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Infection with the pandemic human coronavirus SARS-CoV-2 elicits a respiratory tract disease, termed Coronavirus disease 2019 (COVID-19). While a variable degree of disease-associated symptoms may emerge, severe COVID-19 is commonly associated with respiratory complications such as acute respiratory distress syndrome (ARDS), the necessity for mechanical ventilation or even extracorporeal membrane oxygenation (ECMO). Amongst others, disease outcome depends on age and pre-existing conditions like cardiovascular diseases, metabolic disorders but also age and biological sex. Intriguingly, increasing experimental and clinical evidence suggests that an exacerbated inflammatory response and in particular IgG immune complexes (ICs), significantly contribute to severe and prolonged COVID-19 disease progression. Vast amounts of deposited, unresolved ICs in tissue are capable to initiate an exaggerated Fc gamma receptor (FcγR) mediated signalling cascade which eventually results in common IC-associated organ diseases such as vasculitis, glomerulonephritis and arthritis, comorbidities that have been frequently reported for COVID-19. Moreover and independent of deposited ICs, very recent work identified soluble ICs (sIC) to be also present in the circulation of a majority of severely ill patients, where their systemic abundance correlated with disease severity. Thus, detection of circulating sICs in patients represents a potential marker for critical COVID-19 disease progression. Their detection early after clinical deterioration might become an indicator for the requirement of prompt anti-inflammatory treatment. Here, we review the role of ICs in COVID-19 progression, their possible origins and potential intervention strategies. Graphical abstract

Objectives Recent transcriptome analyses revealed that 15-fold expanded HLA-DR+ CD90+ synovial fibroblasts (SFs) are potential key mediators of inflammation in rheumatoid arthritis (RA). The reasons for the expansion of HLA-DR+ CD90+ SFs are unclear, but genetic signatures indicated a central role of IFNɣ in the generation of this fibroblast subset. In the present study, we investigated the generation of HLA-DR+ CD90+ SFs and their function. We hypothesized that infiltrating leukocytes such as NK cells become activated in situ, provide IFNɣ and thus contribute to the generation of arthritic HLA-DR+ CD90+ SFs. Methods We combined functional assays using primary human materials and focused bioinformatic analyses of mass cytometry and transcriptomics patient datasets. Results We detected enriched and activated FcɣRIIIA(CD16)+ NK cells in synovia from active RA. CD16 recognized immune complexes in synovial fluid, potentially contributing to NK cell activation in RA. In vitro, NK cell-derived IFNɣ induced HLA-DR and an inflammatory, cytokine secreting, HLA-DR+ phenotype in CD90+ SFs. HLA-DR+ CD90+ SFs consecutively activated CD4+ T cells upon receptor crosslinking via superantigens. HLA-DR+ CD90+ SFs also activated CD4+ T cells in absence of superantigens, an effect that was boosted by NK cell-derived IFNɣ and that was four times stronger in RA compared to osteoarthritis. Finally, JAK inhibition prevented HLA-DR induction and blocked pro-inflammatory signals to T cells. Conclusions HLA-DR+ CD90+ SFs are an activation state that can be induced by IFNɣ, likely provided from infiltrating leukocytes such as activated NK cells. The induction of these pro-inflammatory, IL-6 producing and likely antigen-presenting SFs can be targeted by JAK inhibition.

Nonresponse in panel studies can lead to a substantial loss in data quality owing to its potential to introduce bias and distort survey estimates. Recent work investigates the usage of machine learning to predict nonresponse in advance, such that predicted nonresponse propensities can be used to inform the data collection process. However, predicting nonresponse in panel studies requires accounting for the longitudinal data structure in terms of model building, tuning, and evaluation. This study proposes a longitudinal framework for predicting nonresponse with machine learning and multiple panel waves and illustrates its application. With respect to model building, this approach utilizes information from multiple waves by introducing features that aggregate previous (non)response patterns. Concerning model tuning and evaluation, temporal crossvalidation is employed by iterating through pairs of panel waves such that the training and test sets move in time. Implementing this approach with data from a German probability-based mixed-mode panel shows that aggregating information over multiple panel waves can be used to build prediction models with competitive and robust performance over all test waves.

Introduction Precise fibular tunnel placement in posterolateral corner (PLC) reconstruction is crucial in restoring rotational and lateral stability. Despite the recent progress of arthroscopic PLC reconstruction techniques, landmarks for arthroscopic fibular tunnel placement and a comparison to open tunnel placement have not yet been described. This study aimed to (1) identify reasonable soft-tissue and bony landmarks, which can be identified by either arthroscopy, fluoroscopy, or open surgery in anatomic fibular tunnel placement and (2) to compare accuracy and reliability of arthroscopic fibular tunnel placement with open surgery. Materials and Methods In a retrospective study, 41 magnetic resonance images (MRIs) of the knee were analyzed with emphasis on distances of an ideal anatomic fibular tunnel to 11 soft-tissue and bony landmarks. Subsequently, in eight cadaver knees, the ideal fibular tunnel was created arthroscopically and with a standard open technique from antero-latero-inferior to postero-medio-superior with a 2-mm K-wire. Positions of both tunnels were compared on postinterventional computed tomography scans. Results Based on MRI measurements, the anatomic tunnel entry should be 14.50 (±2.18) mm distal to the tip of the fibular styloid and 10.76 (±1.37) mm posterior to the anterior edge of the fibula. The anatomic fibular tunnel exit was located 12.89 (±2.35) mm below the tip of the fibular head. Arthroscopic fibular tunnel placement was reliable in all cases. Instead, in five out of the eight cases with open surgery, the fibular tunnel crossed the defined safety distance to the closest cortical edge/tibiofibular joint (distance Conclusions Reliable soft-tissue and bony landmarks of the fibular head allow arthroscopic anatomic fibular tunnel placement in PLC surgery, which shows a lower risk of tunnel malposition compared with open surgical techniques. Future studies will have to show whether clinical results of arthroscopic PLC reconstruction are in line with this study's technical results. Level of Evidence Level III.

Pulmonary fibrosis is a progressive lung disease characterized by myofibroblast accumulation and excessive extracellular matrix deposition. Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR), a cellular stress response pathway that has been implicated in both inflammatory and fibrotic processes. Here, we sought to investigate the role of the 13 kDa FK506-binding protein (FKBP13), an ER stress-inducible molecular chaperone, in various forms of pulmonary fibrosis. We first characterized the gene and protein expression of FKBP13 in lung biopsy samples from 24 patients with idiopathic pulmonary fibrosis (IPF) and 17 control subjects. FKBP13 expression was found to be elevated in the fibrotic regions of IPF lung tissues, and within this cohort, was correlated with declining forced vital capacity and dyspnea severity. FKBP13 expression was also increased in lung biopsies of patients with hypersensitivity pneumonitis, rheumatoid arthritis, and sarcoidosis-associated interstitial lung disease. We next evaluated the role of this protein using FKBP13-/- mice in a bleomycin model of pulmonary fibrosis. Animals were assessed for lung function and histopathology at different stages of lung injury including the inflammatory (Day 7), fibrotic (Day 21) and resolution (Day 50) phase. FKBP13-/- mice showed increased infiltration of inflammatory cells and cytokines at Day 7, increased lung elastance and fibrosis at Day 21, and impaired resolution of fibrosis at Day 50. These changes were associated with an increased number of cells that stained positive for TUNEL and cleaved caspase 3 in the FKBP13-/- lungs, indicating a heightened cellular sensitivity to bleomycin. Our findings suggest that FKBP13 is a potential biomarker for severity or progression of interstitial lung diseases, and that it has a biologically relevant role in protecting mice against bleomycin-induced injury, inflammation and fibrosis.

A new high field spectrometer has been built to extend the capabilities of the $\beta$-detected nuclear magnetic resonance ($\beta$-NMR) facility at TRIUMF. This new beamline extension allows $\beta$-NMR spectroscopy to be performed with fields up to 200 mT parallel to a sample's surface (perpendicular to the ion beam), allowing depth-resolved studies of local electromagnetic fields with spin polarized probes at a much higher applied magnetic field than previously available in this configuration. The primary motivation and application is to allow studies of superconducting radio frequency (SRF) materials, close to the critical fields of Nb metal, which is extensively used to fabricate SRF cavities. The details of the design considerations and implementation of the ultra-high vacuum (UHV) system, ion optics, beam diagnostics are presented here. Commissioning of the beamline and spectrometer with radioactive ions are also reported here. Future capabilities and applications in other areas are also described., Comment: Co-authors' misspelled names are fixed to conform with their ORCiD. Typho in eq. (1) is fixed

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.

The genome of cowpoxvirus (CPXV) could be considered prototypical for orthopoxviridae (OXPV) since it contains many open reading frames (ORFs) absent or lost in other OPXV, including vaccinia virus (VACV). These additional ORFs are non-essential for growthin vitrobut are expected to contribute to the broad host range, virulence and immune evasion characteristics of CPXV. For instance, unlike VACV, CPXV encodes proteins that interfere with T cell stimulation, either directly or by preventing antigen presentation or co-stimulation. When studying the priming of naïve T cells, we discovered that CPXV, but not VACV, encodes a secreted factor that interferes with activation and proliferation of naïve CD8+ and CD4+ T cells, respectively, in response to anti-CD3 antibodies, but not to other stimuli. Deletion mapping revealed that the inhibitory protein is encoded by CPXV14, a small secreted glycoprotein belonging to the poxvirus immune evasion (PIE) family and containing a smallpoxvirus encoded chemokine receptor (SECRET) domain that mediates binding to chemokines. We demonstrate that CPXV14 inhibition of antibody-mediated T cell activation depends on the presence of Fc-gamma receptors (FcγRs) on bystander cells.In vitro, CPXV14 inhibits FcγR-activation by antigen/antibody complexes by binding to FcγRs with high affinity and immobilized CPXV14 can trigger signaling through FcγRs, particularly the inhibitory FcγRIIB.In vivo, CPXV14-deleted virus showed reduced viremia and virulence resulting in reduced weight loss and death compared to wildtype virus whereas both antibody and CD8+ T cell responses were increased in the absence of CPXV14. Furthermore, no impact of CPXV14-deletion on virulence was observed in mice lacking the inhibitory FcγRIIB. Taken together our results suggest that CPXV14 contributes to virulence and immune evasion by binding to host FcγRs.

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.

In spring 2021, an increasing number of infections was observed caused by the hitherto rarely described SARS-CoV-2 variant A.27 in south-west Germany. From December 2020 to June 2021 this lineage has been detected in 31 countries. Phylogeographic analyses of A.27 sequences obtained from national and international databases reveal a global spread of this lineage through multiple introductions from its inferred origin in Western Africa. Variant A.27 is characterized by a mutational pattern in the spike gene that includes the L18F, L452R and N501Y spike amino acid substitutions found in various variants of concern but lacks the globally dominant D614G. Neutralization assays demonstrate an escape of A.27 from convalescent and vaccine-elicited antibody-mediated immunity. Moreover, the therapeutic monoclonal antibody Bamlanivimab and partially the REGN-COV2 cocktail fail to block infection by A.27. Our data emphasize the need for continued global monitoring of novel lineages because of the independent evolution of new escape mutations. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

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.

Introduction ACL injury is one of the most common injuries of the knee joint in sports. As accompanying osseous injuries of the ACL rupture a femoral impression the so-called lateral femoral notch sign and a posterolateral fracture of the tibial plateau are described. However, frequency, concomitant ligament injuries and when and how to treat these combined injuries are not clear. There is still a lack of understanding with which ligamentous concomitant injuries besides the anterior cruciate ligament injury these bony injuries are associated. Materials and methods One hundred fifteen MRI scans with proven anterior cruciate ligament rupture performed at our center were retrospectively evaluated for the presence of a meniscus, collateral ligament injury, a femoral impression, or a posterolateral impression fracture. Femoral impressions were described according to their local appearance and posterolateral tibial plateau fractures were described using the classification of Menzdorf et al. Results In 29 cases a significant impression in the lateral femoral condyle was detected. There was a significantly increased number of lateral meniscal (41.4% vs. 18.6% p = 0.023) and medial ligament (41.4% vs. 22.1%; p = 0.040) injuries in the group with a lateral femoral notch sign. 104 patients showed a posterolateral bone bruise or fracture of the tibial plateau. Seven of these required an intervention according to Menzdorf et al. In the group of anterior cruciate ligament injuries with posterolateral tibial plateau fracture significantly more lateral meniscus injuries were seen (p = 0.039). Conclusion In the preoperative planning of ACL rupture accompanied with a positive femoral notch sign, attention should be paid to possible medial collateral ligament and lateral meniscus injuries. As these are more likely to occur together. A posterolateral impression fracture of the tibial plateau is associated with an increased likelihood of the presence of a lateral meniscal injury. This must be considered in surgical therapy and planning and may be the indication for necessary early surgical treatment.

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is traditionally considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document that patients who develop soluble circulating IgG immune complexes (sICs) during infection are subject to enhanced immunopathology driven by FcγR activation. Utilizing cell-based reporter systems we provide evidence that sICs are predominantly formed prior to a specific humoral response against SARS-CoV-2. sIC formation, together with increased afucosylation of SARS-CoV-2 specific IgG eventually leads to an enhanced CD16 (FcγRIII) activation of immune cells reaching activation levels comparable active systemic lupus erythematosus (SLE) disease. Our data suggest a vicious cycle of escalating immunopathology driven by an early formation of sICs in predisposed patients. These findings reconcile the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19.Clinical implicationsThe identification of sICs as drivers of an escalating immunopathology in predisposed patients opens new avenues regarding intervention strategies to alleviate critical COVID-19 progression.Graphical abstractA vicious cycle of immunopathology in COVID-19 patients is driven by soluble multimeric immune complexes (sICs). SARS-CoV-2 infection triggers sIC formation in prone individuals. Activation of FcγRIII/CD16 expressing immune cells by sICs precedes a humoral response to SARS-CoV2 infection. sICs and infection add to IgG afucosylation, further enhancing FcγRIII/CD16 activation by opsonized targets. High inflammation induces further sIC mediated immune cell activation ultimately leading to an escalating immunopathology.

Findings from recent transcriptome analyses of the synovium of patients with rheumatoid arthritis (RA) have revealed that 15-fold expanded HLA-DR+CD90+ synovial fibroblasts potentially act as key mediators of inflammation. The reasons for the expansion of HLA-DR+CD90+ synovial fibroblasts are unclear, but genetic signatures indicate that interferon-γ (IFNγ) plays a central role in the generation of this fibroblast subset. The present study was undertaken to investigate the generation, function and therapeutically intended blockage of HLA-DR+CD90+ synovial fibroblasts.We combined functional assays using primary human materials and focused bioinformatic analyses of mass cytometry and transcriptomics patient data sets.We detected enriched and activated Fcγ receptor type IIIa-positive (CD16+) NK cells in the synovial tissue from patients with active RA. Soluble immune complexes were recognized by CD16 in a newly described reporter cell model, a mechanism that could be contributing to the activation of natural killer (NK) cells in RA. In vitro, NK cell-derived IFNγ induced HLA-DR on CD90+ synovial fibroblasts, leading to an inflammatory, cytokine-secreting HLA-DR+CD90+ phenotype. HLA-DR+CD90+ synovial fibroblasts consecutively activated CD4+ T cells upon receptor crosslinking via superantigens. HLA-DR+CD90+ synovial fibroblasts also activated CD4+ T cells in the absence of superantigens, an effect that was initiated by NK cell-derived IFNγ and that was 4 times stronger in patients with RA compared to patients with osteoarthritis. Finally, JAK inhibition in synovial fibroblasts prevented HLA-DR induction and blocked proinflammatory signals to T cells.The HLA-DR+CD90+ phenotype represents an activation state of synovial fibroblasts during the process of inflammation in RA that can be induced by IFNγ, likely generated from infiltrating leukocytes such as activated NK cells. The induction of these proinflammatory, interleukin-6-producing, and likely antigen-presenting synovial fibroblasts can be targeted by JAK inhibition.

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.

Injuries of the posterolateral corner (PLC) of the knee lead to chronic lateral and external rotational instability. Successful treatment of PLC injuries requires an understanding of the complex anatomy and biomechanics of the PLC. Several open PLC reconstruction techniques have been published. It is understood that anatomic reconstruction is superior to extra-anatomic techniques, leading to better clinical results. An open, anatomic, fibula-based technique for reconstruction to address lateral and rotational instability has been described. However, when an open technique is used, surgeon and patient are faced with disadvantages, such as soft tissue damage or exposure of vulnerable structures. Few arthroscopic techniques for tibia- or fibula-based reconstruction of rotational posterolateral instability have been described. A complete arthroscopic stabilization of the combined lateral and posterolateral rotational instability of the knee has not yet been described. We therefore present the first all-arthroscopic technique for complete PLC reconstruction, based on an open technique described previously. All relevant landmarks of the PLC can be arthroscopically visualized in detail, allowing safe and effective treatment of PLC injuries.

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.

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.

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. Previously described FcγR interaction assays are limited to certain FcγRs, lack scalability and flexibility, are not indicative of receptor activation or lack sensitivity towards sIC size. We developed a comprehensive reporter cell panel detecting individual activation of FcγRs from humans and the mouse. The reporter cell lines were integrated into an assay format that provides flexible read-outs enabling the quantification of sIC reactivity via ELISA or a fast detection using flow cytometry. This identified FcγRIIA(H) and FcγRIIIA as the most sIC-sensitive FcγRs in our test system. Applying the assay we demonstrate that sICs versus immobilized ICs are fundamentally different FcγR-ligands with regard to FcγR preference and signal strength. Reaching a detection limit in the very low nanomolar range, the assay proved also to be sensitive to sIC stoichiometry and size enabling for the first time a complete reproduction of the Heidelberger-Kendall precipitation 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 new methodology provides a sensitive, scalable and comprehensive tool to evaluate the size, amount and bioactivity of sICs in all settings.One Sentence SummaryIn this study we established a comprehensive FcγR reporter cell assay enabling the detection and quantification of soluble immune complexes generated in experimental and clinical settings.

Background: Coronavirus disease 2019 (COVID-19)–related critical illness and acute illness are associated with a 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 decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19–related critical illness and acute illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest. The panel included 3 patient representatives. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020). 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, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 2 recommendations. The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19–related critical illness or acute illness who do not have confirmed or suspected VTE. Conclusions: These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. They will be updated using a living recommendation approach as new evidence becomes available., Visual Abstract

Background: Osteoporosis affects elderly patients of both sexes. It is characterized by an increased fracture risk due to defective remodeling of the bone microarchitecture. It affects in particular postmenopausal women due to their decreased levels of estrogen. Preclinical studies with animals demonstrated that loss of estrogen had a negative effect on bone healing and that increasing the estrogen level led to a better bone healing. We asked whether increasing the estrogen level in menopausal patients has a beneficial effect on bone mineral density (BMD) during callus formation after a bone fracture.Methods: To investigate whether estrogen has a beneficial effect on callus BMD of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13 years ± 11.99) were treated with estrogen and 45 patients (75.62 years ± 10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and six weeks after the surgery. Comparative measurements were performed at the fractured site and at the corresponding position of the non-fractured arm.Results: We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients.Conclusions: Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on callus BMD as measured by pQCT, as recently shown in preclinical animal models.Trial registration: Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858. Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858.

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 cell-mediated 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.Graphical AbstractNK cells elicit a powerful antibody-mediated antiviral response through ADCC. gp68 (ochroid) binds IgG in a 2:1 ratio reducing, but not abolishing accessibility of immune complexes to FcγRIII+ (dark blue) immune effector cells such as NK cells. gp34 (red, natively forming a dimer (Sprague et al., 2008)) effectively internalizes immune complexes making them unavailable to surveilling FcγRIII+ effector cells but cannot compete with FcγRIII for a similar binding region on IgG. Supported by functional evaluation, we propose a model in which g34 and gp68 work in cooperation to achieve efficient antagonization of antibody-mediated effector mechanisms.

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.

The anterior cruciate ligament (ACL)-tear is a common injury in orthopaedic trauma. Depending on the energy of impact fractures of the posterolateral tibial plateau are often associated. Different morphologic variants of posterolateral tibial plateau impaction fractures have been described in the setting of an ACL-tear. Up to now an algorithm of treatment for a combined injury of a posterolateral tibial head fracture and an injury to the anterior cruciate ligament is missing. We present a retrospective study with clinical and radiological analysis of posterolateral fractures in combination with ACL-tear. Impressions with a depth of more than 2 mm and/or a width that outreaches more than half of the posterior horn of the lateral meniscus with additional 3. degree positive pivot-shift-test indicated surgical treatment of the fracture with additional ACL repair or reconstruction. Clinical evaluation included follow-up examination, Visual Analog Scale (VAS), International Knee Documentation Committee Score (IKDC), functional and radiological Rasmussen score. 20 patients were included with a mean age of 43.6 ± 12.4 years. Mean follow-up was 18,2 ± 13,5 months. The fracture was arthroscopically reduced and percutaneously fixed with a screw osteosynthesis (Group 1), reduced via a dorsal approach without (Group 2) or with an autologous bone graft (Group 3). Subjective IKDC score was 79,15 ± 6,07. Functional Rasmussen scores ranged from 27 to 30 (mean 28 ± 2.71). Radiological Rasmussen scores ranged from 16 to 18 points (mean 16.75 ± 1.33). According to IKDC score (p = 0.60), functional Rasmussen score (p = 0.829) and radiological Rasmussen score (p = 0.679) no significant discrepancy between the groups were seen. There was no failure of the ACL graft recorded. Posterolateral tibial plateau fractures in combination with an ACL-tear, can cause persistent instability and increase rotational instability. Indication for treatment of these fractures is still under debate. From the biomechanical aspect the lack of more than 50% of the posterior horn of the lateral meniscus and dislocation/depression of more than 2 mm results in an increased rotational instability of the ACL deficient knee. Combined surgical treatment with ACL repair or reconstruction is a safe procedure that results in good, short-term clinical outcome, if our algorithm is followed. In addition this study shows, that majority of posterolateral tibial plateau fractures can be treated arthroscopically.

Background The skeletal disease osteoporosis affects primarily postmenopausal women. It is characterized by increased fracture risk due to defective remodeling of bone tissue and a pathological bone microarchitecture in response to the decreased levels of estrogen. Osteoporosis is clinically silent up until a first fracture occurs. Therefore, the diagnosis of the disease is usually late. Recent preclinical studies with mice, rats and rabbits suggested that estrogen treatment enhances the healing effect after bone fractures. Here we asked whether transdermally applied estrogen, which restores the systemic premenopausal level of estrogen, has a beneficial effect on fracture healing of postmenopausal women as observed in preclinical models. Methods To investigate whether estrogen has a beneficial effect on bone fracture healing of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13 years ± 11.99) were treated with estrogen and 45 patients (75.62 years ± 10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and six weeks after the surgery. Results We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients. Conclusions Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on bone fracture healing.

Purpose Anatomic reduction in tibial plateau fractures remains to be demanding. For further visualisation of and approach to the joint surface an extended lateral approach using a lateral femoral epicondyle osteotomy and subluxation of the lateral meniscus was recently described. First clinical and radiographic mid-term results of this technique are presented in this feasibility study. Method Ten complex tibial plateau fractures treated with extended lateral approach and lateral meniscal subluxation were prospectively analysed. Clinical and radiographic results were objectified according to the Rasmussen scores. Results After a median follow-up of 8.6 (IQR 4.3) months good to excellent clinical and radiographic results were noted. The clinical Rasmussen Score showed a median of 25 (IQR 2.8) and radiographic a median of 17 (IQR 2.0) points. Conclusion Good to excellent clinical and radiological scores were obtained after using an extended lateral approach with lateral femoral epicondyle osteotomy and central meniscus subluxation. No approach specific complications could be observed.

The goal of surgical reconstruction of comminuted tibial plateau fractures is an anatomical reconstruction and stable fixation of the articular surface. This can be difficult due to poor visualization of the posterolateral and central segments of the articular surface of the proximal tibia. To improve visualization, the lateral approach can be extended with an osteotomy of the femoral epicondyle. In most cases, use of the extended lateral approach allows the whole lateral plateau to be visualized. Nevertheless, in some cases, an osteotomy alone is not enough to expose the entire fracture, especially the central segments of the tibial plateau. For these specific cases, we developed an additional technical trick that significantly improves articular visualization; the lateral meniscocapsular fibers are dissected allowing for central subluxation of the lateral meniscus, while leaving the anterior and posterior roots intact. With central subluxation of the lateral meniscus in comminuted tibial plateau fractures, the joint surface can be completely visualized, allowing an anatomical reduction even in highly complex fractures.

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.

The objective of this study is to report the institutions experiences with standardized 2D computer-navigated percutaneous iliosacral screw placement (CNS), as well as the conventional fluoroscopically assisted screw placement method (CF) over a period of 10 years. A total of 604 patients with sacral fractures (OTA B and C) were treated at the institution. Cases with both, a preoperative and postoperative CT scan were included for further analysis. With this prerequisite, a total of 136 cases were included. The quality of screw positioning, length of operation and intraoperative radiation exposure were recorded and compared. Moreover, it was analyzed whether the presence of dysmorphic sacra influenced the precision of screw positioning. Two hundred and thirty-two screws were implanted in 136 patients (100 navigated, 36 conventional). The duration of the average procedure was similar in the two groups [49.8 min (p = 0.7) conventional group (CF) vs. 48.0 min computer-navigated (CNS) group]. With computer navigation, radiation exposure was significantly reduced by almost half [128.3 vs. 65.2 s (p = 0.023)]. Screw placement was more accurate in the navigation group (79.03% CF vs. 86.47% CNS). The presence of dysmorphic sacral foramina or an increased alar slope increased the incidence of screw malpositioning. The conventional percutaneous method and a standardized 2D navigated method have similar rates of malpositioning. Dysmorphic upper sacral foramina and increased alar slope were identified as risk factors for screw malpositioning. Radiation exposure rates were reduced by half when using computer navigation. Therefore, computer navigation in iliosacral screw placement is recommended as method of choice.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are life-threatening diseases with a high burden of symptoms. Although depression, anxiety, and reduced health related quality of life (HRQOL) have also been reported, a comparative analysis which explores these traits and their underlying factors was lacking. A retrospective analysis of depression, anxiety, and health related QOL was conducted using a Hospital anxiety and depression scale (HADS) as well as the SF-36 HRQOL questionnaire. Results from these tools were compared with haemodynamic and functional parameters in 70 PAH and 23 CTEPH outpatients from a German tertiary care center specializing in pulmonary hypertension. Although HRQOL was reduced in both cohorts of patients, individuals diagnosed with CTEPH scored lower in nearly all SF-36 parameters. Significance was noted in both “mental health” (p = 0.01) and “mental component summary score” (MCS) (p = 0.02). Depression was also more frequent in patients with CTEPH (56%) than in patients with PAH (30%), (p = 0.03). Overall, depression and anxiety correlated with most SF-36 scales in both PAH and CTEPH. In CTEPH, depression also correlated with the Borg Dyspnea Scale (r = 0.44, p = 0.01). These patients also had significantly lower pCO2 levels than the PAH cohort reflecting more severe ventilation/perfusion mismatch. All other haemodynamic and functional parameters did not differ across the groups. While both cohorts of patients suffer from a reduced HRQOL as well as depression and anxiety, decreases in mental health parameters are more pronounced in the CTEPH cohort. This suggests a strong effort to improve early detection, especially in dyspneic patients with classical risk factors for CTEPH and PAH and argues for mental illness interventions alongside routine clinical care provided to patients diagnosed with PAH or CTEPH.

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.