Unexpected synergistic and antagonistic antibiotic activity against Staphylococcus biofilms.

Objectives: To evaluate putative anti-staphylococcal biofilm antibiotic combinations used in the management of periprosthetic joint infections (PJIs). Methods: Using the dissolvable bead biofilm assay, the minimum biofilm eradication concentration (MBEC) was determined for the most commonly used antimicrobial agents and combination regimens against staphylococcal PJIs. The established fractional inhibitory concentration (FIC) index was modified to create the fractional biofilm eradication concentration (FBEC) index to evaluate synergism or antagonism between antibiotics. Results: Only gentamicin (MBEC 64 mg/L) and daptomycin (MBEC 64 mg/L) were observed to be effective antistaphylococcal agents at clinically achievable concentrations. Supplementation of gentamicin with daptomycin, vancomycin or ciprofloxacin resulted in a similar or lower MBEC than gentamicin alone (FBEC index 0.25-2). Conversely, when rifampicin, clindamycin or linezolid was added to gentamicin, there was an increase in the MBEC of gentamicin relative to its use as a monotherapy (FBEC index 8-32). Conclusions: This study found that gentamicin and daptomycin were the only effective single-agent antibiotics against established Staphylococcus biofilms. Interestingly the addition of a bacteriostatic antibiotic was found to antagonize the ability of gentamicin to eradicate Staphylococcus biofilms.

The inhalation effects of by-products from chlorination of heated indoor swimming pools on spinal development in pup mice.

INTRODUCTION: It has been postulated that swimming in heated indoor swimming pools in the first year of life is associated with the development of spinal deformity in children. We explored in pup mice whether exposure to certain disinfection by-products resulting from chlorination of heated pools would affect the future development of the spinal column. METHODS: Mice, from birth and for 28 consecutive days, were exposed to chemicals known to be created by disinfection by-products of indoor heated swimming pools. The study made use of a body fluid analogue and a chlorine source to recreate the conditions found in municipal pools. A cohort of 51 wild-type C57B6 mice, male and female, were divided into two groups: experimental (n = 29) and controls (n = 22). 24 mice were observed for 8 months (32 weeks), with 27 culled at 4 months (16 weeks). Serial CT scanning was used to assess the spines. RESULTS: Exposure to disinfection by-products resulted in an increase in the normal thoracic kyphotic spinal angle of the mice when compared with their controls at 10 weeks; experimental mice kyphosis range 35-82° versus 29-38° in controls. At 14 weeks the kyphosis of the experimental mice had reduced in size but never to that of the control group. CONCLUSION: We have demonstrated the ability to influence spinal development in pup mice through environmental factors and shown that the developmental deformity became evident only after a significant latent period.

Patient-reported outcome metrics following total knee arthroplasty are influenced differently by patients' body mass index.

PURPOSE: This study investigated the impact of body mass index (BMI) on improvement in patient outcomes (pain, function, joint awareness, general health and satisfaction) following total knee arthroplasty (TKA). METHODS: Data were obtained for primary TKAs performed at a single centre over a 12-month period. Data were collected pre-operatively and 12-month postoperatively with the Oxford Knee Score (OKS) measuring pain and function, the EQ-5D-3L measuring general health status, the Forgotten Joint Score-12 (FJS-12) measuring joint awareness and a single question on treatment satisfaction. Change in scores following surgery was compared across the BMI categories identified by the World Health Organization (< 25.0, 25.0-29.9, 30.0-34.9, 35.0-39.9 and ≥ 40.0). Differences in postoperative improvement between the BMI groups were analysed with an overall Kruskal-Wallis test, with post hoc pairwise comparisons between BMI groups with Mann-Whitney tests. RESULTS: Of 402 patients [mean age 70.7 (SD 9.2); 55.2% women] 15.7% were normal weight (BMI < 25.0), 33.1% were overweight (BMI 25.0-29.9), 28.2% had class I obesity (BMI 30.0-34.9), 16.2% had class II obesity (BMI 35.0-39.9), and 7.0% had class III obesity (BMI ≥ 40.0). Postoperative change in OKS (n.s.) and EQ-5D-3L (n.s.) was not associated with BMI. Higher BMI group was associated with less improvement in FJS-12 scores (p = 0.010), reflecting a greater awareness of the operated joint during activity in the most obese patients. Treatment satisfaction was associated with BMI category (p = 0.029), with obese patients reporting less satisfaction. CONCLUSIONS: In TKA patients, outcome parameters are influenced differently by BMI. Our study showed a negative impact of BMI on postoperative improvement in joint awareness and satisfaction scores, but there was no influence on pain, function or general health scores. This information may be useful in terms of setting expectations expectation in obese patients planning to undergo TKA. LEVEL OF EVIDENCE: Level 1.

A patient's perception of their hospital stay influences the functional outcome and satisfaction of total knee arthroplasty.

INTRODUCTION: To assess whether patient satisfaction with their hospital stay influences the early outcome of total knee arthroplasty (TKA). METHODS: During a 5-year period patients undergoing primary TKA at the study centre had prospective outcome data recorded (n = 2264). The Oxford knee score (OKS) and the short form (SF)-12 were recorded pre-operatively and 1 year post-operatively when satisfaction with their TKA was also assessed. Patient satisfaction with their hospital stay was also evaluated and their reasons for it were qualitatively documented. RESULTS: Decreasing level of satisfaction with their hospital stay was associated with a significantly worse post-operative OKS (p < 0.001) and SF-12 score (p < 0.001). Multivariable regression analysis confirmed that the patient's perceived level of satisfaction with their hospital stay was an independent predictor of change in the OKS (p < 0.001) and SF-12 score (p < 0.006) after adjusting for confounding variables. Patient satisfaction with their TKA was significantly influenced by their hospital experience, decreasing from 96% in those with an excellent experience to 42% in those with a poor experience. Food, staff/care, and the hospital environment were the most frequent reasons of why patients rated their hospital experience as fair or poor. CONCLUSION: A patient's perception of their inpatient hospital experience after surgery is an important modifiable predictor of early functional outcome and satisfaction with TKA.

The use of hyperosmotic saline for chondroprotection: implications for orthopaedic surgery and cartilage repair.

OBJECTIVE: Articular cartilage may experience iatrogenic injury during routine orthopaedic/arthroscopic procedures. This could cause chondrocyte death, leading to cartilage degeneration and posttraumatic osteoarthritis. In an in vitro cartilage injury model, chondrocyte death was reduced by increasing the osmolarity of normal saline (NS), the most commonly-used irrigation solution. Here, we studied the effect of hyperosmolar saline (HS) on chondrocyte viability and cartilage repair in an in vivo injury model. DESIGN: Cartilage injury was induced by a single scalpel cut along the patellar groove of 8 week old rats in the absence of irrigation or with either NS (300 mOsm) or HS (600 mOsm). The percentage of cell death (PCD) within the injured area was assessed using confocal microscopy. Repair from injury was evaluated by histology/immunostaining, and inflammatory response by histology, cytokine array analysis and ELISA (enzyme-linked immunosorbent assay). RESULTS: The PCD in saline-irrigated joints was increased compared to non-irrigated (NI) joints [PCD = 20.8% (95%CI; 14.5, 27.1); PCD = 9.14% (95%CI; 6.3, 11.9); P = 0.0017]. However, hyperosmotic saline reduced chondrocyte death compared to NS (PCD = 10.4% (95%CI; 8.5, 12.3) P = 0.0024). Repair score, type II collagen and aggrecan levels, and injury width, were significantly improved with hyperosmotic compared to NS. Mild synovitis and similar changes in serum cytokine profile occurred in all operated joints irrespective of experimental group. CONCLUSIONS: Hyperosmotic saline significantly reduced the chondrocyte death associated with scalpel-induced injury and enhanced cartilage repair. This irrigation solution might be useful as a simple chondroprotective strategy and may also reduce unintentional cartilage injury during articular reconstructive surgery and promote integrative cartilage repair, thereby reducing the risk of posttraumatic osteoarthritis.

The minimal clinically important difference in the Oxford knee score and Short Form 12 score after total knee arthroplasty.

PURPOSE: The aim of this study was to identify the minimal clinically important difference (MCID) in the Oxford knee score (OKS) and Short Form (SF-) 12 score after total knee arthroplasty (TKA). METHODS: Prospective pre-operative and 1 year post-operative OKS and SF-12 scores for 505 patients undergoing a primary TKA for osteoarthritis were collected during a one-year period. Patient satisfaction with their (1) patient relief and (2) functional outcome was used as the anchor questions. Their response to each question was recorded using a 5-point Likert scale: excellent, very well, well, fair, and poor. Simple linear regression was used to calculate the MCID for improvement in the OKS and physical component of the SF-12 score according to the level of patient satisfaction with their pain relief and function. RESULTS: The OKS improved by 15.5 (95 % CI 14.7-16.4) points and the SF-12 physical component score improved by 10.1 (95 % CI 9.1-11.2) points for the study cohort. The level of patient satisfaction with their pain relief and function correlated with the improvement in the OKS (r = 0.56; p < 0.001, and r = 0.56; p < 0.001) and the physical component of the SF-12 score (r = 0.51; p < 0.001, and r = 0.60; p < 0.001), respectively. The MCID for the OKS was 5.0 (95 % CI 4.4-5.5) and 4.3 (95 % CI 3.8-4.8) points and for the physical component of the SF-12, it was 4.5 (95 % CI 3.9-5.2) and 4.8 (95 % CI 4.2-5.4) points for pain relief and function, respectively. CONCLUSION: The MCID identified for the OKS and SF-12 physical component score after TKA is the best available estimate and can be used to power studies and ensure that a statistical difference is also recognised by a patient.

Rapid in situ chondrocyte death induced by Staphylococcus aureus toxins in a bovine cartilage explant model of septic arthritis.

OBJECTIVE: To assess in situ chondrocyte viability following exposure to a laboratory strain and clinical isolates of Staphylococcus aureus. METHODS: Bovine cartilage explants were cultured in the presence of S. aureus 8325-4 (laboratory strain), clinical S. aureus isolates or non-infected culture medium of pH values 7.4, 6.4 and 5.4. All clinical isolates were isolated from the joint aspirates of patients presenting with S. aureus-induced septic arthritis (SA). At designated time points, in situ chondrocyte viability was assessed within defined regions-of-interest in the axial and coronal plane following live- and dead-cell image acquisition using the fluorescent probes 5-chloromethylfluorescein diacetate (CMFDA) and propidium iodide (PI), respectively, and confocal laser-scanning microscopy (CLSM). Cartilage water content, following S. aureus 8325-4 exposure, was obtained by measuring cartilage wet and dry weights. RESULTS: S. aureus 8325-4 and clinical S. aureus isolates rapidly reduced in situ chondrocyte viability (>45% chondrocyte death at 40 h). The increased acidity, observed during bacterial culture, had a minimal effect on chondrocyte viability. Chondrocyte death commenced within the superficial zone (SZ) and rapidly progressed to the deep zone (DZ). Simultaneous exposure of SZ and DZ chondrocytes to S. aureus 8325-4 toxins found SZ chondrocytes to be more susceptible to the toxins than DZ chondrocytes. Cartilage water content was not significantly altered compared to non-infected controls. CONCLUSIONS: Toxins released by S. aureus have a rapid and fatal action on in situ chondrocytes in this experimental model of SA. These data advocate the prompt and thorough removal of bacteria and their toxins during the treatment of SA.

Do modern total knee replacements offer better value for money? A health economic analysis.

PURPOSE: Cost effectiveness is an increasingly important factor in today's healthcare environment, and selection of arthroplasty implant is not exempt from such concerns. Quality adjusted life years (QALYs) are the typical tool for this type of evaluation. Using this methodology, joint arthroplasty has been shown to be cost effective; however, studies directly comparing differing prostheses are lacking. METHODS: Data was gathered in a single-centre prospective double-blind randomised controlled trial comparing the outcome of modern and traditional knee implants, using the Short Form 6 dimensional (SF-6D) score and quality adjusted life year (QALY) methodology. RESULTS: There was significant improvement in the SF-6D score for both groups at one year (p < 0.0001). The calculated overall life expectancy for the study cohort was 15.1 years, resulting in an overall QALY gain of 2.144 (95% CI 1.752-2.507). The modern implant group demonstrated a small improvement in SF-6D score compared to the traditional design at one year (0.141 versus 0.143, p = 0.94). This difference resulted in the modern implant costing £298 less per QALY at one year. CONCLUSION: This study demonstrates that modern implant technology does not influence the cost-effectiveness of TKA using the SF-6D and QALY methodology. This type of analysis however assesses health status, and is not sensitive to joint specific function. Evolutionary design changes in implant technology are thus unlikely to influence QALY analysis following joint replacement, which has important implications for implant procurement.

Relating age and micro-architecture with apparent-level elastic constants: a micro-finite element study of female cortical bone from the anterior femoral midshaft.

Homogenized elastic properties are often assumed for macro-finite element (FE) models used in orthopaedic biomechanics. The accuracy of material property assignments may have a strong effect on the ability of these models to make accurate predictions. For cortical bone, most macro-scale FE models assume isotropic elastic material behaviour and do not include variation of material properties due to bone micro-architecture. The first aim of the present study was to evaluate the variation of apparent-level (homogenized) orthotropic elastic constants of cortical bone with age and indices of bone micro-architecture. Considerable age-dependent differences in porosity were noted across the cortical thickness in previous research. The second aim of the study was to quantify the resulting differences in elastic constants between the periosteum and endosteum. Specimens were taken from the anterior femoral midshaft of 27 female donors (age 53.4 +/- 23.6 years) and micro-FE (gFE) analysis was used to derive orthotropic elastic constants. The variation of orthotropic elastic constants (Young's moduli, shear moduli, and Poisson's ratios) with various cortical bone micro-architectural indices was investigated. The ratio of canal volume to tissue volume, Ca.V/TV, analogous to porosity, was found to be the strongest predictor (r2(ave) = 0.958) of the elastic constants. Age was less predictive (r2(ave) = 0.385) than Ca.V/TV. Elastic anisotropy increased with increasing Ca.V/TV, leading to lower elastic moduli in the transverse, typically less frequently loaded, directions. Increased Ca.V/TV led to a more substantial reduction in elastic constants at the endosteal aspect than at the periosteal aspect. The results are expected to be most applicable in similar midshaft locations of long bones; specific analysis of other sites would be necessary to evaluate elastic properties elsewhere. It was concluded that Ca.V/TV was the most predictive of cortical bone elastic constants and that considerable periosteal-endosteal variations in these constants can develop with bone loss.

Monitoring of fracture healing. Update on current and future imaging modalities to predict union.

Fracture nonunion causes considerable patient morbidity and an associated burden to society. Traditional reliance on radiographs to monitor union has limitations as bridging callus of long bone fractures can take three or more months to occur. Computed Tomographic (CT) scanning is becoming increasingly popular and can evaluate bridging callus in the late stages of healing to confirm union. The use of dynamic contrast enhanced Magnetic Resonance Imaging (MRI) and advances in nuclear imaging may yield benefits in the assessment of the infected nonunion. Emerging evidence supports the use of ultrasound to detect bridging callus prior to radiographic confirmation and it may be of use to predict patients at high risk of nonunion. This paper is part of a Supplement supported by The Osteosynthesis and Trauma Care Foundation (OTCF).

Reduction in patient outcomes but implant-derived preservation of function following total knee arthroplasty: longitudinal follow-up of a randomized controlled trial.

AIMS: There are comparatively few randomized studies evaluating knee arthroplasty prostheses, and fewer still that report longer-term functional outcomes. The aim of this study was to evaluate mid-term outcomes of an existing implant trial cohort to document changing patient function over time following total knee arthroplasty using longitudinal analytical techniques and to determine whether implant design chosen at time of surgery influenced these outcomes. METHODS: A mid-term follow-up of the remaining 125 patients from a randomized cohort of total knee arthroplasty patients (initially comprising 212 recruited patients), comparing modern (Triathlon) and traditional (Kinemax) prostheses was undertaken. Functional outcomes were assessed with the Oxford Knee Score (OKS), knee range of movement, pain numerical rating scales, lower limb power output, timed functional assessment battery, and satisfaction survey. Data were linked to earlier assessment timepoints, and analyzed by repeated measures analysis of variance (ANOVA) mixed models, incorporating longitudinal change over all assessment timepoints. RESULTS: The mean follow-up of the 125 patients was 8.12 years (7.3 to 9.4). There was a reduction in all assessment parameters relative to earlier assessments. Longitudinal models highlight changes over time in all parameters and demonstrate large effect sizes. Significant between-group differences were seen in measures of knee flexion (medium-effect size), lower limb power output (large-effect size), and report of worst daily pain experienced (large-effect size) favouring the Triathlon group. No longitudinal between-group differences were observed in mean OKS, average daily pain report, or timed performance test. Satisfaction with outcome in surviving patients at eight years was 90.5% (57/63) in the Triathlon group and 82.8% (48/58) in the Kinemax group, with no statistical difference between groups (p = 0.321). CONCLUSION: At a mean 8.12 years, this mid-term follow-up of a randomized controlled trial cohort highlights a general reduction in measures of patient function with patient age and follow-up duration, and a comparative preservation of function based on implant received at time of surgery. Cite this article: Bone Joint J 2020;102-B(4):434-441.

What is the role of ultrasound in fracture management?: Diagnosis and therapeutic potential for fractures, delayed unions, and fracture-related infection.

OBJECTIVES: The aim of this study was to review the current evidence and future application for the role of diagnostic and therapeutic ultrasound in fracture management. METHODS: A review of relevant literature was undertaken, including articles indexed in PubMed with keywords "ultrasound" or "sonography" combined with "diagnosis", "fracture healing", "impaired fracture healing", "nonunion", "microbiology", and "fracture-related infection". RESULTS: The use of ultrasound in musculoskeletal medicine has expanded rapidly over the last two decades, but the diagnostic use in fracture management is not routinely practised. Early studies have shown the potential of ultrasound as a valid alternative to radiographs to diagnose common paediatric fractures, to detect occult injuries in adults, and for rapid detection of long bone fractures in the resuscitation setting. Ultrasound has also been shown to be advantageous in the early identification of impaired fracture healing; with the advent of 3D image processing, there is potential for wider adoption. Detection of implant-related infection can be improved by ultrasound mediated sonication of microbiology samples. The use of therapeutic ultrasound to promote union in the management of acute fractures is currently a controversial topic. However, there is strong in vitro evidence that ultrasound can stimulate a biological effect with potential clinical benefit in established nonunions, which supports the need for further investigation. CONCLUSION: Modern ultrasound image processing has the potential to replace traditional imaging modalities in several areas of trauma practice, particularly in the early prediction of impaired fracture healing. Further understanding of the therapeutic application of ultrasound is required to understand and identify the use in promoting fracture healing.Cite this article: J. A. Nicholson, S. T. J. Tsang, T. J. MacGillivray, F. Perks, A. H. R. W. Simpson. What is the role of ultrasound in fracture management? Diagnosis and therapeutic potential for fractures, delayed unions, and fracture-related infection. Bone Joint Res 2019;8:304-312. DOI: 10.1302/2046-3758.87.BJR-2018-0215.R2.

Non-union: Indications for external fixation.

External fixation is currently used as the definitive mode of fracture stabilisation in the management of ˜50% of long-bone non-unions. Distinction between non-union and delayed union is a diagnostic dilemma especially in fractures healing by primary bone repair. This distinction is important, as non-unions are not necessarily part of the same spectrum as delayed unions. The aetiology of a fracture non-union is usually multifactorial and the factors can be broadly categorized into mechanical factors, biological (local and systemic) factors, and infection. Infection is present in ˜40% of fracture non-unions, often after open fractures or impaired wound healing, but in 5% of all non-unions infection is present without any clinical or serological suspicion. General indications for external fixation include clinical scenarios where; 1) percutaneous correction of alignment, or mechanical stimulation of the non-union site is required; 2) fixation of juxta-articular or 'emmental' bone fragments is necessary; and 3) staged bone or soft tissue reconstruction is anticipated. Specific anatomical indications include infected non-unions of the tibia, humerus, and juxta-articular bone. External fixation is an essential tool in the management of fracture non-unions. However, with greater understanding of the outcomes associated with both external and internal fixation the relative indications are now being refined.

Experimental and numerical investigation into the influence of loading conditions in biomechanical testing of locking plate fracture fixation devices.

OBJECTIVES: Secondary fracture healing is strongly influenced by the stiffness of the bone-fixator system. Biomechanical tests are extensively used to investigate stiffness and strength of fixation devices. The stiffness values reported in the literature for locked plating, however, vary by three orders of magnitude. The aim of this study was to examine the influence that the method of restraint and load application has on the stiffness produced, the strain distribution within the bone, and the stresses in the implant for locking plate constructs. METHODS: Synthetic composite bones were used to evaluate experimentally the influence of four different methods of loading and restraining specimens, all used in recent previous studies. Two plate types and three screw arrangements were also evaluated for each loading scenario. Computational models were also developed and validated using the experimental tests. RESULTS: The method of loading was found to affect the gap stiffness strongly (by up to six times) but also the magnitude of the plate stress and the location and magnitude of strains at the bone-screw interface. CONCLUSIONS: This study demonstrates that the method of loading is responsible for much of the difference in reported stiffness values in the literature. It also shows that previous contradictory findings, such as the influence of working length and very large differences in failure loads, can be readily explained by the choice of loading condition.Cite this article:Bone Joint Res 2018;7:111-120.

A novel organ culture model of a joint for the evaluation of static and dynamic load on articular cartilage.

OBJECTIVES: The purpose of this study was to create a novel ex vivo organ culture model for evaluating the effects of static and dynamic load on cartilage. METHODS: The metatarsophalangeal joints of 12 fresh cadaveric bovine feet were skinned and dissected aseptically, and cultured for up to four weeks. Dynamic movement was applied using a custom-made machine on six joints, with the others cultured under static conditions. Chondrocyte viability and matrix glycosaminoglycan (GAG) content were evaluated by the cell viability probes, 5-chloromethylfluorescein diacetate (CMFDA) and propidium iodide (PI), and dimethylmethylene blue (DMMB) assay, respectively. RESULTS: Chondrocyte viability in the static model decreased significantly from 89.9% (sd 2.5%) (Day 0) to 66.5% (sd 13.1%) (Day 28), 94.7% (sd 1.1%) to 80. 9% (sd 5.8%) and 80.1% (sd 3.0%) to 46.9% (sd 8.5%) in the superficial quarter, central half and deep quarter of cartilage, respectively (p < 0.001 in each zone; one-way analysis of variance). The GAG content decreased significantly from 6.01 µg/mg (sd 0.06) (Day 0) to 4.71 µg/mg (sd 0.06) (Day 28) (p < 0.001; one-way analysis of variance). However, with dynamic movement, chondrocyte viability and GAG content were maintained at the Day 0 level over the four-week period without a significant change (chondrocyte viability: 92.0% (sd 4.0%) (Day 0) to 89.9% (sd 0.2%) (Day 28), 93.1% (sd 1.5%) to 93.8% (sd 0.9%) and 85.6% (sd 0.8%) to 84.0% (sd 2.9%) in the three corresponding zones; GAG content: 6.18 µg/mg (sd 0.15) (Day 0) to 6.06 µg/mg (sd 0.09) (Day 28)). CONCLUSION: Dynamic joint movement maintained chondrocyte viability and cartilage GAG content. This long-term whole joint culture model could be of value in providing a more natural and controlled platform for investigating the influence of joint movement on articular cartilage, and for evaluating novel therapies for cartilage repair.Cite this article: Y-C. Lin, A. C. Hall, A. H. R. W. Simpson. A novel organ culture model of a joint for the evaluation of static and dynamic load on articular cartilage. Bone Joint Res 2018;7:205-212. DOI: 10.1302/2046-3758.73.BJR-2017-0320.