The impact of COVID-19 on major trauma (ISS>15) in London, across its four Level 1 centres.

INTRODUCTION: The COVID-19 pandemic has led to reconfiguration of healthcare resources to manage increased demand for acute hospital beds and intensive care places. Concerns were raised regarding continuing provision of critical care for non-COVID patients during the pandemic. The aim of this study was to assess the impact of the COVID-19 pandemic on patients admitted with major trauma (Injury Severity Score >15) across the four Level 1 trauma centres in London. METHODS: Data were collected from all four major trauma centres (MTCs) in London using the Trauma Audit and Research Network database and from local databases at each centre. A 2-month period from 5 March to 5 May 2020 was selected and the same period during 2019 was used to compare changes due to the pandemic. RESULTS: There was a 31% decrease in overall number of patients presenting to the four MTCs during the COVID-19 period compared with 2019. There was no difference in patient demographics or mechanism of injury between the two periods. Sports-related injuries and proportion of self-presentation to hospital were reduced slightly during the pandemic, although the differences were not statistically significant. The mortality rate and association between mortality and injury severity were similar. Proportion of patients requiring intensive care unit facilities also did not change. CONCLUSION: Despite diversion of critical care resources to deal with COVID-related admissions, we did not observe a change in mortality rate or proportion of severely injured patients requiring critical care. Our results suggest London MTCs were able to provide their usual standard of care for critically injured major trauma (Injury Severity Score >15) patients during the pandemic.

A Prospective Study of Cosmetic Outcomes for Patients Treated with Breast Conservation and Radiation Therapy using Shorter Fractionation Schedules at Auckland Hospital, New Zealand.

AIMS: Breast cosmesis is an important outcome for women after breast conservation. It has been shown to be correlated with better patient satisfaction, sexuality and self-esteem. This study reports the subjective and objective breast cosmesis outcomes for women treated at Auckland Hospital Radiation Oncology Department using hypofractionated radiation therapy. MATERIALS AND METHODS: Breast cosmesis was evaluated using a subjective questionnaire and standardised photographs before radiation, at 6 weeks, 1 year, 3 years and 5 years after radiation. Objective evaluation of the photographs and completion of questionnaires were undertaken by clinicians at the same time points. The questionnaire evaluated global cosmesis on a four-point scale - excellent (E), good (G), fair (F) and poor (P). Patient, tumour and treatment factors were evaluated to assess the impact on cosmesis. RESULTS: Three hundred and fifty-eight patients completed the baseline assessments and two hundred and two patients completed the 5-year assessments. Sixty-eight per cent of patients at baseline and 70% at 5 years scored their cosmesis as E/G compared with 52% and 51%, respectively, by clinician assessment. Age >50 years, separation ≤25 cm, non-diabetic, T1 tumours, node negative, quadrant of the scar, no boost and no adjuvant endocrine therapy were correlated with E/G cosmesis. On multivariate analysis at baseline, the individual breast factors that were significantly associated with a score of E/G cosmesis were breast shape (P = 0.028) and scar appearance (P = 0.001). At 5 years, breast shape (P = 0.003), nipple shape (P = 0.019) and scar appearance (P = 0.001) were found to be significant. CONCLUSION: This study shows that most women reported no significant change in their breast cosmesis after hypofractionated radiation treatment over 5 years and that a number of patient, tumour and treatment factors may impact on breast cosmesis.

Microbiological and functional outcomes after open extremity fractures sustained overseas: The experience of a UK level I trauma centre.

BACKGROUND: Open extremity fractures carry a high risk of limb loss and poor functional outcomes. Transfer of extremity trauma patients from developing countries and areas of conflict adds further layers of complexity due to challenges in the delivery of adequate care. The combination of extensive injuries, transfer delays and complex microbiology presents unique challenges. METHODS: A retrospective review was conducted to analyse the surgical and microbiological themes of patients with open extremity fractures transferred from overseas to our institution (Imperial College NHS Trust) between January 2011 and January 2016. RESULTS: Twenty civilian patients with 21 open extremity fractures were referred to our unit from 11 different countries. All patients had poly-microbial wound contamination on initial surveillance cultures. Five patients (25%) underwent amputation depending on the extent of osseous injury; positive surveillance cultures did not preclude limb reconstruction, with seven patients undergoing complex reconstruction and eight undergoing simple reconstruction to achievewound coverage. Hundred percent of patients demonstrated infection-free fracture union on discharge. CONCLUSION: Patients with open extremity fractures transferred from overseas present the unique challenge of poly-microbial infection in addition to extensive traumatic wounds. Favourable outcomes can be achieved despite positive microbiological findings on tissue culture with adequate antimicrobial therapy. The decision to salvage the limb and the complexity of reconstruction used should be based on the chance of achieving meaningful functional recovery, mainly determined by the extent of bony injury. The complexity of reconstruction was based on the predicted long-term functionality of the salvaged limb.

The treatment of segmental tibial fractures: does patient preference differ from surgeon choice?

INTRODUCTION: Segmental tibial fractures are complex injuries with a prolonged recovery time. Current definitive treatment options include intramedullary fixation or a circular external fixator. However, there is uncertainty as to which surgical option is preferable and there are no sufficiently rigorous multi-centre trials that have answered this question. The objective of this study was to determine whether patient and surgeon opinion was permissive for a randomised controlled trial (RCT) comparing intramedullary nailing to the application of a circular external fixator. MATERIALS AND METHODS: A convenience questionnaire survey of attending surgeons was conducted during the United Kingdom's Orthopaedic Trauma Society annual meeting 2017 to determine the treatment modalities used for a segmental tibial fracture (n=63). Patient opinion was obtained from clinical patients who had been treated for a segmental tibial fracture as part of a patient and public involvement focus group with questions covering the domains of surgical preference, treatment expectations, outcome, the consent process and follow-up regime (n=5). RESULTS: Based on the surgeon survey, 39% routinely use circular frame fixation following segmental tibial fracture compared to 61% who use nail fixation. Nail fixation was reported as the treatment of choice for a closed injury in a healthy patient in 81% of surgeons, and by 86% for a patient with a closed fracture who was obese. Twenty-one percent reported that they would use a nail for an open segmental tibia fracture in diabetics who smoked, whilst 57% would opt for a nail for a closed injury with compartment syndrome, and only 27% would use a nail for an open segmental injury in a young fit sports person. The patient and public preference exercise identified that sleep, early functional outcomes and psychosocial measures of outcomes are important. CONCLUSION: We concluded that a RCT comparing definitive fixation with an intramedullary nail and a circular external fixator is justified as there remains uncertainty on the optimal surgical management for segmental tibial fractures. Furthermore, psychosocial factors and early post-operative outcomes should be reported as core outcome measures as part of such a trial.

Improving the care of patients with severe open fractures of the tibia: the effect of the introduction of Major Trauma Networks and national guidelines.

AIMS: The management of open lower limb fractures in the United Kingdom has evolved over the last ten years with the introduction of major trauma networks (MTNs), the publication of standards of care and the wide acceptance of a combined orthopaedic and plastic surgical approach to management. The aims of this study were to report recent changes in outcome of open tibial fractures following the implementation of these changes. PATIENTS AND METHODS: Data on all patients with an open tibial fracture presenting to a major trauma centre between 2011 and 2012 were collected prospectively. The treatment and outcomes of the 65 Gustilo Anderson Grade III B tibial fractures were compared with historical data from the same unit. RESULTS: The volume of cases, the proportion of patients directly admitted and undergoing first debridement in a major trauma centre all increased. The rate of limb salvage was maintained at 94% and a successful limb reconstruction rate of 98.5% was achieved. The rate of deep bone infection improved to 1.6% (one patient) in the follow-up period. CONCLUSION: The reasons for these improvements are multifactorial, but the major trauma network facilitating early presentation to the major trauma centre, senior orthopaedic and plastic surgical involvement at every stage and proactive microbiological management, may be important factors. TAKE HOME MESSAGE: This study demonstrates that a systemised trauma network combined with evidence based practice can lead to improvements in patient care.

Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer.

BACKGROUND: Insulin-like growth factors (IGF-I and IGF-II) signal via the type 1 IGF receptor (IGF-1R) and IGF-II also activates the insulin receptor isoform A (IR-A). Signalling via both receptors promotes tumour growth, survival and metastasis. In some instances IGF-II action via the IR-A also promotes resistance to anti-IGF-1R inhibitors. This study assessed the efficacy of two novel modified IGF-binding protein-2 (IGFBP-2) proteins that were designed to sequester both IGFs. The two modified IGFBP-2 proteins were either protease resistant alone or also lacked the ability to bind extracellular matrix (ECM). METHODS: The modified IGFBP-2 proteins were tested in vitro for their abilities to inhibit cancer cell proliferation and in vivo to inhibit MCF-7 breast tumour xenograft growth. RESULTS: Both mutants retained low nanomolar affinity for IGF-I and IGF-II (0.8-2.1-fold lower than IGFBP-2) and inhibited cancer cell proliferation in vitro. However, the combined protease resistant, non-matrix-binding mutant was more effective in inhibiting MCF-7 tumour xenograft growth and led to inhibition of angiogenesis. CONCLUSIONS: By removing protease cleavage and matrix-binding sites, modified IGFBP-2 was effective in inhibiting tumour growth and reducing tumour angiogenesis.

Do screening trial recruitment logs accurately reflect the eligibility criteria of a given clinical trial? Early lessons from the RAVES 0803 trial.

AIMS: Maintaining clinical trial screening logs and reporting data from such logs are given importance due to the relevance of a trial's patient population to the generalisability of its findings. However, screening logs may not always reflect a clinical trial's true target population. The aim of the present study was to define and compare 'apparent recruitment' to a trial as captured in a clinical trial screening log with 'true recruitment', which considers all potentially eligible patients. The Trans Tasman Radiation Oncology Group (TROG) 0803 RAVES clinical trial was used to examine the above. MATERIALS AND METHODS: A prospective, surgical database was interrogated for the 12 month period to identify patients potentially eligible for the TROG 0803 RAVES trial. Information on whether patients were referred to a RAVES trial recruitment site and reasons for non-referral were obtained. RESULTS: Of 92 men undergoing radical prostatectomy, 28 met the RAVES clinical trial eligibility criteria. Fifteen of the 28 eligible men were assessed at a RAVES trial site, with five being ultimately recruited to RAVES (33% 'apparent recruitment fraction' as captured by the site's trial screening log). The 'true recruitment fraction' was 5/28 (18%). CONCLUSION: Screening logs at a recruiting trial site may underestimate the trial's target population and overestimate recruitment. Only a subpopulation of all eligible patients may be captured in trial screening logs and subsequently reported on. This may affect the generalisability of the trial's reported findings.

Ex vivo restimulation of human PBMC expands a CD3+CD4-CD8- γδ+ T cell population that can confound the evaluation of CD4 and CD8 T cell responses to vaccination.

The measurement of vaccine-induced humoral and CD4(+) and CD8(+) cellular immune responses represents an important correlate of vaccine efficacy. Accurate and reliable assays evaluating such responses are therefore critical during the clinical development phase of vaccines. T cells play a pivotal role both in coordinating the adaptive and innate immune responses and as effectors. During the assessment of cell-mediated immunity (CMI) in subjects participating in a large-scale influenza vaccine trial, we identified the expansion of an IFN-γ-producing CD3(+)CD4(-)CD8(-) γδ (+) T cell population in the peripheral blood of 90/610 (15%) healthy subjects. The appearance of CD3(+)CD4(-)CD8(-) γδ (+) T cells in the blood of subjects was transient and found to be independent of the study cohort, vaccine group, subject gender and ethnicity, and ex vivo restimulation conditions. Although the function of this population and relevance to vaccination are unclear, their inclusion in the total vaccine-specific T-cell response has the potential to confound data interpretation. It is thus recommended that when evaluating the induction of IFN-γ-producing CD4(+) and CD8(+) immune responses following vaccination, the CD3(+)CD4(-)CD8(-) γδ (+) T cells are either excluded or separately enumerated from the overall frequency determination.

Validation of a one-stop carpal tunnel clinic including nerve conduction studies and hand therapy.

INTRODUCTION: Carpal tunnel syndrome is the most common hand disorder. We describe a pathway that includes clinical assessment, neurophysiological testing, surgery and physical therapy all at the same visit. METHODS: All referrals for carpal tunnel syndrome were screened for inclusion in a 'one-stop' surgeon-led clinic. Prospective clinical data collected included patient reported outcome measures and satisfaction scores, touch threshold, pinch and grip strength. Patients were assessed clinically, underwent nerve conduction studies and surgery as indicated, all on the same day. Baseline and one-year follow-up data were analysed for 57 patients (62 hands). RESULTS: There was significant improvement in all domains of the Boston Carpal Tunnel and Michigan hand Outcomes questionnaires, grip strength and touch threshold. There were no adverse events. The total mean operating time was 12.8 minutes (range: 5-15 minutes) and the mean tourniquet time was 2.5 minutes (range: 1-11 minutes). Using a dual theatre model produced a short mean turnaround time of 14.8 minutes (range: 2-37 minutes). Patient satisfaction as judged using a Picker questionnaire was very high. CONCLUSIONS: A highly efficient clinical service involving both diagnostics and treatment can be delivered at a single hospital visit while maintaining optimal outcomes and high patient satisfaction.

The microbiological basis for a revised antibiotic regimen in high-energy tibial fractures: preventing deep infections by nosocomial organisms.

BACKGROUND: Deep surgical site infections (SSI's) complicate Gustilo IIIB tibial fractures in 8-13% of cases. Antibiotic prophylaxis typically covers environmental contaminants. However, nosocomial organisms are usually implicated in deep infection. We used the microbiological profile of infected Gustilo IIIB tibial fractures to define a new, dynamic prophylactic regimen which recognises the need for prophylaxis against nosocomial organisms at the time of definitive closure. METHODS: The microbiological profiles of Gustilo IIIB tibial fractures presenting over a 2-year period from January 2006 to December 2007 were reviewed. The environmental contaminants were compared with the organisms isolated from deep SSI's and correlated with the prophylactic antibiotic regimen used. RESULTS: Fifty-two patients were included. Nine developed a deep tissue infection. The pathogens implicated included resistant Enterococci, Pseudomonas, Enterobacter and MRSA. Standard antibiotic prophylaxis provided cover for these combinations in only one of nine cases. This would have improved to eight of nine cases with the use of teicoplanin and gentamicin, given as a one-time dose during definitive soft-tissue closure. Specimens taken from wound debridement were neither sensitive nor specific for the subsequent development of deep infection and did not predict the organisms responsible. CONCLUSIONS: Following high-energy open fracture, a single prophylactic antibiotic regimen directed against environmental wound contaminants does not provide cover for the organisms responsible for deepest SSI's and may have depopulated the niche, promoting nosocomial contamination prior to definitive closure. We advocate a dynamic prophylactic strategy, tailoring a second wave of prophylaxis against nosocomial organisms at the time of definitive wound closure, and at the same time avoiding the potential complications of prolonged antibiotic use.

Improving lower limb salvage following fractures with vascular injury: a systematic review and new management algorithm.

BACKGROUND: Lower limb fractures with vascular injuries are associated with a high rate of secondary amputation. Reducing ischaemic time is vital for limb salvage. However, the optimal sequence of surgical management remains unclear. We aimed to review the literature to establish an evidence-based management algorithm. METHODS: All identifiable English language or translated literature related to the surgical sequence of lower limb fractures with vascular injuries was reviewed. RESULTS: A total of 101 cases described in 10 publications (median age: 31; range: 2.5-76) were suitable for analysis. The mean MESS was 4.2. The limb-salvage rate with an ischaemic time of less than 6h was 87%, falling to 61% when ischaemic time exceeded 6h. A preoperative angiography caused a significant delay. The rate of re-vascularisation within 6h improved from 46% (33 of 71) to 90% (27 of 30) with the use of a shunt (p=0.04), with a mean ischaemic time of 3.8h (+/-1.7h, 1 standard deviation (SD)) versus 7.6h (+/-3.8h, 1SD) in those re-vascularised using grafts (p<0.001). The amputation rate of 27% was reduced to 13% by using shunts. CONCLUSION: Early recognition of vascular injury is vital. Formal angiograms are unnecessary and cause crucial delays. A vascular shunt can significantly reduce ischaemic time, enabling unhurried assessment of the feasibility of limb salvage, debridement of demonstrably non-viable tissue and safe skeletal fixation prior to definitive vascular and soft-tissue repair.

Pulmonary delivery of ISCOMATRIX influenza vaccine induces both systemic and mucosal immunity with antigen dose sparing.

Using a large animal model, we evaluated whether delivery of influenza vaccine via its mucosal site of infection could improve vaccine effectiveness. Unexpectedly, pulmonary immunization with extremely low antigen doses (0.04 microg influenza) induced serum antibody levels equivalent to those resulting from a current human vaccine equivalent (15 microg unadjuvanted influenza, subcutaneously) and vastly superior lung mucosal antibodies. Induction of this potent response following lung vaccination was dependent on addition of ISCOMATRIX adjuvant and deep lung delivery. Functional antibody activity, marked by hemagglutination inhibition, was only present in the lungs of animals that received adjuvanted vaccine via the lungs, suggesting this approach could potentially translate to improved protection. The 375-fold reduction in antigen dose and improved mucosal antibody responses, compared to the current vaccine, suggests that mucosal delivery via the pulmonary route may be particularly relevant in the event of an influenza pandemic, when vaccine supplies are unlikely to meet demand.

The relationship between osteonecrosis of the proximal femur identified by MRI and lesions proven by histological examination.

Total hip replacement in patients with advanced osteonecrosis of the femoral head is often complicated by early loosening of the femoral component. Recent evidence has suggested that abnormal bone extending into the proximal femur may be responsible for the early failure of the femoral component. We aimed to identify which patients were at high risk of early failure by evaluating gadolinium-enhanced MR images of histologically-confirmed osteonecrotic lesions beyond the femoral head. Although the MR signal intensity has been shown to correlate well with osteonecrosis in the femoral head, it was found to be relatively insensitive at identifying lesions below the head, with a sensitivity of only 51% and a predictive value of a negative result of only 48%. However, the specificity was 90%, with the predictive value of a positive MRI finding being 86%. Only those patients with osteonecrosis of the femoral head secondary to sickle-cell disease, who are known to be at high risk of early loosening, had changes in the MR signal in the greater trochanter and the femoral shaft. This observation suggests that changes in the MR signal beyond the femoral head may represent osteonecrotic lesions in areas essential for the fixation of the femoral component. Pre-operative identification of such lesions in the neck of the femur may be important when considering hip resurfacing for osteonecrosis of the femoral head, following which early loosening of the femoral component and fracture of the neck are possible complications.

Management of severe open tibial fractures: the need for combined orthopaedic and plastic surgical treatment in specialist centres.

Although it is widely accepted that grade IIIB open tibial fractures require combined specialised orthopaedic and plastic surgery, the majority of patients in the UK initially present to local hospitals without access to specialised trauma facilities. The aim of this study was to compare the outcome of patients presenting directly to a specialist centre (primary group) with that of patients initially managed at local centres (tertiary group). We reviewed 73 consecutive grade IIIB open tibial shaft fractures with a mean follow-up of 14 months (8 to 48). There were 26 fractures in the primary and 47 in the tertiary group. The initial skeletal fixation required revision in 22 (47%) of the tertiary patients. Although there was no statistically-significant relationship between flap timing and flap failure, all the failures (6 of 63; 9.5%) occurred in the tertiary group. The overall mean time to union of 28 weeks was not influenced by the type of skeletal fixation. Deep infection occurred in 8.5% of patients, but there were no persistently infected fractures. The infection rate was not increased in those patients debrided more than six hours after injury. The limb salvage rate was 93%. The mean limb functional score was 74% of that of the normal limb. At review, 67% of patients had returned to employment, with a further 10% considering a return after rehabilitation. The times to union, infection rates and Enneking limb reconstruction scores were not statistically different between the primary and tertiary groups. The increased complications and revision surgery encountered in the tertiary group suggest that severe open tibial fractures should be referred directly to specialist centres for simultaneous combined management by orthopaedic and plastic surgeons.

Apoptosis--a significant cause of bone cell death in osteonecrosis of the femoral head.

Osteonecrosis of the femoral head usually affects young individuals and is responsible for up to 12% of total hip arthroplasties. The underlying pathophysiology of the death of the bone cells remains uncertain. We have investigated nitric oxide mediated apoptosis as a potential mechanism and found that steroid- and alcohol-induced osteonecrosis is accompanied by widespread apoptosis of osteoblasts and osteocytes. Certain drugs or their metabolites may have a direct cytotoxic effect on cancellous bone of the femoral head leading to apoptosis rather than purely necrosis.

ISCOMATRIX adjuvant: a potent inducer of humoral and cellular immune responses.

ISCOMATRIX adjuvant is capable of inducing broad and potent humoral and cellular immune responses. The components are well defined and the manufacturing process is simple and robust. Many vaccines containing the ISCOMATRIX adjuvant have been tested in a range of animal models, including human and non-human primates. Strong antibody and T cell responses have been induced in these studies. The antibody response is often achieved with lesser amounts of antigen than other adjuvant systems and the maximal responses have also been reached more quickly. Both CD4+ and CD8+ T cell responses are induced with the cytotoxic T lymphocyte responses being very long lived. Additionally, ISCOMATRIX adjuvant can be used in vaccines for induction of mucosal immune responses. This review provides an overview of the immune responses that can be elicited using ISCOMATRIX vaccines and the current state of knowledge regarding the mechanism of action of this adjuvant.

Orthopaedic manifestations of tuberculosis.

An estimated 1 million people will be infected with tuberculosis worldwide in the first 20 years of the 21st century. If the disease is not recognized and treated early the morbidity and mortality of this condition will rise. This article highlights the varying manifestations of tuberculosis from an orthopaedic perspective.

Cemented revision total hip arthroplasty with impaction bone grafting in Gaucher's disease.

Total hip arthroplasty in Gaucher's disease has been associated with high rates of loosening after all types of arthroplasty. We present a patient with type 1 Gaucher's disease who underwent revision cemented total hip arthroplasty for aseptic loosening after 12 months of enzyme replacement therapy. Major osteolysis was managed by impaction morcellized bone grafting. An excellent clinical and radiographic result was obtained at 5-year follow-up. Enzyme replacement therapy combined with modern revision techniques may offer improved outcomes for patients with Gaucher's disease.

Local immune responses to influenza antigen are synergistically enhanced by the adjuvant ISCOMATRIX.

The peripheral (draining) lymph node, as the primary site of immune induction, determines the course of systemic responses to an injected antigen. Lymphatic duct cannulation procedures in sheep were used to investigate local immunoreactivity to human influenza virus antigen (Flu ag) admixed with the adjuvant ISCOMATRIX (IMX). Compared to Flu ag or IMX alone, the co-administration of Flu ag and IMX (Flu ag+IMX) synergistically enhanced a number of immunological responses (lymphocyte and blast migration from the node, antigen-specific antibody levels and IL6 output in efferent lymph, and antigen-induced proliferation in cultured efferent lymph cells). Together, these results demonstrate that IMX is an immune modulator, and that lymphatic duct cannulation procedures may be used to evaluate antigen/adjuvant combinations for vaccine development.