The robustness of glenohumeral centering measurements in dependence of shoulder rotation and their predictive value in shoulders with rotator cuff tears

OBJECTIVE De-centering of the shoulder joint on radiographs is used as indicator for severity of rotator cuff tears and as predictor for clinical outcome after surgery. The objective of the study was to assess the effect of malrotation on glenohumeral centering on radiographs and to identify the most reliable parameter for its quantification. SUBJECTS AND METHODS In this retrospective study (2014-2018), 249 shoulders were included: 92 with imaging-confirmed supra- and infraspinatus tears (rupture; 65.2 ± 9.9 years) and 157 without tears (control; 41.1 ± 13.0 years). On radiographs in neutral position and external rotation, we assessed three radiographic parameters to quantify glenohumeral centering: acromiohumeral distance (ACHD), craniocaudal distance of the humeral head and glenoid center (Deutsch), and scapulohumeral arch congruity (Moloney). Non-parametric statistics was performed. RESULTS In both positions, only the distance parameters ACHD (< 0.5 mm) and Deutsch (< 1 mm) were comparable in the two study groups rupture and control. Comparing the parameters between the study groups revealed only ACHD to be significantly different with a reduction of more than 2 mm in the rupture group. Among the parameters, ACHD ≤ 6 mm was the only cut-off discriminating rupture (12-21% of the shoulders with ACHD ≤ 6 mm) and control (none of the shoulders with ACHD ≤ 6 mm). Ninety percent of shoulders with ACHD ≤ 6 mm presented with a massive rotator cuff tear (defined as ≥ 67% of the greater tuberosity exposed). CONCLUSION Glenohumeral centering assessed by ACHD and Deutsch is not affected by rotation in shoulders with and without rotator cuff tear. An ACHD ≤ 6 mm has a positive predictive value of 90% for a massive rotator cuff tear

The robustness of glenohumeral centering measurements in dependence of shoulder rotation and their predictive value in shoulders with rotator cuff tears.

OBJECTIVE De-centering of the shoulder joint on radiographs is used as indicator for severity of rotator cuff tears and as predictor for clinical outcome after surgery. The objective of the study was to assess the effect of malrotation on glenohumeral centering on radiographs and to identify the most reliable parameter for its quantification. SUBJECTS AND METHODS In this retrospective study (2014-2018), 249 shoulders were included: 92 with imaging-confirmed supra- and infraspinatus tears (rupture; 65.2 ± 9.9 years) and 157 without tears (control; 41.1 ± 13.0 years). On radiographs in neutral position and external rotation, we assessed three radiographic parameters to quantify glenohumeral centering: acromiohumeral distance (ACHD), craniocaudal distance of the humeral head and glenoid center (Deutsch), and scapulohumeral arch congruity (Moloney). Non-parametric statistics was performed. RESULTS In both positions, only the distance parameters ACHD (< 0.5 mm) and Deutsch (< 1 mm) were comparable in the two study groups rupture and control. Comparing the parameters between the study groups revealed only ACHD to be significantly different with a reduction of more than 2 mm in the rupture group. Among the parameters, ACHD ≤ 6 mm was the only cut-off discriminating rupture (12-21% of the shoulders with ACHD ≤ 6 mm) and control (none of the shoulders with ACHD ≤ 6 mm). Ninety percent of shoulders with ACHD ≤ 6 mm presented with a massive rotator cuff tear (defined as ≥ 67% of the greater tuberosity exposed). CONCLUSION Glenohumeral centering assessed by ACHD and Deutsch is not affected by rotation in shoulders with and without rotator cuff tear. An ACHD ≤ 6 mm has a positive predictive value of 90% for a massive rotator cuff tear

Treatment of Knee Dislocation With Primary Repair and Suture Augmentation: A Viable Solution.

BACKGROUND Different surgical techniques have been described for the treatment of knee dislocation (KD). Nonoperative approaches are frequently combined with surgical reconstruction using auto- or allograft. PURPOSE To evaluate the midterm results of primary surgical repair and suture augmentation to treat KD. STUDY DESIGN Case series; Level of evidence, 4. METHODS A total of 22 patients (5 women, 17 men; mean age, 45 ± 15 years) with KD were evaluated at a mean of 49 ± 16 months after surgical treatment that included primary repair and suture augmentation. Magnetic resonance imaging, stress radiographs, and outcome scores were obtained at the follow-up. Clinical examination including hop tests and force measurements for flexion and extension was performed. RESULTS The mean difference in pre- to postinjury Tegner scores was -2 ± 1. The outcome scores showed mean values of 84 ± 15 (Lysholm), 73 ± 15 (International Knee Documentation Committee) and 65 ± 25 (Anterior Cruciate Ligament-Return to Sport after Injury scale). Compared with the uninjured knee, the range of motion of the injured knee was reduced by 21° ± 12°. Twelve patients felt fit enough to perform hop tests and showed a mean deficit of 7% ± 17%° compared with the uninjured leg. The mean force deficit was 19% ± 18% for extension and 8% ± 16% for flexion. Stress radiographs revealed an 11 ± 7-mm higher anteroposterior translation on the injured side. Four patients had secondary ligament reconstructions due to persistent instability and 7 underwent arthroscopic arthrolysis due to stiffness. A significant increase of osteoarthritis was found for the medial, lateral, and patellofemoral compartments (P = .007, .004, and .006, respectively). CONCLUSION Primary repair and suture augmentation of KD led to satisfactory clinical midterm results despite persistent radiological instability and a significant increase in osteoarthritis. This technique allows the return to activities of daily living without subjective instability in most nonathletic patients. Secondary ligament reconstructions should be performed if relevant instability persists to decrease the risk of secondary meniscal and cartilage damage

Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solutionoriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research – a multi-stakeholder workshop report

Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory

A novel bioreactor system capable of simulating the in vivo conditions of synovial joints.

Any significant in vitro evaluation of cartilage tissue engineering and cartilage repair strategies has to be performed under the harsh conditions encountered in vivo within synovial joints. To this end, we have developed a novel automated physiological robot reactor system (PRRS) capable of recapitulating complex physiological motions and load patterns within an environment similar to that found in the human knee. The PRRS consists of a mechanical stimulation unit (MSU) and an automatic sample changer (ASC) within an environment control box (ECB) in which the humidity, temperature, and gas composition are tightly regulated. The MSU has three linear (orthogonal) axes and one rotational degree of freedom (around the z-axis). The ASC provides space for up to 24 samples, which can be allocated to individual stimulation patterns. Cell-seeded scaffolds and ex vivo tissue culture systems were established to demonstrate the applicability of the PRRS to the investigation of the effect of load and environmental conditions on engineering and maintenance of articular cartilage in vitro. The bioreactor is a flexible system that has the potential to be applied for culturing connective tissues other than cartilage, such as bone and intervertebral disc tissue, even though the mechanical and environmental parameters are very different

Gadolinium-Based Contrast Agents and Free Gadolinium Inhibit Differentiation and Activity of Bone Cell Lineages.

OBJECTIVES Administration of gadolinium-based contrast agents (GBCA) in magnetic resonance imaging results in the long-term retention of gadolinium (Gd) in tissues and organs, including the bone, and may affect their function and metabolism. This study aims to investigate the effects of Gd and GBCA on the proliferation/survival, differentiation, and function of bone cell lineages. MATERIALS AND METHODS Primary murine osteoblasts (OB) and osteoclast progenitor cells (OPC) isolated from C57BL/6J mice were used to test the effects of Gd3+ (12.5-100 μM) and GBCA (100-2000 μM). Cultures were supplemented with the nonionic linear Gd-DTPA-BMA (gadodiamide), ionic linear Gd-DTPA (gadopentetic acid), and macrocyclic Gd-DOTA (gadoteric acid). Cell viability and differentiation were analyzed on days 4-6 of the culture. To assess the resorptive activity of osteoclasts, the cells were grown in OPC cultures and were seeded onto layers of amorphous calcium phosphate with incorporated Gd. RESULTS Gd3+ did not affect OB viability, but differentiation was reduced dose-dependently up to 72.4% ± 6.2%-73.0% ± 13.2% (average ± SD) at 100 μM Gd3+ on days 4-6 of culture as compared with unexposed controls (P < 0.001). Exposure to GBCA had minor effects on OB viability with a dose-dependent reduction up to 23.3% ± 10.2% for Gd-DTPA-BMA at 2000 μM on day 5 (P < 0.001). In contrast, all 3 GBCA caused a dose-dependent reduction of differentiation up to 88.3% ± 5.2% for Gd-DTPA-BMA, 49.8% ± 16.0% for Gd-DTPA, and 23.1% ± 8.7% for Gd-DOTA at 2000 μM on day 5 (P < 0.001). In cultures of OPC, cell viability was not affected by Gd3+, whereas differentiation was decreased by 45.3% ± 9.8%-48.5% ± 15.8% at 100 μM Gd3+ on days 4-6 (P < 0.05). Exposure of OPC to GBCA resulted in a dose-dependent increase in cell viability of up to 34.1% ± 11.4% at 2000 μM on day 5 of culture (P < 0.001). However, differentiation of OPC cultures was reduced on day 5 by 24.2% ± 9.4% for Gd-DTPA-BMA, 47.1% ± 14.0% for Gd-DTPA, and 38.2% ± 10.0% for Gd-DOTA (P < 0.001). The dissolution of amorphous calcium phosphate by mature osteoclasts was reduced by 36.3% ± 5.3% upon incorporation of 4.3% Gd/Ca wt/wt (P < 0.001). CONCLUSIONS Gadolinium and GBCA inhibit differentiation and activity of bone cell lineages in vitro. Thus, Gd retention in bone tissue could potentially impair the physiological regulation of bone turnover on a cellular level, leading to pathological changes in bone metabolism

Multiplanar reformation improves identification of the anterolateral ligament with MRI of the knee.

The anterolateral ligament (ALL) is subject of the current debate concerning rotational stability in case of anterior cruciate ligament (ACL) injuries. Today, reliable anatomical and biomechanical evidence for its existence and course is available. Some radiologic studies claim to be able to identify the ALL on standard coronal plane MRI sections. In the experience of the authors, however, ALL identification on standard MRI sequences frequently fails and is prone to errors. The reason for this mainly lies in the fact, that the entire ALL often cannot be identified on a single MRI image. This study aimed to establish an MRI evaluation protocol improving the visualization of the ALL, using multiplanar reformation (MPR) with the goal to be able to evaluate the ALL on one MRI image. A total of 47 knee MRIs performed due to atraumatic knee pain between 2018 and 2019 without any pathology were analyzed. Identification of the ALL was performed twice by an orthopedic surgeon and a radiologist on standard coronal plane and after MPR. For the latter axial and coronal alignment was obtained with the femoral condyles as a reference. Then the coronal plane was adjusted to the course of the ALL with the lateral epicondyle as proximal reference. Visualization of the ALL was rated as "complete" (continuous ligamentous structure with a tibial and femoral insertion visible on one coronal image), "partial" (only parts of the ALL like the tibial insertion were visible) and "not visible". The distances of its tibial insertion to the bony joint line, Gerdy's tubercle and the tip of the fibular head were measured. On standard coronal images the ALL was fully visible in 17/47, partially visible in 27/47, and not visible in 3/47 cases. With MPR the ALL was fully visible in 44/47 and not visible in 3/47 cases. The median distance of its tibial insertion to the bony joint line, Gerdy's tubercle and the tip of the fibular head were 9, 21 and 25 mm, respectively. The inter- (ICC: 0.612; 0.645; 0.757) and intraobserver (ICC: 0.632; 0.823; 0.857) reliability was good to excellent. Complete visualization of the ALL on a single MRI image is critical for its identification and evaluation. Applying multiplanar reformation achieved reliable full-length visualization of the ALL in 94% of cases. The described MPR technique can be applied easily and fast in clinical routine. It is a reliable tool to improve the assessment of the ALL

Transforming growth factor beta signaling is essential for the autonomous formation of cartilage-like tissue by expanded chondrocytes.

Cartilage is a tissue with limited self-healing potential. Hence, cartilage defects require surgical attention to prevent or postpone the development of osteoarthritis. For cell-based cartilage repair strategies, in particular autologous chondrocyte implantation, articular chondrocytes are isolated from cartilage and expanded in vitro to increase the number of cells required for therapy. During expansion, the cells lose the competence to autonomously form a cartilage-like tissue, that is in the absence of exogenously added chondrogenic growth factors, such as TGF-βs. We hypothesized that signaling elicited by autocrine and/or paracrine TGF-β is essential for the formation of cartilage-like tissue and that alterations within the TGF-β signaling pathway during expansion interfere with this process. Primary bovine articular chondrocytes were harvested and expanded in monolayer culture up to passage six and the formation of cartilage tissue was investigated in high density pellet cultures grown for three weeks. Chondrocytes expanded for up to three passages maintained the potential for autonomous cartilage-like tissue formation. After three passages, however, exogenous TGF-β1 was required to induce the formation of cartilage-like tissue. When TGF-β signaling was blocked by inhibiting the TGF-β receptor 1 kinase, the autonomous formation of cartilage-like tissue was abrogated. At the initiation of pellet culture, chondrocytes from passage three and later showed levels of transcripts coding for TGF-β receptors 1 and 2 and TGF-β2 to be three-, five- and five-fold decreased, respectively, as compared to primary chondrocytes. In conclusion, the autonomous formation of cartilage-like tissue by expanded chondrocytes is dependent on signaling induced by autocrine and/or paracrine TGF-β. We propose that a decrease in the expression of the chondrogenic growth factor TGF-β2 and of the TGF-β receptors in expanded chondrocytes accounts for a decrease in the activity of the TGF-β signaling pathway and hence for the loss of the potential for autonomous cartilage-like tissue formation

Chondrocytes within osteochondral grafts are more resistant than osteoblasts to tissue culture at 37°C

It is proposed that an ideal osteochondral allograft for cartilage repair consists of a devitalized bone but functional cartilage. The different modes of nutrient supply in vivo for bone (vascular support) and cartilage (diffusion) suggest that a modulation of storage conditions could differentially affect the respective cells, resulting in the proposed allograft. For this purpose, osteochondral tissues from porcine humeral heads were either cultured at 37°C for up to 24 hr or stored at 4°C for 24 hr, the temperature at which osteochondral allografts are routinely stored. Functionality of the cells was assessed by in situ hybridization for transcripts encoding collagen types I and II. At 37°C, a time-dependent significant reduction of the bone surface covered with functional cells was observed with only 5% ± 5% coverage left at 24 hr compared with 41% ± 10% at 0 hr. Similarly, cartilage area containing functional cells was significantly reduced from 84% ± 7% at 0 hr to 70% ± 3% after 24 hr. After 24 hr at 4°C, a significantly reduced amount of functional cells covering bone surfaces was observed (27% ± 5%) but not of cells within the cartilage (79% ± 8%). In the applied experimental setup, bone cells were more affected by tissue culture at 37°C than cartilage cells. Even though chondrocytes appear to be more sensitive to 37°C than to 4°C, the substantially reduced amount of functional bone cells at 37°C warrants further investigation of whether a preincubation of osteochondral allografts at 37°C--prior to regular storage at 4°C--might result in an optimized osteochondral allograft with devitalized bone but viable cartilage