients with pre-existing multimorbidity. CONCLUSIONS: Among patients who underwent LVAD implantation, health care utilization was high in the early post-LVAD discharge phase and was influenced by socio-economic position. Multimorbidity influenced the number of in-hospital days and redeemed prescriptions during the 2 year follow-up.

Influence of socioeconomic status on rates of advanced heart failure therapies.

BACKGROUND: Socioeconomic deprivation is associated with a lower likelihood of referral for advanced heart failure (HF) evaluation, but it is not known whether it influences rates of advanced HF therapies independently of key hemodynamic measures and comorbidity following advanced HF evaluation in a universal healthcare system. METHODS: We linked data from a single-center Danish clinical registry of consecutive patients evaluated for advanced HF with patient-level information on socioeconomic status. Patients were divided into groups based on the level of education (low, medium, and high), combined degree of socioeconomic deprivation (low, medium, and high), and household income quartiles. Rates of the combined outcome of left ventricular assist device implantation or heart transplantation (advanced HF therapy) with death as a competing risk were estimated with cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, central venous pressure, cardiac index, and comorbidities. RESULTS: We included 629 patients, median age 53 years, of whom 77% were men. During a median follow-up of 5 years, 179 (28%) underwent advanced HF therapy. The highest level of education was associated with higher rates (high vs low, adjusted HR 1.81 95% CI 1.14-2.89, p = 0.01), whereas household income quartile groups (Q4 vs Q1, adjusted HR 1.37 95% CI 0.76-2.47, p = 0.30) or groups of combined socioeconomic deprivation (high vs low degree of deprivation, adjusted HR 0.86 95% CI 0.50-1.46, p = 0.56) were not significantly associated with rates of advanced HF therapy. CONCLUSIONS: Patients with a lower level of education might be disfavored for advanced HF therapies and could require specific attention in the advanced HF care center.

Quantification of lipid mediator metabolites in human urine from asthma patients by electrospray ionization mass spectrometry: controlling matrix effects.

Eicosanoids (e.g., prostaglandins and leukotrienes) are inflammatory signaling molecules that are metabolized and excreted in urine. The quantification of eicosanoid metabolites in human urine has been demonstrated to provide insight into the inflammatory and oxidative stress status of the individual. However, urine is a complex matrix that can exhibit profound matrix effects for quantification via liquid chromatography coupled to mass spectrometry (LC-MS/MS). This phenomenon can lead to impairment and biasing of results, because the sample background is dependent on the fluid intake and water-salt balance. Herein we describe an analytical methodology to address these limitations via the normalization of extracted urine volume by the ratio of absorbance at 300 nm to an optimized reference material. The platform is composed of 4 LC-MS/MS methods that collectively quantify 26 lipid mediators and their metabolites, with on-column limits of detection between 0.55 and 15 fmol. Prior to optimization, internal standards exhibited strong matrix effects with up to 50% loss of signal. Notably, the accuracy of exact deuterated structural analogues was found to vary based upon the number of incorporated deteurium. The platform was used to analyze urine from 16 atopic asthmatics under allergen provocation, showing increases in metabolites of prostaglandin D2, cysteinyl leukotrienes, and isoprostanes following the challenge. This method presents a functional and reproducible approach to addressing urine-specific matrix effects that can be readily formatted for quantifying large numbers of samples.

Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome.

OBJECTIVE: The novel P2Y12 antagonist ticagrelor inhibits adenosine diphosphate (ADP)-induced platelet aggregation more potently than clopidogrel and reduces the incidence of myocardial infarction and total death in patients with an acute coronary syndrome (ACS). Furthermore, ticagrelor inhibits adenosine reuptake and increases coronary flow reserve during adenosine infusion in man. We wanted to determine whether ticagrelor improves peripheral arterial function in patients with a previous ACS compared to patients treated with aspirin, clopidogrel, or prasugrel. METHODS: 127 patients with a previous ACS (>3 months to <3 years ago) on maintenance dose of (1) no ADP blocker (n = 35); (2) clopidogrel 75 mg (n = 35); (3) prasugrel 10 mg (n = 32), or (4) ticagrelor 90 mg twice daily (n = 25) were evaluated with peripheral arterial tonometry after forearm ischemia. RESULTS: Ticagrelor improves peripheral arterial function compared to the other groups [(1) controls 1.78 ± 0.53; (2) clopidogrel 1.78 ± 0.45; (3) prasugrel 1.64 ± 0.33, and (4) ticagrelor 2.25 ± 0.54 (means ± SD)] with a significance of p < 0.01 for ticagrelor versus no ADP blocker, p < 0.01 for ticagrelor versus clopidogrel, and p < 0.001 for ticagrelor versus prasugrel. There were fewer patients with endothelial dysfunction (<1.67 reactive hyperemia index) in the ticagrelor group (12%) compared to aspirin (51%), clopidogrel (46%), and prasugrel (53%) (p < 0.01). CONCLUSION: Treatment with ticagrelor improves peripheral endothelial function compared to no ADP blocker, clopidogrel, or prasugrel treatment.

Importance of heart failure duration for development of pulmonary hypertension in advanced heart failure.

BACKGROUND AND OBJECTIVES: Pulmonary vascular resistance (PVR) is critical when evaluating candidacy for advanced heart failure (HF) therapies, but risk factors for elevated PVR are not well studied. We hypothesized that HF duration would be associated with elevated PVR. METHODS: Danish single-center registry of consecutive in- and outpatients undergoing right heart catheterization as part of advanced HF work up. The relation between HF duration and PVR was estimated by regression analysis. Finally, the relation between PVR and long-term mortality was assessed by Cox proportional hazards regression and Kaplan-Meier analyses. RESULTS: A total of 549 patients (77% men, median age 54 (43-61) years, median HF duration 1.6 years (0.1-7.1)) were included. Univariate linear regression displayed an association between longer HF duration and increasing PVR (p = 0.014). PVR > 3 WU was present in 92 patients (17%) who were older (median p < 0.001) and had longer HF duration (p = 0.03). HF duration (per 1 year increase) did not predict PVR > 3 WU after adjustment for covariables (OR 1.00; p = 0.99). During a mean follow-up time of 4.5 years, there were 240 (44%) deaths. Increasing PVR was associated with elevated all-cause mortality risk (adjusted HR 1.24; p < 0.001). PVR > 3 WU was associated with higher mortality (adjusted HR 1.49; p = 0.027). CONCLUSION: Longer duration of HF was associated with higher PVR in patients with advanced HF, but this association disappeared in multivariate analyses. Longer HF duration per se likely does not cause elevated PVR and should not discourage evaluation for heart transplantation.

Long-Term Medical Treatment and Adherence in Patients With Left Ventricular Assist Devices: A Danish Nationwide Cohort Study.

The use of a left ventricular assist device (LVAD) in treating advanced heart failure has increased. However, data regarding medical treatment and adherence following LVAD implantation is sparse, particularly whether socioeconomic factors (cohabitation status, educational level, employment status, and income) and multimorbidity influence these aspects, which are known to impact adherence in heart failure patients. We performed a nationwide cohort study of 119 patients with LVAD implanted between January 1, 2006, and December 31, 2018, who were discharged alive with LVAD therapy. We linked individual-level data from clinical LVAD databases, the Scandiatransplant Database, and Danish medical and administrative registers. Medical treatment 90-day pre-LVAD and 720-day post-LVAD were assessed using descriptive statistics in 90-day intervals. Medication adherence (proportion of days covered ≥80%) was assessed 181- to 720-day post-LVAD. The proportions of patients using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (88.7%), beta-blockers (67.0%), mineralocorticoid receptor antagonists (62.9%), warfarin (87.6%), and aspirin (55.7%) within 90-day post-LVAD were higher than pre-LVAD and were stable during follow-up. Medication adherence ranged from 86.7% (aspirin) to 97.8% (warfarin). Socioeconomic factors and multimorbidity did not influence medical medication use and adherence. Among LVAD patients, medical treatment and adherence are at high levels, regardless of socioeconomic background and multimorbidity.

Structural Characterization of Nanoparticle-Supported Lipid Bilayer Arrays by Grazing Incidence X-ray and Neutron Scattering.

Arrays of nanoparticle-supported lipid bilayers (nanoSLB) are lipid-coated nanopatterned interfaces that provide a platform to study curved model biological membranes using surface-sensitive techniques. We combined scattering techniques with direct imaging, to gain access to sub-nanometer scale structural information on stable nanoparticle monolayers assembled on silicon crystals in a noncovalent manner using a Langmuir-Schaefer deposition. The structure of supported lipid bilayers formed on the nanoparticle arrays via vesicle fusion was investigated using a combination of grazing incidence X-ray and neutron scattering techniques complemented by fluorescence microscopy imaging. Ordered nanoparticle assemblies were shown to be suitable and stable substrates for the formation of curved and fluid lipid bilayers that retained lateral mobility, as shown by fluorescence recovery after photobleaching and quartz crystal microbalance measurements. Neutron reflectometry revealed the formation of high-coverage lipid bilayers around the spherical particles together with a flat lipid bilayer on the substrate below the nanoparticles. The presence of coexisting flat and curved supported lipid bilayers on the same substrate, combined with the sub-nanometer accuracy and isotopic sensitivity of grazing incidence neutron scattering, provides a promising novel approach to investigate curvature-dependent membrane phenomena on supported lipid bilayers.

Initiation of eplerenone or spironolactone, treatment adherence, and associated outcomes in patients with new-onset heart failure with reduced ejection fraction: a nationwide cohort study.

BACKGROUND: The mineralocorticoid receptor antagonists (MRAs) eplerenone and spironolactone are beneficial in heart failure with reduced ejection fraction (HFrEF), but have not been prospectively compared. We compared clinical outcomes, daily dosages, and discontinuation rates for the two drugs in a nationwide cohort. METHODS: We identified all patients with HFrEF in the period 2016-2020, who were alive and had initiated MRA treatment at study start, 180 days after HF diagnosis. We estimated the 2-year risk of a composite of death and HF hospitalization, as well as each component separately, using Kaplan-Meier, cumulative incidence functions, and Cox proportional hazards models adjusted for age, sex, and comorbidities. Secondly, we assessed treatment withdrawal, cross-over, and daily drug dosage. RESULTS: We included 7479 patients; 653 (9%) on eplerenone and 6840 (91%) on spironolactone. Patients in the eplerenone group were younger (median age 65 vs. 69 years), and more often men (91% vs. 68%), both P < 0.001. In adjusted analyses, with spironolactone as reference, there were no differences in the risk of the composite of all-cause death and HF hospitalization (HR 1.02, 95% CI 0.82-1.27), all-cause death (HR 0.93, 95% CI 0.67-1.30), or HF hospitalization (HR 1.10, 95% CI 0.84-1.42). Treatment withdrawal occurred in 34% in the eplerenone group and 53% in the spironolactone group (P < 0.001), treatment cross-over in 3%, and 10%, respectively. Daily dose >25 mg at 12 months, was observed in 230 patients (37%) in the eplerenone group and 771 patients (12%) in the spironolactone (P < 0.001). CONCLUSIONS: In a contemporary nationwide cohort of patients with new-onset HFrEF who initiated MRA, we found no differences in clinical outcomes associated with initiation of eplerenone vs. spironolactone. Treatment was more frequently withdrawn, and daily drug dosage was lower among patients treated with spironolactone.

HSP10 as a Chaperone for Neurodegenerative Amyloid Fibrils.

Neurodegenerative diseases (NDs) are associated with accumulated misfolded proteins (MPs). MPs oligomerize and form multiple forms of amyloid fibril polymorphs that dictate fibril propagation and cellular dysfunction. Protein misfolding processes that impair protein homeostasis are implicated in onset and progression of NDs. A wide variety of molecular chaperones safeguard the cell from MP accumulation. A rather overlooked molecular chaperone is HSP10, known as a co-chaperone for HSP60. Due to the ubiquitous presence in human tissues and protein overabundance compared with HSP60, we studied how HSP10 alone influences fibril formation in vitro of Alzheimer's disease-associated Aß1-42. At sub-stoichiometric concentrations, eukaryotic HSP10s (human and Drosophila) significantly influenced the fibril formation process and the fibril structure of Aß1-42, more so than the prokaryotic HSP10 GroES. Similar effects were observed for prion disease-associated prion protein HuPrP90-231. Paradoxically, for a chaperone, low concentrations of HSP10 appeared to promote fibril nucleation by shortened lag-phases, which were chaperone and substrate dependent. Higher concentrations of chaperone while still sub-stoichiometric extended the nucleation and/or the elongation phase. We hypothesized that HSP10 by means of its seven mobile loops provides the chaperone with high avidity binding to amyloid fibril ends. The preserved sequence of the edge of the mobile loop GGIM(V)L (29-33 human numbering) normally dock to the HSP60 apical domain. Interestingly, this segment shows sequence similarity to amyloidogenic core segments of Aß1-42, GGVVI (37-41), and HuPrP90-231 GGYML (126-130) likely allowing efficient competitive binding to fibrillar conformations of these MPs. Our results propose that HSP10 can function as an important molecular chaperone in human proteostasis in NDs.

Changing the Office Design to Activity-Based Flexible Offices: A Longitudinal Study of How Managers' Leadership Behaviours Are Perceived.

This longitudinal study examines the impact of office type on employees' perception of managers' leadership behaviours, which is an unexplored area. The expanding research related to activity-based flexible offices (AFOs) has mainly focused on employees' working conditions and health outcomes, not on the changes in leadership behaviours when moving from traditional offices to AFOs. Office workers (n = 261) from five office sites within a large Swedish government agency were included in a controlled study of a natural intervention. At four sites, traditional offices were replaced by AFOs, while workers at one site with no relocation acted as the control. The same employees rated different leadership behaviours in a web-based questionnaire at baseline and at one follow-up. The analyses showed that relocations from cell and open-plan offices to AFOs were clearly related to a decrease in the perception of relation-oriented leadership behaviours. However, coming from open-plan offices to AFOs also decreased the perception of the other leadership dimensions. As expected, the control group was stable over time in their perceptions. This emphasises the need for organisations to provide managers with prerequisites so they can keep up with behaviours that support employees' performance and health when office designs and ways of working are changed.

Exercise therapy for whiplash-associated disorders: a systematic review and meta-analysis.

OBJECTIVES: Acute as well as chronic pain syndromes are common after whiplash trauma and exercise therapy is proposed as one possible intervention strategy. The aim of the present systematic review was to evaluate the effect of exercise therapy in patients with Whiplash-Associated Disorders for the improvement of neck pain and neck disability, compared with other therapeutic interventions, placebo interventions, no treatment, or waiting list. CONTENT: The review was registered in Prospero (CRD42017060356) and conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A literature search in PubMed, Scopus and Cochrane from inception until January 13, 2020 was combined with a hand search to identify eligible randomized controlled studies. Abstract screening, full text assessment and risk of bias assessment (Cochrane RoB 2.0) were conducted by two independent reviewers. SUMMARY: The search identified 4,103 articles. After removal of duplicates, screening of 2,921 abstracts and full text assessment of 100 articles, 27 articles that reported data for 2,127 patients were included. The included articles evaluated the effect of exercise therapy on neck pain, neck disability or other outcome measures and indicated some positive effects from exercise, but many studies lacked control groups not receiving active treatment. Studies on exercise that could be included in the random-effect meta-analysis showed significant short-term effects on neck pain and medium-term effects on neck disability. OUTLOOK: Despite a large number of articles published in the area of exercise therapy and Whiplash-Associated Disorders, the current evidence base is weak. The results from the present review with meta-analysis suggests that exercise therapy may provide additional effect for improvement of neck pain and disability in patients with Whiplash-Associated Disorders.

Shear-induced nanostructural changes in micelles formed by sugar-based surfactants with varied anomeric configuration.

HYPOTHESIS: The self-assembly of long tail sugar-based surfactants into worm-like micelles has recently been demonstrated, and the rheological properties of such systems have been shown to be tuneable through subtle modifications of the molecular characteristics of the surfactant monomer. In particular, the anomeric configuration of the hexadecylmaltoside headgroup was shown to induce profound changes in the nanostructure and rheology of the system. The origin of such changes is hypothesised to arise from differences in the structure and relaxation of the micellar networks in the semi-dilute regime. EXPERIMENTS: Here we explore the molecular background to the flow properties of the two anomers of hexadecylmaltoside (α- and ß-C16G2) by directly connecting their rheological behaviour to the micelle morphology. For this purpose, 1-3 plane rheo-small-angle neutron scattering measurements, using a Couette cell geometry, probed the structural changes in the micellar phase under shear. The effect of surfactant anomeric configuration, surfactant concentration, temperature and mixing ratio of the two anomers were investigated. The static micelle structure in the semi-dilute regime was determined using the polymer reference interaction site model. FINDINGS: The segmental alignment of the micellar phase was studied under several flow conditions, showing that the shear-thinning behaviour relates to the re-arrangement of ß-C16G2 worm-like micelles, whilst shorter α-C16G2 micelles are considerably less affected by the flow. The results are rationalised in terms of micelle alignment and disruption of the entangled network, providing a detailed mechanism by which sugar-based surfactants control the rheology of the fluid. To further enable future studies, we provide the complete code for modelling micelle structure in the semi-dilute regime using the polymer reference interaction site model.