Can metabolic profiling provide a new description of osteoarthritis and enable a personalised medicine approach?

Osteoarthritis (OA) is a multifactorial disease contributing to significant disability and economic burden in Western populations. The aetiology of OA remains poorly understood, but is thought to involve genetic, mechanical and environmental factors. Currently, the diagnosis of OA relies predominantly on clinical assessment and plain radiographic changes long after the disease has been initiated. Recent advances suggest that there are changes in joint fluid metabolites that are associated with OA development. If this is the case, biochemical and metabolic biomarkers of OA could help determine prognosis, monitor disease progression and identify potential therapeutic targets. Moreover, for focussed management and personalised medicine, novel biomarkers could sub-stratify patients into OA phenotypes, differentiating metabolic OA from post-traumatic, age-related and genetic OA. To date, OA biomarkers have concentrated on cytokine action and protein signalling with some progress. However, these remain to be adopted into routine clinical practice. In this review, we outline the emerging metabolic links to OA pathogenesis and how an elucidation of the metabolic changes in this condition may provide future, more descriptive biomarkers to differentiate OA subtypes.

Differences in the composition of hip and knee synovial fluid in osteoarthritis: a nuclear magnetic resonance (NMR) spectroscopy study of metabolic profiles.

OBJECTIVE: The hip and knee joints differ biomechanically in terms of contact stresses, fluid lubrication and wear patterns. These differences may be reflected in the synovial fluid (SF) composition of the two joints, but the nature of these differences remains unknown. The objective was to identify differences in osteoarthritic hip and knee SF metabolites using metabolic profiling with Nuclear Magnetic Resonance (NMR) spectroscopy. DESIGN: Twenty-four SF samples (12 hip, 12 knee) were collected from patients with end-stage osteoarthritis (ESOA) undergoing hip/knee arthroplasty. Samples were matched for age, gender, ethnicity and had similar medical comorbidities. NMR spectroscopy was used to analyse the metabolites present in each sample. Principal Component Analysis and Orthogonal Partial Least Squares Discriminant Analysis were undertaken to investigate metabolic differences between the groups. Metabolites were identified using 2D NMR spectra, statistical spectroscopy and by comparison to entries in published databases. RESULTS: There were significant differences in the metabolic profile between the groups. Four metabolites were found in significantly greater quantities in the knee group compared to the hip group (N-acetylated molecules, glycosaminoglycans, citrate and glutamine). CONCLUSIONS: This is the first study to indicate differences in the metabolic profile of hip and knee SF in ESOA. The identified metabolites can broadly be grouped into those involved in collagen degradation, the tricarboxylic acid cycle and oxidative metabolism in diseased joints. These findings may represent a combination of intra and extra-articular factors.

Does using anatomical models improve patient satisfaction in orthopaedic consenting? Single-blinded randomised controlled trial.

BACKGROUND: Patient satisfaction in consenting is a major pillar of clinical governance and healthcare quality assessment. The purpose was to observe the effect of using 3D anatomical models of knee and shoulder joints on patient satisfaction during informed consent in the largest single-blinded randomised controlled trial in this field. METHODS: 52 patients undergoing elective knee or shoulder surgery were randomised into two groups when being consented. The intervention group (n = 26) was shown an anatomical model of the knee/shoulder joint while the control group (n = 26) was given only a verbal explanation without a model. Patients rated their satisfaction on the validated Medical Interview Satisfaction Scale (MISS-26) questionnaire. Semi-structured interviews were analysed for specific themes to determine key factors that influenced patient satisfaction. The mean score ±SD were calculated with significance set at p < 0.05. RESULTS: There was a significant difference in the overall satisfaction between the control and intervention cohorts (MISS-26 score 4.33 [86.6%] ± 0.646 vs 4.70 [94.0%] ± 0.335 respectively, 7.4% improvement, 8.5% difference, p = 0.01). Behavioural criteria showed a 13% increase in satisfaction (p = 0.02). Semi-structured interviews determined that the factors influencing satisfaction included the surgeon's interpersonal manner, the use of the visual aid and seeing the consultant surgeon in clinic. All patients in the intervention cohort identified factors contributing to their satisfaction, whereas a fifth of the control cohort claimed nothing at all made them feel satisfied. CONCLUSION: Anatomical models as visual aids significantly increased patient satisfaction during the consenting process and played an integral part of the surgeon's explanation. Patients exposed to anatomical models also claimed to be more satisfied with the surgeon's inter-personal skills. This study recommends the use of anatomical models, which are both cost-effective and easily implementable, during explanation and consent for orthopaedic procedures.

A systematic review of the small molecule studies of osteoarthritis using nuclear magnetic resonance and mass spectroscopy.

OBJECTIVE: To perform a systematic review of the small molecule metabolism studies of osteoarthritis utilising nuclear magnetic resonance (NMR) or mass spectroscopy (MS) analysis (viz., metabolomics or metabonomics), thereby providing coherent conclusions and reference material for future study. METHOD: We applied PRISMA guidelines (PROSPERO 95068) with the following MESH terms: 1. "osteoarthritis" AND ("metabolic" OR "metabonomic" OR "metabolomic" OR "metabolism") 2. ("synovial fluid" OR "cartilage" OR "synovium" OR "serum" OR "plasma" OR "urine") AND ("NMR" or "Mass Spectroscopy"). Databases searched were "Medline" and "Embase". Studies were searched in English and excluded review articles not containing original research. Study outcomes were significant or notable metabolites, species (human or animal) and the Newcastle-Ottawa Score. RESULTS: In the 27 studies meeting the inclusion criteria, there was a shift towards anaerobic and fatty acid metabolism in OA disease, although whether this represents the inflammatory state remains unclear. Lipid structure and composition was altered within disease subclasses including phosphatidyl choline (PC) and the sphingomyelins. Macromolecular proteoglycan destruction was described, but the correlation to disease factors was not demonstrated. Collated results suggested arachidonate signalling pathways and androgen sex hormones as future metabolic pathways for investigation. CONCLUSION: Our meta-analysis demonstrates significant small molecule differences between sample types, between species (such as human and bovine), with potential OA biomarkers and targets for local or systemic therapies. Studies were limited by numbers and a lack of disease correlation. Future studies should use NMR and MS analysis to further investigate large population subgroups including inflammatory arthropathy, OA subclasses, age and joint differences.

Hip fracture litigation: A 10-year review of NHS Litigation Authority data and the effect of national guidelines.

We present a review evaluating all litigation claims relating to hip fractures made in a 10-year period between 2005 and 2015. Data was obtained from the NHS Litigation Authority through a freedom of information request. All claims relating to hip fractures were reviewed. During the period analysed, 216 claims were made, of which 148 were successful (69%). The total cost of settling these claims was in excess of £5 million. The introduction of a best-practice tariff by the Department of Health in 2010 was designed to improve the quality of care for hip fracture patients. This was followed by guidance from the National Institute for Health and Clinical Excellence in 2011 and the British Orthopaedic Association in 2012. We analysed claims submitted before and after these guidelines were introduced and no significant difference in the number of claims was noted. The most common cause for litigation was a delay in diagnosis, which accounted for 86 claims in total (40%). Despite the presence of these guidelines and targets, there has not been a significant reduction in the number of claims or an improvement in diagnostic accuracy. This may be due to an increasing level of litigation in the UK but we must also question whether we are indeed providing best-practice care to our hip fracture patients and whether these guidelines need further review.

Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysis.

OBJECTIVES: The objective of this study was to perform a meta-analysis of all randomised controlled trials (RCTs) comparing surgical and non-surgical management of fractures of the proximal humerus, and to determine whether further analyses based on complexity of fracture, or the type of surgical intervention, produced disparate findings on patient outcomes. METHODS: A systematic review of the literature was performed identifying all RCTs that compared surgical and non-surgical management of fractures of the proximal humerus. Meta-analysis of clinical outcomes was performed where possible. Subgroup analysis based on the type of fracture, and a sensitivity analysis based on the type of surgical intervention, were also performed. RESULTS: Seven studies including 528 patients were included. The overall meta-analysis found that there was no difference in clinical outcomes. However, subgroup and sensitivity analyses found improved patient outcomes for more complex fractures managed surgically. Four-part fractures that underwent surgery had improved long-term health utility scores (mean difference, MD 95% CI 0.04 to 0.28; p = 0.007). They were also less likely to result in osteoarthritis, osteonecrosis and non/malunion (OR 7.38, 95% CI 1.97 to 27.60; p = 0.003). Another significant subgroup finding was that secondary surgery was more common for patients that underwent internal fixation compared with conservative management within the studies with predominantly three-part fractures (OR 0.15, 95% CI 0.04 to 0.63; p = 0.009). CONCLUSION: This meta-analysis has demonstrated that differences in the type of fracture and surgical treatment result in outcomes that are distinct from those generated from analysis of all types of fracture and surgical treatments grouped together. This has important implications for clinical decision making and should highlight the need for future trials to adopt more specific inclusion criteria.Cite this article: S. Sabharwal, N. K. Patel, D. Griffiths, T. Athanasiou, C. M. Gupte, P. Reilly. Trials based on specific fracture configuration and surgical procedures likely to be more relevant for decision making in the management of fractures of the proximal humerus: Findings of a meta-analysisBone Joint Res 2016;5:470-480. DOI: 10.1302/2046-3758.510.2000638.

The cost of trauma operating theatre inefficiency.

The National Health Service (NHS) is currently facing a financial crisis with a projected deficit of £2billion by the end of financial year 2015/16. As operating rooms (OR) are one of the costliest components in secondary care, improving theatre efficiency should be at the forefront of efforts to improve health service efficiency. The objectives of this study were to characterize the causes of trauma OR delays and to estimate the cost of this inefficiency. A 1-month prospective single-centre study in St. Mary's Hospital. Turnaround time (TT) was used as the surrogate parameter to measure theatre efficiency. Factors including patient age, ASA score and presence of surgical and anaesthetic consultant were evaluated to identify positive or negative associations with theatre delays. Inefficiency cost was calculated by multiplying the time wasted with staff capacity costs and opportunity costs, found to be £24.77/minute. The commonest causes for increased TT were delays in sending for patients (50%) and problems with patient transport to the OR (31%). 461 min of delay was observed in 12 days, equivalent to loss of £951.58/theatre/day. Non-statistically significant trends were seen between length of delays and advancing patient age, ASA score and absence of either a senior clinician or an anaesthetic consultant. Interestingly, the trend was not as strong for absence of an anaesthetic consultant. This study found delays in operating TT to represent a sizable cost, with potential efficiency savings based on TT of £347,327/theatre/year. Further study of a larger sample is warranted to better evaluate the identified trends.

Cost analysis of the surgical treatment of fractures of the proximal humerus: an evaluation of the determinants of cost and comparison of the institutional cost of treatment with the national tariff.

AIMS: The aims of this study were to estimate the cost of surgical treatment of fractures of the proximal humerus using a micro-costing methodology, contrast this cost with the national reimbursement tariff and establish the major determinants of cost. METHODS: A detailed inpatient treatment pathway was constructed using semi-structured interviews with 32 members of hospital staff. Its content validity was established through a Delphi panel evaluation. Costs were calculated using time-driven activity-based costing (TDABC) and sensitivity analysis was performed to evaluate the determinants of cost RESULTS: The mean cost of the different surgical treatments was estimated to be £3282. Although this represented a profit of £1138 against the national tariff, hemiarthroplasty as a treatment choice resulted in a net loss of £952. Choice of implant and theatre staffing were the largest cost drivers. Operating theatre delays of more than one hour resulted in a loss of income DISCUSSION: Our findings indicate that the national tariff does not accurately represent the cost of treatment for this condition. Effective use of the operating theatre and implant discounting are likely to be more effective cost containment approaches than control of bed-day costs. TAKE HOME MESSAGE: This cost analysis of fractures of the proximal humerus reinforces the limitations of the national tariff within the English National Health Service, and underlines the importance of effective use of the operating theatre, as well as appropriate implant procurement where controlling costs of treatment is concerned.

The cost of adverse events from knee surgery in the United Kingdom: an in-depth review of the National Health Service Litigation Authority database.

BACKGROUND: There has been a significant rise in the number and value of claims against the National Health Service (NHS), with limited studies on litigation in orthopaedic surgery and none in knee surgery alone. We aimed to examine claims against the NHS involving all aspects of knee surgery with respect to costs and trends. CLINICAL RELEVANCE: To raise awareness of the reasons for litigation in knee surgery, thus potentially improve patient care and reduce future claims. METHODS: We analysed the NHS litigation authority (NHSLA) database for all orthopaedic surgery claims reported to the NHSLA between 2005 and 2010, with calculation of litigation success rates and odds ratios for those relating to knee surgery. RESULTS: There were 515 cases identified from the 4609 orthopaedic cases in the NHSLA database (11.2%): 298 (58%) involving total knee replacements (TKRs), 11 (2%) involving unicondylar knee replacements, and 90 cases (30%) remaining open. The total pay out for closed cases was £10.45 million and amputation following TKR resulted in the highest single pay out. Litigation success rates for claimants were highest for retained drains (100%), incorrect prosthesis/prosthesis size (78%), renal failure (75%), poor outcome requiring further surgery (74%) and malalignment (71%). There were also 60 cases of delayed diagnosis which resulted in pay outs totalling £2.90 million. Based on these data, projected future pay out costs for the open TKR cases were estimated to be £2.71 million. CONCLUSION: Litigation success rates for TKR were highest following technical errors such as malalignment compared to events less under the surgeon's control, such as infection. The number of claims involving incorrect prosthesis/size continues to be of concern. Despite the increased availability of imaging modalities, missed diagnosis also resulted in substantial pay outs.

The role of simulation in developing surgical skills.

Surgical training has followed the master-apprentice model for centuries but is currently undergoing a paradigm shift. The traditional model is inefficient with no guarantee of case mix, quality, or quantity. There is a growing focus on competency-based medical education in response to restrictions on doctors' working hours and the traditional mantra of "see one, do one, teach one" is being increasingly questioned. The medical profession is subject to more scrutiny than ever before and is facing mounting financial, clinical, and political pressures. Simulation may be a means of addressing these challenges. It provides a way for trainees to practice technical tasks in a protected environment without putting patients at risk and helps to shorten the learning curve. The evidence for simulation-based training in orthopedic surgery using synthetic models, cadavers, and virtual reality simulators is constantly developing, though further work is needed to ensure the transfer of skills to the operating theatre.

The anterolateral ligament: Anatomy, length changes and association with the Segond fracture.

There have been differing descriptions of the anterolateral structures of the knee, and not all have been named or described clearly. The aim of this study was to provide a clear anatomical interpretation of these structures. We dissected 40 fresh-frozen cadaveric knees to view the relevant anatomy and identified a consistent structure in 33 knees (83%); we termed this the anterolateral ligament of the knee. This structure passes antero-distally from an attachment proximal and posterior to the lateral femoral epicondyle to the margin of the lateral tibial plateau, approximately midway between Gerdy's tubercle and the head of the fibula. The ligament is superficial to the lateral (fibular) collateral ligament proximally, from which it is distinct, and separate from the capsule of the knee. In the eight knees in which it was measured, we observed that the ligament was isometric from 0° to 60° of flexion of the knee, then slackened when the knee flexed further to 90° and was lengthened by imposing tibial internal rotation.

Current concepts of the management of anterior cruciate ligament injuries in children.

Recent reports have suggested an increase in the number of anterior cruciate ligament (ACL) injuries in children, although their true incidence is unknown. The prognosis of the ACL-deficient knee in young active individuals is poor because of secondary meniscal tears, persistent instability and early-onset osteoarthritis. The aim of surgical reconstruction is to provide stability while avoiding physeal injury. Techniques of reconstruction include transphyseal, extraphyseal or partial physeal sparing procedures. In this paper we review the management of ACL tears in skeletally immature patients.

Extra-articular techniques in anterior cruciate ligament reconstruction: a literature review.

This annotation considers the place of extra-articular reconstruction in the treatment of anterior cruciate ligament (ACL) deficiency. Extra-articular reconstruction has been employed over the last century to address ACL deficiency. However, the technique has not gained favour, primarily due to residual instability and the subsequent development of degenerative changes in the lateral compartment of the knee. Thus intra-articular reconstruction has become the technique of choice. However, intra-articular reconstruction does not restore normal knee kinematics. Some authors have recommended extra-articular reconstruction in conjunction with an intra-articular technique. The anatomy and biomechanics of the anterolateral structures of the knee remain largely undetermined. Further studies to establish the structure and function of the anterolateral structures may lead to more anatomical extra-articular reconstruction techniques that supplement intra-articular reconstruction. This might reduce residual pivot shift after an intra-articular reconstruction and thus improve the post-operative kinematics of the knee.

Review of successful litigation against english health trusts in the treatment of adults with orthopaedic pathology: clinical governance lessons learned.

BACKGROUND: Reviewing litigation brought against health institutions is a clinical governance issue and can help to prevent further cases. While large-scale databases are rare, the British National Health Service Litigation Authority deals with claims brought against all public health trusts in England. METHODS: We reviewed all 2312 successful cases pertaining to adult orthopaedic claims between 2000 and 2006 in an effort to establish trends of litigation and highlight specific areas of concern such that orthopaedic health care could be potentially improved. A total of 1473 entries had sufficient detail to be considered in our study. RESULTS: There were 4,847,841 elective and trauma-related orthopaedic procedures performed between 2000 and 2006 in the United Kingdom. Compared with the number of cases performed, the frequency of successful litigation is relatively low but financially costly to the National Health Service. From 2000 to 2006, a total of more than US$321,695,072 was paid in adult orthopaedic surgery-related settlements. The most common reason for successful litigation was due to the presence and sequelae of infection (123 cases). In the remaining cases, successful litigation appeared to be related to two common themes: the consent process and the mismanagement of orthopaedic conditions, particularly fractures, cauda equina syndrome, and compartment syndrome. CONCLUSIONS: These findings highlight the fact that education and vigilance remain important components of orthopaedic training as many of the cases of successful litigation had a preventable cause.

Postoperative fall after the use of the 3-in-1 femoral nerve block for knee surgery: a report of four cases.

We present a serious postoperative complication related to the use of femoral nerve block in 4 patients, each of whom fell and sustained further injury. Preoperatively, all patients underwent a 3-in-1 femoral nerve block with 30 to 35 ml of 0.25% levobupivacaine with 1:200,000 epinephrine, with guidance by a nerve stimulator. After the falls, neurological examination of the operated legs revealed reduced 2-point discrimination, pain, and/or light touch sensation. All patients underwent further operation for the fall injury and had delayed full weight bearing. We recommend that, after having a femoral nerve block, patients should undergo enhanced postoperative evaluation of blockade and proprioceptive function to ensure safe neurological function before mobilisation.

Tuberculous arthritis of the knee with Staphylococcus superinfection.

We describe a case of septic arthritis of the knee in which the diagnosis of tuberculosis was masked by an initial culture growth of Staphylococcus aureus. This led to a delay in diagnosis and an adverse outcome. In the appropriate clinical setting, we suggest that the index of suspicion for skeletal tuberculosis be raised in developed countries in order to avoid diagnostic delay, by requesting cultures for acid-fast bacilli and synovial biopsies at arthroscopy. Moreover, antituberculosis therapy should be started whilst awaiting the results of culture if the clinical history and biopsies are strongly suggestive of the diagnosis.

Comparative anatomy of the meniscofemoral ligament in humans and some domestic mammals.

The purpose of this study was to investigate the presence, position and relative sizes of the meniscofemoral ligaments (MFL) in three quadrupeds and humans and relate these to the caudal slope of the lateral tibial plateau. Canine, ovine and equine stifles and human knees were dissected to identify the presence of MFLs, their obliquity in relation to the caudal cruciate ligaments (CCL), the relative size and shape of the MFLs compared with the CCL, the points of femoral attachment of the MFLs and CCL, and the distance between the MFLs and CCL at their midpoints. The lateral tibial condyle was divided sagittally with a handsaw and the caudal slope was measured. An MFL was present in all quadrupeds. It was caudal to the CCL, being analogous to the human posterior MFL. There was no structure analogous to the human anterior MFL, a structure that has a different femoral attachment from the human posterior MFL and MFLs in other species examined. The meniscotibial attachments were of varying sizes. The size ratio between the MFL and CCL was greater in all three quadrupeds than it was in the human knee. The MFL lies more obliquely than the CCL in all species examined. The caudal tibial slope was steeper in the quadrupeds. In the stifle joints of quadrupeds, the MFL is a substantial structure and appears to be related to the caudal tibial slope. It is known to resist caudal translation of the tibia in conjunction with the lateral meniscus. This must be borne in mind when considering its function in the human knee.

Anatomy of the posterior cruciate ligament and the meniscofemoral ligaments.

This paper describes the anatomy of the posterior cruciate ligament (PCL) and the meniscofemoral ligaments (MFLs). The fibres of the PCL may be split into two functional bundles; the anterolateral bundle (ALB) and the posteromedial bundle (PMB), relating to their femoral attachments. The tibial attachment is relatively compact, with the ALB anterior to the PLB. These bundles are not isometric: the ALB is tightest in the mid-arc of knee flexion, the PMB is tight at both extension and deep flexion. At least one MFL is present in 93% of knees. On the femur, the anterior MFL attaches distal to the PCL, close to the articular cartilage; the posterior MFL attaches proximal to the PCL. They both attach distally to the posterior horn of the lateral meniscus. Their slanting orientation allows the MFLs to resist tibial posterior drawer.

Iliopsoas bursitis following total hip replacement.

We report the imaging features of a 52-year-old man presenting with a groin mass and gross lower limb oedema secondary to venous occlusion by massive cystic enlargement of the iliopsoas bursa 4 years after uncemented primary total hip replacement. Ultrasonography of the groin mass demonstrated a large cystic lesion extending into the pelvis. CT showed displacement of the external iliac vessels with venous compression. Bursography showed the bursa's margins and no communication with the hip joint. Diagnostic aspiration excluded infection, but fluid recollection occurred subsequently. Complete resolution of symptoms, including limb swelling, followed surgical excision with no recurrence at the 5-year follow-up. We believe iliopsoas bursitis occurred as a tissue response to polyethylene wear within the prosthetic hip and occurred even in the absence of loosening or a direct communication between bursa and joint.

An anatomical study of meniscal allograft sizing.

Meniscus-to-femoral condyle congruity is essential for the development of circumferential hoop stresses and thus function of the meniscus. When meniscal allograft transplantation is performed using bony anchorage of the insertional ligaments, accurate graft-to-host size matching is therefore essential. The standard method currently employed for size matching of meniscal allografts is to rely on plain radiographs of the host's knee, from which expected meniscal dimensions are measured. This study aimed to examine the correlation between tibial plateau dimensions and meniscal dimensions. We studied 44 donor tibial plateaus with medial and lateral meniscal allografts attached intact. Meniscal and tibial plateau dimensions were measured. Linear regression analysis was used to calculate expected meniscal dimensions from each specimen's plateau dimensions. Using specific medial and lateral tibial plateau width and length measurements, meniscal dimensions could be predicted with a mean error of only 5.0+/-6.4%. When predicting meniscal dimensions from only total bony plateau width, the mean error observed was 6.2+/-8.0%. The difference between the two methods was not statistically significant. The results suggest that meniscal dimensions can be predicted accurately from tibial plateau measurements, with only small mean errors. However, potential size mismatches should be carefully borne in mind by surgeons using meniscal allografts.