A mathematical model of signalling molecule-mediated processes during regeneration of osteochondral defects after chondrocyte implantation.

Treating bone-cartilage defects is a fundamental clinical problem. The ability of damaged cartilage to self-repair is limited due to its avascularity. Left untreated, these defects can lead to osteoarthritis. Details of osteochondral defect repair are elusive, but animal models indicate healing occurs via an endochondral ossification-like process, similar to that in the growth plate. In the growth plate, the signalling molecules parathyroid hormone-related protein (PTHrP) and Indian Hedgehog (Ihh) form a feedback loop regulating chondrocyte hypertrophy, with Ihh inducing and PTHrP suppressing hypertrophy. To better understand this repair process and to explore the regulatory role of signalling molecules on the regeneration process, we formulate a reaction-diffusion mathematical model of osteochondral defect regeneration after chondrocyte implantation. The drivers of healing are assumed to be chondrocytes and osteoblasts, and their interaction via signalling molecules. We model cell proliferation, migration and chondrocyte hypertrophy, and matrix production and conversion, spatially and temporally. We further model nutrient and signalling molecule diffusion and their interaction with the cells. We consider the PTHrP-Ihh feedback loop as the backbone mechanisms but the model is flexible to incorporate extra signalling mechanisms if needed. Our mathematical model is able to represent repair of osteochondral defects, starting with cartilage formation throughout the defect. This is followed by chondrocyte hypertrophy, matrix calcification and bone formation deep inside the defect, while cartilage at the surface is maintained and eventually separated from the deeper bone by a thin layer of calcified cartilage. The complete process requires around 48 months. A key highlight of the model demonstrates that the PTHrP-Ihh loop alone is insufficient and an extra mechanism is required to initiate chondrocyte hypertrophy, represented by a critical cartilage density. A parameter sensitivity study reveals that the timing of the repair process crucially depends on parameters, such as the critical cartilage density, and those describing the actions of PTHrP to suppress hypertrophy, such as its diffusion coefficient, threshold concentration and degradation rate.

Assessment of the effectiveness of weight-adjusted antibiotic administration, for reduced duration, in surgical prophylaxis of primary hip and knee arthroplasty.

BACKGROUND: Prophylactic antibiotics have significantly led to a reduction in the risk of post-operative surgical site infections (SSI) in orthopaedic surgery. The aim of using antibiotics for this purpose is to achieve serum and tissue drug levels that exceed, for the duration of the operation, the minimum inhibitory concentration of the likely organisms that are encountered. Prophylactic antibiotics reduce the rate of SSIs in lower limb arthroplasty from between 4% and 8% to between 1% and 3%. Controversy, however, still surrounds the optimal frequency and dosing of antibiotic administration. AIM: To evaluate the impact of introduction of a weight-adjusted antibiotic prophylaxis regime, combined with a reduction in the duration of administration of post-operative antibiotics on SSI incidence during the 2 years following primary elective total hip and knee arthroplasty. METHODS: Following ethical approval, patients undergoing primary total hip arthroplasty (THA)/total knee arthroplasty (TKA) with the old regime (OR) of a preoperative dose [cefazolin 2 g intravenously (IV)], and two subsequent doses (2 h and 8 h), were compared to those after a change to a new regime (NR) of a weight-adjusted preoperative dose (cefazolin 2 g IV for patients < 120 kg; cefazolin 3g IV for patients > 120 kg) and a post-operative dose at 2 h. The primary outcome in both groups was SSI rates during the 2 years post-operatively. RESULTS: A total of n = 1273 operations (THA n = 534, TKA n = 739) were performed in n = 1264 patients. There was no statistically significant difference in the rate of deep (OR 0.74% (5/675) vs NR 0.50% (3/598); fishers exact test P = 0.72), nor superficial SSIs (OR 2.07% (14/675) vs NR 1.50% (9/598); chi-squared test P = 0.44) at 2 years post-operatively. With propensity score weighting and an interrupted time series analysis, there was also no difference in SSI rates between both groups [RR 0.88 (95%CI 0.61 to 1.30) P = 0.46]. CONCLUSION: A weight-adjusted regime, with a reduction in number of post-operative doses had no adverse impact on SSI incidence in this population.

An electroencephalography-based sleep index and supervised machine learning as a suitable tool for automated sleep classification in children.

STUDY OBJECTIVES: Although sleep is frequently disrupted in the pediatric intensive care unit, it is currently not possible to perform real-time sleep monitoring at the bedside. In this study, spectral band powers of electroencephalography data are used to derive a simple index for sleep classification. METHODS: Retrospective study at Erasmus MC Sophia Children's Hospital, using hospital-based polysomnography recordings obtained in non-critically ill children between 2017 and 2021. Six age categories were defined: 6-12 months, 1-3 years, 3-5 years, 5-9 years, 9-13 years, and 13-18 years. Candidate index measures were derived by calculating spectral band powers in different frequent frequency bands of smoothed electroencephalography. With the best performing index, sleep classification models were developed for two, three, and four states via decision tree and five-fold nested cross-validation. Model performance was assessed across age categories and electroencephalography channels. RESULTS: In total 90 patients with polysomnography were included, with a mean (standard deviation) recording length of 10.3 (1.1) hours. The best performance was obtained with the gamma to delta spectral power ratio of the F4-A1 and F3-A1 channels with smoothing. Balanced accuracy was 0.88, 0.74, and 0.57 for two-, three-, and four-state classification. Across age categories, balanced accuracy ranged between 0.83 and 0.92 and 0.72 and 0.77 for two- and three-state classification, respectively. CONCLUSIONS: We propose an interpretable and generalizable sleep index derived from single-channel electroencephalography for automated sleep monitoring at the bedside in non-critically ill children ages 6 months to 18 years, with good performance for two- and three-state classification. CITATION: van Twist E, Hiemstra FW, Cramer ABG, et al. An electroencephalography-based sleep index and supervised machine learning as a suitable tool for automated sleep classification in children. J Clin Sleep Med. 2024;20(3):389-397.

Midterm outcome of superior capsular reconstruction using doubled acellular human dermal allograft for irreparable rotator cuff tear.

BACKGROUND: Thicker (folded) facia lata autografts have been shown to be superior to thinner grafts and single-layered acellular human dermal (HD) allografts for superior capsular reconstruction (SCR) in biomechanical studies. The aim of this study was to evaluate the midterm clinical outcomes following SCR for irreparable supraspinatus tears using doubled (folded) HD allograft. METHODS: Thirty-two patients who had undergone SCR using doubled HD allograft between February 2012 and January 2020 were recruited in a continuous manner in this retrospective study. The inclusion criteria were SCR performed for irreparable supraspinatus tear and a minimum of 2 years' follow-up. The primary outcome measure was the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score. The secondary outcome measures were complications and revision surgery. A subgroup analysis was performed between patients who received a "standard" graft of mean 3-mm thickness or a "thick" graft of mean 4.4-mm thickness. RESULTS: One patient was lost to follow-up. A total of 31 patients (31 shoulder joints) were analyzed with a mean follow-up duration of 48 months (range, 25-96 months). Following surgery, there was significant improvement in the ASES score from 18.1 ± 14.3 (preoperative) to 76.3 ± 25.1 (postoperative) (P < .001), with a satisfactory clinical outcome obtained in 83.8% of the patients. In a subset of 8 patients completing 5 years' follow-up, the clinical improvements were sustained. The percentage of patients with a clinically successful outcome was higher among those with thick grafts compared to those with standard grafts, although this failed to reach statistical significance (94.4% vs. 69.2%, risk ratio 1.36, 95% confidence interval 0.93-1.99, P = .13). One patient within the standard group underwent revision surgery. CONCLUSION: SCR for irreparable rotator cuff tears with doubled HD allograft results in improved clinical outcomes and low reoperation at midterm follow-up duration.

Circumferential Periosteal Release to Treat Paediatric Leg Length Discrepancy: Medium Term Outcomes.

Aims: This study aims to report the medium term outcomes of circumferential periosteal release of the distal femur and distal tibia in treating paediatric leg length discrepancy (LLD). Materials and methods: A retrospective case series was performed on all patients undergoing circumferential periosteal release of the distal femur and/or tibia between 2006 and 2019. Data collected included demographics, surgical indications, post-operative leg lengths, and complications. Leg length discrepancy was calculated as actual values and percentages of the longest limb length. Final actual and percentage discrepancies were compared to initial discrepancies using a paired t-test. Patterns of discrepancy over time were analysed using linear mixed models. Results: Eighteen patients (11 males) were identified, who underwent 25 procedures. The mean age at first surgery was 5.8 (range, 2-13). The commonest indication was congenital limb deficiency (7 patients). Five patients underwent repeat periosteal release, and one patient had three releases. The mean follow-up was 63 months [standard deviation (SD), 33.9]. Fifteen patients had sufficient data for statistical analysis.The mean actual discrepancy decreased from 2.07 cm (SD, 1.07) to 1.12 cm (SD, 1.62), and the mean relative discrepancy from 4.3% (SD, 2.8) to 1.5% (SD, 2.4). Significant mean reductions were seen in both actual discrepancies [0.61 cm (95% CI: 0.05-1.16; p = 0.034)], and percentage discrepancy [2.10% (95% CI: 1.0-3.1, p = <0.001]). In five patients, the operated limb overgrew the contralateral limb. Patients whose operated limb overgrew still had a reduction in LLD, with a mean residual discrepancy less than 1 cm (mean 0.7 cm, 95% CI: From -0.9 to 2.4). Conclusion: Circumferential periosteal release produces a significant decrease in both actual and percentage LLD. We believe this procedure is best indicated in younger patients with congenital LLD in whom the discrepancy is predicted to increase as they age. Clinical significance: Circumferential periosteal release produces a significant decrease in LLD. This procedure can be used to manage symptoms during growth, particularly at the point where orthotic usage may become problematic, and to potentially reduce the magnitude of surgery needed at an older age. How to cite this article: Chatterton BD, Kuiper JH, Williams DP. Circumferential Periosteal Release to Treat Paediatric Leg Length Discrepancy: Medium Term Outcomes. Strategies Trauma Limb Reconstr 2023;18(2):67-72.

Comparison of Knee Articular Cartilage Defect Size Between Measurements Obtained on Preoperative MRI Versus During Arthrotomy.

Background: Treatment decisions for cartilage defects are often based on lesion size. Magnetic resonance imaging (MRI) is widely used to diagnose cartilage defects noninvasively; however, their size estimated from MRI may differ from defect sizes measured during arthrotomy, especially after debridement to healthy cartilage if undergoing autologous chondrocyte implantation. Purpose/Hypothesis: The purpose of this study was to evaluate the reliability of 2 methods to assess knee cartilage defect size on preoperative MRI and determine their accuracy in predicting postdebridement defect sizes recorded during arthrotomy. It was hypothesized that defect size would be predicted more accurately by the total area of abnormal articular cartilage rather than the area of full-thickness cartilage loss as identified on MRI. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: This study included 64 patients (mean age, 41.8 ± 9.6 years) who underwent autologous cell therapy. Each patient received a 3-T MRI at 6.1 ± 3.0 weeks before cell implantation. Three raters, a radiologist, a surgeon, and a scientist, measured (1) the full-thickness cartilage defect area and (2) the total predicted abnormal cartilage area, identified by an abnormal signal on MRI. Interrater reliability was assessed using the intraclass correlation coefficient (ICC). Actual pre- and postdebridement defect sizes were obtained from intraoperative surgical notes. Postdebridement surgical measurements were considered the clinical reference standard and were compared with the radiologist's MRI measurements. Results: Eighty-seven defects were assessed, located on the lateral (n = 8) and medial (n = 26) femoral condyle, trochlea (n = 17), and patella (n = 36). The interrater reliability of the cartilage defect measurements on MRI was good to excellent for the full-thickness cartilage defect area (ICC = 0.74) and the total predicted abnormal cartilage area (ICC = 0.78). The median full-thickness cartilage defect area on MRI underestimated the median postdebridement defect area by 78.3%, whereas the total predicted abnormal cartilage area measurement underestimated the postdebridement defect area by 14.3%. Conclusion: Measuring the full-thickness cartilage defect area on MRI underestimated the area to treat, whereas measuring the total abnormal area provided a better estimate of the actual defect size for treatment.

Microcirculatory Monitoring in Children with Congenital Heart Disease Before and After Cardiac Surgery.

In this prospective observational study, we investigated whether congenital heart disease (CHD) affects the microcirculation and whether the microcirculation is altered following cardiac surgery with cardiopulmonary bypass (CPB). Thirty-eight children with CHD undergoing cardiac surgery with CPB and 35 children undergoing elective, non-cardiac surgery were included. Repeated non-invasive sublingual microcirculatory measurements were performed with handheld vital microscopy. Before surgery, children with CHD showed similar perfused vessel densities and red blood cell velocities (RBCv) but less perfused vessels (p < 0.001), lower perfusion quality (p < 0.001), and higher small vessel densities (p = 0.039) than children without CHD. After cardiac surgery, perfused vessel densities and perfusion quality of small vessels declined (p = 0.025 and p = 0.032), while RBCv increased (p = 0.032). We demonstrated that CHD was associated with decreased microcirculatory perfusion and increased capillary recruitment. The microcirculation was further impaired after cardiac surgery. Decreased microcirculatory perfusion could be a warning sign for altered tissue oxygenation and requires further exploration.

Bringing the Nature Futures Framework to life: creating a set of illustrative narratives of nature futures.

To halt further destruction of the biosphere, most people and societies around the globe need to transform their relationships with nature. The internationally agreed vision under the Convention of Biological Diversity-Living in harmony with nature-is that "By 2050, biodiversity is valued, conserved, restored and wisely used, maintaining ecosystem services, sustaining a healthy planet and delivering benefits essential for all people". In this context, there are a variety of debates between alternative perspectives on how to achieve this vision. Yet, scenarios and models that are able to explore these debates in the context of "living in harmony with nature" have not been widely developed. To address this gap, the Nature Futures Framework has been developed to catalyse the development of new scenarios and models that embrace a plurality of perspectives on desirable futures for nature and people. In this paper, members of the IPBES task force on scenarios and models provide an example of how the Nature Futures Framework can be implemented for the development of illustrative narratives representing a diversity of desirable nature futures: information that can be used to assess and develop scenarios and models whilst acknowledging the underpinning value perspectives on nature. Here, the term illustrative reflects the multiple ways in which desired nature futures can be captured by these narratives. In addition, to explore the interdependence between narratives, and therefore their potential to be translated into scenarios and models, the six narratives developed here were assessed around three areas of the transformative change debate, specifically, (1) land sparing vs. land sharing, (2) Half Earth vs. Whole Earth conservation, and (3) green growth vs. post-growth economic development. The paper concludes with an assessment of how the Nature Futures Framework could be used to assist in developing and articulating transformative pathways towards desirable nature futures. Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-023-01316-1.

A pilot randomised controlled trial assessing standard versus dermal patch-augmented rotator cuff repair found no adverse effects and suggest future trials need a minimum of 150 patients.

PURPOSE: The aims of this pilot randomised controlled trial (RCT) were to assess the safety and efficacy of a human dermal allograft patch and assess the feasibility of a future RCT comparing retear rate and functional outcome 12 months following standard and augmented double-row rotator cuff repair. METHODS:  A pilot RCT was conducted among patients undergoing arthroscopic repair of rotator cuff tear measuring between 1 and 5 cm. They were randomised to either augmented (double-row repair with human acellular dermal patch) or standard (double-row repair only). The primary outcome was rotator cuff retear determined on MRI scan at 12 months using the Sugaya's classification (grade 4 or 5). All adverse events were recorded. Functional assessment was performed at baseline and 3, 6, 9, and 12 months post-surgery using clinical outcome scores. Safety was assessed by complications and adverse effects, and feasibility by recruitment, follow-up rate and proof of concept statistical analyses of a future trial. RESULTS: Between 2017 and 2019, 63 patients were considered for inclusion. Twenty-three patients were excluded, leaving 40 patients (20 per group) in the final study population. The mean tear sizes were 3.0 cm in the augmented and 2.4 cm in the standard group. There was one adhesive capsulitis in the augmented group, with no other adverse events. Retear was observed in 4/18 (22%) of patients in the augmented and 5/18 (28%) in the standard group. In both groups, functional outcome improved significantly which was clinically meaningful for all scores, with no difference between groups. Retear rate increased with tear size. Future trials are feasible but need a minimum total sample size of 150 patients. CONCLUSION:  Clinically meaningful improved function without adverse effects was found with human acellular dermal patch-augmented cuff repairs. LEVEL OF EVIDENCE: Level II.

Relationship Between Activity Level and Knee Function Is Influenced by Negative Affect in Patients Undergoing Cell Therapy for Articular Cartilage Defects in the Knee.

Background: Increased activity level is generally reported to be positively related to improved knee function after knee surgery. However, little research has been conducted into this relationship on an individual patient basis, or the influence of demographic and psychosocial factors such as patient affect-the subjective experience of emotion. Hypothesis: The relationship between postoperative activity level and knee function will vary between patients and will be influenced by the patients' affect and demographic characteristics. Study Design: Cohort study; Level of evidence, 3. Methods: Activity, knee function, demographic, and affect data were collected from patients enrolled in an ongoing trial for the treatment of articular cartilage lesions at preoperative and 2-, 12-, and 15-month postoperative points. Quantile mixed regression modeling was used to determine the patient-to-patient variation in activity level and knee function. Multiple linear regression and partial correlation analyses were performed to determine whether demographic characteristics and patient affect were associated with this variation. Results: A total of 62 patients were included in the study (23 female; 39 male; mean age, 38.3 ± 9.5 years). We found substantial variation between patients in the relationship between activity level and knee function, with most patients (n = 56) demonstrating a positive relation (positive slope), but 6 patients demonstrating a negative relation (negative slope). A negative affect (NA) score was significantly correlated with the slope between activity level and knee function (r S = -0.30; P = .018) and was a significant individual predictor of knee function at 15 months postoperatively (coefficient = -3.5; P = .025). Conclusion: Our results suggest that the relationship between activity level and knee function varies between patients. The patients with a higher NA score were likely to report smaller improvements in knee function with increasing activity levels compared with those with a lower NA score.

Histological and Radiological Assessment of Endogenously Generated Repair Tissue In Vivo Following a Chondral Harvest.

OBJECTIVE: To examine repair tissue formed approximately 15 months after a chondral harvest in the human knee. DESIGN: Sixteen individuals (12 males, 4 females, mean age 36 ± 9 years) underwent a chondral harvest in the trochlea as a pre-requisite for autologous chondrocyte implantation (ACI) treatment. The harvest site was assessed via MRI at 14.3 ± 3.2 months and arthroscopy at 15 ± 3.5 months (using the Oswestry Arthroscopy Score [O-AS] and the International Cartilage Repair Society Arthroscopy Score [ICRS-AS]). Core biopsies (1.8 mm diameter, n = 16) of repair tissue obtained at arthroscopy were assessed histologically (using the ICRS II and OsScore histology scores) and examined via immunohistochemistry for the presence of collagen types I and II. RESULTS: The mean O-AS and ICRS-AS of the repaired harvest sites were 7.2 ± 3.2 and 10.1 ± 3.5, respectively, with 80.3% ± 26% repair fill depth on MRI. The histological quality of the repair tissue formed was variable, with some hyaline cartilage present in 50% of the biopsies; where this occurred, it was associated with a significantly higher ICRS-AS than those with no hyaline cartilage present (median 11 vs. 7.5, P = 0.049). Collagen types I and II were detected in 12/14 and 10/13 biopsies, respectively. CONCLUSIONS: We demonstrate good-quality structural repair tissue formed following cartilage harvest in ACI, suggesting this site can be useful to study endogenous cartilage repair in humans. The trochlea is less commonly affected by osteoarthritis; therefore, location may be critical for spontaneous repair. Understanding the mechanisms and factors influencing this could improve future treatments for cartilage defects.

A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee.

BACKGROUND: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. PURPOSE: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. RESULTS: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, -1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation (P = .03; 6.4 points in favor of ACI; 95% CI, -0.4 to 13.1). More participants experienced a serious adverse event with ACI (P = .02). CONCLUSION: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. REGISTRATION: International Standard Randomised Controlled Trial Number: 48911177.

Adverse Events in Pediatric Critical Care Nonsurvivors With a Low Predicted Mortality Risk: A Multicenter Case Control Study.

OBJECTIVES: Some patients with a low predicted mortality risk in the PICU die. The contribution of adverse events to mortality in this group is unknown. The aim of this study was to estimate the occurrence of adverse events in low-risk nonsurvivors (LN), compared with low-risk survivors (LS) and high-risk PICU survivors and nonsurvivors, and the contribution of adverse events to mortality. DESIGN: Case control study. Admissions were selected from the national Dutch PICU registry, containing 53,789 PICU admissions between 2006 and 2017, in seven PICUs. PICU admissions were stratified into four groups, based on mortality risk (low/high) and outcome (death/survival). Random samples were selected from the four groups. Cases were "LN." Control groups were as follows: "LS," "high-risk nonsurvivors" (HN), and "high-risk survivors" (HS). Adverse events were identified using the validated trigger tool method. SETTING: Patient chart review study. PATIENTS: Children admitted to the PICU with either a low predicted mortality risk (< 1%) or high predicted mortality risk (≥ 30%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 419 patients were included (102 LN, 107 LS, 104 HN, and 106 HS). LN had more complex chronic conditions (93.1%) than LS (72.9%; p < 0.01), HN (49.0%; p < 0.001), and HS (48.1%; p < 0.001). The occurrence of adverse events in LN (76.5%) was higher than in LS (13.1%) and HN (47.1%) ( p < 0.001). The most frequent adverse events in LN were hospital-acquired infections and drug/fluid-related adverse events. LN suffered from more severe adverse events compared with LS and HS ( p < 0.001). In 30.4% of LN, an adverse event contributed to death. In 8.8%, this adverse event was considered preventable. CONCLUSIONS: Significant and preventable adverse events were found in low-risk PICU nonsurvivors. 76.5% of LN had one or more adverse events. In 30.4% of LN, an adverse event contributed to mortality.

Greater trochanteric pain syndrome: focused shockwave therapy versus an ultrasound guided injection: a randomised control trial.

BACKGROUND: Greater trochanteric pain syndrome (GTPS) is a common problem with an incidence of 1.8-5.6 per 1000 population. Physiotherapy, anti-inflammatories, corticosteroid injections and surgery have all been described in the management of GTPS, with limited, temporal success. Extracorporeal shockwave therapy (ESWT) has been proposed as a potential non-invasive management option for this difficult presentation. METHOD: We ran a prospective, 2-arm, single-blinded, randomised control trial comparing focused shockwave therapy (f-ESWT) to an ultrasound guided corticosteroid injection. Primary outcome measure was the visual analogue pain score. Secondary outcome measures included the Harris Hip Score (HHS) and Trendelenburg test for function; SF-36 for quality of life (QoL); and a Likert scale question for subjective assessment of symptom improvement. RESULTS: 104 patients (10 males and 94 females), of mean age 61.5 years were recruited. 53 were randomised to receive ESWT and 51 to receive an image-guided injection. 11 patients were lost to follow-up. There were no significant differences in baseline scores between groups.At 3 months, pain, function and QoL scores had improved in both groups but were not statistically significant. The Trendelenburg test was significantly improved in the f-ESWT group with 80% patients being negative compared to 20% at baseline (p < 0.001).At 12 months, across all outcomes, the ESWT group had significantly improved scores compared to the injection group; VAS 37.1 versus 55.0 (p = 0.007, 95% confidence interval [CI], 6.3-30.8), HHS 69.7 versus 57.5 (p = 0.002, 95% CI, -20.0 to -4.6) and SF-36 52.4 versus 47.7 (p = 0.048, 95% CI, -9.31 to -0.04). The improvement in Trendelenburg test was maintained in the ESWT group, but the injection group had reverted to baseline (p < 0.001). CONCLUSIONS: We have shown f-ESWT is an effective treatment for patients with GTPS. We would advocate f-ESWT as an effective non-invasive treatment modality for this challenging patient population.Trial Registration No. ISRCTN8338223.

DNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon.

Genetic variants in the DNA methyltransferase 3 A (DNMT3A) locus have been associated with inflammatory bowel disease (IBD). DNMT3A is part of the epigenetic machinery physiologically involved in DNA methylation. We show that DNMT3A plays a critical role in maintaining intestinal homeostasis and gut barrier function. DNMT3A expression is downregulated in intestinal epithelial cells from IBD patients and upon tumor necrosis factor treatment in murine intestinal organoids. Ablation of DNMT3A in Caco-2 cells results in global DNA hypomethylation, which is linked to impaired regenerative capacity, transepithelial resistance and intercellular junction formation. Genetic deletion of Dnmt3a in intestinal epithelial cells (Dnmt3aΔIEC) in mice confirms the phenotype of an altered epithelial ultrastructure with shortened apical-junctional complexes, reduced Goblet cell numbers and increased intestinal permeability in the colon in vivo. Dnmt3aΔIEC mice suffer from increased susceptibility to experimental colitis, characterized by reduced epithelial regeneration. These data demonstrate a critical role for DNMT3A in orchestrating intestinal epithelial homeostasis and response to tissue damage and suggest an involvement of impaired epithelial DNMT3A function in the etiology of IBD.

Bridging Theories for Ecosystem Stability Through Structural Sensitivity Analysis of Ecological Models in Equilibrium.

Ecologists are challenged by the need to bridge and synthesize different approaches and theories to obtain a coherent understanding of ecosystems in a changing world. Both food web theory and regime shift theory shine light on mechanisms that confer stability to ecosystems, but from different angles. Empirical food web models are developed to analyze how equilibria in real multi-trophic ecosystems are shaped by species interactions, and often include linear functional response terms for simple estimation of interaction strengths from observations. Models of regime shifts focus on qualitative changes of equilibrium points in a slowly changing environment, and typically include non-linear functional response terms. Currently, it is unclear how the stability of an empirical food web model, expressed as the rate of system recovery after a small perturbation, relates to the vulnerability of the ecosystem to collapse. Here, we conduct structural sensitivity analyses of classical consumer-resource models in equilibrium along an environmental gradient. Specifically, we change non-proportional interaction terms into proportional ones, while maintaining the equilibrium biomass densities and material flux rates, to analyze how alternative model formulations shape the stability properties of the equilibria. The results reveal no consistent relationship between the stability of the original models and the proportionalized versions, even though they describe the same biomass values and material flows. We use these findings to critically discuss whether stability analysis of observed equilibria by empirical food web models can provide insight into regime shift dynamics, and highlight the challenge of bridging alternative modelling approaches in ecology and beyond.

Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular Dystrophy.

OBJECTIVE: The North Star Ambulatory Assessment (NSAA) is a validated 17-item functional rating scale and widely used to assess motor function in boys with Duchenne muscular dystrophy (DMD). The SARS-CoV-2 pandemic and subsequent Government 'lockdown' resulted in no face-to-face clinic visits hence the motor abilities were not monitored. The aim was to investigate whether the NSAA was feasible and reliable by video assessment. METHOD: Ten ambulant DMD boys were selected from the electronic hospital records. Two physiotherapists scored the boys' NSAA independently and the intraclass correlation coefficient was used to assess agreement. The video scores were compared to two previous NSAA in-clinic scores. RESULTS: Mean scores (SD) for clinic visit one were 22.6 (4.19) and clinic visit two 21.8 (5.3). The two physiotherapists video mean scores were 20.6 (5.66) for physiotherapist 1 and 20.6 (6.53) for physiotherapist 2. The intraclass correlation coefficient was 0.98 (95% CI 0.93-1.00) for the total NSAA and 1.00 (95% CI 1.00 to 1.00) for the rise time. The mean decline in score from clinic visit one (-12 months) to video assessment was 2.0 (2.8SD). CONCLUSION: The results from the study suggest that video NSAA is partially feasible and reliable.

Osteochondral Lesions of the Ankle Treated with Bone Marrow Concentrate with Hyaluronan and Fibrin: A Single-Centre Study.

Osteochondral defects of the ankle (OCD) are being increasingly identified as a clinically significant consequence of injury to the ankle, with the potential to lead to osteoarthritis if left untreated. The aim of this retrospective cohort study was to evaluate a single-stage treatment of OCD, based on bone marrow aspirate (BMA) centrifuged to produce bone marrow concentrate (BMC). In a dual syringe, the concentrate was mixed with thrombin in one syringe, whereas hyaluronan and fibrinogen were mixed in a second syringe. The two mixtures were then injected and combined into the prepared defect. Clinical outcome and quality of life scores (MOXFQ and EQ-5D) were collected at baseline and yearly thereafter. Multilevel models were used to analyse the pattern of scores over time. Ninety-four patients were treated between 2015 and 2020. The means of each of the three components of the MOXFQ significantly improved between baseline and 1 year (p < 0.001 for each component), with no further change from year 1 to year 3. The EQ-5D index also improved significantly from baseline to 1 year, with no evidence for further change. Our results strongly indicate that this BMC treatment is safe for, and well tolerated by, patients with OCD of the ankle as both primary treatment and those who have failed primary treatment. This technique provides a safe, efficacious alternative to currently employed cartilage repair techniques, with favourable outcomes and a low complication rate at 36 months.

Contralateral strength training attenuates muscle performance loss following anterior cruciate ligament (ACL) reconstruction: a randomised-controlled trial.

PURPOSE: To investigate the effects of cross-education (CE) exercise on strength and performance at 10 and 24 weeks post anterior cruciate ligament (ACL) surgery. METHODS: Design: randomised controlled trial. N = 44 ACL-reconstruction patients, randomly-allocated into: CE: strength training of the non-operative limb, or CON: sham exercise of upper limb stretching. Each patient underwent standardised ACL rehabilitation, plus 8 weeks of thrice weekly CE or CON, commencing at 2 weeks post surgery. The primary outcome was quadriceps peak force (QPF) of the ACL-reconstructed limb at 10 weeks post surgery. Secondary measures were hamstrings peak force (HPF), rate of force development (RFD) and International Knee Documentation Committee score (IKDC) at 10 and 24 weeks; QPF and hop for distance (HOP) at 24 weeks post surgery. RESULTS: CE significantly attenuated the decline in QPF of the ACL-reconstructed limb at 10 weeks compared to CON (16.6% decrease vs. 32.0%, respectively); that advantage was not retained at 24 weeks. A training effect was observed in the trained limb for HPF and QPF, which was retained at 24 weeks. No significant differences were observed for IKDC, HOP, RFD, or HPF of the reconstructed limb. Inter-limb symmetry (ILS) ranged from 0.78 to 0.89 and was not significantly different between groups. CONCLUSION: High-intensity CE strength training attenuated the post-operative decline in QPF and should be considered in early-phase ACL rehabilitation. ILS data showed good symmetry, but it masked significantly inferior performance between groups and should be used with caution. TRIAL REGISTRATION NUMBER: NCT02722876.

Clinical validation of the Oswestry-Bristol Classification as part of a decision algorithm for trochlear dysplasia surgery.

AIMS: The Oswestry-Bristol Classification (OBC) is an MRI-specific assessment tool to grade trochlear dysplasia. The aim of this study is to validate clinically the OBC by demonstrating its use in selecting treatments that are safe and effective. METHODS: The OBC and the patellotrochlear index were used as part of the Oswestry Patellotrochlear Algorithm (OPTA) to guide the surgical treatment of patients with patellar instability. Patients were assigned to one of four treatment groups: medial patellofemoral ligament reconstruction (MPFLr); MPFLr + tibial tubercle distalization (TTD); trochleoplasty; or trochleoplasty + TTD. A prospective analysis of a longitudinal patellofemoral database was performed. Between 2012 and 2018, 202 patients (233 knees) with a mean age of 24.2 years (SD 8.1), with recurrent patellar instability were treated by two fellowship-trained consultant sports/knee surgeons at The Robert Jones and Agnes Hunt Orthopaedic Hospital. Clinical efficacy of each treatment group was assessed by Kujala, International Knee Documentation Committee (IKDC), and EuroQol five-dimension questionnaire (EQ-5D) scores at baseline, and up to 60 months postoperatively. Their safety was assessed by complication rate and requirement for further surgery. The pattern of clinical outcome over time was analyzed using mixed regression modelling. RESULTS: In all, 135 knees (mean age 24.9 years (SD 9.4)) were treated using a MPFLr. Ten knees (7.4%) required additional surgery. A total of 50 knees (mean age 24.4 years (SD 6.3)) were treated using MPFLr + TTD. Ten (20%) required additional surgery. A total of 20 knees (mean age 19.5 years (SD 3.0)) were treated using trochleoplasty + TTD. Three patients (15%) required additional surgery. In each treatment group, there was a significant improvement in Kujala, IKDC, and EQ-5D at one year postoperatively (p < 0.001) with a recognized level of overall complication rate. CONCLUSION: The OBC is a valid assessment tool to grade patients with trochlear dysplasia and, when used as part of the OPTA, helps to determine treatments that are safe and effective. This fulfils the requirements for its application in mainstream clinical practice. Cite this article: Bone Joint J 2021;103-B(10):1586-1594.