Abstract

Abstract

Abstract

COVID-19 confers a three-fold increased mortality risk among hip fracture patients. The aims were to investigate whether vaccination was associated with: i) lower mortality risk, and ii) lower likelihood of contracting COVID-19 within 30 days of fracture.

This nationwide cohort study included all patients aged >50 years with a hip fracture between 01/03/20-31/12/21. Data from the Scottish Hip Fracture Audit were collected and included: demographics, injury and management variables, discharge destination, and 30-day mortality status. These variables were linked to population-level records of COVID-19 vaccination and testing.

There were 13,345 patients with a median age of 82.0 years (IQR 74.0–88.0), and 9329/13345 (69.9%) were female. Of 3022/13345 (22.6%) patients diagnosed with COVID-19, 606/13345 (4.5%) were COVID-positive within 30 days of fracture. Multivariable logistic regression demonstrated that vaccinated patients were less likely to be COVID-positive (odds ratio (OR) 0.41, 95% confidence interval (CI) 0.34–0.48, p<0.001) than unvaccinated patients. 30-day mortality rate was higher for COVID-positive than COVID-negative patients (15.8% vs 7.9%, p < 0.001). Controlling for confounders (age, sex, comorbidity, deprivation, pre-fracture residence), unvaccinated patients with COVID-19 had a greater mortality risk than COVID-negative patients (OR 2.77, CI 2.12–3.62, p < 0.001), but vaccinated COVID19-positive patients were not at increased risk (OR 0.93, CI 0.53–1.60, p = 0.783).

Vaccination was associated with lower COVID-19 infection risk. Vaccinated COVID-positive patients had a similar mortality risk to COVID-negative patients, suggesting a reduced severity of infection. This study demonstrates the efficacy of vaccination in this vulnerable patient group, and presents essential data for future outbreaks.

Early changes within articular cartilage during human idiopathic osteoarthritis are poorly understood. However alterations to chondrocyte morphology occur with the development of fine cytoplasmic processes and cell clusters, potentially playing a role in cartilage degeneration. The aggrecanase ADAMTS-4 (A disintegrin and metalloproteinase with thrombospondin motifs-4) has been implicated as an important factor in cartilage degradation, so we investigated the relationship between chondrocyte morphology and levels of ADAMTS-4 in both non-degenerate and mildly osteoarthritic human cartilage.

Human femoral heads were obtained following consent from patients undergoing hip arthroplasty following femoral neck fracture. Cartilage explants of normal (grade 0; G0) and mildly osteoarthritic (grade 1; G1) cartilage were labelled with the cytoplasmic dye CMFDA (5-chloromethylfluorescein-diacetate). Explants were cryosectioned (30μm sections), and labelled for ADAMTS-4 by fluorescence immunohistochemistry. Sections were imaged with confocal microscopy, allowing the semi-quantitative analysis of ADAMTS-4 and 3D visualisation of in situ cell morphology.

With cartilage degeneration from G0 to G1, there was a decrease in the proportion of chondrocytes with normal rounded morphology (P<0.001) but an increase in the proportion of cells with processes (P<0.01) and those in clusters (P<0.001;[4(1653)]; femoral heads:cells). Although average levels of ADAMTS-4 for all cells was the same between G0 and G1 (P>0.05), a change was evident in the distribution curves for cell-specific ADAMTS-4 labelling. Cell-by-cell analysis showed that ADAMTS-4 levels were higher in chondrocytes with cytoplasmic processes compared to normal cells (P=0.044) however cells in clusters had lower levels than normal cells (P=0.003;[3(436)]). Preliminary data suggested that ADAMTS-4 levels increased with larger chondrocyte clusters.

These results suggest complex heterogeneous changes to levels of cell-associated ADAMTS-4 with early cartilage degeneration – increasing in cells with processes and initially decreasing in clusters. Increased levels of ADAMTS-4 are likely to produce focal areas of matrix weakness potentially leading to early cartilage degeneration.

The development of cytoplasmic processes from in situ chondrocytes is a characteristic feature of early osteoarthritis in human cartilage. The processes involve cytoskeletal elements and are distinct from the short primary cilia described in human chondrocytes. Vimentin is an intermediate filament playing an essential structural and signal-transduction role. We determined cellular levels and distribution of vimentin in chondrocytes of different morphologies in non-degenerate and mildly osteoarthritic cartilage.

Femoral heads were obtained after consent from patients undergoing hip arthroplasty following femoral neck fracture. Cartilage explants were graded as non-degenerate (grade 0;G0) or mildly osteoarthritic (grade 1;G1) and labelled with the cytoplasmic dye CMFDA (5-chloromethylfluorescein-diacetate) for cell shape. Explants were cryosectioned and labelled for vimentin by fluorescence immunohistochemistry. In situ chondrocyte morphology was identified by confocal microscopy as either normal (rounded/elliptical) or abnormal (with one or more cytoplasmic process of ≥2µm) and vimentin levels and distribution determined semi-quantitatively and related to chondrocyte morphology.

When all cells in G0 and G1 cartilage were compared, there was no difference between average levels of vimentin per cell (P=0.144)[6(261)];femoral heads:cells). When cells were separated on the basis of morphology, there was no difference between vimentin levels in cells with one or more cytoplasmic process compared to those of normal morphology (P>0.05;[6(261)]). However vimentin levels were much greater at the base of cytoplasmic processes compared to distant areas of the same cells (P=0.021)[5(29)]).

Although overall levels of chondrocyte vimentin do not change in these early stages of osteoarthritis, the formation and structure of these substantial chondrocyte cytoplasmic processes involves changes to its distribution. These morphological changes are similar to those occurring during chondrocyte de-differentiation to fibroblasts reported in osteoarthritis which results in the formation of mechanically-inferior fibro-cartilage. Alterations to chondrocyte vimentin distribution either directly or indirectly may play a role in cartilage degeneration.

Cartilage degeneration and loss are key events in the initiation and progression of osteoarthritis (OA). Changes to chondrocyte volume and morphology (in the form of cytoplasmic processes) and thus cell phenotype are implicated, as they lead to the production of a mechanically-weakened extracellular matrix. The chondrocyte cytoskeleton is intimately linked to cell volume and morphology and hence we have investigated alterations to levels and distribution of chondrocyte F-actin that occur during early OA.

The femoral heads (FH) from hip joints (N=16) were obtained with ethical permission and patient consent following femoral neck fracture. Cartilage was assessed as grade 0 (non-degenerate) and grade 1 (superficial fibrillation) using OARSI criteria. In situ chondrocyte volume and F-actin distribution were assessed using the fluorescent indicators (5-chloromethyl fluorescein diacetate (CMFDA)) and phalloidin, and imaged and quantified by confocal microscopy, Imaris^TM and ImageJ software.

There were no differences between the volume or total F-actin levels of in situ chondrocytes within the superficial zone of grade 0 (n=164 cells) compared to grade 1 (n=145) cartilage (P>0.05). However, a more detailed analysis of phalloidin labelling was performed, which demonstrated significant increases in both intense punctuate (IP) or intense areas (IA) (P<0.0001; P=0.0175 respectively). A preliminary analysis of IP and IA F-actin labelling suggested that while the former did not appear to be associated with changes to chondrocyte morphology, most of the cytoplasmic processes were associated with the presence of IA at the starting point of the protrusion.

These results demonstrate marked changes to F-actin distribution in chondrocytes in the very early stages of cartilage degeneration as occurs in OA. These subtle changes are probably an early indication of a change to the chondrocyte phenotype and thus worthy of further study as they may lead to deleterious alterations to matrix metabolism and ultimately cartilage weakening.

Articular cartilage has poor repair potential and the tissue formed is mechanically incompetent. Mesenchymal stromal cells (MSCs) show chondrogenic properties and the ability to re-grow cartilage, however a viable human model for testing cartilage regeneration and repair is lacking. Here, we describe an ex vivo pre-clinical femoral head model for studying human cartilage repair using MSCs.

Human femoral heads (FHs) were obtained following femoral neck fracture with ethical permission/patient consent and full-depth cartilage wells made using a 3mm biopsy punch. Pancreas-derived mesenchymal stromal cells (P-MSC) were prepared in culture media at ~5000 cells/20µl and added to each well and leakage prevented with fibrin sealant. After 24hrs, the sealant was removed and medium replaced with StemPro^TM chondrogenesis differentiation medium. The FHs were incubated (37^oC;5% CO₂) for 3wks, followed by a further 3wks in standard medium with 10% human serum with regular medium changes throughout. Compared to wells with medium only, A-MSCs produced a thin film across the wells which was excised en-block, fixed with 4% paraformaldehyde and frozen for cryo-sectioning.

The cell/tissue films varied in thickness ranging over 20-440µm (82±21µm; mean±SEM; N=3 FHs). The thickness of MSC films abutting the cartilage wells was variable but generally greater (15-1880µm) than across the wells, suggesting an attachment to native articular cartilage. Staining of the films using safranin O (for glycosaminoglycans; quantified using ImageJ) was variable (3±8%; mean±SEM; N=3) but in one experiment reached 20% of the adjacent cartilage. A preliminary assessment of the repair tissue gave an O'Driscoll score of 10/24 (24 is best).

These preliminary results suggest the ex vivo femoral head model has promise for studying the capacity of MSCs to repair cartilage directly in human tissue, although optimising MSCs to produce hyaline-like tissue is essential.

Supported by the CSO (TCS/17/32).

Hip fracture patients are vulnerable to delirium. This study examined the associations between delirium and outcomes including mortality, length of stay, post-discharge care requirements, and readmission.

This cohort study collected validated healthcare data for all hip fracture patients aged ≥50 years that presented to a high-volume centre between March 2020-November 2021. Variables included: demographics, delirium status, COVID-19 status, treatment factors, and outcome measures. Wilcoxon rank sum or Chi-squared tests were used for baseline differences, Cox proportional hazard regression for mortality, logistic regression for post-discharge care requirements and readmission, and linear regression for length of stay. Analyses were adjusted for age, sex, deprivation, pre-fracture residence type and COVID-19.

There were 1822 patients (mean age 81 years; 72% female) of which 496/1822 (27.2%) had delirium (4AT score ≥4). Of 371/1822 (20.4%) patients that died within 180 days of admission, 177/371 (47.7%) had delirium during the acute stay. Delirium was associated with an increased 30- and 180-day mortality risk (adjusted HR 1.74 (95%CI 1.15-2.64; p=0.009 and 1.74 (1.36-2.22; p<0.001), respectively), ten day longer total inpatient stay [adj. B.coef 9.80 (standard error 2.26); p<0.001] and three-fold greater odds of higher care requirements on discharge [Odds Ratio 3.07 (95% Confidence Interval 2.27-4.15; p<0.001)].

More than a quarter of patients had delirium during the hip fracture stay, and this was independently associated with increased mortality, longer length of stay, and higher post-discharge care requirements. These findings are relevant for prognostication and service planning, and emphasise the importance of effective delirium screening and evidence-based interventions in this vulnerable population.

Multiligament knee injuries (MLKI) are associated with significant morbidity and healthcare requirements. The primary aim of this study is to report the patient reported outcomes measures (PROMs) after reconstructive surgery.

Patients undergoing surgery for MLKI between 2014 and 2018 in the single large-volume trauma centre were included. Electronic patient records were reviewed for demographic data, details of surgery and complications. PROMs collected were EQ-5D-5L, Lysholm Knee Score (LKS), UCLA Activity and Sport and patient satisfaction.

Thirty-five patients were included. Mean age was 31 years (range 16-66), and 71% were male. The most common mechanism of injury was sports-related (71%). Obesity was present in eight (23%) patients. No vascular injuries were recorded and four patients sustained nerve injuries. PROMs were available for 18 patients (51%) with a median follow up of 4.5 years. Median EQ-5D-5L was 0.78 (IQR 0.14). Median LKS was 84.5 (IQR 21) and there was no correlation with time to surgery (p=0.43). Grade of MLKI did not impact LKS (p=0.09). Fifteen patients (83%) saw a reduction in their activity level. All patients were satisfied with their surgical treatment. Recurrent instability was noted in four patients (11%). Three patients (8%) required further surgery (one revision reconstruction, one meniscectomy, one conversion to a hinged knee replacement.

This study demonstrates two groups of patients who sustain MLKI: the sporting population and obese patients. Health related quality of life, functional outcomes and satisfaction are high after surgery. Time to surgery did not impact on functional outcomes.

This international multicentre retrospective cohort study aimed to assess: 1) prevalence of COVID-19 in hip fracture patients, 2) effect on mortality, and 3) clinical factors associated mortality among COVID-19-positive patients.

A collaboration among 112 centres in 14 nations collected data on all patients with a hip fracture between 1st March-31st May 2020. Patient, injury and surgical factors were recorded, and outcome measures included admission duration, COVID-19 and 30-day mortality status.

There were 7090 patients and 651 (9.2%) were COVID-19-positive. COVID-19 was independently associated with male sex (p=0.001), residential care (p<0.001), inpatient fall (p=0.003), cancer (p=0.009), ASA grade 4–5 (p=0.008; p<0.001), and longer admission (p<0.001). Patients with COVID-19 had a significantly lower chance of 30-day survival versus those without (72.7% versus 92.6%, p<0.001), and COVID-19 was independently associated with increased 30-day mortality risk (p<0.001). Increasing age (p=0.028), male sex (p<0.001), renal (p=0.017) and pulmonary disease (p=0·039) were independently associated with higher 30-day mortality risk in patients with COVID-19 when adjusting for confounders.

The prevalence of COVID-19 in hip fracture patients was 9% and was independently associated with a three-fold increased 30-day mortality risk. Clinical factors associated with mortality among COVID-19-positive hip fracture patients were identified for the first time. This is the largest study, and the only global cohort, reporting on the effect of COVID-19 in hip fracture patients. The findings provide a benchmark against which to determine vaccine efficacy in this vulnerable population and are especially important in the context of incomplete vaccination programmes and the emergence of vaccine-resistant strains.

Abstract

Abstract

Abstract

Background

National hip fracture programmes are becoming widespread, but this practice is nascent and varied. The Scottish Hip Fracture Audit (SHFA) was an early adopter of this strategy and is credited with substantial systemic improvements in quality and outcomes.

Hip fracture care is complex multi-disciplinary. We hypothesise that quality of care is affected by variance in resources between ‘in-hours’ (Monday-Friday, 0800–1700) and ‘out-of-hours’ services.

This prospective multicentre national cohort study assessed quality of care by evaluating adherence to the evidence-based Scottish Standards of Care for Hip Fracture Patients. Data was collected by the Scottish Hip Fracture Audit for 15174 patients admitted to any of 22 Scottish hospitals from January 2014-April 2018.

11197/15174 (73.8%) patients were admitted out-of-hours. They were significantly less likely to meet the following Standards: ED Big-6-Bundle (OR 0.85, p= 0.002); Time in ED <4 hours (OR 0.76, p< 0.001); avoidance of repeated fasting (OR 0.80, p< 0.001), and avoidance of prolonged fluid fasting (OR 0.83, p< 0.001). Out-of-hours admissions were more likely to receive: geriatric assessment <3 days (OR 1.16, p< 0.001); OT input <3 days (OR 1.10, p= 0.013), and PT input <2 days (OR 1.44, p< 0.001). There were no significant differences for: Time to Theatre <36 hours; Inpatient Care Bundle <24 hours, and Post-op Day 1 Mobilisation.

Quality of hip fracture care is affected by time of admission. ED care is poorer out-of-hours, which may reflect limited resources, and out-of-hours admissions are more likely to be excessive fasted excessively. Weekday in-hours admissions are less likely to receive geriatric and allied health professional input in the days following admission, which may reflect the reduced weekend services. Examination of out-of-hours service organisation is required for the pursuit of consistent, equitable care for hip fracture patients.

Introduction

Subacromial corticosteroid injection is widely used in the treatment of Subacromial Impingement Syndrome (SIS). There is increasing interest in using ultrasound (US) to improve the accurate placement of injections. This study investigated whether the accuracy of placement of US-guided subacromial corticosteroid injections influences patients' outcome of pain and function.

Chondrocytes are essential to the maintenance of articular cartilage and it is thought that chondrocyte death occurs early in septic arthritis. Understanding the causes of chondrocyte death will allow the development of chondroprotective strategies to improve long-term outcomes following septic arthritis.

We utilised a murine model of septic arthritis using intra-articular injection of 10µL of a 10⁷ concentration of S. aureus suspended in PBS. Seventy-five adult male C57/Bl6 mice were randomised to receive injection of either S. aurues 8325-4 (a wild-type of S. aurues capable of alpha toxin production), DU1090 (an isogenic mutant of 8325-4 that is identical to 8325-4 other than being incapable of producing alpha toxin) or a PBS control. Establishment of septic arthritis was confirmed through gait changes (5 mice/group), limb swelling and histological changes (10 mice/group). 10 animals from each group were sacrificed at 48 hours and the injected knee joints were dissected before being stained with CFMDA (labelling live chondrocytes green) and PI (labelling dead chondrocytes red). The samples were imaged using a confocal laser scanning microscope and the percentage of chondrocyte death was calculated.

Mice injected with S. aureus 8325-4 or DU1090 developed septic arthritis with evidence of weight loss, limb swelling and gait changes whereas these were absent in the control group. There was a significantly higher level of chondrocyte death in the group infected with 8325-4 (2.7% chondrocyte viability) when compared to DU1090 (73.9% chondrocyte viability) and PBS injected mice (95% chondrocyte viability). One-Way ANOVA revealed that the difference between each group was statistically different (p < 0.05).

Alpha toxin is the major damaging toxin in S. aurues septic arthritis. Any adverse effect of the immune system is negligible in comparison. Development of treatments counteracting the effect of alpha toxin is required.

Articular cartilage has very poor repair potential, however it has an extraordinary capacity to withstand physiological mechanical loads in an intact joint. The nature and extent of chondrocyte death in articular cartilage following many forms of injury (trephine, scalpel, osteotome, sutures and drilling) has been characterised, but the ability to bear mechanical injury from iatrogenic surgical interventions is still unknown.

A standard arthroscopic probe was moved at varying physiological pressures along the articular cartilage of joint before staining with fluorescent dyes to allow live/dead cell imaging using laser confocal scanning microscopy and imaging software, Image J. Bovine metatarsal phalangeal joints and fresh human cadaveric femoral condyles were used.

The probe caused statistically significant chondrocyte death in bovine cartilage (p=0.02). Mild pressure 5% cell death, moderate (standard arthroscopic technique pressure) 22% and severe pressure 38%. A similar result was seen in human tissue with 24% cell death at moderate pressure compared to a control (p=0.0699).

The widely assumed benign arthroscopic probe produces significant cell death in articular cartilage when used at standard operating pressures.

Purpose of the study and background

The CONNECT trial evaluated a theory-based intervention to increase low back pain patients' adherence to treatment recommendations through physiotherapists' communication behaviour. Bridging the gap between evidence and evidence-based practice, we aimed to develop an implementation intervention to support physiotherapists in translating the CONNECT communication training into practice.