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.

Exploratory insights into novel prehabilitative neuromuscular exercise-conditioning in total knee arthroplasty.

BACKGROUND: Contemporary strategies for prehabilitation and rehabilitation associated with total knee arthroplasty (TKA) surgery have focused on improving joint range-of-motion and function with less emphasis on neuromuscular performance beneficially affecting joint stability. Furthermore, prehabilitation protocols have been found to be too long and generic-in-effect to be considered suitable for routine clinical practice. METHODS: A pragmatic exploratory controlled trial was designed to investigate the efficacy of a novel, acute prehabilitative neuromuscular exercise-conditioning (APNEC) in patients electing TKA. Adults electing unilateral TKA were assessed and randomly allocated to exercise-conditioning (APNEC, n = 15) and usual care (Control, n = 14) from a specialised orthopaedic hospital, in the United Kingdom. APNEC prescribed nine stressful exercise-conditioning sessions for the knee extensors of the surgery leg, accrued over one week (3 sessions·week-1; 36 exercise repetitions in total; machine, gravity-loaded) and directly compared with usual care (no exercise). Prescribed exercise stress ranged between 60%-100% of participant's daily voluntary strength capacity, encompassing purposefully brief muscular activations (≤ 1.5 s). Baseline and follow-up indices of neuromuscular performance focusing on muscle activation capacity (electromechanical delay [EMD], rate of force development [RFD] and peak force [PF]) were measured ipsilaterally using dynamometry and concomitant surface electromyography (m. rectus femoris[RF] and m. vastus lateralis[VL]). RESULTS: Group mean ipsilateral knee extensor muscular activation capacity (EMDRF [F(3,57) = 53.5; p < 0.001]; EMDVL [F(3,57) = 50.0; p < 0.001]; RFD [F(3,57) = 10.5; p < 0.001]) and strength (PF [F(3,57) = 16.4; p < 0.001]) were significantly increased following APNEC (Cohen's d, 0.5-1.8; 15% to 36% vs. baseline), but unchanged following no exercise control (per protocol, group by time interaction, factorial ANOVA, with repeated measures), with significant retention of gains at 1-week follow-up (p < 0.001). CONCLUSIONS: The exploratory APNEC protocol elicited significant and clinically-relevant improvement and its retention in neuromuscular performance in patients awaiting TKA. TRIAL REGISTRATION: (date and number): clinicaltrial.gov: NCT03113032 (4/04/2017) and ISRCTN75779521 (3/5/2017).

Apelin is expressed throughout the human kidney, is elevated in chronic kidney disease & associates independently with decline in kidney function.

AIMS: Chronic kidney disease (CKD) is common and cardiovascular disease (CVD) is its commonest complication. The apelin system is a potential therapeutic target for CVD but data relating to apelin in CKD are limited. We examined expression of the apelin system in human kidney, and investigated apelin and Elabela/Toddler (ELA), the endogenous ligands for the apelin receptor, in patients with CKD. METHODS: Using autoradiography, immunohistochemistry and enzyme-linked immunosorbent assay, we assessed expression of apelin, ELA and the apelin receptor in healthy human kidney, and measured plasma apelin and ELA in 155 subjects (128 patients with CKD, 27 matched controls) followed up for 5 years. Cardiovascular assessments included blood pressure, arterial stiffness (pulse wave velocity) and brachial artery flow-mediated dilation. Surrogate markers of endothelial function (plasma asymmetric dimethylarginine and endothelin-1) and inflammation (C-reactive protein and interleukin-6) were measured. RESULTS: The apelin system was expressed in healthy human kidney, throughout the nephron. Plasma apelin concentrations were 60% higher in women than men (6.48 [3.62-9.89] vs. 3.95 [2.02-5.85] pg/mL; P < .0001), and increased as glomerular filtration rate declined (R = -0.41, P < .0001), and albuminuria rose (R = 0.52, P < .0001). Plasma apelin and ELA were associated with vascular dysfunction. Plasma apelin associated independently with a 50% decline in glomerular filtration rate at 5 years. CONCLUSION: We show for the first time that the apelin system is expressed in healthy human kidney. Plasma apelin is elevated in CKD and may be a potential biomarker of risk of decline in kidney function. Clinical studies exploring the therapeutic potential of apelin agonism in CKD are warranted.

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.

An In Vitro System to Study the Effect of Subchondral Bone Health on Articular Cartilage Repair in Humans.

Chondrocyte-based cartilage repair strategies, such as articular chondrocyte implantation, are widely used, but few studies addressed the communication between native subchondral bone cells and the transplanted chondrocytes. An indirect co-culture model was developed, representing a chondrocyte/scaffold-construct repair of a cartilage defect adjoining bone, where the bone could have varying degrees of degeneration. Human BM-MSCs were isolated from two areas of subchondral bone in each of five osteochondral tissue specimens from five patients undergoing knee arthroplasty. These two areas underlaid the macroscopically and histologically best and worst cartilage, representing early and late-stage OA, respectively. BM-MSCs were co-cultured with normal chondrocytes suspended in agarose, with the two cell types separated by a porous membrane. After 0, 7, 14 and 21 days, chondrocyte-agarose scaffolds were assessed by gene expression and biochemical analyses, and the abundance of selected proteins in conditioned media was assessed by ELISA. Co-culture with late-OA BM-MSCs resulted in a reduction in GAG deposition and a decreased expression of genes encoding matrix-specific proteins (COL2A1 and ACAN), compared to culturing with early OA BM-MSCs. The concentration of TGF-ß1 was significantly higher in the early OA conditioned media. The results of this study have clinical implications for cartilage repair, suggesting that the health of the subchondral bone may influence the outcomes of chondrocyte-based repair strategies.

Clinical burden, risk factor impact and outcomes following myocardial infarction and stroke: A 25-year individual patient level linkage study.

BACKGROUND: Understanding trends in the incidence and outcomes of myocardial infarction and stroke, and how these are influenced by changes in cardiovascular risk factors can inform health policy and healthcare provision. METHODS: We identified all patients 30 years or older with myocardial infarction or stroke in Scotland. Risk factor levels were determined from national health surveys. Incidence, potential impact fractions and burden attributable to risk factor changes were calculated. Risk of subsequent fatal and non-fatal events (myocardial infarction, stroke, bleeding and heart failure hospitalization) were calculated with multi-state models. FINDINGS: From 1990 to 2014, there were 372,873 (71±13 years) myocardial infarctions and 290,927 (74±13 years) ischemic or hemorrhagic strokes. Age-standardized incidence per 100,000 fell from 1,069 (95% confidence interval, 1,024-1,116) to 276 (263-290) for myocardial infarction and from 608 (581-636) to 188 (178-197) for ischemic stroke. Systolic blood pressure, smoking and cholesterol decreased, but body-mass index increased, and diabetes prevalence doubled. Changes in risk factors accounted for a 74% (57-91%) reduction in myocardial infarction and 68% (55-83%) reduction in ischemic stroke. Following myocardial infarction, the risk of death decreased (30% to 20%), but non-fatal events increased (20% to 24%) whereas the risk of both death (47% to 34%) and non-fatal events (22% to 17%) decreased following stroke. INTERPRETATION: Over the last 25 years, substantial reductions in myocardial infarction and ischemic stroke incidence are attributable to major shifts in risk factor levels. Deaths following the index event decreased for both myocardial infarction and stroke, but rates remained substantially higher for stroke. FUNDING: British heart foundation.

A National Registry Study of Patient and Renal Survival in Adult Nephrotic Syndrome.

INTRODUCTION: We aimed to determine the mortality rate, cause of death, and rate of end-stage kidney disease (ESKD) in adults with nephrotic syndrome (NS). METHODS: We conducted a national registry-based study, including all 522 adults who had a kidney biopsy for NS in Scotland in 2014-2017. We linked the Scottish Renal Registry to death certificate data. We performed survival and Cox proportional hazards analyses, accounting for competing risks of death and ESKD. We compared mortality rates with those in the age- and sex-matched general population. RESULTS: A total of 372 patients had primary NS; 150 had secondary NS. Over a median follow-up of 866 days, 110 patients (21%) died. In patients with primary NS, observed versus population 3-year mortality was 2.1% (95% CI 0.0%-4.6%) versus 0.9% (0.8%-1.0%) in patients aged <60 years and 24.9% (18.4%-30.8%) versus 9.4% (8.3%-10.5%) in those aged ≥60 years. In secondary NS, this discrepancy was 17.1% (5.6%-27.2%) versus 1.1% (0.9%-1.2%) in <60-year-olds and 49.4% (36.6%-59.7%) versus 8.1% (6.6%-9.6%) in ≥60-year-olds. In primary NS, cardiovascular causes accounted for 28% of deaths, compared with 18% in the general population. Eighty patients (15%) progressed to ESKD. Incidence of ESKD by 3 years was 8.4% (95% CI 4.9%-11.7%) in primary and 35.1% (24.3%-44.5%) in secondary NS. Early remission of proteinuria and the absence of early acute kidney injury (AKI) were associated with lower rates of death and ESKD. CONCLUSIONS: Adults with NS have high rates of death and ESKD. Cardiovascular causes account for excess mortality in primary NS.

Isolated medial patellofemoral ligament reconstruction significantly improved quality of life in patients with recurrent patella dislocation.

PURPOSE: The purpose of this study was to measure the improvement in quality of life (QoL) following isolated anatomical double-bundle medial patellofemoral ligament reconstruction. METHODS: This is a single-centre, prospective study of 56 consecutive patients (57 knees) who underwent isolated MPFL reconstruction between 2014 and 2017. Functional outcome and QoL were assessed with the Kujala score and the EQ-5D-3L questionnaire, respectively. Objective outcomes were obtained through clinical examination at the latest follow-up assessing redislocation rate, patella apprehension test, patellar tilt, pain and range of motion. RESULTS: The median Kujala score increased from 60 (range 31-96) to 92 (range 34-100) at latest follow-up (p < 0.001). The median EQ-5D index also increased, from 0.69 (range 0.10-1) at baseline to 1 (range 0.16-1) at latest follow-up (p < 0.001), as well as the median EQ-5D VAS from 75 (range 20-95) to 92 (range 40-100) (p < 0.001). Four dimensions of the EQ-5D were significantly improved except for the anxiety/depression scores. Female patients reported lower scores at baseline and at latest follow-up, for all three outcomes (Kujala, EQ-5D index, EQ-5D VAS), however there was no evidence that gender negatively impacted on the benefit of surgery. The re-dislocation rate was 0%. Apprehension and patellar tilt test were negative in all patients and no flexion deficit was identified at latest follow-up. Two patients had tenderness along the reconstruction requiring femoral screw removal in one of them. CONCLUSIONS: Isolated anatomical double-bundle aperture MPFL reconstruction, offered significantly improved short-term QoL along with excellent functional outcome. Female patients scored lower, but this did not affect the overall outcome. Including QoL tools in the assessment of ligament reconstruction operations, such as the MPFL, can provide more accurate understanding of the overall patient benefit. LEVEL OF EVIDENCE: II.

Efficacy and safety of autologous cell therapies for knee cartilage defects (autologous stem cells, chondrocytes or the two): randomized controlled trial design.

AIM: The main aim of this trial is to test the safety and efficacy of autologous stromal/stem cells, chondrocytes or the two combined in the treatment of knee cartilage defects. PATIENTS & METHODS: Patients with symptomatic chondral/osteochondral defects will be randomized to cell therapy treatment with one of three cell populations (1:1:1). The primary efficacy outcome is a functional knee score (Lysholm) at 15 months post-treatment and the primary safety outcome is the incidence of adverse events. Secondary objectives are to analyze repair tissues, quality of life and cost-utility assessments. Exploratory objectives are to identify predictors for success/potency and dose-response relationships. RESULTS & CONCLUSION: This trial has been carefully designed so that valuable scientific and clinical information can be gathered throughout and in the final analysis.

Pre-surgery exercise and post-operative physical function of people undergoing knee replacement surgery: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To summarize the evidence regarding the effectiveness and dose-response characteristics of pre-operative exercise programmes on post-operative physical function following total knee arthroplasty. DATA SOURCES: CINAHL, Cochrane Library, PubMed, SPORTDiscus and EMBASE. STUDY SELECTION: Randomized controlled trials were eligible if they provided full description of physiological stress (i.e. mode, frequency, intensity and duration). DATA EXTRACTION: Data extraction and evaluation were performed by one reviewer. Methodological quality of the selected studies was assessed using the Physiotherapy Evidence Database scale. DATA SYNTHESIS: Twelve candidate studies were identified, but only 3 papers satisfied all inclusion criteria: 2 studies evaluated the effect of resistance training and 1 trial investigated proprioceptive training. The latter study elicited significantly enhanced post-operative gains in function for indices of standing balance (overall stability index: Hedges' g = -1; anteroposterior stability index: Hedges' g = -1.15; 6 weeks post-surgery). Results of meta-analysis based on the findings of 2 studies showed that, compared with controls, prehabilitative exercise involving resistance training offered no additional gains in isometric quadriceps muscle strength at 6 and 12 weeks post-operatively. CONCLUSION: Despite a potential for efficacy of exercise-based conditioning, this review highlights the scarcity of robust dose-response evidence to guide the formulation of total knee arthroplasty prehabilitation effectively.

Lateral meniscal cyst causing irreversible peroneal nerve palsy.

We report an unusual case of irreversible foot drop occurring secondary to a large lateral meniscal cyst. We discuss the presentation and management of this rare case and highlight some of the less common causes of foot drop.

Implementation of an enhanced recovery programme following pancreaticoduodenectomy.

OBJECTIVES: The aim of this prospective study was to investigate the implementation of an enhanced recovery after surgery (ERAS) programme following pancreaticoduodenectomy (PD). METHODS: Patients undergoing PD were managed according to an ERAS protocol. Outcome measures included postoperative mortality, morbidity, hospitalization and 30-day readmission rate. Key protocol targets were: nasogastric tube (NGT) removal [postoperative day (PoD) 1]; resumption of oral fluids (PoD 1); urinary catheter removal (PoD 3); high-dependency unit (HDU) discharge (PoD 3); tolerating diet (PoD 4); drain removal (PoD 5), and hospital discharge (PoD 6). RESULTS: Data were collected for 50 patients (24 male; median age 67 years). Rates of mortality, morbidity and readmission were 4%, 46% and 4%, respectively. The median length of postoperative hospitalization was 10 days. The proportions of patients achieving key targets were: 78% for NGT removal; 82% for resumption of oral fluids; 48% for urinary catheter removal; 82% for HDU discharge; 86% for tolerating diet; 84% for meeting mobility targets, and 72% for drain removal. One patient was discharged by PoD 6, eight patients by PoD 7, 15 patients by PoD 8 and 26 patients (52%) by PoD 10. Discharge was delayed in 16 patients for social or transport-related reasons. CONCLUSIONS: The ERAS protocol was implemented safely. Achieving certain targets was challenging. Non-medical causes remain a significant factor in delayed discharge following PD.

Intraoperative assessment of acetabular orientation: technical note.

Acetabular surgery is frequently utilized to manage developmental dysplasia of the hip and hip problems associated with cerebral palsy. During the operation, accurate correction of the orientation of the acetabular fragment is necessary. We describe a technique that enables accurate assessment of the coronal plane alteration in orientation. Intraoperative image intensifier records were compared with postoperative films and the accuracy of the coronal plane correction was evaluated. We found the intraoperative sourcil angle closely correlated to the postoperative angle to within 1°. The Spearman correlation coefficient was R=0.97, suggesting a close relationship between the two measurements.