The plasma proteome is linked with left ventricular and left atrial function parameters in patients with chronic heart failure.

BACKGROUND: Examining the systemic biological processes in the heterogeneous syndrome of heart failure with reduced ejection fraction (HFrEF), as reflected by circulating proteins, in relation to echocardiographic characteristics, may provide insights into HF pathophysiology. OBJECTIVE: We investigated the link of 4210 repeatedly measured circulating proteins with repeatedly measured echocardiographic parameters, as well as with elevated left atrial pressure (LAP), in HFrEF patients, to provide insights into underlying mechanisms. METHODS: In 173 HFrEF patients, we performed six-monthly echocardiography and trimonthly blood sampling during a median follow-up of 2.7(IQR:2.5-2.8) years. We investigated circulating proteins in relation to echocardiographic parameters of left ventricular (left ventricular ejection fraction[LVEF], global longitudinal strain[GLS]), and left atrial function (left atrial reservoir strain[LASr]) and elevated LAP(E/e' ratio >15), and used gene enrichment analyses to identify underlying pathophysiological processes. RESULTS: We found 723, 249, 792 and 427 repeatedly measured proteins, with significant associations with LVEF, GLS, LASr and E/e' ratio, respectively. Proteins associated with LASr reflected pathophysiological mechanisms mostly related to the extracellular matrix (ECM). Proteins associated with GLS reflected cardiovascular biological processes and diseases, whereas those associated with LVEF reflected processes involved in the sympathetic nervous system. Moreover, 49 proteins were associated with elevated LAP; after correction for LVEF, three proteins remained: Cystatin-D, Fibulin-5 and HSP40. CONCLUSION: Circulating proteins show varying associations with different echocardiographic parameters in HFrEF patients. These findings suggest that pathways involved in atrial and ventricular dysfunction, as reflected by the plasma proteome, are distinct.

Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Resolution of Virtual Depth Sectioning from Four-Dimensional Scanning Transmission Electron Microscopy.

One approach to three-dimensional structure determination using the wealth of scattering data in four-dimensional (4D) scanning transmission electron microscopy (STEM) is the parallax method proposed by Ophus et al. (2019. Advanced phase reconstruction methods enabled by 4D scanning transmission electron microscopy, Microsc Microanal25, 10-11), which determines the scattering matrix and uses it to synthesize a virtual depth-sectioning reconstruction of the sample structure. Drawing on an equivalence with a hypothetical confocal imaging mode, we derive contrast transfer and point spread functions for this parallax method applied to weakly scattering objects, showing them identical to earlier depth-sectioning STEM modes when only bright field signal is used, but that improved depth resolution is possible if dark field signal can be used. Through a simulation-based study of doped Si, we show that this depth resolution is preserved for thicker samples, explore the impact of shot noise on the parallax reconstructions, discuss challenges to making use of dark field signal, and identify cases where the interpretation of the parallax reconstruction breaks down.

Volume imaging by tracking sparse topological features in electron micrograph tilt series.

The sensitive coherent interference of electron waves arising from a specimen is useful for revealing subtle structural information in electron micrographs, which can be important for minimising dose and for rapid imaging. In general, dynamical diffraction is expected due to the useful strong interactions of electrons with matter, which can create phase contrast that violates the requisite Radon projection assumption for tomography. It is for these reasons that incoherent imaging modalities such as high angle annular dark field have been favoured to date in electron tomography of crystalline specimens, to access a monotonic relationship between specimen thickness and micrograph intensity. Here we use a geometric approach to track topological features that are robust to perturbation of the imaging conditions, to enable 3D reconstructions from electron microscope tilt series under imaging conditions that violate the Radon projection assumption, with an emphasis on phase contrast. Invoking a sparsity assumption, we demonstrate that topological features can be reliably tracked in 3D using a differential geometric form of stereoscopy, to circumvent departures from the projection approximation and reduce noise by effecting segmentation of interest points from the outset. We demonstrate this approach on a variety of different specimen and data types, from polyhedral nanoparticles, to steel dislocation networks, cryo-EM cellular structures and 3D diffuse diffraction of a relaxor ferroelectric.

Magnetic properties and signatures of ordering in triangular lattice antiferromagnet KCeO2.

The magnetic ground state and the crystalline electric field level scheme of the triangular lattice antiferromagnet KCeO2 are investigated. Below TN=300 mK, KCeO2 develops signatures of magnetic order in specific heat measurements and low energy inelastic neutron scattering data. Trivalent Ce3+ ions in the D3d local environment of this compound exhibit large splittings among the lowest three 4f1 Kramers doublets defining for the free ion the J=5/2 sextet and a ground state doublet with dipole character, consistent with recent theoretical predictions in M. S. Eldeeb et al. Phys. Rev. Materials 4, 124001 (2020). An unexplained, additional local mode appears, and potential origins of this anomalous mode are discussed.

Factors limiting quantitative phase retrieval in atomic-resolution differential phase contrast scanning transmission electron microscopy using a segmented detector.

Quantitative differential phase contrast imaging of materials in atomic-resolution scanning transmission electron microscopy using segmented detectors is limited by various factors, including coherent and incoherent aberrations, detector positioning and uniformity, and scan-distortion. By comparing experimental case studies of monolayer and few-layer graphene with image simulations, we explore which parameters require the most precise characterisation for reliable and quantitative interpretation of the reconstructed phases. Coherent and incoherent lens aberrations are found to have the most significant impact. For images over a large field of view, the impact of noise and non-periodic boundary conditions are appreciable, but in this case study have less of an impact than artefacts introduced by beam deflections coupling to beam scanning (imperfect tilt-shift purity).

Suppressing dynamical diffraction artefacts in differential phase contrast scanning transmission electron microscopy of long-range electromagnetic fields via precession.

It is well known that dynamical diffraction varies with changes in sample thickness and local crystal orientation (due to sample bending). In differential phase contrast scanning transmission electron microscopy (DPC-STEM), this can produce contrast comparable to that arising from the long-range electromagnetic fields probed by this technique. Through simulation we explore the scale of these dynamical diffraction artefacts and introduce a metric for the magnitude of their contribution to the contrast. We show that precession over an angular range of a few milliradian can suppress this contribution to the contrast by one-to-two orders of magnitude. Our exploration centres around a case study of GaAs near the [011] zone-axis orientation using a probe-forming aperture semiangle on the order of 0.1 mrad at 300 keV, but the trends found and methodology used are expected to apply more generally.

A population-based epidemiological study of neuromyelitis optica spectrum disorder in Hungary.

BACKGROUND AND PURPOSE: The goal of this study was to determine the prevalence and incidence of neuromyelitis optica spectrum disorder (NMOSD) in Hungary based on the 2015 International Panel of NMO Diagnosis (IPND) criteria. METHODS: A retrospective population-based cohort study was conducted of 6.4 million Hungarians (age ≥ 16 years) between 1 January 2006 and 31 December 2016. Possible NMOSD patients were selected via multistage re-evaluation from multiple sources. Crude and sex- and serostatus-specific prevalence (per 100 000 persons) and incidence rates (per 1 000 000 person-years) from 2006 to 2015 were estimated and age-adjusted rates were determined. RESULTS: Of 2262 study candidates, 154 NMOSD patients (age ≥ 16 years) with onset until 31 December 2016 were identified based on 2015 IPND criteria. The prevalence analysis on 1 January 2016 included 123 NMOSD living cases, resulting in a prevalence of 1.91 [95% confidence interval (CI) 1.52-2.28] per 100 000 persons. The 101 incident cases emerging from the observed 76 394 288 person-years provided an incidence rate of 1.32 (95% CI 1.08-1.61) per 1 000 000 person-years. Age-adjusted prevalence was 1.87 (95% CI 1.56-2.23) per 100 000 persons and incidence was 1.20 (95% CI 0.98-1.46) per 1 000 000 person-years. CONCLUSIONS: In this first report of a large population-based epidemiological study from an Eastern European Caucasian population using robust case validation, a greater prevalence and incidence of NMOSD was found compared to previous large studies in Caucasian populations.

[Possibilities and perspectives of hyperspectral imaging in visceral surgery]. / Möglichkeiten und Perspektiven der Hyperspektralbildgebung in der Viszeralchirurgie.

HyperSpectral Imaging (HSI) technology enables quantitative tissue analyses beyond the limitations of the human eye. Thus, it serves as a new diagnostic tool for optical properties of diverse tissues. In contrast to other intraoperative imaging methods, HSI is contactless, noninvasive, and the administration of a contrast medium is not necessary. The duration of measurements takes only a few seconds and the surgical procedure is only marginally disturbed. Preliminary HSI applications in visceral surgery are promising with the potential of optimized outcomes. Current concepts, possibilities and new perspectives regarding HSI technology together with its limitations are discussed in this article.

The effect of intensified nonverbal facilitation of swallowing on dysphagia after severe acquired brain injury: A randomised controlled pilot study.

BACKGROUND: There is little high-level evidence for the effect of the nonverbal facilitation of swallowing on swallowing ability in the subacute stage of rehabilitation following severe acquired brain injury (ABI). OBJECTIVE: To pilot test a randomised controlled trial to determine the effect of an intensification of the nonverbal facilitation of swallowing on dysphagia. METHODS: Ten patients with severe ABI and dysphagia were randomised into two groups at a highly specialised neurorehabilitation clinic.The intervention group received an intensification of the nonverbal facilitation of swallowing and the control group received basic care of the face and mouth in addition to treatment as usual for two sessions of 20 minutes per day for three weeks.Outcomes were Functional Oral Intake Scale (FOIS), Penetration Aspiration Scale (PAS), and electrophysiological swallowing specific parameters (EMBI). RESULTS: The intensified intervention was feasible. PAS and FOIS scores improved in both groups, with no differences between groups. The swallowing specific parameters reflected clinically observed changes in swallowing. CONCLUSIONS: PAS and FOIS are feasible instruments to measure dysphagia. It is possible and valid to measure swallowing frequency and kinematics using electromyography and bioimpedance. The definitive study should have widened inclusion criteria and optimise intervention timing to maintain patient arousal.

Braiding and Fusion of Non-Abelian Vortex Anyons.

We have studied topology and dynamics of quantum vortices in spin-2 Bose-Einstein condensates. By computationally modeling controllable braiding and fusion of these vortices, we have demonstrated that certain vortices in such spinor condensates behave as non-Abelian anyons. We identify these anyons as fluxon, chargeon, and dyon quasiparticles. The pertinent anyon models are defined by the quantum double of the underlying discrete non-Abelian symmetry group of the condensate ground state order parameter.

Myocardial injury and mortality in patients with excessive oxygen administration before cardiac arrest.

INTRODUCTION: Hyperoxia after cardiac arrest may be associated with higher mortality, and trials have found that excess oxygen administration in patients with myocardial infarction is associated with increased infarct size. The effect of hyperoxia before cardiac arrest is sparsely investigated. Our aim was to assess the association between excessive oxygen administration before cardiac arrest and the extent of subsequent myocardial injury. METHODS: We performed a retrospective study including patients who had in-hospital cardiac arrest during 2014 in the Capital Region of Denmark. We excluded patients without peripheral oxygen saturation measurements within 48 hours before cardiac arrest. Patients were divided in three groups of pre-arrest oxygen exposure, based on average peripheral oxygen saturation and supplemental oxygen. Primary outcome was peak troponin concentration within 30 days. Secondary outcomes included 30-day mortality. Data were analyzed using multiple logistic regression and Wilcoxon rank sum test. RESULTS: Of 163 patients with cardiac arrest, 28 had excessive oxygen administration (17%), 105 had normal oxygen administration (64%) and 30 had insufficient oxygen administration (18%) before cardiac arrest. Peak troponin was median 224 ng/L in the excessive oxygen administration group vs 365 ng/L in the normal oxygen administration group (P = .54); 20 of 28 (71%) in the excessive oxygen administration group died within 30 days compared to 54 of 105 (51%) in the normal oxygen administration group. (OR 1.87, 95% CI 0.56-6.19) CONCLUSIONS: Excessive oxygen administration within 48 hours before in-hospital cardiac arrest was not statistically associated with significantly higher peak troponin or mortality.

High contrast at low dose using a single, defocussed transmission electron micrograph.

For many soft-matter specimens, transmission electron microscopists face the double-bind of low contrast images, due to weakly-scattering specimens, alongside severe limits on the electron dose that can be used before the specimen is damaged by the electron beam. The combination of these effects causes the resultant micrographs to have very low signal-to-noise. It is well known that varying the defocus aberration can enhance image contrast in electron microscopy. For single-material objects where the variation of absorption and phase contrast are functions of one another, since both are governed by the variation in thickness profile, we show that the thickness profile can be reconstructed at very low dose. The algorithm, first established in X-ray imaging, requires some a priori information but only a single defocussed image of the region of interest, making it more dose efficient than either a conventional transport-of-intensity phase reconstruction (which would require two images and tends to amplify noise), or an absorption-contrast analysis of a single in-focus image recorded at the same electron dose (which does not benefit from the significant signal-to-noise enhancement of the present algorithm). These findings are presented through both simulations and experimental data.

Simple Wave-Optical Superpositions as Prime Number Sieves.

We encode the sequence of prime numbers into simple superpositions of identical waves, mimicking the archetypal prime number sieve of Eratosthenes. The primes are identified as zeros accompanied by phase singularities in a physically generated wave field for integer valued momenta. Similarly, primes are encoded in the diffraction pattern from a simple single aperture and in the harmonics of a single vibrating resonator. Further, diffraction physics connections to number theory reveal how to encode all Gaussian primes, twin primes, and how to construct wave fields with amplitudes equal to the divisor function at integer spatial frequencies. Remarkably, all of these basic diffraction phenomena reveal that the naturally irregular sequence of primes can arise from trivially ordered wave superpositions.

Vacancy induced formation of nanoporous silicon, carbon and silicon carbide.

Nanoporous semiconductors are used in a range of applications from sensing and gas separation, to photovoltaics, rechargeable batteries, energetic materials and micro electro mechanical systems. In most cases porosity occurs in conjunction with the competing process of amorphisation, creating a complicated material that responds differently to strain and density changes, depending on the composition. In this paper we use simple computational workflow involving Monte Carlo simulation, numerical characterisation and statistical analysis to explore the development of amorphous and nanoporous carbon, silicon and silicon carbide. We show that amorphous regions in Si and SiC form in advance of nanopores, and are essential in stabilising the nanopores once developed. Carbon prefers a porous structure at lower strains than amorphisation and exhibits a bimodal change in the structure which correlates with the change in C-C bond angles from tetrahedral sp3-like bonds to hexagonal sp2-like bonds as the strain increases. These results highlight how both of these processes can be analysed simultaneously using reliable interatomic forcefields or density functionals, provided sufficient samples are included to support the statistics.

Structural brain maturation differs between preterm and term piglets, whereas brain activity does not.

AIM: The aim of the study was to investigate whether amplitude-integrated electroencephalography (aEEG) and cerebral magnetic resonance imaging (MRI) in preterm piglets would provide measures of cerebral functional, microstructural and anatomical maturation, which might reflect the signs of functional brain immaturity, documented in preterm piglets. METHODS: During July-October 2013 at the NEOMUNE Centre, Copenhagen University, Denmark, 31 preterm (90% gestation) and 10 term piglets underwent aEEG on days 1, 2, 4 and 11, and MRI on day 25. Physical activity levels were recorded. RESULTS: Preterm showed delayed neonatal arousal and physical activity, relative to term piglets. Preterm piglets had lower growth rates and brain volume than term piglets, but aEEG patterns were similar. MRI mean diffusivity was also similar, but fractional anisotropy (FA) was lower in preterm piglets (p < 0.001). CONCLUSION: Functional brain maturation, as assessed by aEEG, was relatively advanced in preterm piglets. Conversely, the low FA in the preterm piglets suggests that the white matter microstructure remains less mature in preterm compared to term piglets at postnatal day 25. The results might be utilised to define whether and how preterm piglets may contribute to preclinical models for brain development in preterm infants.

Radiation exposure of adrenal vein sampling: a German Multicenter Study

Objective: Adrenal vein sampling (AVS) represents the current diagnostic standard for subtype differentiation in primary aldosteronism (PA). However, AVS has its drawbacks. It is invasive, expensive, requires an experienced interventional radiologist and comes with radiation exposure. However, exact radiation exposure of patients undergoing AVS has never been examined. Design and Methods: We retrospectively analyzed radiation exposure of 656 AVS performed between 1999 and 2017 at four university hospitals. The primary outcomes were dose area product (DAP) and fluoroscopy time (FT). Consecutively the effective dose (ED) was approximately calculated. Results: Median DAP was found to be 32.5 Gy*cm2 (0.3­3181) and FT 18 min (0.3­184). The calculated ED was 6.4 mSv (0.1­636). Remarkably, values between participating centers highly varied: Median DAP ranged from 16 to 147 Gy*cm2, FT from 16 to 27 min, and ED from 3.2 to 29 mSv. As main reason for this variation, differences regarding AVS protocols between centers could be identified, such as number of sampling locations, frames per second and the use of digital subtraction angiographies. Conclusions: This first systematic assessment of radiation exposure in AVS not only shows fairly high values for patients, but also states notable differences among the centers. Thus, we not only recommend taking into account the risk of radiation exposure, when referring patients to undergo AVS, but also to establish improved standard operating procedures to prevent unnecessary radiation exposure.

Higher chlorzoxazone clearance in obese children compared with nonobese peers.

AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-∞ value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ.

Incidence of neuromyelitis optica spectrum disorder in the Central Denmark Region.

OBJECTIVES: Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) may be misdiagnosed as multiple sclerosis. The aim of this study was to (i) to measure AQP4-IgG in patients who fulfilled the clinical and radiological criteria of NMOSD in the Central Denmark Region and (ii) to estimate the incidence of NMOSD in the region, according to both the 2006 Wingerchuk criteria and the 2015 International Panel for NMO Diagnosis criteria. MATERIALS AND METHODS: Medical records of all patients diagnosed with a demyelinating disorder in the region from 1 January 2012 to 31 December 2013 were reviewed. Patients were classified as having (i) "NMO" if the 2006 criteria were met, (ii) "NMOSD with AQP4-IgG" or (iii) "NMOSD without/unknown AQP-IgG" if the new 2015 NMOSD criteria were met. Patients with core symptoms were invited to provide a blood sample for AQP4-IgG analysis with an enzyme-linked immunosorbent assay and a cell-based indirect immunofluorescence assay. RESULTS: In 191 patients with core symptoms, one met the 2015 NMOSD with AQP4-IgG criteria. Two patients met the 2006 NMO and 2015 NMOSD without/unknown AQP4-IgG criteria. Among 108 patients providing a blood sample, all were seronegative. The estimated incidence of NMO (2006 criteria) and NMOSD (2015 criteria) was 0.08 and 0.12 per 100 000 person-years, respectively. CONCLUSION: NMO/NMOSD is a rare disease in the Central Denmark Region, with a considerably lower incidence rate than previously estimated in a neighbouring region.