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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.

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.

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.

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.

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.

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.

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.

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.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been associated with fibrotic lung disease, although exactly how they modulate this process remains unclear. Here we investigated the role of GRP78, the main UPR regulator, in an experimental model of lung injury and fibrosis. Grp78(+/-) , Chop(-/-) and wild type C57BL6/J mice were exposed to bleomycin by oropharyngeal intubation and lungs were examined at days 7 and 21. We demonstrate here that Grp78(+/-) mice were strongly protected from bleomycin-induced fibrosis, as shown by immunohistochemical analysis, collagen content and lung function measurements. In the inflammatory phase of this model, a reduced number of lung macrophages associated with an increased number of TUNEL-positive cells were observed in Grp78(+/-) mice. Dual immunohistochemical and in situ hybridization experiments showed that the macrophage population from the protected Grp78(+/-) mice was also strongly positive for cleaved caspase-3 and Chop mRNA, respectively. In contrast, the administration of bleomycin to Chop(-/-) mice resulted in increased quasi-static elastance and extracellular matrix deposition associated with an increased number of parenchymal arginase-1-positive macrophages that were negative for cleaved caspase-3. The data presented indicate that the UPR is activated in fibrotic lung tissue and strongly localized to macrophages. GRP78- and CHOP-mediated macrophage apoptosis was found to protect against bleomycin-induced fibrosis. Overall, we demonstrate here that the fibrotic response to bleomycin is dependent on GRP78-mediated events and provides evidence that macrophage polarization and apoptosis may play a role in this process. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5–7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting 7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause representing the most common form of idiopathic interstitial pneumonias. It is believed that the development of IPF is influenced by both genetic and environmental factors. The pathogenesis of IPF is complex, and many contributing factors to fibrogenesis are known to date. In recent years there have been important advances in the understanding of the pathogenesis of IPF. A large number of experimental studies have highlighted the importance of epithelial cell injury, fibroblast differentiation and myofibroblast activation, the involvement of inflammatory and progenitor cells, and the effect of genetic and epigenetic factors. IPF is characterized by progressive fibroblast proliferation and differentiation followed by excessive deposition of extracellular matrix (ECM). This results in the damage to the structure of the lung, which eventually causes dyspnea and respiratory failure in patients with IPF. This fibrotic ECM microenvironment is characterized by altered biochemical and biomechanical properties and stores abundant amounts of growth factors, all of which can affect the behavior of structural lung cells and also inflammatory cells. This chapter summarizes the newest insights into the pathogenesis of IPF and tries to describe how this knowledge helps to find new therapies for the patients who are suffering from this devastating disease.

Normal progression of osteoporosis or the rigid reinforcement of the fractured vertebral body with polymethyl methacrylate (PMMA) cement is being discussed as a cause for adjacent-level fractures after vertebroplasty. The purpose of this study was to investigate whether augmentation with low stiffness cement can decrease the risk of adjacent-level fractures in low-quality bone.Eighteen female osteoporotic lumbar specimens (L1-L5) were harvested and divided into three groups according to bone mineral density: (I) native; (II) PMMA; (III) modified PMMA (lower stiffness). For the PMMA and modified PMMA groups, a compression fracture was first mechanically induced in L3, and then the fracture received vertebroplasty treatment. The cement stiffness reduction of the modified PMMA group was achieved via an addition of 8 mL of serum to the typical PMMA base. All specimens were exposed to cyclic loading (4 Hz) and a stepwise increasing applied peak force. Cement stiffness was tested according to ISO 5833.A 51% decrease in cement stiffness was achieved in the modified PMMA group (954 ± 141 vs. 1,937 ± 478 MPa, p0.001). Fatigue fracture force (the force level during cyclic loading at which the deformation experienced a sudden increase; FFF) was significantly affected by bone quality (r (2) = 0.39, p = 0.006) and by the initial fracture force (the force necessary to create the initial fracture in L3 prior to augmentation; r (2) = 0.82, p0.001). Using initial fracture force as a covariate, the FFF of the modified PMMA group (1,764 ± 49 N) was significantly higher than in the PMMA group (1,544 ± 55 N; p = 0.03).A possible method to reduce adjacent-level fractures after vertebroplasty in patients with reduced bone quality could be the use of a lower modulus cement. Therefore, mixing cement with biocompatible fluids could prove useful to tailor cement properties in the operating theater.

Background: Patients with chronic thromboembolic pulmonary disease (CTED) have persistent pulmonary vascular obstruction and exercise intolerance without pulmonary hypertension at rest and may benefit from pulmonary endarterectomy. However, up to now, CTED has been poorly characterized. Objectives: This study aimed to analyze the exercise capacity and limiting factors in CTED. Methods: We compared right heart catheterization and cardiopulmonary exercise test results of patients with CTED [mean pulmonary artery pressure (mPAP) at rest Results: Subjects with CTED show a reduced oxygen uptake [median 76/interquartile range (IQR) 22% pred.] and work rate (median 76/IQR 21 W). The work rate was significantly lower compared to control subjects (p = 0.04) but not significantly different from CTEPH patients (p = 0.66). Oxygen pulse and breathing reserve were normal. CTED subjects showed decreased end-tidal CO2 at anaerobic threshold (28.4/4.3 mm Hg), an elevated VE/VCO2 slope (42.5/23.5), breathing equivalents (EQO2 32.0/8.7, EQCO2 39.5/8.8), alveolar-capillary oxygen gradient (34.7/15.5 mm Hg) and capillary end-tidal carbon dioxide gradient (8.8/5.7 mm Hg) compared to control subjects (p < 0.001). The degree of limitation was similar to that in CTEPH. Conclusions: Despite an mPAP of

Background Early diagnosis and prediction of traumatic brain injury (TBI) is essential for determining treatment strategies and allocating resources. This study evaluated the predictive accuracy of Glasgow Coma Scale (GCS) verbal, motor and eye components alone, or in addition to pupil size and reactivity, for TBI. Methods A retrospective cohort analysis of data from 51 425 severely injured patients registered in the Trauma Registry of the German Society for Trauma Surgery from 1993 to 2009 was undertaken. Only directly admitted patients alive on admission and with complete data on GCS, pupil size and pupil reactivity were included. The unadjusted predictive roles of GCS components and pupil parameters, alone or in combination, were modelled using area under the receiver operating characteristic (AUROC) curve analyses and multivariable logistic regression regarding presence of TBI and death. Results Some 24 115 patients fulfilled the study inclusion criteria. Best accuracy for outcome prediction was found for pupil reactivity (AUROC 0·770, 95 per cent confidence interval 0·761 to 0·779) and GCS motor component (AUROC 0·797, 0·788 to 0·805), with less accuracy for GCS eye and verbal components. The combination of pupil reactivity and GCS motor component (AUROC 0·822, 0·814 to 0·830) outmatched the predictive accuracy of GCS alone (AUROC 0·808, 0·800 to 0·815). Pupil reactivity and size were significantly correlated (rs = 0·56, P < 0·001). Patients displaying both unequal pupils and fixed pupils were most likely to have TBI (95·1 per cent of 283 patients). Good outcome (Glasgow Outcome Scale score 4 or more) was documented for only 1929 patients (8·0 per cent) showing fixed and bilateral dilated pupils. Conclusion The best predictive accuracy for presence of TBI was obtained using the GCS components. Pupil reactivity together with the GCS motor component performed best in predicting death.

Proximal femoral fractures will gain increasing importance in the future due to the epidemiological development. Osteoporosis is often a limiting factor in the achievement of implant stability. New nailing systems offer the possibility of augmentation of the femoral neck component with cement. The aim of this study was to perform a biomechanical comparison of implant stability in osteoporotic pertrochanteric fractures using the proximal femoral nail antirotation (PFNA, Synthes GmbH, Umkirch, Germany) with cement augmented and non-augmented blades.Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXA) in six pairs of fresh-frozen human femurs. Standardised pertrochanteric fractures (AO31-A2.3) were treated with a PFNA. Cement augmentation was performed in six constructs. Axial loading was applied according to a single-leg-stance model using a hydraulic testing machine increasing to 1400N over 10,000 cycles. Biomechanical comparisons between the two groups that were comparable concerning BMD, tip-apex-distance and native stiffness were made with regard to postoperative stiffness, survived cycles, load to failure, failure mechanism and axial displacement.The stiffness of all stabilised femurs was significantly lower than for native specimens (native 702.5±159.6N/mm vs. postoperative 275.4±53.8N/mm, p0.001). Stiffness after instrumentation was significantly greater for the cement augmented group than for the non-augmented group (300.6±46.7N/mm vs. 250.3±51.6N/mm, respectively, p=0.001). Five of the twelve constructs survived cyclic testing. Statistically significant differences of the BMD were detected between survived and failed constructs (0.79±0.17g/cm(2) vs. 0.45±0.12g/cm(2), respectively, p=0.028). The failure loads for specimens surviving 10,000 cycles were 4611.9±2078.9N in the cement augmented group (n=3) and 4516.3N and 3253.5N in the non-augmented group (n=2). Postoperative stiffness was found to be a positive predictor of maximum force to failure (R(2)=0.83, p=0.02).The results of this biomechanical study show that cement augmentation of the PFNA increases the implant stability in osteoporotic pertrochanteric fractures. Further studies are necessary to evaluate this procedure in providing long term clinical results.