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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.

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.

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

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

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.

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.

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.

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

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.

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.

In an era of mass migration, social scientists, populist parties and social movements raise concerns over the future of immigration-destination societies. What impacts does this have on policy and social solidarity? Comparative cross-national research, relying mostly on secondary data, has findings in different directions. There is a threat of selective model reporting and lack of replicability. The heterogeneity of countries obscures attempts to clearly define data-generating models. P-hacking and HARKing lurk among standard research practices in this area.This project employs crowdsourcing to address these issues. It draws on replication, deliberation, meta-analysis and harnessing the power of many minds at once. The Crowdsourced Replication Initiative carries two main goals, (a) to better investigate the linkage between immigration and social policy preferences across countries, and (b) to develop crowdsourcing as a social science method. The Executive Report provides short reviews of the area of social policy preferences and immigration, and the methods and impetus behind crowdsourcing plus a description of the entire project. Three main areas of findings will appear in three papers, that are registered as PAPs or in process.

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

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

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.

For posterior spinal stabilization, loosening of pedicle screws at the bone-screw interface is a clinical complication, especially in the osteoporotic population. Axial pullout testing is the standard pre-clinical testing method for new screw designs although it has questioned clinical relevance. The aim of this study was to determine the fixation strength of three current osteoporotic fixation techniques and to investigate whether or not pullout testing results can directly relate to those of the more physiologic fatigue testing. Thirty-nine osteoporotic, human lumbar vertebrae were instrumented with pedicle screws according to four treatment groups: (1) screw only (control), (2) prefilled augmentation, (3) screw injected augmentation, and (4) unaugmented screws with an increased diameter. Toggle testing was first performed on one pedicle, using a cranial-caudal sinusoidal, cyclic (1.0 Hz) fatigue loading applied at the screw head. The initial compressive forces ranged from 25 to 75 N. Peak force increased stepwise by 25 N every 250 cycles until a 5.4-mm screw head displacement. The contralateral screw then underwent pure axial pullout (5 mm/min). When compared to the control group, screw injected augmentation increased fatigue force (27 %, p = 0.045) while prefilled augmentation reduced fatigue force (−7 %, p = 0.73). Both augmentation techniques increased pullout force compared to the control (ps

At TRIUMF development of a 50 MeV electron accelerator is well under way. Five 1.3 GHz, superconducting 9-cell cavities will accelerate 10 mA electrons to a production target to produce rare isotopes. Each cavity will provide 10 MV accelerating voltage. Plans to upgrade the accelerator in the future to a small ring with ERL capabilities requires that the shunt impedance of the dipole higher order modes to be less than 10 M Ω . The design of the accelerator incorporates beam line absorbers to reduce the shunt impedance of potentially dangerous dipole modes. The performance of the absorber is dependant on its electrical conductivity at the operational temperature. Measurements of the electrical conductivity in RF fields of a sample of the proposed beam line absorber material at room temperature and at its operational temperature will be presented for frequencies between 1.3 and 2.4 GHz.

A combined anterior and posterior surgical approach is generally recommended in the treatment of severe congenital kyphosis, despite the fact that the anterior vascular supply of the spine and viscera are at risk during exposure. The aim of this study was to determine whether the surgical treatment of severe congenital thoracolumbar kyphosis through a single posterior approach is feasible, safe and effective. We reviewed the records of ten patients with a mean age of 11.1 years (5.4 to 14.1) who underwent surgery either by pedicle subtraction osteotomy or by vertebral column resection with instrumented fusion through a single posterior approach. The mean kyphotic deformity improved from 59.9° (45° to 110°) pre-operatively to 17.5° (3° to 40°) at a mean follow-up of 47.0 months (29 to 85). Spinal cord monitoring was used in all patients and there were no complications during surgery. These promising results indicate the possible advantages of the described technique over the established procedures. We believe that surgery should be performed in case of documented progression and before structural secondary curves develop. Our current strategy after documented progression is to recommend surgery at the age of five years and when 90% of the diameter of the spinal canal has already developed. Cite this article: Bone Joint J 2013;95-B:1527–32.

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

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

Recent studies suggest that calcium and 25-[OH]-cholecalciferol represent substantial co-factors in fracture healing. However, there still seems to be no sustainable consensus regarding the influence on fracture healing patterns. In this study, the influence of calcium and vitamin D levels on fracture callus formation was prospectively analysed using pQCT scan.94 postmenopausal females with distal radius fractures and consecutive surgery were included. Calcium, 25-[OH]-cholecalciferol, parathyroid hormone and bone-specific alkaline phosphatase levels were obtained prior surgical treatment and after 6 weeks. A pQCT scan was performed on both sites. Bone mineral density and fracture callus area were determined after detecting the outer border contour at a threshold of 280 mg/ccm. Patients received daily supplements of 1000 mg calcium and 880 IU 25-[OH]-cholecalciferol.Mean 25-[OH]-cholecalciferol level was 19.61 ± 21.87 ng/ml, mean parathyroid hormone level was 52.6 ± 58.9 ng/l and mean Ca level was 2.23 ± 0.35 mmol/l. After 6 weeks of supplementation a significant increase of calcium (p0.001) and 25-[OH]-cholecalciferol (p0.001), and a significant decrease of parathyroid hormone (p0.001) levels were observed. Sixth week follow-up fracture callus area correlated significantly with postoperative normal range calcium levels on the fractured site (p = 0.006). Bone mineral density correlated with age (p0.001), but not with calcium and 25-[OH]-cholecalciferol levels after 6 weeks. All fractures presented timely adequate callus formation.Calcium and parathyroid hormone serum levels influence fracture callus area interpreted as fracture callus formation patterns. Calcium levels within physiological range accounted for highest fracture callus area. Therefore, a balanced calcium homeostasis is required for appropriate callus formation.

Due to increasing life expectancy we see a rising number of joint replacements. Along with the proximal prosthesis in the femur, more and more people have a second implant on the distal ipsilateral side. This might be a retrograde nail or a locking plate to treat distal femur fractures or a constrained knee prosthesis in the case of severe arthrosis. All these constructs can lead to fractures between the implants. The goal of this study was to evaluate the risk of stress risers for interprosthetic fractures of the femur.Thirty human cadaveric femurs were divided into five groups: (1) femurs with a prosthesis on the proximal side only, (2) hip prosthesis on the proximal end and a distal femur nail, (3) femurs with both a hip prosthesis and a constrained knee prosthesis, (4) femurs with a hip prosthesis on the proximal side and a 4.5-mm distal femur locking plate; the locking plate was 230 mm in length, with ten holes in the shaft, and (5) femurs with a proximal hip prosthesis and a 4.5-mm distal femur locking plate; the locking plate was 342 mm in length, with 16 holes in the shaft.Femurs with a hip prosthesis and knee prosthesis showed significantly higher required fracture force compared to femurs with a hip prosthesis and a distal retrograde nail. Femurs with a distal locking plate of either length showed a higher required fracture force than those with the retrograde nail.The highest risk for a fracture in the femur with an existing hip prosthesis comes with a retrograde nail. A distal locking plate for the treatment of supracondylar fractures leads to a higher required fracture force. The implantation of a constrained knee prosthesis that is not loosened on the ipsilateral side does not increase the risk for a fracture.

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.

Several studies have evaluated quantitative anatomic data for direct lateral mass screw fixation. To analyze anatomic landmarks and safe zones for optimal screw placement through the posterior arc of the human atlas, morphometric parameters of 41 adult native human atlas specimens were quantitatively measured. Internal dimensions of the atlas (lateral mass, maximum and minimum intraosseous screw length), minimum height and width of the posterior arc and optimal screw insertion angles were defined on pQCT scans. By this, an optimal posterior screw insertion point (OIP) and a preferable screw direction (PSD) through the posterior arch into the lateral mass of C1 were defined. External dimensions (transverse and sagittal diameter) as well as the width of the mid-portion of C1 lateral mass were significantly higher in male specimens. The mean height of the posterior arch at the vertebral artery groove was 4.1 +/- 0.8 mm in female and 4.6 +/- 0.9 mm in male specimens. The optimal screw insertion point was located 21.6 +/- 1.7 mm in female and 23.6 +/- 2.3 mm in male lateral from the posterior tubercle of C1 (P0.01). The preferable screw direction was a mean medial inclination of 7.9 +/- 1.9 degrees in female and 7.3 +/- 2.7 degrees in male specimens and a mean rostral direction of 2.4 +/- 1.8 degrees in female and 3.1 +/- 1.7 degrees in male specimens. In conclusion, the presented study provides information for the use and design of upper cervical spine instrumentation techniques, such as screw placement to C1 via the posterior arch. The characterization of working areas and safe zones (OIP, PSD) might contribute to a minimization of screw malposition in this highly demanding instrumentation technique.