In response to the COVID-19 pandemic public health measures were implemented to limit virus spread. After initial implementation of a province-wide lockdown (Stage 1), there followed a sequential ease of restrictions through Stages 2 and 3 over a 6-month period from March to September 2020 (Table 1). We aimed to determine the impact of COVID-19 public health measures on the epidemiology of operative paediatric orthopaedic trauma and to determine differential effects of each stage of lockdown.

A retrospective cohort study was performed comparing all emergency department (ED) visits for musculoskeletal trauma and operatively treated orthopaedic trauma cases at a Level-1 paediatric trauma center during Mar-Sep 2020 (pandemic), compared with Mar-Sep 2019 (pre-pandemic). All operative cases were analyzed based on injury severity, mechanism of injury (MOI) and anatomic location (AL). Comparisons between groups were assessed using chi-square testing for categorical variables, and student t-tests and Fisher's exact tests for continuous variables.

During the pandemic period, ED visits for orthopaedic trauma decreased compared to pre-pandemic levels by 23% (1370 vs 1790 patients) and operative treatment decreased by 28% (283 vs 391 patients). There was a significant decrease in the number of operative cases per day in lockdown Stage 1 (1.25 pandemic vs 1.90 pre- pandemic; p < 0 .001) and Stage 2 (1.65 pandemic vs 3.03 pre-pandemic; p< 0.001) but no difference in operative case number during Stage 3 (2.18 pandemic vs 2.45 pre-pandemic; p=0.35). Significant differences were found in MOI and AL during Stage 1 (p < 0 .001) and Stage 2 (p < 0 .001) compared to pre-pandemic. During Stage 1 and 2, playground injuries decreased by 95% and 82%, respectively; sports injuries decreased by 79% and 13%, and trampoline injuries decreased 44% and 43%, compared to pre-pandemic. However, self-propelled transit injuries (bicycles/skateboards) increased during Stage 1 and Stage 2 by 67% and 28%, respectively compared to pre- pandemic. During lockdown Stage 3 there were no differences in MOI nor AL. There were no significant differences in injury severity in any lockdown stage compared to pre-pandemic.

COVID-19 lockdown measures significantly reduced the burden of operative paediatric orthopaedic trauma. Differences in volume, mechanism and pattern of injuries varied by lockdown stage offering evidence of the burden of operative trauma related to specific childhood activities.

These findings will assist health systems planning for future pandemics and suggest that improvements in safety of playgrounds and self-propelled transit are important in reducing severe childhood injury requiring operative intervention.

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Bone regeneration includes a well-orchestrated series of biological events of bone induction and conduction. Among them, the Wnt/β-catenin signaling pathway is critical for bone regeneration. Being involved in several developmental processes, Wnt/β-catenin signaling must be safely targeted. There are currently only few specific therapeutic agents which are FDA-approved and already entered clinical trials. A published work has shown that Tideglusib, a selective and irreversible small molecule non-ATP-competitive glycogen synthase kinase 3-β(GSK-3β) inhibitor currently in trial for Alzheimer's patients, can promote tooth growth and repair cavities. [1]Despite some differences, they are some similarities between bone and tooth formation and we hypothesise that this new drug could represent a new avenue to stimulate bone healing.

In this work, we locally delivered Tideglusib (GSK3β inhibitor) in the repair of femoral cortical window defects and investigated bone regeneration. A biodegradable FDA-approved collagen sponge was soaked in GSK-3βinhibitor solution or vehicle only (DMSO) and was implanted in 1 × 2 mm unicortical defects created in femora of 35 adult wild-type male mice. Bone defect repair on control and experimental (GSK-3βinhibitor) groups was assessed after 1 week (n=22), 2 weeks (n=24) and 4 weeks (n=24) with microCT and histological analysis foralkaline phosphatase (ALP, osteoblast activity), tartrate resistant acid phosphatase (TRAP, osteoclasts), and immunohistochemistry to confirm the activation of the Wnt/β-catenin pathway.

Our results showed that Tideglusib significantly enhanced cortical bone bridging (20.6 ±2.3) when compared with the control (12.7 ±1.9, p=0.001). Activity of GSK-3β was effectively downregulated at day 7 and 14 resulting in a higher accumulation of active β-catenin at day 14 in experimental group (2.5±0.3) compared to the control (1.1±0.2, p=0.03). Furthermore, the onset of ALP activity appears earlier in the experimental group (day 14, 1.79±0.28), a level of activity never reached at any end-point by the control defects. At 4 weeks treatment, we observed a significant drop in ALP in the experimental group (0.47±0.05) compared to the control (1.01±0.19, p=0.02) and a decrease in osteoclast (experimental=1.32±0.36, control=2.23±0.67, p=0.04).

Local downregulation of GSK-3β by tideglusib during bone defect repair resulted in significant increase in amount of new bone formation. The early upregulation of osteoblast activity is one explanation of bone healing augmentation. This is likely the effect of upregulation of β-catenin following pharmaceutical inhibition of GSK-3β since β-catenin activation is known to positively regulate osteoblasts, once committed to the osteoblast lineage. As a GSK-3β inhibitor, Tideglusib demonstrates a different mechanism of action compared with other GSK-3β antagonists as treatment was started immediately upon injury and did not interfere with precursor cells recruitment and commitment. This indicates that tideglusib could be used at the fracture site during the initial intraoperative internal fixation without the need for further surgery. This safe and FDA-approved drug could be used in prevention of non-union in patients presenting with high risk for fracture-healing complications.