Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus

Lichen sclerosus is a common, acquired chronic inflammatory skin disease of unknown etiology, although circulating autoantibodies to the glycoprotein extracellular matrix protein 1 (ECM1) have been detected in most patients’ sera. We have examined the nature of ECM1 epitopes in lichen sclerosus sera, developed an ELISA system for serologic diagnosis, and assessed clinicopathological correlation between ELISA titer and disease. Epitope-mapping studies revealed that lichen sclerosus sera most frequently recognized the distal second tandem repeat domain and carboxyl-terminus of ECM1. We analyzed serum autoantibody reactivity against this immunodominant epitope in 413 individuals (95 subjects with lichen sclerosus, 161 normal control subjects, and 157 subjects with other autoimmune basement membrane or sclerosing diseases). The ELISA assay was highly sensitive; 76 of 95 lichen sclerosus patients (80.0%) exhibited IgG reactivity. It was also highly specific (93.7%) in discriminating between lichen sclerosus and other disease/control sera. Higher anti-ECM1 titers also correlated with more longstanding and refractory disease and cases complicated by squamous cell carcinoma. Furthermore, passive transfer of affinity-purified patient IgG reproduced some histologic and immunopathologic features of lichen sclerosus skin. This new ELISA is valuable for the accurate detection and quantification of anti-ECM1 autoantibodies. Moreover, the values may have clinical significance in patients with lichen sclerosus

Fortnightly Fluctuations in the O-C Diagram of CS 1246

Dominated by a single, large-amplitude pulsation mode, the rapidly-pulsating hot subdwarf B star CS 1246 is a prime candidate for a long-term O-C diagram study. We collected nearly 400 hours of photometry with the PROMPT telescopes over a time span of 14 months to begin looking for secular variations in the pulse timings. Interestingly, the O-C diagram is dominated by a strong sinusoidal pattern with a period of 14.1 days and an amplitude of 10.7 light-seconds. Underneath this sine wave is a secular trend implying a decrease in the 371.7-s pulsational period of Pdot = -1.9 x 10^-11, which we attribute to the evolution of the star through the H-R diagram. The sinusoidal variation could be produced by the presence of a low-mass companion, with m sin i ~ 0.12 Msun, orbiting the subdwarf B star at a distance of 20 Rsun. An analysis of the combined light curve reveals the presence of a low-amplitude first harmonic to the main pulsation mode.Comment: Accepted for publication in MNRAS. 11 pages, 8 figures, 5 table

Clinical severity classes in COVID-19 pneumonia have distinct immunological profiles, facilitating risk stratification by machine learning

ObjectiveClinical triage in coronavirus disease 2019 (COVID-19) places a heavy burden on senior clinicians during a pandemic situation. However, risk stratification based on serum biomarker bioprofiling could be implemented by a larger, nonspecialist workforce.MethodMeasures of Complement Activation and inflammation in patientS with CoronAvirus DisEase 2019 (CASCADE) patients (n = 72), (clinicaltrials.gov: NCT04453527), classified as mild, moderate, or severe (by support needed to maintain SpO2 > 93%), and healthy controls (HC, n = 20), were bioprofiled using 76 immunological biomarkers and compared using ANOVA. Spearman correlation analysis on biomarker pairs was visualised via heatmaps. Linear Discriminant Analysis (LDA) models were generated to identify patients likely to deteriorate. An X-Gradient-boost (XGB) model trained on CASCADE data to triage patients as mild, moderate, and severe was retrospectively employed to classify COROnavirus Nomacopan Emergency Treatment for covid 19 infected patients with early signs of respiratory distress (CORONET) patients (n = 7) treated with nomacopan.ResultsThe LDA models distinctly discriminated between deteriorators, nondeteriorators, and HC, with IL-27, IP-10, MDC, ferritin, C5, and sC5b-9 among the key predictor variables during deterioration. C3a and C5 were elevated in all severity classes vs. HC (p < 0.05). sC5b-9 was elevated in the “moderate” and “severe” categories vs. HC (p < 0.001). Heatmap analysis shows a pairwise increase of negatively correlated pairs with IL-27. The XGB model indicated sC5b-9, IL-8, MCP1, and prothrombin F1 and F2 were key discriminators in nomacopan-treated patients (CORONET study).ConclusionDistinct immunological fingerprints from serum biomarkers exist within different severity classes of COVID-19, and harnessing them using machine learning enabled the development of clinically useful triage and prognostic tools. Complement-mediated lung injury plays a key role in COVID-19 pneumonia, and preliminary results hint at the usefulness of a C5 inhibitor in COVID-19 recovery

Hedgehog-GLI mediated control of renal formation and malformation

CAKUT is the leading cause of end-stage kidney disease in children and comprises a broad spectrum of phenotypic abnormalities in kidney and ureter development. Molecular mechanisms underlying the pathogenesis of CAKUT have been elucidated in genetic models, predominantly in the mouse, a paradigm for human renal development. Hedgehog (Hh) signaling is critical to normal embryogenesis, including kidney development. Hh signaling mediates the physiological development of the ureter and stroma and has adverse pathophysiological effects on the metanephric mesenchyme, ureteric, and nephrogenic lineages. Further, disruption of Hh signaling is causative of numerous human developmental disorders associated with renal malformation; Pallister-Hall Syndrome (PHS) is characterized by a diverse spectrum of malformations including CAKUT and caused by truncating variants in the middle-third of the Hh signaling effector GLI3. Here, we outline the roles of Hh signaling in regulating murine kidney development, and review human variants in Hh signaling genes in patients with renal malformation

Action research and democracy

This contribution explores the relationship between research and learning democracy. Action research is seen as being compatible with the orientation of educational and social work research towards social justice and democracy. Nevertheless, the history of action research is characterized by a tension between democracy and social engineering. In the social-engineering approach, action research is conceptualized as a process of innovation aimed at a specific Bildungsideal. In a democratic approach action research is seen as research based on cooperation between research and practice. However, the notion of democratic action research as opposed to social engineering action research needs to be theorized. So called democratic action research involving the implementation by the researcher of democracy as a model and as a preset goal, reduces cooperation and participation into instruments to reach this goal, and becomes a type of social engineering in itself. We argue that the relationship between action research and democracy is in the acknowledgment of the political dimension of participation: ‘a democratic relationship in which both sides exercise power and shared control over decision-making as well as interpretation’. This implies an open research design and methodology able to understand democracy as a learning process and an ongoing experiment

Hydrogen-like nitrogen radio line from hot interstellar and warm-hot intergalactic gas

Hyperfine structure lines of highly-charged ions may open a new window in observations of hot rarefied astrophysical plasmas. In this paper we discuss spectral lines of isotopes and ions abundant at temperatures 10^5-10^7 K, characteristic for warm-hot intergalactic medium, hot interstellar medium, starburst galaxies, their superwinds and young supernova remnants. Observations of these lines will allow to study bulk and turbulent motions of the observed target and will broaden the information about the gas ionization state, chemical and isotopic composition. The most prospective is the line of the major nitrogen isotope having wavelength 5.65 mm (Sunyaev and Churazov 1084). Wavelength of this line is well-suited for observation of objects at z=0.15-0.6 when it is redshifted to 6.5-9 mm spectral band widely-used in ground-based radio observations, and, for example, for z>=1.3, when the line can be observed in 1.3 cm band and at lower frequencies. Modern and future radio telescopes and interferometers are able to observe the absorption by 14-N VII in the warm-hot intergalactic medium at redshifts above z=0.15 in spectra of brightest mm-band sources. Sub-millimeter emission lines of several most abundant isotopes having hyperfine splitting might also be detected in spectra of young supernova remnants.Comment: 12 pages, 5 figures, accepted by Astronomy Letters; v3: details added; error fixe

Rapidly rotating second-generation progenitors for the blue hook stars of {\omega} Cen

Horizontal Branch stars belong to an advanced stage in the evolution of the oldest stellar galactic population, occurring either as field halo stars or grouped in globular clusters. The discovery of multiple populations in these clusters, that were previously believed to have single populations gave rise to the currently accepted theory that the hottest horizontal branch members (the blue hook stars, which had late helium-core flash ignition, followed by deep mixing) are the progeny of a helium-rich "second generation" of stars. It is not known why such a supposedly rare event (a late flash followed by mixing) is so common that the blue hook of {\omega} Cen contains \sim 30% of horizontal branch stars 10 , or why the blue hook luminosity range in this massive cluster cannot be reproduced by models. Here we report that the presence of helium core masses up to \sim 0.04 solar masses larger than the core mass resulting from evolution is required to solve the luminosity range problem. We model this by taking into account the dispersion in rotation rates achieved by the progenitors, whose premain sequence accretion disc suffered an early disruption in the dense environment of the cluster's central regions where second-generation stars form. Rotation may also account for frequent late-flash-mixing events in massive globular clusters.Comment: 44 pages, 8 figures, 2 tables in Nature, online june 22, 201

Play&tune: user feedback in the development of a serious game for optimizing hearing aid orientation

Many hearing aid (HA) users are dissatisfied with HA performance in social situations. One way to improve HA outcomes is training the users to understand how HAs work. Play&Tune was designed to provide this training and to foster autonomy in hearing rehabilitation. We carried out two prototype evaluations and a prerelease evaluation of Play&Tune with 71 HA users, using an interview or online survey. Users gave detailed feedback on their experiences with the app. Most participants enjoyed learning about HAs and expressed a desire for autonomy over their HA settings. Our case study reinforces the importance of user feedback during app development

Masses for Galactic Beat Cepheids

Accurate mass determinations for Cepheids may be used to determine the degree of excess mixing in the interiors of their main-sequence progenitors : the larger the excess mixing, the larger the luminosity of the Cepheid of a given mass, or the smaller the mass of a Cepheid with given luminosity. Dynamical masses determined recently for a few Cepheid binaries indicate excess mixing somewhat stronger than that corresponding to the convective overshoot models by Schaller et al. Beat Cepheids can be used similarly to test main-sequence mixing in stellar interiors. The period ratios for beat Cepheids depend on luminosity, heavy element abundance, and mass. By comparing pulsational models and the obser- T eff, vationally derived luminosity, metallicities, and period ratios it is possible to obtain masses for these T eff, stars, the so-called beat masses. With the old opacities masses much smaller than the evolutionary masses were obtained. With the new OPAL opacities a beat mass close to the dynamical mass was obtained for the binary beat Cepheid Y Carinae, showing that it is now possible to obtain reliable beat masses. In this paper, we determine beat masses for seven Galactic beat Cepheids for which photometric and spectroscopic data are available. We Ðnd an average mass around 4.2 ^ 0.3 for these stars, M_ though the actual error limits for each star may be larger mainly because of uncertainties in E(B[V ) and the heavy element abundances. (As derived spectroscopically, beat Cepheids are in general metalpoor, with The relation between the derived beat masses and the luminosities [0.4[[Fe/H][ 0.0). again indicates excess mixing that is somewhat larger than that corresponding to the models by Schaller et al

Analysis and applications of respiratory surface EMG:report of a round table meeting

Surface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited—in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.</p