Recruitment and baseline characteristics of young adults at risk of early-onset knee osteoarthritis after ACL reconstruction in the SUPER-Knee trial.

Objectives: The study aims to (1) report the process of recruiting young adults into a secondary knee osteoarthritis prevention randomised controlled trial (RCT) after anterior cruciate ligament reconstruction (ACLR); (2) determine the number of individuals needed to be screened to include one participant (NNS) and (3) report baseline characteristics of randomised participants. Methods: The SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER)-Knee RCT compares SUPER and minimal intervention for young adults (aged 18-40 years) with ongoing symptoms (ie, mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score subscales (KOOS4)) 9-36 months post-ACLR. The NNS was calculated as the number of prospective participants screened to enrol one person. At baseline, participants provided medical history, completed questionnaires (demographic, injury/surgery, rehabilitation characteristics) and underwent physical examination. Results: 1044 individuals were screened to identify 567 eligible people, from which 184 participants (63% male) enrolled. The sample of enrolled participants was multicultural (29% born outside Australia; 2% Indigenous Australians). The NNS was 5.7. For randomised participants, mean±SD age was 30±6 years. The mean body mass index was 27.3±5.2 kg/m2, with overweight (43%) and obesity (21%) common. Participants were, on average, 2.3 years post-ACLR. Over half completed <8 months of postoperative rehabilitation, with 56% having concurrent injury/surgery to meniscus and/or cartilage. The most affected KOOS (0=worst, 100=best) subscale was quality of life (mean 43.7±19.1). Conclusion: Young adults post-ACLR were willing to participate in a secondary osteoarthritis prevention trial. Sample size calculations should be multiplied by at least 5.7 to provide an estimate of the NNS. The SUPER-Knee cohort is ideally positioned to monitor and intervene in the early development and trajectory of osteoarthritis. Trial registration number: ACTRN12620001164987.

Knee Confidence, Fear of Movement, and Psychological Readiness for Sport in Individuals With Knee Conditions: A Systematic Review and Meta-analysis.

OBJECTIVES: To (1) compare activity-related psychological factors between individuals with and without knee conditions, and (2) assess associations between these factors and objective measures of function in individuals with knee conditions. DESIGN: A priori registered systematic review with meta-analysis. LITERATURE SEARCH: MEDLINE-Ovid, Embase-Ovid, Scopus-Elsevier, CINAHL-EBSCO, SPORTDiscus-EBSCO, and Cochrane Library were searched to May 27, 2022. STUDY SELECTION CRITERIA: We included peer-reviewed primary data studies (observational and experimental) of human participants with and without knee conditions reporting knee confidence, fear of movement/avoidance beliefs, and/or psychological readiness to return to sport (RTS) or reporting correlations between these factors and objective measures of function in knee conditions. DATA SYNTHESIS: Where possible, data were pooled by knee conditions, otherwise performed narrative syntheses. The Downs and Black checklist assessed the methodological quality of the included studies. RESULTS: Forty studies (3546 participants with knee conditions; 616 participants without knee conditions) were included. There was very low-certainty evidence of higher fear of movement in individuals with knee osteoarthritis (standardized mean difference [SMD], 0.46; 95% confidence interval [CI]: 0.41, 0.52), but not in individuals with patellofemoral pain (SMD, 0.66; 95% CI: -7.98, 9.29) when compared with those without knee conditions. There was very low-certainty evidence of no differences in psychological readiness to RTS after anterior cruciate ligament reconstruction (SMD, -1.14; 95% CI: -2.97, 0.70) compared to no knee condition, and negligible to weak positive correlations between psychological readiness to RTS and objective measures of function. CONCLUSION: There was very low-certainty evidence of higher fear of movement in individuals with knee osteoarthritis compared to those without, and very low-certainty evidence of no correlations between these factors and objective measures of function following anterior cruciate ligament reconstruction. J Orthop Sports Phys Ther 2024;54(4):1-14. Epub 29 January 2024. doi:10.2519/jospt.2024.12070.

Synthesis of portimines reveals the basis of their anti-cancer activity.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Does the one-leg rise test reflect quadriceps strength in individuals following anterior cruciate ligament reconstruction?

OBJECTIVE: To explore if one-leg rise test performance is associated with quadriceps strength following anterior cruciate ligament reconstruction (ACLR). DESIGN: Cross-sectional. PARTICIPANTS: 100 individuals (50 females, 50 males) aged 18-40 years, 9-36 months post-ACLR with ongoing knee symptoms (KOOS4 <80/100). MAIN OUTCOME MEASURES: Number of one-leg rise repetitions (using an adjustable-height plinth) and isometric quadriceps strength using isokinetic dynamometry (60° flexion, normalised to body mass). Multivariable fractional polynomial regression models adjusted for sex explored relationships between one-leg rise performance (repetitions) and quadriceps strength (Nm/kg) for each limb. RESULTS: A non-linear, increasing association between one-leg rise performance and quadriceps strength was observed, with the rate of increase attenuating at higher values of one-leg rise performance. Similar relationships were observed in the ACLR (ß = 0.15, 95%CI 0.10 to 0.20; adjusted r2 = 0.51) and contralateral limb (ß = 0.14, 95%CI 0.08 to 0.19; r2 = 0.42). CONCLUSION: The one-leg rise test can be an indicator of quadriceps strength in individuals after ACLR, enabling clinicians to easily monitor quadriceps strength recovery without specialised equipment. With the relationship between one-leg rise performance and quadriceps strength attenuating with a larger number of one-leg rises achieved, other factors (e.g., motivation, endurance) likely contribute to one-leg rise performance at higher values.

A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.

Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and characterization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50 = 0.7-10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50 = 3.8-36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.

Let's talk about sex (and gender) after ACL injury: a systematic review and meta-analysis of self-reported activity and knee-related outcomes.

OBJECTIVE: Investigate sex/gender differences in self-reported activity and knee-related outcomes after anterior cruciate ligament (ACL) injury. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Seven databases were searched in December 2021. ELIGIBILITY CRITERIA: Observational or interventional studies with self-reported activity (including return to sport) or knee-related outcomes after ACL injury. RESULTS: We included 242 studies (n=123 687, 43% females/women/girls, mean age 26 years at surgery). One hundred and six studies contributed to 1 of 35 meta-analyses (n=59 552). After ACL injury/reconstruction, very low-certainty evidence suggests females/women/girls had inferior self-reported activity (ie, return to sport, Tegner Activity Score, Marx Activity Scale) compared with males/men/boys on most (88%, 7/8) meta-analyses. Females/women/girls had 23%-25% reduced odds of returning to sport within 1-year post-ACL injury/reconstruction (12 studies, OR 0.76 95% CI 0.63 to 0.92), 1-5 years (45 studies, OR 0.75 95% CI 0.69 to 0.82) and 5-10 years (9 studies, OR 0.77 95% CI 0.57 to 1.04). Age-stratified analysis (<19 years) suggests female athletes/girls had 32% reduced odds of returning to sport compared with male athletes/boys (OR 0.68, 95% CI 0.41 to 1.13, I2 0.0%). Very low-certainty evidence suggests females/women/girls experienced inferior knee-related outcomes (eg, function, quality of life) on many (70%, 19/27) meta-analyses: standardised mean difference ranging from -0.02 (Knee injury and Osteoarthritis Outcome Score, KOOS-activities of daily living, 9 studies, 95% CI -0.05 to 0.02) to -0.31 (KOOS-sport and recreation, 7 studies, 95% CI -0.36 to -0.26). CONCLUSIONS: Very low-certainty evidence suggests inferior self-reported activity and knee-related outcomes for females/women/girls compared with males/men/boys after an ACL injury. Future studies should explore factors and design targeted interventions to improve outcomes for females/women/girls. PROSPERO REGISTRATION NUMBER: CRD42021205998.

Trajectory of knee health in runners with and without heightened osteoarthritis risk: the TRAIL prospective cohort study protocol.

INTRODUCTION: Running is one of the most popular recreational activities worldwide, due to its low cost and accessibility. However, little is known about the impact of running on knee joint health in runners with and without a history of knee surgery. The primary aim of this longitudinal cohort study is to compare knee joint structural features on MRI and knee symptoms at baseline and 4-year follow-up in runners with and without a history of knee surgery. Secondary aims are to explore the relationships between training load exposures (volume and/or intensity) and changes in knee joint structure and symptoms over 4 years; explore the relationship between baseline running biomechanics, and changes in knee joint structure and symptoms over 4 years. In addition, we will explore whether additional variables confound, modify or mediate these associations, including sex, baseline lower-limb functional performance, knee muscle strength, psychological and sociodemographic factors. METHODS AND ANALYSIS: A convenience sample of at least 200 runners (sex/gender balanced) with (n=100) and without (n=100) a history of knee surgery will be recruited. Primary outcomes will be knee joint health (MRI) and knee symptoms (baseline; 4 years). Exposure variables for secondary outcomes include training load exposure, obtained daily throughout the study from wearable devices and three-dimensional running biomechanics (baseline). Additional variables include lower limb functional performance, knee extensor and flexor muscle strength, biomarkers, psychological and sociodemographic factors (baseline). Knowledge and beliefs about osteoarthritis will be obtained through predefined questions and semi-structured interviews with a subset of participants. Multivariable logistic and linear regression models, adjusting for potential confounding factors, will explore changes in knee joint structural features and symptoms, and the influence of potential modifiers and mediators. ETHICS AND DISSEMINATION: Approved by the La Trobe University Ethics Committee (HEC-19524). Findings will be disseminated to stakeholders, peer-review journals and conferences.

Unilateral tests of lower-limb function as prognostic indicators of future knee-related outcomes following anterior cruciate ligament injury: a systematic review and meta-analysis of 13 150 adolescents and adults.

OBJECTIVE: To investigate the prognostic capacity of individual hop tests, hop test batteries and other unilateral functional performance tests following anterior cruciate ligament (ACL) injury. DESIGN: Systematic review with meta-analysis. DATA SOURCES: Six databases searched up to June 2021. ELIGIBILITY CRITERIA: Studies reporting associations between unilateral lower-limb function (eg, hop tests) following ACL injury and future (≥3 months) knee-related outcomes. RESULTS: Of 42 included studies (13 150 participants), all assessed the single-forward hop test and 32 assessed a repeated-forward hop test (crossover hop, triple hop, 6m-timed hop), mostly within a year after ACL injury/reconstruction. Results of meta-analyses indicated that higher single-forward and repeated-forward hop limb symmetry were associated with higher odds of return-to-sport 1-3 years post-ACL reconstruction (OR 2.15; 95% CI 1.30 to 3.54; OR 2.11; 95% CI 1.23 to 3.60, respectively). Higher single-forward and repeated-forward hop limb symmetry was associated with better self-reported symptoms and function 1-37 years after ACL injury (OR 2.51; 95% CI 1.62 to 3.88; OR 4.28; 95% CI 1.65 to 11.08, respectively). Higher limb symmetry on a repeated-forward hop does not appear to be associated with higher odds of successful rehabilitation without ACL reconstruction (OR 1.51; 95% CI 0.94 to 2.44). Achieving ≥90% limb symmetry on the single-forward hop was associated with reduced odds of knee osteoarthritis 5-37 years after ACL injury (OR 0.46; 95% CI 0.23 to 0.94). CONCLUSION: Very low certainty evidence suggests single-forward and repeated-forward hop tests are prognostic indicators for important knee-related outcomes in individuals after ACL injury and may help stratify individuals at risk of poor outcomes to target rehabilitation interventions. PROSPERO REGISTRATION NUMBER: CRD42018092197.

SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER) versus minimal intervention for young adults at risk of knee osteoarthritis after ACL reconstruction: SUPER-Knee randomised controlled trial protocol.

INTRODUCTION: Anterior cruciate ligament injury and reconstruction (ACLR) is often associated with pain, functional loss, poor quality of life and accelerated knee osteoarthritis development. The effectiveness of interventions to enhance outcomes for those at high risk of early-onset osteoarthritis is unknown. This study will investigate if SUpervised exercise-therapy and Patient Education Rehabilitation (SUPER) is superior to a minimal intervention control for improving pain, function and quality of life in young adults with ongoing symptoms following ACLR. METHODS AND ANALYSIS: The SUPER-Knee Study is a parallel-group, assessor-blinded, randomised controlled trial. Following baseline assessment, 184 participants aged 18-40 years and 9-36 months post-ACLR with ongoing symptoms will be randomly allocated to one of two treatment groups (1:1 ratio). Ongoing symptoms will be defined as a mean score of <80/100 from four Knee injury and Osteoarthritis Outcome Score (KOOS4) subscales covering pain, symptoms, function in sports and recreational activities and knee-related quality of life. Participants randomised to SUPER will receive a 4-month individualised, physiotherapist-supervised strengthening and neuromuscular programme with education. Participants randomised to minimal intervention (ie, control group) will receive a printed best-practice guide for completing neuromuscular and strengthening exercises following ACLR. The primary outcome will be change in the KOOS4 from baseline to 4 months with a secondary endpoint at 12 months. Secondary outcomes include change in individual KOOS subscale scores, patient-perceived improvement, health-related quality of life, kinesiophobia, physical activity, thigh muscle strength, knee function and knee cartilage morphology (ie, lesions, thickness) and composition (T2 mapping) on MRI. Blinded intention-to-treat analyses will be performed. Findings will also inform cost-effectiveness analyses. ETHICS AND DISSEMINATION: This study is approved by the La Trobe University and Alfred Hospital Ethics Committees. Results will be presented in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: ACTRN12620001164987.

Muscle strength and osteoarthritis of the knee: a systematic review and meta-analysis of longitudinal studies.

OBJECTIVE: To evaluate the sex-specific association between low knee extensor and flexor muscle strength and the risk of knee structural worsening. MATERIALS AND METHODS: Systematic searches in five databases identified longitudinal studies (≥ 1 year follow-up) reporting an association between knee extensor or flexor strength and structural decline in individuals with, or at risk of, knee osteoarthritis. Results were pooled for tibiofemoral and patellofemoral osteoarthritis worsening (and stratified by sex/gender where possible) using a random-effects meta-analysis estimating the risk ratio and 95% confidence interval or a best-evidence synthesis. Risk of bias and overall certainty of evidence were assessed. RESULTS: Fourteen studies were included with participants (mean age 27-72 years) with osteoarthritis (n = 8), at risk of osteoarthritis (n = 3), or a combination with, or at risk of, osteoarthritis (n = 3). Low knee extensor strength was associated with an increased risk of worsening tibiofemoral (12 studies: RR 1.18, 95% CI 1.04 to 1.35) and patellofemoral osteoarthritis (4 studies: RR 1.62, 95% CI 1.01 to 2.61). Significant associations between low knee extensor strength and worsening tibiofemoral osteoarthritis were observed for women (4 studies: RR 1.25, 95% CI 1.04 to 1.51) but not men (4 studies: RR 1.10, 95% CI 0.87 to 1.39). Low knee flexor strength increased the risk of worsening tibiofemoral osteoarthritis (5 studies: RR 1.16, 95% CI 1.07 to 1.26). Ten studies were high risk of bias, and all estimates were graded as very low certainty of evidence. CONCLUSION: Low knee extensor and flexor strength increased the risk of worsening tibiofemoral osteoarthritis. Low knee extensor strength increased the risk of worsening patellofemoral osteoarthritis. The relationship between low knee extensor strength and worsening tibiofemoral osteoarthritis may be modified by sex/gender.