Rune B. Jakobsen

An analysis of the quality of cartilage repair studies.

BACKGROUND Most lesions of articular cartilage do not heal spontaneously and may lead to secondary osteoarthritis. It is not known whether the optimistic reports on the short and long-term results of several different cartilage repair techniques are based on sound methodological quality. METHODS We performed a literature search in MEDLINE, CINAHL, the Cochrane Central Register, and EMBASE and included studies in which the primary aim of the investigation was to report the outcome after cartilage repair in the knee with use of microfracture, autologous osteochondral transplantation, autologous periosteal transplantation, or autologous chondrocyte implantation. We scored the quality of the studies using a modified Coleman Methodology Score with ten criteria, which results in a final score between 0 and 100. Studies were also assessed with use of the level-of-evidence rating used in the American Volume of The Journal of Bone and Joint Surgery. We collected data on the year of publication, the reported postoperative results, and the outcome measures used to assess the results. RESULTS Sixty-one studies involving a total of 3987 surgical procedures were included. The average methodology score was 43.5 of 100. Methodological deficiencies were found with respect to five criteria: the type of study, description of the rehabilitation protocol, outcome criteria, outcome assessment, and subject selection process. Large variations in the reported outcome were seen within each treatment modality, and no significant differences were found between each kind of therapy (p = 0.11). The methodology score correlated positively with the level-of-evidence rating (r = 0.668, p < 0.0001), but there were large variations in the methodology score within each level. The linear regression analysis weighted by the number of patients demonstrated a negative yet not significant correlation between the methodology score and the results reported in nineteen studies with use of the Lysholm Scale (r = -0.29, p = 0.19). A total of twenty-seven different clinical outcome measurement scales were used to assess outcome. CONCLUSIONS The generally low methodological quality found in the studies included in this analysis indicates that caution is required when interpreting results after surgical cartilage repair. Firm recommendations on which procedure to choose cannot be given at this time on the basis of these studies. More attention should be paid to methodological quality when designing, performing, and reporting clinical studies. LEVEL OF EVIDENCE Therapeutic Level III.

The Reproducibility and Repeatability of Varus Stress Radiographs in the Assessment of Isolated Fibular Collateral Ligament and Grade-III Posterolateral Knee Injuries An in Vitro Biomechanical Study

BACKGROUND Objective measures to quantitate the amount of lateral compartment opening for patients with lateral and posterolateral knee injuries have not been well documented. The purpose of the present study was to measure lateral compartment opening secondary to applied varus stresses following posterolateral corner structure sectioning and to develop radiographic guidelines to quantify the amount of lateral compartment gapping seen with these injuries. METHODS Ten nonpaired fresh-frozen cadaver lower extremities were used. Two varus loads, a 12-Nm moment and a clinician-applied varus stress, were applied to the intact knees and after sequential sectioning of the fibular collateral ligament, popliteus tendon, popliteofibular ligament, and anterior and posterior cruciate ligaments to simulate degrees of posterolateral knee and associated combined cruciate ligament injuries. The shortest distance between the most distal subchondral bone surface of the lateral femoral condyle and the corresponding lateral tibial plateau was measured to quantify lateral compartment opening and was analyzed on digital radiographs. Three observers were used to determine interobserver reproducibility and intraobserver repeatability. RESULTS In the intact knee, the mean lateral compartment gapping due to a 12-Nm moment and a clinician-applied varus stress was 8.9 and 9.7 mm, respectively. Lateral gapping significantly increased by 2.1 and 2.7 mm in association with sectioning of the fibular collateral ligament and by 3.4 and 4.0 mm in knees with a simulated posterolateral corner injury for each respective load-application technique (p < 0.0001 for all comparisons). Intraobserver repeatability was high, with all observers independently obtaining an intraclass correlation coefficient of 0.99, whereas the analysis of interobserver reproducibility demonstrated an intraclass correlation coefficient of 0.97. CONCLUSIONS Measurements with use of current clinical digital imaging systems can be used to quantify the amount of lateral compartment knee opening. Clinicians should suspect an isolated fibular collateral ligament injury if opening on clinician-applied varus stress radiographs increases by approximately 2.7 mm and a grade-III posterolateral corner injury if values increase by approximately 4.0 mm. CLINICAL RELEVANCE Varus stress radiographs appear to provide an objective and reproducible measure of lateral compartment gapping that should prove useful for the diagnosis, management, and postoperative follow-up of patients with fibular collateral ligament and posterolateral knee injuries.

microRNA-140 Targets RALA and Regulates Chondrogenic Differentiation of Human Mesenchymal Stem Cells by Translational Enhancement of SOX9 and ACAN

Lesions of articular cartilage do not heal spontaneously. One treatment strategy would be to make cartilage in the laboratory by directed chondrogenic differentiation of mesenchymal stem cells (MSCs). To promote our understanding of the molecular control of chondrogenesis, we have compared the changes in microRNAs (miRNAs) during in vitro chondrogenesis of MSCs with those observed in uncultured and dedifferentiated articular chondrocytes (ACs). Several miRNAs showed a reciprocal relationship during the differentiation of MSCs and dedifferentiation of ACs. miR-140-5p and miR-140-3p changed the most during in vitro chondrogenesis, they were the miRNAs most highly expressed in tissue-engineered chondrocytes, and they were also among the miRNAs most highly expressed in uncultured ACs. There was a 57% overlap for the 100 most highly expressed miRNAs in differentiated MSCs and uncultured ACs, but for other miRNAs, the expression pattern was quite different. We transiently and stably inhibited and overexpressed miR-140-5p and miR-140-3p in differentiating MSCs and dedifferentiating ACs, respectively, to describe global effects and identify and validate new targets. Surprisingly, SOX9 and aggrecan proteins were found to be downregulated in anti-miR-140 transduced differentiating MSCs despite unchanged mRNA levels. This suggests that miR-140 stimulates in vitro chondrogenesis by the upregulation of these molecules at the protein level. RALA, a small GTPase, was identified as a miR-140 target and knockdown experiments showed that RALA regulated SOX9 at the protein level. These observations shed new light on the effect of miR-140 for chondrogenesis in vitro and in vivo.

Clinical studies on posterior cruciate ligament tears have weak design

Very few studies in the literature focus on isolated PCL injury. Recent studies are in general more optimistic with regard to the results than previous reports. There are few randomized controlled trials and few prospective comparative studies, which may limit the value of the reported results. The goal of the present study was to evaluate the methodology of published studies according to a well-established scoring system. Studies with a high success rate have a low score on methodology design. This study was based on systematic review and level 3 evidence. We performed a literature search and included studies in which the primary aim was to report the outcome after management of isolated PCL injury. The quality of the studies was evaluated using a modified Coleman methodology score, which results in a score between 0 and 100. Studies were also assessed with use of level-of-evidence rating. We collected data on the year of publication, reported results after surgery and conservative treatment, and the outcome scales used to assess the results. Forty studies were included. The average methodology score was 52. No significant difference in outcome was detected between conservative and surgical management. Our hypothesis that a low Coleman score would yield a good clinical result was not verified. This could be caused by the fact that there were very few studies with a high Coleman score. The Coleman methodology score correlated positively with the year of publication and with the level-of-evidence rating. In the 40 reported studies, 12 different outcome scales were used. In conclusion, the generally low methodological quality shows that caution is required when interpreting results after management of injury to the PCL. Firm recommendations on what treatment to choose cannot be given at this time on the basis of these studies. More attention should be paid to methodological quality when designing, conducting and reporting trials.

Analysis of the Effects of Five Factors Relevant to In Vitro Chondrogenesis of Human Mesenchymal Stem Cells Using Factorial Design and High Throughput mRNA-Profiling

The in vitro process of chondrogenic differentiation of mesenchymal stem cells for tissue engineering has been shown to require three-dimensional culture along with the addition of differentiation factors to the culture medium. In general, this leads to a phenotype lacking some of the cardinal features of native articular chondrocytes and their extracellular matrix. The factors used vary, but regularly include members of the transforming growth factor β superfamily and dexamethasone, sometimes in conjunction with fibroblast growth factor 2 and insulin-like growth factor 1, however the use of soluble factors to induce chondrogenesis has largely been studied on a single factor basis. In the present study we combined a factorial quality-by-design experiment with high-throughput mRNA profiling of a customized chondrogenesis related gene set as a tool to study in vitro chondrogenesis of human bone marrow derived mesenchymal stem cells in alginate. 48 different conditions of transforming growth factor β 1, 2 and 3, bone morphogenetic protein 2, 4 and 6, dexamethasone, insulin-like growth factor 1, fibroblast growth factor 2 and cell seeding density were included in the experiment. The analysis revealed that the best of the tested differentiation cocktails included transforming growth factor β 1 and dexamethasone. Dexamethasone acted in synergy with transforming growth factor β 1 by increasing many chondrogenic markers while directly downregulating expression of the pro-osteogenic gene osteocalcin. However, all factors beneficial to the expression of desirable hyaline cartilage markers also induced undesirable molecules, indicating that perfect chondrogenic differentiation is not achievable with the current differentiation protocols.

Epigenetic Regulation of Nestin Expression During Neurogenic Differentiation of Adipose Tissue Stem Cells

Adipose-tissue-derived stem cells (ASCs) have received considerable attention due to their easy access, expansion potential, and differentiation capacity. ASCs are believed to have the potential to differentiate into neurons. However, the mechanisms by which this may occur remain largely unknown. Here, we show that culturing ASCs under active proliferation conditions greatly improves their propensity to differentiate toward osteogenic, adipogenic, and neurogenic lineages. Neurogenic-induced ASCs express early neurogenic genes as well as markers of mature neurons, including voltage-gated ion channels. Nestin, highly expressed in neural progenitors, is upregulated by mitogenic stimulation of ASCs, and as in neural progenitors, then repressed during neurogenic differentiation. Nestin gene (NES) expression under these conditions appears to be regulated by epigenetic mechanisms. The neural-specific, but not muscle-specific, enhancer regions of NES are DNA demethylated by mitogenic stimulation, and remethylated upon neurogenic differentiation. We observe dynamic changes in histone H3K4, H3K9, and H3K27 methylation on the NES locus before and during neurogenic differentiation that are consistent with epigenetic processes involved in the regulation of NES expression. We suggest that ASCs are epigenetically prepatterned to differentiate toward a neural lineage and that this prepatterning is enhanced by demethylation of critical NES enhancer elements upon mitogenic stimulation preceding neurogenic differentiation. Our findings provide molecular evidence that the differentiation repertoire of ASCs may extend beyond mesodermal lineages.

Publication and non-publication of drug trial results: a 10-year cohort of trials in Norwegian general practice

Objectives Previously, we identified a 10-year cohort of protocols from applications to the Norwegian Medicines Agency 1998–2007, consisting of 196 drug trials in general practice. The aim of this study was to examine whether trial results were published and whether trial funding and conflicts of interest were reported. Design Cohort study of trials with systematic searches for published results. Setting Clinical drug trials in Norwegian general practice. Methods We performed systematic literature searches of MEDLINE, Embase and CENTRAL to identify publications originating from each trial using characteristics such as test drug, comparator and patient groups as search terms. When no publication was identified, we contacted trial sponsors for information regarding trial completion and reference to any publications. Main outcome measures We determined the frequency of publication of trial results and trial characteristics associated with publication of results. Results Of the 196 trials, 5 were never started. Of the remaining 191 trials, 71% had results published in a journal, 11% had results publicly available elsewhere and 18% of trials had no results available. Publication was more common among trials with an active comparator drug (χ2 test, p=0.040), with a larger number of patients (total sample size≥median, p=0.010) and with a longer trial period (duration≥median, p=0.025). Trial funding was reported in 85% of publications and increased over time, as did reporting of conflicts of interest among authors. Among the 134 main journal articles from the trials, 60% presented statistically significant results for the investigational drug, and the conclusion of the article was favourable towards the test drug in 78% of papers. Conclusions We did not identify any journal publication of results for 29% of the general practice drug trials. Trials with an active comparator, larger and longer trials were more likely to be published.

Bone and Cartilage from Stem Cells: Growth Optimalization and Stabilization of Cell Phenotypes

Engineered cells replacing tissues should mimic the three-dimensional (3D) structure and reflect the different cell phenotypes exhibited by the lost or damaged tissue (Raimondi 2006; Keung, Healy et al. 2010). The engineered cells should also demonstrate a certain plasticity, i.e. an ability to adapt to the environment, in which they are deposited, reflecting the minute differences in features necessary to rebuild a functional tissue, which is able to renew itself over time (Grad and Salzmann 2009; Ohishi, Chiusaroli et al. 2009; Tare, Kanczler et al. 2010). Osteoblastic cells in bone need to be able to involve themselves in a remodelling cycle with osteoclasts (Hanada, Hanada et al. 2010; Trouvin and Goeb 2010), which may be recruited from surrounding bone structures, and/or may be furnished as preosteoclasts within the population of osteoblasts. Furthermore, the osteoblasts should be able to undergo a distinct alteration in terms of life-span defined characteristics (Lian and Stein 2003; Lian, Stein et al. 2006; Gordeladze, Reseland et al. 2009), including the transition to osteocytes. Finally, the newly formed engineered tissue does not survive unless it develops a vascular network (Matsumoto, Kuroda et al. 2008; Grellier, Bordenave et al. 2009) furnishing the bone tissue with oxygen, growth factors and nutrients. Chondrocytes in engineered cartilage should be able to produce an extracellular matrix reflecting the composition, water-binding capacity and mechanical characteristics of true

Examining participant perceptions of an interprofessional simulation-based trauma team training for medical and nursing students

ABSTRACT High quality care relies on interprofessional teamwork. We developed a short simulation-based course for final year medical, nursing and nursing anaesthesia students, using scenarios from emergency medicine. The aim of this paper is to describe the adaptation of an interprofessional simulation course in an undergraduate setting and to report participants’ experiences with the course and students’ learning outcomes. We evaluated the course collecting responses from students through questionnaires with both closed-ended and open-ended questions, supplemented by the facilitators’ assessment of students’ performance. Our data is based on responses from 310 students and 16 facilitators who contributed through three evaluation phases. In the analysis, we found that students reported emotional activation and learning outcomes within the domains self-insight and stress management, understanding of the leadership role, insight into teamwork, and skills in team communication. In subsequent questionnaire studies students reported having gained insights about communication, teamwork and leadership, and they believed they would be better leaders of teams and/or team members after having completed the course. Facilitators’ observations suggested a progress in students’ non-technical skills during the course. The facilitators observed that nursing anaesthesia students seemed to be more comfortable in finding their role in the team than the two other groups. In conclusion, we found that an interprofessional simulation-based emergency team training course with a focus on leadership, communication and teamwork, was feasible to run on a regular basis for large groups of students. The course improved the students’ team skills and received a favourable evaluation from both students and faculty.

Compensation after treatment for anterior cruciate ligament injuries: a review of compensation claims in Norway from 2005 to 2015

PurposeTo assess the most common reasons for complaints following anterior cruciate ligament (ACL) injuries reported to the Norwegian System of Patient Injury Compensation (NPE), and to view these complaints in light of the ACL reconstructions (ACL-Rs) reported to the Norwegian Knee Ligament Registry (NKLR).MethodData from the NPE and the NKLR were collected for the study period (2005–2015). The age and gender and type of complaint and reason for granted compensation were collected from the NPE, while the graft choice and total number of ACL-R were collected from the NKLR. Risk for successful grant was estimated for graft type.Results18,810 primary ACL-Rs were reported to the NKLR during the study period. A hamstring graft was used in 12,437 (66.1%) but the bone-patellar tendon-bone (BPTB) became the graft of choice at the end of the study period. 240 patients filed a complaint to the NPE, of which 101 were granted compensation. The odds ratio for a claim being granted following a hamstring graft was 2.9 compared to that of a BPTB graft (p = 0.002) The most common reason for compensation was a hospital-acquired infection in 39 patients (38.6%) followed by inadequate surgical technique (27, 26.7%) and delayed diagnosis (13, 12.9%). Of the 39 patients with infection, 27 had received a hamstring graft and six a BPTB graft (two patients were not reconstructed, data missing for three patients). Of the 27 patients who were granted compensation due to inadequate surgical technique, 24 had received a hamstring graft and three a BPTB graft.ConclusionInfection and inadequate surgical technique are the most common causes for granted compensation from the NPE following ACL injury. Hamstring grafts have a threefold risk of complication that yields compensation from the NPE compared to BPTB grafts. This information is relevant for patients and surgeons when choosing graft type. The trend of increased use of BPTB grafts is warranted based on the results from this study.Level of evidenceLevel III.