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INTRODUCTION: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m(2) in the avacopan group and 4.1 ml/min per 1.73 m(2) in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m(2). METHODS: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. RESULTS: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m(2). At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m(2) in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m(2), respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. CONCLUSION: Among patients with baseline eGFR ≤20 ml/min per 1.73 m(2) in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

Learning analytics defines itself with a focus on data from learners and learning environments, with corresponding goals of understanding and optimizing student learning. In this regard, learning analytics research, ideally, should be characterized by studies that make use of data from learners engaged in education systems, should measure student learning, and should make efforts to intervene and improve these learning environments. However, a common concern among members of the learning analytics research community is that these standards are not being met. In two analysis waves, we review a large and comprehensive sample of research articles from the proceedings of the three most recent Learning Analytics and Knowledge conferences, the premier conference venue for learning analytics research, and from articles published during the same time in the Journal of Learning Analytics (over the years of 2020, 2021, and 2022). We find that 37.4% of articles do not analyze data from learners in an education system, 71.1% do not include any measure of learning, and 89.0% of articles do not attempt to intervene in the learning environment. We contrast these findings with the stated definition of learning analytics and infer, like others before us, that scholarship in learning analytics research presently lacks clear direction toward its stated goals. We invite critical discussion of these findings from the learning analytics community, through open peer commentary.

In a pilot study, electron-density (ED) and ED Laplacian distributions were reconstructed for the challenging case of CaB6 (Pearson symbol cP7) with conceptually fractional B—B bonds from quantum-chemically calculated structure-factor sets with resolutions 0.5 Å–1 ≤ [sin(θ)/λ]max ≤ 5.0 Å–1 by means of Fourier-synthesis techniques. Convergence of norm deviations of the distributions obtained with respect to the reference ones was obtained in the valence region of the unit cell. The QTAIM (quantum theory of atoms in molecules) atomic charges, and the ED and ED Laplacian values at the characteristic critical points of the Fourier-synthesized distributions have been analysed for each resolution and found to display a convergent behaviour with increasing resolution. The presented method(exponent) (ME) type of Fourier-synthesis approach can qualitatively reconstruct all characteristic chemical bonding features of the ED from valence-electron structure-factor sets with resolutions of about 1.2 Å–1 and beyond, and from all-electron structure-factor sets with resolutions of about 2.0 Å–1 and beyond. Application of the ME type of Fourier-synthesis approach for reconstruction of ED and ED Laplacian distributions at experimental resolution is proposed to complement the usual extrapolation to infinite resolution in Hansen–Coppens multipole model derived static ED distributions.

In 2017, 1I/`Oumuamua was identified as the first known interstellar object in the Solar System. Although typical cometary activity tracers were not detected, `Oumuamua exhibited a significant non-gravitational acceleration. To date there is no explanation that can reconcile these constraints. Due to energetic considerations, outgassing of hyper-volatile molecules is favored over heavier volatiles like H2O and CO2. However, there are are theoretical and/or observational inconsistencies with existing models invoking the sublimation of pure H2 , N2, and CO. Non-outgassing explanations require fine-tuned formation mechanisms and/or unrealistic progenitor production rates. Here we report that the acceleration of `Oumuamua is due to the release of entrapped molecular hydrogen which formed through energetic processing of an H2O-rich icy body. In this model, `Oumuamua began as an icy planetesimal that was irradiated at low temperatures by cosmic rays during its interstellar journey, and experienced warming during its passage through the Solar System. This explanation is supported by a large body of experimental work showing that H2 is efficiently and generically produced from H2O ice processing, and that the entrapped H2 is released over a broad range of temperatures during annealing of the amorphous water matrix. We show that this mechanism can explain many of `Oumuamua's peculiar properties without fine-tuning. This provides further support that `Oumuamua originated as a planetesimal relic broadly similar to Solar System comets., Author's version; 23 pages, 3 figures

Einleitung: Komorbidität und Polypharmazie sind ein wesentlicher Grund für Morbidität und Hospitalisierung bei Patienten mit rheumatoider Arthritis. Konventionelle (cs) und gezielte (ts) synthetische DMARDs haben potenzielle Wechselwirkungen mit einer Vielzahl von Medikamenten. Außerdem [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Performing arts computing environments have received little attention in the educational sphere; yet, they offer opportunities for learners to validate their efforts, ideas, and skills through showcasing their work in a public-facing performance. In this work, we explore an out-of-school dance and computing educational program run by the organization, STEM From Dance. The organizational mission is to create an equitable learning experience for young women of color to engage with computing while exposing them to STEM careers. Through an analysis of eleven interviews with youth participants, instructors, and the executive director, we examine how the social, cultural, and political dimensions of the learning environment facilitate identity work in computing and dance. Our findings point to three primary activities used by the organization to promote equity: (1) providing psychological safety through a supportive community environment, (2) meaningfully engaging with learners’ social and cultural context through creative work with constructionist artifacts, and (3) actively promoting identity work as women of color in computing and STEM through both artifact work and community events. Applying the constructs of identity and psychological safety we explore the tensions and synergies of designing for equity in this performing arts and computing learning environment. We demonstrate how the seemingly contradictory elements of a high-stakes performance within a novice learning environment provides unique opportunities for supporting young women of color in computing, making them non-negotiable in the organization’s efforts to promote equity and inclusion. Our work illustrates how attending closely to the sociocultural dimensions in a constructionist learning environment provides lenses for navigating equity, identity work, and support for inclusive computing.

ZUSAMMENFASSUNGDie Sarkoidose ist in Nordeuropa die häufigste granulomatöse Erkrankung. Sie kann prinzipiell nahezu alle Organe betreffen. Die Lunge ist jedoch mit 90–95 % das am häufigsten betroffene Organ. Die pulmonale Sarkoidose kann von einem asymptomatischen Befall bis hin zu einer interstitiellen Fibrose mit schwer eingeschränkter Lungenfunktion auftreten. Mit dem konventionellen Röntgen wird die pulmonale Sarkoidose in 4 Typen unterteilt. Neben der Lungenfunktion ist der radiologische Befallstyp mit entscheidend für die Therapieindikation. Wichtige Bausteine in der Diagnostik sind neben der radiologischen Bildgebung die Bestimmung der Lungenfunktion sowie die Bronchoskopie zur histologischen Diagnosesicherung. Daneben muss bei möglichem Multiorganbefall eine umfangreiche Organdiagnostik zur Erfassung weiterer Organmanifestationen erfolgen. Die Therapie besteht an erster Stelle aus der Gabe von Glukokortikoiden sowie bei unzureichender Wirkung oder Steroid-induzierten Nebenwirkungen aus der zusätzlichen Gabe von Immunsuppressiva. Hier steht an vorderster Stelle eine Therapie mit Methotrexat (MTX).

Estimation of long-term quality of life in patients sustaining Traumatic brain injuries is a difficult but important task during the early hospitalization. There are very limited tools to assess these outcomes, therefore we aimed to develop a predictive model for quality-of-life that could be used in hospitalized adults with TBIs.The TRACK-TBI dataset was used to identify adult patients with TBI from 2014 to 2018. Multiple variables were assessed to predict favorable versus unfavorable scores on the Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS).We included 1549 subjects. 57% had a favorable outcome, and were more likely to have private insurance, higher GCS scores, and fewer comorbidities. A model (TBI-PRO) for 3, 6, and 12-month QOLIBRI score was created. The AUROCs for predicting 3, 6 and 12-month favorable QOLIBRI scores were 0.81, 0.79, and 0.76, respectively.The TBI-PRO model adequately estimates long-term outcomes in patients with TBI.

Managing risk effectively is essential for a business to be successful, and thus understanding risk is vital for business executives. Effective risk management increases firm value, whereas poor risk management will damage shareholder wealth. In this article, we examine the risk literacy of business executives and find significant variation among the leaders we sample. Our findings suggest that business executives would be well served to evaluate their own risk literacy (and remediate, if necessary), to work to increase risk literacy in the company’s employees, and to include risk literacy as an important and routine part of the firm’s overall culture. Because the importance of risk literacy increases with business complexity, we believe that risk literacy will only become more important in the future.

We provide evidence for partial deconfinement -- the deconfinement of a SU($M$) subgroup of the SU($N$) gauge group -- by using lattice Monte Carlo simulations. We take matrix models as concrete examples. By appropriately fixing the gauge, we observe that the $M\times M$ submatrices deconfine. This gives direct evidence for partial deconfinement at strong coupling. We discuss the applications to QCD and holography., Comment: 49 pages, 24 figures, 3 tables. Version accepted for publication on JHEP

Due to its heterogeneity, the prediction of posttraumatic stress disorder (PTSD) development after traumtic injury is difficult. Recent machine learning approaches have yielded insight into predicting PTSD symptom trajectories. Using data collected within 1 month of traumatic injury, we applied eXtreme Gradient Boosting (XGB) to classify admitted and discharged patients (hospitalized, n = 192; nonhospitalized, n = 214), recruited from a Level 1 trauma center, according to PTSD symptom trajectories. Trajectories were identified using latent class mixed models on PCL-5 scores collected at baseline, 1-3 months posttrauma, and 6 months posttrauma. In both samples, nonremitting, remitting, and resilient PTSD symptom trajectories were identified. In the admitted patient sample, a unique delayed trajectory emerged. Machine learning classifiers (i.e., XGB) were developed and tested on the admitted patient sample and externally validated on the discharged sample with biological and clinical self-report baseline variables as predictors. For external validation sets, prediction was fair for nonremitting versus other trajectories, areas under the curve (AUC = .70); good for nonremitting versus resilient trajectories, AUCs = .73-.76; and prediction failed for nonremitting versus remitting trajectories, AUCs = .46-.48. However, poor precision (.57) across all models suggests limited generalizability of nonremitting symptom trajectory prediction from admitted to discharged patient samples. Consistency in symptom trajectory identification across samples supports prior studies on the stability of PTSD symptom trajectories following trauma exposure; however, continued work and replication with larger samples are warranted to understand overlapping and unique predictive features of PTSD in different traumatic injury populations.

The aim of this study is to evaluate risk factors for non-attendance to post-discharge, hospital follow-up appointments for traumatically injured patients who underwent exploratory laparotomy.This is a retrospective chart review of patients who underwent exploratory laparotomy for traumatic abdominal injury at an urban, Midwestern, level I trauma center with clinic follow-up scheduled after discharge. Clinically, relevant demographic characteristics, patients' distance from hospital, and the presence of staples, sutures, and drains requiring removal were collected. Descriptive statistics of categorical variables were calculated as totals and percentages and compared with a chi-squared test or Fisher's exact when appropriate.The sample included 183 patients who were largely assaultive trauma survivors (68%), male (80%), and black (53%) with a mean age of 35.4 ± 14.9 years. Overall, 18.5% no-showed for their follow-up appointment. On multivariate analysis for clinic no-show; length of stay (odds ratio = 0.92 [0.84-0.99], P = 0.04) and the need for suture, staple, or drain removal were protective for clinic attendance (odds ratio = 5.59 [1.07-7.01], P = 0.04). Overall, 12 patients (6.4%) were readmitted. Forty patients (18.3%) had their follow-up in the emergency department (ED). On multivariate regression of risk factors for ED visits, the only statistically significant factors (P 0.05) were clinic appointment no-show (OR = 2.81) and self-pay insurance (OR = 4.78).Abdominal trauma patients are at high risk of no-show for follow-up appointments and no-show visits are associated with ED visits. Future work is needed evaluating interventions to improve follow-up.

CSF1 receptor-related leukoencephalopathy is a rare genetic disorder presenting with severe, adult-onset white matter dementia as one of the leading symptoms. Within the central nervous system, the affected CSF1-receptor is expressed exclusively in microglia cells. Growing evidence implicates that replacing the defective microglia with healthy donor cells through hematopoietic stem cell transplant might halt disease progression. Early initiation of that treatment is crucial to limit persistent disability. However, which patients are suitable for this treatment is not clear, and imaging biomarkers that specifically depict lasting structural damage are lacking. In this study, we report on two patients with CSF1R-related leukoencephalopathy in whom allogenic hematopoietic stem cell transplant at advanced disease stages led to clinical stabilization. We compare their disease course with that of two patients admitted in the same timeframe to our hospital, considered too late for treatment, and place our cases in context with the respective literature. We propose that the rate of clinical progression might be a suitable stratification measure for treatment amenability in patients. Furthermore, for the first time we evaluate [18F] florbetaben, a PET tracer known to bind to intact myelin, as a novel MRI-adjunct tool to image white matter damage in CSF1R-related leukoencephalopathy. In conclusion, our data add evidence for allogenic hematopoietic stem cell transplant as a promising treatment in CSF1R-related leukoencephalopathy patients with slow to moderate disease progression.

Understanding the mercury cycle in the Arctic is important due to the harmful bioaccumulation of its toxic form, methylmercury, in wildlife and ultimately Arctic residents. Gaseous elemental mercury (Hg(0)) is relatively well-mixed across the northern hemisphere atmosphere due to its long atmospheric lifetime. Hg(0) can be oxidized, especially in the Arctic spring during halogen-driven depletion events. The resulting gaseous oxidized mercury (Hg(II)) is relatively quickly deposited onto snow, either directly or via condensing onto particles, forming particulate mercury (PHg). It is generally understood that a large fraction of the deposited Hg(II) and PHg is photoreduced to Hg(0) and re-emitted to the atmosphere. However, mercury remaining in the snowpack till melt can become bioavailable through entering the ocean.There is a severe lack of Hg(II) and PHg observations in the central Arctic, particularly over sea ice, limiting our understanding of the mercury cycle in that region and inhibiting us from quantifying mercury budgets in all environmental compartments and particularly where it unfolds its harmful neurotoxic effects. Moreover, most of the observational efforts aiming at creating process understanding focused on spring during mercury depletion events or the snow melt period, leaving large knowledge gaps for fall and winter.Here, we show atmospheric observations of PHg during MOSAiC, measured with an aerosol mass spectrometer in fall and spring over the central Arctic pack ice. In both seasons, PHg concentrations correlate strongly with wind speed and chloride, suggesting a mechanical (wind-driven) process behind atmospheric PHg related partly to blowing snow. In addition, there are significant differences between fall and spring observations (e.g. no atmospheric mercury depletion events in fall), suggesting that various processes are at play.This wind-driven process has hitherto not been reported and is different from observations at land-based stations as well as previous measurements over sea ice that ascribed the formation of PHg to adsorption of Hg(II) onto pre-existing aerosols or diamond dust rather than aerosolization from the snow pack. We hypothesize, based on snow chemical analyzes and literature, that the elevated halide content in snow on sea ice creates complexes of PHg, which are much harder to photoreduce than Hg(II), leading to a larger PHg content in snow. These processes of forming PHg and wind-driven aerosolization have implications for the mercury content of snow and the distances over which PHg is re-deposited after atmospheric transport given that the lifetime of PHg is about one order of magnitude larger than that of Hg(II) in the atmosphere.

Sea salt aerosols play a critical role in aerosol-radiation and aerosol-cloud interactions. Salty blowing snow has been hypothesized as an important source of sea salt aerosol in polar regions. The snow over sea ice can become salty by upward brine migration or deposition of sea spray produced from leads or transported from the ice edge. Wind-driven resuspension and sublimation of the snow is hypothesized to leave salty aerosol particles behind. Our understanding of aerosol emissions from blowing snow is based mainly on modeling studies, and direct observations to validate this process are sparse. The year-long Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) expedition, with its integrated measurements and sampling of frequent winter storms, is well suited to enhance our understanding of coupled Arctic system processes. Here, we focus on the impact of blowing snow and high wind speed events on aerosol number concentrations, size distributions, optical properties and cloud condensation nuclei (CCN) concentrations. Total aerosol number concentrations were significantly enhanced during high-wind speed periods, also concurrent with increased scattering aerosol coefficients and CCN concentrations. We further present a process-based characterization of the blowing snow events during MOSAiC and identify the influence of environmental variables on aerosol emissions. Our observations provide new insights into wind-driven aerosol in the central Arctic and may help to validate modelling studies and inform parameterization improvement particularly with respect to aerosol direct and indirect radiative forcing.

Given the role of human intuition in current drug design efforts, crowd-sourced 'citizen scientist' games have the potential to greatly expand the pool of potential drug designers. Here, we introduce ‘Drugit', the small molecule design mode of the online ‘citizen science’ game Foldit. We demonstrate its utility for design with a use case to identify novel binders to the von Hippel Lindau E3 ligase. Several thousand molecule suggestions were obtained from players in a series of 10 puzzle rounds. The proposed molecules were then evaluated by in silico methods and by an expert panel and selected candidates were synthesized and tested. One of these molecules, designed by a player, showed dose-dependent shift perturbations in protein-observed NMR experiments. The co-crystal structure in complex with the E3 ligase revealed that the observed binding mode matched in major parts the player’s original idea. The completion of one full design cycle is a proof of concept for the Drugit approach and highlights the potential of involving citizen scientists in early drug discovery.

Memories enable the retrieval of specific events in the past while building generalizable knowledge that guides inference in new situations. According to a prominent conceptualization, serving both of these adaptive functions requires pattern separation, pattern completion, and generalization as distinct sets of complementary component processes. It is not known whether these three processes are separable in early childhood or whether they originally represent a single dimension of memorability that differentiates in middle childhood. Based on a selection of13 memory tasks, we will address this question though hypothesis-guided tests of differences in the factor structure of memory performance between younger and older groups of children (two groups, 48–59 versus 72–83 months of age, n = 120per group) using structural equation modeling. The results of this study will pave the way for a process-based and systemic understanding of memory development during childhood.

Aspartate is a limiting metabolite in proliferating cells with its production closely linked to glutamine and mitochondrial metabolism. To date, measuring aspartate concentrations in live cells was deemed impossible. We present iAspSnFR, a genetically-encoded biosensor for intracellular aspartate, engineered by displaying and screening biosensor libraries in HEK293 cells. In live cells, iAspSnFR exhibits a dynamic range of 130% fluorescence change and detects reduced aspartate levels upon glutamine deprivation or glutaminase inhibition. Furthermore, iAspSnFR tracks aspartate uptake by excitatory amino acid transporters, or of asparagine after co-expression of an asparaginase. Importantly, iAspSnFR reports aspartate depletions upon electron transport chain inhibition, and therefore it can serve as a proxy for mitochondrial respiration. Consequently, iAspSnFR can dissect the major cellular pathways of aspartate production, offering immediate applications, particularly in cancer biology, such as screening small molecules targeting aspartate and glutamine metabolism.

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ARF1 as a crucial negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene expression. Disease-associated, GTPase-defective, ARF1 results in increased cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial fusion causing cGAS activation by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show that ARF1 has an unexpected dual role in maintaining cGAS-STING homeostasis, through the promotion of mitochondrial fusion and STING recycling.

Robust evidence points to mnemonic deficits in older adults related to dedifferentiated, i.e., less distinct, neural responses during memory encoding. However, less is known about retrieval-related dedifferentiation and its role in age-related memory decline. In this study, younger and older adults were scanned both while incidentally learning face and house stimuli and while completing a surprise recognition memory test. Using pattern similarity searchlight analyses, we looked for indicators of neural dedifferentiation during retrieval and asked whether this might explain interindividual differences in memory performance. Our findings revealed age-related reductions in neural distinctiveness during memory retrieval as well as in encoding-retrieval reinstatement in visual processing regions. We further demonstrated that the degree to which patterns elicited during encoding were reinstated during retrieval tracked variability in memory performance better than retrieval-related distinctiveness only. All in all, we contribute to meager existing evidence for age-related neural dedifferentiation during memory retrieval. We propose that the recognition task (as opposed to a cued recall task) may have revealed impairment in perceptual processing in older adults, leading to particularly widespread age differences in neural distinctiveness. We additionally provide support for the idea that well-defined reactivation of encoding patterns plays a major role in successful memory retrieval.