K.I. Barton

Single intra-articular dexamethasone injection immediately post-surgery in a rabbit model mitigates early inflammatory responses and post-traumatic osteoarthritis-like alterations.

Despite surgical reconstruction of the anterior cruciate ligament, a significant number of patients will still develop post‐traumatic osteoarthritis (PTOA). Our objective was to determine if mitigating aspects of the acute phase of inflammation following a defined knee surgery with a single administration of a glucocorticoid could prevent the development of PTOA‐like changes within an established rabbit model of surgically induced PTOA. An early and late post‐surgical time‐point was investigated in this study (48 h and 9 weeks post‐surgery) in which the following groups were repeated (each n = 6, for a total of 24 rabbits per time‐point, and 48 rabbits used in the study): control (age/sex matched), sham (arthrotomy), drill injury (arthrotomy + two drill holes to a non‐cartilaginous area of the femoral notch), and drill injury + single intra‐articular (IA) injection of dexamethasone (DEX). At 48 h post‐surgery, DEX treatment significantly lowered the mRNA levels for a subset of pro‐inflammatory mediators, and significantly lowered the histological grade. Nine weeks post surgery, DEX treatment significantly lowered the histological scores (presented as effect size) for synovium (3.8), lateral femoral condyle (3.9), and lateral tibial cartilage (5.1) samples. Thus, DEX likely acts to prevent injury induced inflammation that could contribute to subsequent joint damage.

Characterization of proteoglycan 4 and hyaluronan composition and lubrication function of ovine synovial fluid following knee surgery.

The objective of this study was to determine changes in (1) proteoglycan 4 (PRG4) and hyaluronan (HA) concentration, (2) HA molecular weight (MW) distribution, and (3) cartilage boundary lubricating ability of synovial fluid (SF) from surgical sham (SHAM), anterior cruciate ligament (ACL)/medial collateral ligament (MCL) transection, and lateral meniscectomy (MEN) in a post‐knee surgery ovine model. Ovine SF (oSF) was collected at euthanization 20 weeks after surgery, with the contralateral joint serving as the non‐operative control. PRG4 and HA concentration in oSF was measured by sandwich enzyme‐linked immunosorbent assay, and HA MW distribution by agarose gel electrophoresis. Cartilage boundary lubricating ability of oSF was measured by a cartilage–cartilage friction test. PRG4 and HA concentration in SHAM, ACL/MCL, and MEN oSF were similar in comparison to the contralateral control (CTRL) oSF. The HA MW distribution in the operated oSF for all ranges were similar to the respective CTRL oSF. The kinetic coefficients of friction in operated and CTRL oSF were similar in all groups, and were significantly lower than saline. These results indicate oSF lubricant composition and function at 20 weeks post‐knee surgery were similar to contralateral CTRL, and suggest earlier time points post surgery warrant further investigation.

Use of pre‐clinical surgically induced models to understand biomechanical and biological consequences of PTOA development

Post‐traumatic osteoarthritis (PTOA) development is often observed following traumatic knee injuries involving key stabilising structures such as the cruciate ligaments or the menisci. Both biomechanical and biological alterations that follow knee injuries have been implicated in PTOA development, although it has not been possible to differentiate clearly between the two causal factors. This review critically examines the outcomes from pre‐clinical lapine and ovine injury models arising in the authors’ laboratories and differing in severity of PTOA development and progression. Specifically, we focus on how varying severity of knee injuries influence the subsequent alterations in kinematics, kinetics, and biological outcomes. The immediate impact of injury on the lubrication capacity of the joint is examined in the context of its influence on biomechanical alterations, thus linking the biological changes to abnormal kinematics, leading to a focus on the potential areas for interventions to inhibit or prevent development of the disease. We believe that PTOA results from altered cartilage surface interactions where biological and biomechanical factors intersect, and mitigating acute joint inflammation may be critical to prolonging PTOA development.

Posttraumatic Osteoarthritis Development and Progression in an Ovine Model of Partial Anterior Cruciate Ligament Transection and Effect of Repeated Intra-articular Methylprednisolone Acetate Injections on Early Disease:

Background: Partial anterior cruciate ligament (p-ACL) ruptures are a common injury of athletes. However, few preclinical models have investigated the natural history and treatment of p-ACL injuries. Purpose: To (1) demonstrate whether a controlled p-ACL injury model (anteromedial band transection) develops progressive gross morphological and histological posttraumatic osteoarthritis (PTOA)–like changes at 20 and 40 weeks after the injury and (2) investigate the efficacy of repeated (0, 5, 10, and 15 weeks) intra-articular injections of methylprednisolone acetate (MPA; 80 mg/mL) in the mitigation of potential PTOA-like changes after p-ACL transection. Study Design: Controlled laboratory study. Methods: Twenty-one 3- to 5-year-old female Suffolk-cross sheep were allocated to 4 groups: (1) nonoperative controls (n = 5), (2) 20 weeks after p-ACL transection (n = 5), (3) 40 weeks after p-ACL transection (n = 6), and (4) 20 weeks after p-ACL transection + MPA (n = 5). Gross morphological grading and histological analyses were conducted. mRNA expression levels for inflammatory, degradative, and structural molecules were assessed. Results: p-ACL transection led to significantly more combined gross damage (P = .008) and significant aggregate histological damage (P = .009) at 40 weeks after p-ACL transection than the nonoperative controls, and damage was progressive over time. Macroscopically, MPA appeared to slightly mitigate gross damage at 20 weeks after p-ACL transection in some animals. However, microscopic analysis revealed that repeated MPA injections after p-ACL transection led to significant loss in proteoglycan content compared with the nonoperative controls and 20 weeks after p-ACL transection (P = .008 and P = .008, respectively). Conclusion: p-ACL transection led to significant gross and histological damage by 40 weeks, which was progressive over time. Multiple repeated MPA injections were not appropriate to mitigate injury-related damage in a p-ACL transection ovine model as significant proteoglycan loss was observed in MPA-treated knees. Clinical Relevance: A p-ACL injury leads to slow and progressive PTOA-like joint damage, and multiple repeated injections of glucocorticoids may be detrimental to the knee joint in the long term.

The Need for an Executive Leadership Curriculum in Scientist-Clinician Training Programs

The health of Canadians depends on effective leadership among health care providers to facilitate the translation of new health discoveries into clinical practice. Clinician-scientists play an important role in bridging the gap between research and clinical practice, and require effective leadership skills to advance clinical practice successfully. To accelerate the leadership development in clinician scientist trainees, with the aim of developing strong leaders in administration and health advocacy, the Leaders in Medicine (LIM) training program at the University of Calgary created an Executive Leadership Coaching Program involving three phases: 1) an evidence-based evaluation tool, the Core Values IndexTM (CVI), that was used to identify the key drivers behind how individuals can be most effective in making their contribution; 2) small group workshops to debrief the results of the CVI assessment; and 3) one-on-one executive coaching sessions to facilitate the discovery, development and deployment of individual leadership capabilities. Coaching in leadership strategies enables clinician-scientist trainees to lead, influence, manage and deliver science-based improvements into the practice of medicine. We strongly recommend that other Canadian scientist-clinician training programs consider opportunities like the ones we offer to our LIM trainees. This training has important implications for the delivery of healthcare in Canada.

Newsletter Spring 2018:Clinician Investigator Trainee Association of Canada (CITAC)

A decade of CITAC Annual General Meetings: 2007-2017 In 2007, the Clinician Investigator Trainee Association of Canada (CITAC) launched its inaugural Annual General Meeting (AGM). The AGM has since become a major annual event, jointly organized by CITAC and leaders from the Canadian Society for Clinical Investigation (CSCI), and continues to provide a forum for clinician investigator (CI) trainees to exchange ideas, advance career prospects and engage with the broader community. Indeed, since its inception, all Canadian institutions with medical doctor and clinician investigator (MD+CI) training programs have participated in the AGM, while more than 1,000 trainees have registered as CITAC members. The 10th CITAC-CSCI AGM was recently held in Toronto (November 20-22, 2017). There were nearly 200 attendees, including CI trainees, faculty member and physician leaders from across Canada (Figure 1A, 1B). Trainees spanning diverse career stages had opportunities to participate in interactive poster sessions, workshops and lectures by leading physician-scientists. These exercises were designed to encourage and enhance networking, career development and mentorship for prospective physician-scientists.