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Introduction: Growth differentiation factor 15 (GDF-15) is considered as a biomarker of inflammatory and myocardial tissue injury. However, metformin increases plasma GDF-15, and may be responsible for the metabolic benefits (e.g. weight loss, decrease in Hemoglobin A1c and systolic blood pressure, and improvement in insulin resistance) effects in type 2 diabetes (T2D). Recently, sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated increment in GDF-15 in a proteomic analysis in T2D patients. Hypothesis: To examine SGLT2i’s effect on GDF-15 in HFrEF patients. Methods: This multicenter, randomized, double-blind, placebo-controlled exploratory sub-study enrolled 190 stable HFrEF patients with an ejection fraction of 40% or below. Patients were randomized (1:1) to empagliflozin 10 mg once daily or matching placebo for 12 weeks. Outcome measures were changes from baseline in GDF-15, high sensitive C-reactive protein (hsCRP), and high sensitive troponin T (hsTNT) adjusted for age, sex, BMI, T2D. Results: Mean age was 64 (SD, 11) years; 85% male, 13% with T2D, mean ejection fraction 29 (SD, 8)). Empagliflozin significantly increased GDF-15 compared to placebo [Empagliflozin: baseline, median (interquartile range (IQR)) 1177 (899-1720) pg/mL, follow-up, 1394 (970-1942) pg/mL: Placebo: baseline 1299 (915-1849) pg/mL, follow-up, 1276 (879-1924) pg/mL, adjusted ratio of change (1.10 [95% confidence interval (CI), 1.04-1.17]: p=0.002). There was no significant change in hsCRP (1.13 [95%CI, 0.89-1.43]: p=0.31), nor in hsTNT (1.09 [95%CI, 0.98-1.20]: p=0.12) (Figure 1). Conclusions: Empagliflozin significantly increased GDF-15 in predominantly non-diabetic HFrEF patients regardless of HF etiology, without a concomitant increase in hsCRP, or hsTNT compared to placebo. These results might explain the link between empagliflozin and the metabolic benefits seen in this population.

Recent work on the representation of functions on sets has considered the use of summation in a latent space to enforce permutation invariance. In particular, it has been conjectured that the dimension of this latent space may remain fixed as the cardinality of the sets under consideration increases. However, we demonstrate that the analysis leading to this conjecture requires mappings which are highly discontinuous and argue that this is only of limited practical use. Motivated by this observation, we prove that an implementation of this model via continuous mappings (as provided by e.g. neural networks or Gaussian processes) actually imposes a constraint on the dimensionality of the latent space. Practical universal function representation for set inputs can only be achieved with a latent dimension at least the size of the maximum number of input elements., Comment: Published at the International Conference on Machine Learning (2019)

Model interpretability and systematic, targeted model adaptation present central tenets in machine learning for addressing limited or biased datasets. In this paper, we introduce neural stethoscopes as a framework for quantifying the degree of importance of specific factors of influence in deep networks as well as for actively promoting and suppressing information as appropriate. In doing so we unify concepts from multitask learning as well as training with auxiliary and adversarial losses. We showcase the efficacy of neural stethoscopes in an intuitive physicsdomain. Specifically, we investigate the challenge of visually predicting stability of block towers and demonstrate that the network uses visual cues which makes it susceptible to biases in the dataset. Through the use of stethoscopes we interrogate the accessibility of specific information throughout the network stack and show that we are able to actively de-bias network predictions as well as enhance performance via suitable auxiliary and adversarial stethoscope losses.

Aim: To develop age-, sex-, and ethnic-Appropriate normative reference ranges for standard echocardiographic measurements of the left heart by combining echocardiographic measurements obtained from adult volunteers without clinical cardiovascular disease or significant cardiovascular risk factors, from multiple studies around the world.Methods and results: The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL) collaboration was established and population-based data sets of echocardiographic measurements combined to perform an individual person data meta-Analysis. Data from 43 studies were received, representing 51 222 subjects, of which 22 404 adults aged 18-80 years were without clinical cardiovascular or renal disease, hypertension or diabetes. Quantile regression or an appropriate parametric regression method will be used to derive reference values at the 5th and 95th centile of each measurement against age. Conclusion: This unique data set represents a large, multi-ethnic cohort of subjects resident in a wide range of countries. The resultant reference ranges will have wide applicability for normative data based on age, sex, and ethnicity. © The Author 2013.

Tylose gel containing 400 micrograms prostaglandin E2 in 3 ml gel was injected into the cervical canal of 20 patients with high-risk pregnancy and indication for induction of labor, but with unfavorable cervix. Ten were studied after the first gel application, five during repeat injection, and five after application of gel without PGE2. Blood samples were drawn serially during the first 8 hours for determination of oxytocin and 13,14-dihydro,15-ketoprostaglandin-F2 alpha (PGFM). The PGE2 gel increased the Bishop score within 8 hours in all patients; in half of them, artificial rupture of the membranes could be performed and labor induced without further gel application; in the others, it was repeated every 8 hours until a Bishop score of greater than or equal to 8 was achieved. Fourteen of the 15 PGE2-induced patients delivered vaginally. Mean PGFM levels did not increase significantly during the 8 hours of observation, but in patients who responded with rapid progression, an increase was seen after cervical dilation was 6 cm or more. The mean oxytocin levels increased within 60 minutes after PGE2 application and were increased for the remaining observation period. Application of inactive gel had no effect on cervical ripening nor on oxytocin or PGFM levels.

We show that uniaxial color centers in silicon carbide with hexagonal lattice structure can be used to measure not only the strength but also the polar angle of the external magnetic field with respect to the defect axis with high precision. The method is based on the optical detection of multiple spin resonances in the silicon vacancy defect with quadruplet ground state. We achieve a perfect agreement between the experimental and calculated spin resonance spectra without any fitting parameters, providing angle resolution of a few degrees in the magnetic field range up to several millitesla. Our approach is suitable for ensembles as well as for single spin-3/2 color centers, allowing for vector magnetometry on the nanoscale at ambient conditions.

Site selection is a crucial part of the work flow for installing seismic stations. Here, we report the preparations for a countrywide temporary seismic network in Austria. We describe the specific requirements for a multi-purpose seismic array with 40 km station spacing that will be operative approximately three years. Reftek 151 60 s sensors and Reftek 130/130S digitizers form the core instrumentation of our seismic stations which are mostly installed inside abandoned or occasionally used basements or cellars. We present probabilistic power spectral density analysis to assess noise conditions at selected sites and show exemplary seismic events that were recorded by the preliminary network by the end of July 2015.

Graphene on a dielectric substrate exhibits spatial doping inhomogeneities, forming electron-hole puddles. Understanding and controlling the latter is of crucial importance for unraveling many of graphene's fundamental properties at the Dirac point. Here we show the coexistence and correlation of charge puddles and topographic ripples in graphene decoupled from the metallic substrate it was grown on. The analysis of interferences of Dirac fermion-like electrons yields a linear dispersion relation, indicating that graphene on a metal can recover its intrinsic electronic properties., Comment: 4 figures

Pseudobinary heterostructural alloys of ZnO with MgO or CdO are studied by composing the system locally of clusters with varying ratio of cations. We investigate fourfold (wurtzite structure) and sixfold (rocksalt structure) coordination of the atoms. By means of density functional theory we study a total number of 256 16-atom clusters divided into 22 classes for the wurtzite structure and 16 classes for the rocksalt structure for each of the alloy systems. The fraction with which each cluster contributes to the alloy is determined for a given temperature T and composition x within (i) the generalized quasi-chemical approximation, (ii) the model of a strict-regular solution, and (iii) the model of microscopic decomposition. From the cluster fractions we derive conclusions about the miscibility and the critical compositions at which the average crystal structure changes. Thermodynamic properties such as the mixing free energy and the mixing entropy are investigated for the three different statistics. We discuss the consequences of the two different local lattice structures for characteristic atomic distances, cohesive energies, and the alloys' elasticities. The differences in the properties of Mg_x Zn_{1-x} O and Cd_x Zn_{1-x} O are explained and discussed., Comment: 15 pages, 13 figures

Excitonic effects in optical spectra and electron-hole pair excitations are described by solutions of the Bethe-Salpeter equation (BSE) that accounts for the Coulomb interaction of excited electron-hole pairs. Although for the computation of excitonic optical spectra in an extended frequency range efficient methods are available, the determination and analysis of individual exciton states still requires the diagonalization of the electron-hole Hamiltonian $\hat{H}$. We present a numerically efficient approach for the calculation of exciton states with quadratically scaling complexity, which significantly diminishes the computational costs compared to the commonly used cubically scaling direct-diagonalization schemes. The accuracy and performance of this approach is demonstrated by solving the BSE numerically for the Wannier-Mott two-band model in {\bf k} space and the semiconductors MgO and InN. For the convergence with respect to the $\vk$-point sampling a general trend is identified, which can be used to extrapolate converged results for the binding energies of the lowest bound states., Comment: 13 pages, 12 figures, 1 table, submitted to PRB

An ab initio pseudopotential method based on density functional theory, generalized gradient corrections to exchange and correlation, and projector-augmented waves is used to investigate structural, energetical, electronic and optical properties of MgO, ZnO, and CdO in rocksalt, cesium chloride, zinc blende, and wurtzite structure. In the case of MgO we also examine the nickel arsenide structure and a graphitic phase. The stability of the ground-state phases rocksalt (MgO, CdO) and wurtzite (ZnO) against hydrostatic pressure and biaxial strain is studied. We also present the band structures of all polymorphs as well as the accompanying dielectric functions. We discuss the physical reasons for the anomalous chemical trend of the ground-state geometry and the fundamental gap with the size of the group-II cation in the oxide. The role of the shallow Zn3d and Cd4d electrons is critically examined., Comment: 13 pages, 9 figures

Prostaglandin synthetase inhibitors have been used in clinical trials for the treatment of primary dysmenorrhea on the theory that the disorder may be caused by a high level of prostaglandins. However, a causal role of prostaglandin in dysmenorrhea has not been established, and there is only indirect evidence that the amelioration of dysmenorrhea by prostaglandin synthetase inhibitors is related to their inhibition of prostaglandin synthesis in the uterus. We, therefore, monitored menstrual prostaglandin release in 14 dysmenorrheic patients in a controlled, double-blind, cross-over trial of ibuprofen (Motrin) and in two dysmenorrheic subjects while they were receiving oral contraceptive therapy and while they were not. A total of 89 menstrual cycles were studied. We found that ibuprofen therapy reduced menstrual prostaglandin release and relieved dysmenorrhea but that placebo therapy did not. Oral contraceptives decreased menstrual flow, reduced prostaglandin release and also alleviated dysmenorrhea. We conclude that primary dysmenorrhea is related to a high level of menstrual prostaglandin release. Ibuprofen inhibits prostaglandin synthesis whereas oral contraceptives inhibit ovulation and cyclic endometrial development. Thus, the two drugs suppress endometrial prostaglandin through different mechanisms. Reduction of menstrual prostaglandin release leads to alleviation of dysmenorrhea.

RNAi screening for kinases regulating the functional organization of the early secretory pathway in Drosophila S2 cells has identified the atypical Mitotic Associated Protein Kinase (MAPK) Extracellularly regulated kinase 7 (ERK7) as a new modulator. We found that ERK7 negatively regulates secretion in response to serum and amino acid starvation in both Drosophila and human cells. Under these conditions ERK7 turnover through the proteasome is inhibited and the resulting higher levels of this kinase lead to a modification in a site within the C terminus of Sec16 a key ER exit site component. This post translational modification elicits the cytoplasmic dispersion of Sec16 and the consequent disassembly of the ER exit sites which in turn results in protein secretion inhibition. We found that ER exit site disassembly upon starvation is TOR complex 1 (TORC1) independent showing that under nutrient stress conditions cell growth is not only inhibited at the transcriptional and translational levels but also independently at the level of secretion by inhibiting the membrane flow through the early secretory pathway. These results reveal the existence of new signalling circuits participating in the complex regulation of cell growth.

Two cases of acute venous circulation disorders of the lower extremity are reported. During shock treatment including rehydration and additional application of heparin the circulation disorders were quickly resolved. As etiological factors, difficult delivery due to incomplete breech-footling presentation (case 1) and hypersodium dehydration (case 2) are discussed. Compared with older children infants might have a better prognosis when acute circulation disorders occur.

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Altres ajuts: The study is partially made possible by support of the 'Programme Hospitalier de Recherche Clinique and 'La Foundation de la Recherche Médicale (grant number DEQ20170336759, France). M.T. was supported by the Polish Mothers Memorial Hospital Research Institute (internal grant number 2016/IV/54-GW. LvdZ is supported by a Kolff grant from the Dutch Kidney Foundation (13OKJ36) and a ZonMW-VENI grant from the Netherlands Organisation for Scientific Research (91618036). This project has been supported by ERN ERKNet and ERN eUROGEN, which are partly co-funded by the European Union within the framework of the Third Health Programme 'ERN-2016-Framework Partnership Agreement 2017-2021'. Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1-β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV.