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Fc‐gamma receptor (FcγR) activation by soluble IgG immune complexes (sICs) represents a major mechanism of inflammation in certain autoimmune diseases such as systemic lupus erythematosus (SLE). A robust and scalable test system allowing for the detection and quantification of sIC bioactivity is missing. We developed a comprehensive reporter cell panel detecting activation of FcγRs. The reporter cell lines were integrated into an assay that enables the quantification of sIC reactivity via ELISA or a faster detection using flow cytometry. This identified FcγRIIA(H) and FcγRIIIA as the most sIC‐sensitive FcγRs in our test system. Reaching a detection limit in the very low nanomolar range, the assay proved also to be sensitive to sIC stoichiometry and size reproducing for the first time a complete Heidelberger‐Kendall curve in terms of immune receptor activation. Analyzing sera from SLE patients and mouse models of lupus and arthritis proved that sIC‐dependent FcγR activation has predictive capabilities regarding severity of SLE disease. The assay provides a sensitive and scalable tool to evaluate the size, amount, and bioactivity of sICs in all settings., An assay utilizing a cell‐based reporter system enables the assessment of soluble antibody‐antigen complexes regarding their bioactivity. The comprehensive assay is sensitive to features of sICs that are neglected by current methodology, making it useful in experimental as well as clinical settings.

BackgroundCOVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE).ObjectiveThese evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE.MethodsASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment.ResultsThe panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation.ConclusionsThis recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

Background: COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. Results: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Conclusions: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

Supplemental Digital Content is available in the text., Objectives: To compare different modalities of renal replacement therapy in critically ill adults with acute kidney injury. Data Sources: We searched Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to 25 May, 2020. We included randomized controlled trials comparing the efficacy and safety of different renal replacement therapy modalities in critically ill patients with acute kidney injury. Study Selection: Ten reviewers (working in pairs) independently screened studies for eligibility, extracted data, and assessed risk of bias. Data Extraction: We performed random-effects frequentist network meta-analyses and used the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess certainty of evidence. The primary analysis was a four-node analysis: continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and peritoneal dialysis. The secondary analysis subdivided these four nodes into nine nodes including continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, continuous veno-venous hemodiafiltration, continuous arterio-venous hemodiafiltration, intermittent hemodialysis, intermittent hemodialysis with hemofiltration, slow efficiency extended dialysis, slow efficiency extended dialysis with hemofiltration, and peritoneal dialysis. We set the minimal important difference threshold for mortality as 2.5% (relative difference, 0.04). Data Synthesis: Thirty randomized controlled trials (n = 3,774 patients) proved eligible. There may be no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis (relative risk, 1.04; 95% CI, 0.93–1.18; low certainty), whereas continuous renal replacement therapy demonstrated a possible increase in mortality compared with slow efficiency extended dialysis (relative risk, 1.06; 95% CI, 0.85–1.33; low certainty) and peritoneal dialysis (relative risk, 1.16; 95% CI, 0.92–1.49; low certainty). Continuous renal replacement therapy may increase renal recovery compared with intermittent hemodialysis (relative risk, 1.15; 95% CI, 0.91–1.45; low certainty), whereas both continuous renal replacement therapy and intermittent hemodialysis may be worse for renal recovery compared with slow efficiency extended dialysis and peritoneal dialysis (low certainty). Peritoneal dialysis was probably associated with the shortest duration of renal support and length of ICU stay compared with other interventions (low certainty for most comparisons). Slow efficiency extended dialysis may be associated with shortest length of hospital stay (low or moderate certainty for all comparisons) and days of mechanical ventilation (low certainty for all comparisons) compared with other interventions. There was no difference between continuous renal replacement therapy and intermittent hemodialysis in terms of hypotension (relative risk, 0.92; 95% CI, 0.72–1.16; moderate certainty) or other complications of therapy, but an increased risk of hypotension and bleeding was seen with both modalities compared with peritoneal dialysis (low or moderate certainty). Complications of slow efficiency extended dialysis were not sufficiently reported to inform comparisons. Conclusions: The results of this network meta-analysis suggest there is no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis although continuous renal replacement therapy may increases renal recovery compared with intermittent hemodialysis. Slow efficiency extended dialysis with hemofiltration may be the most effective intervention at reducing mortality. Peritoneal dialysis is associated with good efficacy, and the least number of complications however may not be practical in all settings. Importantly, all conclusions are based on very low to moderate certainty evidence, limited by imprecision. At the very least, ICU clinicians should feel comfortable that the differences between continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and, where clinically appropriate, peritoneal dialysis are likely small, and any of these modalities is a reasonable option to employ in critically ill patients.

Human cytomegalovirus (HCMV) is endowed with multiple highly sophisticated immune evasion strategies. This includes the evasion from antibody mediated immune control by counteracting host Fc-gamma receptor (FcγR) mediated immune control mechanisms such as antibody-dependent cellular cytotoxicity (ADCC). We have previously shown that HCMV avoids FcγR activation by concomitant expression of the viral Fc-gamma-binding glycoproteins (vFcγRs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fcγ sites and achieve efficient antagonization of host FcγR activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host FcγR binding to immune complexes. In doing so, gp68 induces Fcγ accessibility to gp34 and simultaneously limits host FcγR recognition. The synergy of gp34 and gp68 is compelled by the interfering influence of excessive non-immune IgG ligands and highlights conformational changes within the IgG globular chains critical for antibody effector function., eLife digest Human cytomegalovirus is a type of herpes virus that rarely causes symptoms in healthy people but can cause serious complications in unborn babies and in people with compromised immune systems, such as transplant recipients. The virus has found ways to successfully evade the immune system, and once infected, the body retains the virus for life. It deploys an arsenal of proteins that bind to antibodies, specialized proteins the immune system uses to flag virus-infected cells for destruction. This prevents certain cells of the immune system, the natural killer cells, from recognizing and destroying virus-infected cells. These immune-evading proteins are called viral Fc-gamma receptors, or vFcγRs. While it has been previously shown that these receptors are able to evade the immune system, it remained unknown how exactly they prevent natural killer cells from recognizing infected cells. Now, Kolb et al. show that the cytomegalovirus deploys two vFcγRs called gp34 and gp68, which work together to block natural killer cells. The latter reduces the ability of natural killer cells to bind to antibodies on cytomegalovirus-infected cells. This paves the way for gp34 to pull virus proteins from the surface of the infected cell, making them inaccessible to the immune system. Neither protein fully protects virus-infected cells on its own, but together they are highly effective. The experiments reveal further details about how cytomegalovirus uses two defense mechanisms simultaneously to outmaneuver the immune system. Understanding this two-part viral evasion system may help scientists to develop vaccines or new treatments that can protect vulnerable people from diseases caused by the cytomegalovirus.

This paper reports findings from a crowdsourced replication. Eighty-five independent teams attempted a computational replication of results reported in an original study of policy preferences and immigration by fitting the same statistical models to the same data. The replication involved an experimental condition. Random assignment put participating teams into either the transparent group that received the original study and code, or the opaque group receiving only a methods section, rough results description and no code. The transparent group mostly verified the numerical results of the original study with the same sign and p-value threshold (95.7%), while the opaque group had less success (89.3%). Exact numerical reproductions to the second decimal place were far less common (76.9% and 48.1%), and the number of teams who verified at least 95% of all effects in all models they ran was 79.5% and 65.2% respectively. Therefore, the reliability we quantify depends on how reliability is defined, but most definitions suggest it would take a minimum of three independent replications to achieve reliability. Qualitative investigation of the teams’ workflows reveals many causes of error including mistakes and procedural variations. Although minor error across researchers is not surprising, we show this occurs where it is least expected in the case of computational reproduction. Even when we curate the results to boost ecological validity, the error remains large enough to undermine reliability between researchers to some extent. The presence of inter-researcher variability may explain some of the current “reliability crisis” in the social sciences because it may be undetected in all forms of research involving data analysis. The obvious implication of our study is more transparency. Broader implications are that researcher variability adds an additional meta-source of error that may not derive from conscious measurement or modeling decisions, and that replications cannot alone resolve this type of uncertainty.

Introduction: Recently, a novel extended approach for comminuted lateral tibial plateau fractures was introduced. It includes a lateral epicondyle osteotomy and meniscus subluxation allowing for an almost complete overview of the lateral tibial plateau. First clinical results are presented. Hypotheses: We hypothesized, that a superior visualization using the novel approach in demanding cases leads to improved radiologic and clinical outcomes. Methods: A consecutive case series of ten in which the approach was used was followed prospectively. The cases were classified using the “10-segment classification” and the “AO classification”. To evaluate the clinical and radiological results, the Rasmussen score was applied. Results: Excellent to good clinical and radiological results were encountered after a median follow-up of 8,6 (IQR 4,3) months. The clinical score amounted to a median of 25 (IQR 2,8) and the radiological score a median of 17 (IQR 2,0). Conclusion: The early results after the treatment of demanding cased with a high degree of joint comminution presented are promising with excellent to good results, only. At the same time, despite an extended surgical procedure, no complications were encountered in the cohort. As suggested by the authors before, tibial plateau fractures should be managed using a stepwise approach with extension of the approach as individually required.

During the clinical workup of an adolescent male with chronic active EBV disease, it was noted that natural killer (NK) cells of this individual did not express the Fc-receptor CD16A (Fig 1, A). The index patient, born to nonconsanguineous parents, was first seen when he was 11 years old, and an extended workup revealed persistently high levels of EBV-encoded small RNA (EBER) DNA in peripheral blood and multiple-organ infiltration with EBV-positive T lymphocytes including an IgA- and EBV-positive interstitial nephritis that eventually led to renal failure (see Case Report and Table E1 in this article’s Online Repository at www.jacionline.org)., This work was supported by grants SAF2014-58752-R and SAF2017-83265-R to H.T.R. and grant SAF2016-80363-C2-2-R to C.V. (Spanish Science agency/European Regional Development Fund, European Union, AEI/FEDER, EU). The group of M.V.-G. has also received funding from the Spanish Ministry of Science and Innovation (grant nos. RTC-2017-6379-1 and RTI2018-093569-B-I00 [MCIU/AEI/FEDER, EU]) and the regional government of Madrid (grant no. S2017/BMD-3733-2). The group of M.V.-G. also belongs to the research network TENTACLES (RED2018-102411-T) funded by the Spanish Ministry of Science. A.P.P. and A.B.M. acknowledge PhD studentships funded by the National Secretary of Higher Education, Science, Technology and Innovation (SENESCYT, Ecuador) and Spanish Ministry of Economy and Competitivity (MINECO), respectively (SVP-2014-068263). M.M. was supported by grant GCB15152947MELE from Fundación de la Asociación Española contra el Cáncer. Work in the laboratory of H.H. is supported by Infect-ERA grant TANKACY, BMBF 031L0090, and German Research Foundation (DFG) grant HE2526/9-1. E.L.G. has grants from the Spanish Association Against Cancer (AECC) and Carlos III Health Institute (grant no. PI16/01605). C.A.B. acknowledges support from the National Institutes of Health (grant no. DP2AI11219301).

Fiber-reinforced polymers combine the aspects of stiff fibers and light polymer matrix. The arrangement of fibers on the microstructural level significantly affects the mechanical properties on the macroscopic scale, such as stiffness and fracture toughness. Micro-computed tomography systems (μCT) enables a detailed volumetric view into microstructures in a none-destructive way. By performing mechanical test inside a μCT system, the effects of mechanical load onto the microstructure, such as damage initiation and propagation are observed in-situ. Since cyclic load is a common use case for many components, fatigue and cycle load tests are essential for material characterizing. In this contribution, the authors introduce an in-situ μCT setup for cyclic load tests. The test device is designed to generate high-resolution images, in order to observe cracks through different propagation stages. In addition, cracks are three-dimensionally segmented and a crack volume fraction definition is introduced. The presented in-situ test setup and crack characterization method are demonstrated on sheet molding compound specimen, a glass-fiber reinforced thermosetting material system.

Although recent evidence has shown that IL‐6 is involved in enhanced alternative activation of macrophages toward a profibrotic phenotype, the mechanisms leading to their increased secretory capacity are not fully understood. Here, we investigated the effect of IL‐6 on endoplasmic reticulum (ER) expansion and alternative activation of macrophages in vitro. An essential mediator in this ER expansion process is the IRE1 pathway, which possesses a kinase and endoribonuclease domain to cleave XBP1 into a spliced bioactive molecule. To investigate the IRE1‐XBP1 expansion pathway, IL‐4/IL‐13 and IL‐4/IL‐13/IL‐6‐mediated alternative programming of murine bone marrow‐derived and human THP1 macrophages were assessed by arginase activity in cell lysates, CD206 and arginase‐1 expression by flow cytometry, and secreted CCL18 by ELISA, respectively. Ultrastructural intracellular morphology and ER biogenesis were examined by transmission electron microscopy and immunofluorescence. Transcription profiling of 128 genes were assessed by NanoString and Pharmacological inhibition of the IRE1‐XBP1 arm was achieved using STF‐083010 and was verified by RT‐PCR. The addition of IL‐6 to the conventional alternative programming cocktail IL‐4/IL‐13 resulted in increased ER and mitochondrial expansion, profibrotic profiles and unfolded protein response‐mediated induction of molecular chaperones. IRE1‐XBP1 inhibition substantially reduced the IL‐6‐mediated hyperpolarization and normalized the above effects. In conclusion, the addition of IL‐6 enhances ER expansion and the profibrotic capacity of IL‐4/IL‐13‐mediated activation of macrophages. Therapeutic strategies targeting IL‐6 or the IRE1‐XBP1 axis may be beneficial to prevent the profibrotic capacity of macrophages., IL‐6 is known to increase the polarization of alternatively activated macrophages. Here, we show that this hyperpolarization is associated with a dramatic increase in the endoplasmic reticulum, an organelle required for folding of secreted proteins. We show further that the inhibition of a known activator of the Unfolded Protein Response, IRE1, prevents both ER expansion and alternative activation of macrophages, suggesting that targeting the process of ER expansion in alternatively activated macrophages may be considered to prevent the known profibrotic activity of alternatively activated macrophages.

Injuries to the posterolateral corner (PLC) often result in lateral, rotational, and dorsal instability, which need appropriate and differentiated treatment. Besides posterior cruciate ligament reconstruction for posterior instability, the technique according to LaPrade et al. efficiently stabilizes posterolateral rotational and lateral instability as described in Fanelli type B or C injuries. This technique has been exclusively used as an open procedure. In this article, we present an all-arthroscopic technique for the posterolateral stabilization procedure. To achieve this, 5 different arthroscopic portals are needed. The PLC is visualized by a trans-septal approach. Directly posterior to the popliteal tendon, arthroscopic preparation is started and the medial part of the fibular head is exposed. Two anatomic drill channels are placed in the lateral femoral condyle, with one tibial channel in the distal third of the sulcus popliteus and one channel in the fibular head. The popliteal tendon, popliteofibular ligament, and lateral collateral ligament are reconstructed with autologous hamstring tendons. The advantages of an all-arthroscopic anatomic PLC reconstruction are the protection of the soft tissues and the precise anatomic tunnel placement under direct visualization. The described procedure is a safe and anatomic method for posterolateral stabilization.

Background. The influence of increasing lateral plateau widening on the frequency of meniscal and ligamentous lesions in lateral tibial plateau fractures has been examined in very few studies using plain radiographs. Because the amount of this parameter cannot be measured accurately on plain radiographs, the purpose of this survey was to look for a possible correlation between the extent of lateral plateau widening, as measured on multidetector CT (MDCT) scans, and different soft-tissue injuries determined from magnetic resonance imaging (MRI). Materials and Methods. 55 patients with a lateral tibial plateau fracture were included in this retrospective case series. Patient age averaged 52.6 years (SD = 18.0). The degree of lateral plateau widening was measured on CT images. MRIs were screened for meniscal and ligamentous injuries. Results. We found a significant effect of increasing lateral plateau widening on the incidence of lateral meniscus lesions (P = 0.021), lateral collateral ligament tears (P = 0.047), and the overall quantity of meniscal and ligamentous lesions (P = 0.001). Discussion. MRIs are not widely used as a diagnostic tool in lateral plateau fractures of the tibia. Reasons might be the costs and the fact that it is a time-consuming examination. The results of this study may help to estimate the probability of specific soft-tissue lesions in lateral tibial plateau fractures based on measurements of lateral plateau widening on MDCT scans, and they may guide the decision for additional MRI and/or arthroscopically assisted repair.

The processment of information related to a geographic location has long been difficult due to lacking data sources and processing power. The recent changes in the rise of web-based technologies like OpenStreetMap (OSM) and Google Maps change the picture.With R it is possible to execute a large amount of data and to produce appropriate visualisations. The challenge is to find the necessary spatial information. In this paper an overview is given to reflect the possibilities spatial visualisations in the context of social sciences. Moreover, it provides an introduction to spatial visualisation.Sources for spatial data and methods of data collection are described and examples of visualisations are presented.

In 2011, Germany conducted the first census after the reunification. In contrast to a classical census, a register-assisted census was implemented using population register data and an additional sample. This paper provides an overview of how the sampling design recommendations were set up in order to fulfil legal requirements and to guarantee an optimal but still flexible source of information. The aim was to develop a design that fosters an accurate estimation of the main objective of the census, the total population counts. Further, the design should also adequately support the application of small area estimation methods. Some empirical results are given to provide an assessment of selected methods. The research was conducted within the German Census Sampling and Estimation research project, financially supported by the German Federal Statistical Office.

In PIAAC (Programme for the International Assessment of Adult Competencies) inclusion probabilities have to be known for every respondent at each sampling stage in all participating countries. However, in some cases it is not possible to calculate inclusion probabilities for a sample survey analytically – although the underlying design is probabilistic. In such cases, simulation studies can help to estimate inclusion probabilities and thus ensure that the necessary basis for the calculation of design weights is available. In this section, we present a Monte Carlo simulation using the German sample data. During the selection process for PIAAC Germany an error had occurred. Because of that, it was not possible to determine the inclusion probabilities analytically. Therefore a simulation study with 10,000 runs of the erroneous selection process was set up. As a result it was possible to compute the inclusion probabilities for the sample of PIAAC Germany., methods, data, analyses, Vol 8, No 2 (2014)

In this work we investigate superconducting properties of niobium samples via application of the muon spin rotation/relaxation (muSR) technique. We employ for the first time the muSR technique to study samples that are cutout from large and small grain 1.5 GHz radio frequency (RF) single cell niobium cavities. The RF test of these cavities was accompanied by full temperature mapping to characterize the RF losses in each of the samples. Results of the muSR measurements show that standard cavity surface treatments like mild baking and buffered chemical polishing (BCP) performed on the studied samples affect their surface pinning strength. We find an interesting correlation between high field RF losses and field dependence of the sample magnetic volume fraction measured via muSR. The muSR line width observed in ZF-muSR measurements matches the behavior of Nb samples doped with minute amounts of Ta or N impurities. An upper bound for the upper critical field Hc2 of these cutouts is found., 20 pages, 14 figures

Graphical abstract, Highlights • Tick saliva proteins Salp15 and Iric-1 promote tick feeding and pathogen transmission. • We established the first bacterial expression system for soluble Salp15 and Iric-1. • Using this system we mapped monoclonal antibody epitopes on Salp15 and Iric-1. • We defined the interaction sites with Borrelia outer surface protein C (OspC). • We elucidated first secondary structure features in Iric-1 by NMR., Ticks transmit numerous pathogens, including borreliae, which cause Lyme disease. Tick saliva contains a complex mix of anti-host defense factors, including the immunosuppressive cysteine-rich secretory glycoprotein Salp15 from Ixodes scapularis ticks and orthologs like Iric-1 from Ixodesricinus. All tick-borne microbes benefit from the immunosuppression at the tick bite site; in addition, borreliae exploit the binding of Salp15 to their outer surface protein C (OspC) for enhanced transmission. Hence, Salp15 proteins are attractive targets for anti-tick vaccines that also target borreliae. However, recombinant Salp proteins are not accessible in sufficient quantity for either vaccine manufacturing or for structural characterization. As an alternative to low-yield eukaryotic systems, we investigated cytoplasmic expression in Escherichia coli, even though this would not result in glycosylation. His-tagged Salp15 was efficiently expressed but insoluble. Among the various solubility-enhancing protein tags tested, DsbA was superior, yielding milligram amounts of soluble, monomeric Salp15 and Iric-1 fusions. Easily accessible mutants enabled epitope mapping of two monoclonal antibodies that, importantly, cross-react with glycosylated Salp15, and revealed interaction sites with OspC. Free Salp15 and Iric-1 from protease-cleavable fusions, despite limited solubility, allowed the recording of 1H–15N 2D NMR spectra, suggesting partial folding of the wild-type proteins but not of Cys-free variants. Fusion to the NMR-compatible GB1 domain sufficiently enhanced solubility to reveal first secondary structure elements in 13C/15N double-labeled Iric-1. Together, E. coli expression of appropriately fused Salp15 proteins may be highly valuable for the molecular characterization of the function and eventually the 3D structure of these medically relevant tick proteins.