Fracture-related infection: A consensus on definition from an international expert group.

Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare. In order to address this issue, an expert group comprised of a number of scientific and medical organizations has been convened, with the support of the AO Foundation, in order to develop a consensus definition. The process that led to this proposed definition started with a systematic literature review, which revealed that the majority of randomized controlled trials in fracture care do not use a standardized definition of FRI. In response to this conclusion, an international survey on the need for and key components of a definition of FRI was distributed amongst all registered AOTrauma users. Approximately 90% of the more than 2000 surgeons who responded suggested that a definition of FRI is required. As a final step, a consensus meeting was held with an expert panel. The outcome of this process led to a consensus definition of FRI. Two levels of certainty around diagnostic features were defined. Criteria could be confirmatory (infection definitely present) or suggestive. Four confirmatory criteria were defined: Fistula, sinus or wound breakdown; Purulent drainage from the wound or presence of pus during surgery; Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens; Presence of microorganisms in deep tissue taken during an operative intervention, as confirmed by histopathological examination. Furthermore, a list of suggestive criteria was defined. These require further investigations in order to look for confirmatory criteria. In the current paper, an overview is provided of the proposed definition and a rationale for each component and decision. The intention of establishing this definition of FRI was to offer clinicians the opportunity to standardize clinical reports and improve the quality of published literature. It is important to note that the proposed definition was not designed to guide treatment of FRI and should be validated by prospective data collection in the future.

Demystifying damage control in musculoskeletal trauma.

Trauma care has evolved rapidly over the past decade. The benefits of operative fracture management in major trauma patients are well recognised. Concerns over early total care arose when applied broadly. The burden of additional surgical trauma could constitute a second hit, fuelling the inflammatory response and precipitating a decline into acute respiratory distress syndrome, sepsis and multiple organ dysfunction syndrome. Temporary external fixation aimed to deliver the benefits of fracture stabilisation without the risk of major surgery. This damage control orthopaedics approach was advocated for those in extremis and a poorly defined borderline group. An increasing understanding of the physiological response to major trauma means there is now a need to refine our treatment options. A number of large scale retrospective reviews indicate that early definitive fracture fixation is beneficial in the majority of major trauma patients. It is recommended that patients are selected appropriately on the basis of their response to resuscitation. The hope is that this approach (dubbed 'safe definitive fracture surgery' or 'early appropriate care') will herald an era when care is individualised for each patient and their circumstances. The novel Damage Control in Orthopaedic Trauma Surgery course at The Royal College of Surgeons of England aims to equip senior surgeons with the insights and mindset necessary to contribute to this key decision making process as well as also the technical skills to provide damage control interventions when needed, relying on the improved techniques of damage control resuscitation and advances in the understanding of early appropriate care.

Temporal variation in major trauma admissions.

INTRODUCTION: Trauma is a significant cause of morbidity and mortality in the UK. Since the inception of the trauma networks, little is known of the temporal pattern of trauma admissions. METHODS: Trauma Audit and Research Network data for 1 April 2011 to 31 March 2013 were collated from two large major trauma centres (MTCs) in the South East of England: Brighton and Sussex University Hospitals NHS Trust (BSUH) and St George's University Hospitals NHS Foundation Trust (SGU). The number of admissions and the injury severity score by time of admission, by weekdays versus weekend and by month/season were analysed. RESULTS: There were 1,223 admissions at BSUH and 1,241 at SGU. There was significant variation by time of admission; there were more admissions in the afternoons (BSUH p<0.001) and evenings (SGU p<0.001). There were proportionally more admissions at the weekends than on weekdays (BSUH p<0.001, SGU p=0.028). There was significant seasonal variation in admissions at BSUH (p<0.001) with more admissions in summer and autumn. No significant seasonal variation was observed at SGU (p=0.543). CONCLUSIONS: The temporal patterns observed were different for each MTC with important implications for resource planning of trauma care. This study identified differing needs for different MTCs and resource planning should be individualised to the network.

Ionising radiation exposure in paediatric trauma.

INTRODUCTION: Trauma remains the highest cause of paediatric morbidity and mortality. These trauma patients incur radiation exposure during intraoperative management. Medical personnel have the responsibility to ensure observation of the 'as low as reasonably achievable' principle, a practice mandate that minimises ionising radiation exposure. The aim of this study was to quantify the difference in the amount of ionising radiation used by operating surgeons of different grades in paediatric trauma surgery. METHODS: Intraoperative imaging in paediatric trauma surgery between 2008 and 2010 at a UK trauma centre was analysed retrospectively, recording injury demographics, surgeon grade, radiation exposure (dose area product [DAP]) and screening time. A mobile image intensifier was used in all cases and the lowest dose rate was selected for all screening. RESULTS: A total of 782 trauma cases were analysed: 304 procedures (39%) were carried out by consultants, 127 (16%) by senior registrars and 351 (45%) by junior registrars. The mean screening time for consultants was 0.23 minutes (standard deviation [SD]: 0.21 minutes) while for senior registrars it was 0.24 minutes (SD: 0.27 minutes) and for junior registrars 0.47 minutes (SD: 1.5 minutes). The mean DAP for consultants was 58.49Gycm(2) (SD: 53.66Gycm(2)). For senior registrars it was 87.2Gycm(2) (SD: 126.64Gycm(2)) and for junior registrars it was 90.46Gycm(2) (SD: 180.02Gycm(2)). This equates to a 51% increase in screening time and a 35% increase in DAP by a junior registrar compared with a consultant. CONCLUSIONS: Significantly lower screening times and radiation exposure was found in procedures performed by consultants compared with registrars (p<0.001). Given the harmful and unknown long-term effects of ionising radiation exposure in children, we recommend increasing consultant presence in paediatric trauma theatres.

Sernbo score predicts survival after intracapsular hip fracture in the elderly.

INTRODUCTION: The Sernbo score uses four factors (age, social situation, mobility and mental state) to divide patients into a high-risk and a low-risk group. This study sought to assess the use of the Sernbo score in predicting mortality after an intracapsular hip fracture. METHODS: A total of 259 patients with displaced intracapsular hip fractures were included in the study. Data from prospectively generated databases provided 22 descriptive variables for each patient. These included operative management, blood tests and co-mobidities. Multivariate analysis was used to identify significant predictors of mortality. RESULTS: The mean patient age was 85 years and the mean follow-up duration was 1.5 years. The one-year survival rate was 92% (± 0.03) in the low-risk group and 65% (± 0.046) in the high-risk group. Four variables predicted mortality: Sernbo score >15 (p=0.0023), blood creatinine (p=0.0026), ASA (American Society of Anaesthesiologists) grade >3 (p=0.0038) and non-operative treatment (p=0.0377). Receiver operating characteristic curve analysis showed the Sernbo score as the only predictor of 30-day mortality (area under curve 0.71 [0.65-0.76]). The score had a sensitivity of 92% and a specificity of 51% for prediction of death at 30 days. CONCLUSIONS: The Sernbo score identifies patients at high risk of death in the 30 days following injury. This very simple score could be used to direct extra early multidisciplinary input to high-risk patients on admission with an intracapsular hip fracture.

Intramedullary nailing for pathological fractures of the ulna.

Pathological lesions of long bones increase the morbidity of many common cancers. The orthopedic management of metastatic skeletal lesions can be challenging. The ultimate aim is to provide patients with a painless, functional limb. We present a report of two cases were a novel minimally invasive long bone nailing technique has been utilized to achieve skeletal stability and alleviation of symptoms.

Should unstable extra-articular distal radial fractures be treated with fixed-angle volar-locked plates or percutaneous Kirschner wires? A prospective randomised controlled trial.

Fractures of the distal radius are commonly treated with cast immobilisation; however, those potentially unstable injuries with dorsal comminution may need operative intervention. This intervention is usually with manipulation and Kirschner wires but advances in locking-plate technology have enabled surgeons to achieve anatomical reconstruction of complex fracture patterns, even in poor-quality osteoporotic bone.To ascertain if fixed-angle volar-locked plates confer a significant benefit over manipulation and Kirschner-wire stabilisation, we prospectively randomised 56 adult patients with isolated, closed,unilateral, unstable extra-articular fractures into two treatment groups, one fixed with K-wires and the other fixed with a volar locking plate.Functional outcomes were assessed using Gartland and Werley and Disabilities of the Arm, Shoulder and Hand (DASH) scores. These were statistically better in the plate group at 3 and 6 months.Radiological assessment showed statistically better results at 6 weeks, 3 months and 6 months, postoperatively.In the plate group, there was no significant loss of fracture reduction.

Scaphoid bone bruising--probably not the precursor of asymptomatic non-union of the scaphoid.

The MRI finding of bone marrow oedema, without fracture, following trauma to the scaphoid has been called a 'bone bruise'. A similar injury is found in the knee, considered benign and managed conservatively. In the scaphoid, there is the concern that this lesion may lead to scaphoid non-union. This study addresses that concern. The clinical and radiological findings of 41 patients with a scaphoid bone bruise on MRI are described, an MRI classification system proposed and clinical outcomes investigated. Patients were immobilised for 6 weeks. At 3 months, 8 remained symptomatic and had repeat MRI. Four of these showed complete resolution of the bruise, the others improvement. At 6 months, 2 of the 8 complained of minor, intermittent discomfort but progressed to resolution of symptoms. This study suggests that the scaphoid bone bruise is a benign injury with predictable recovery and is unlikely to result in long-term morbidity in the form of non-union.

Stimulation of guanosine-5'-o-(3-[35S]thio)triphosphate binding in digitonin-permeabilized C6 rat glioma cells: evidence for an organized association of mu-opioid receptors and G protein.

The guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding assay for the determination of relative opioid efficacy has been adapted to measure G protein activation in digitonin-permeabilized C6 rat glioma cells expressing a cloned mu-opioid receptor. The mu-agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) caused a 3-fold increase in [35S]GTPgammaS binding over basal in a naloxone-sensitive manner. Relative mu-agonist efficacy was DAMGO > fentanyl > or = morphine > buprenorphine. Nalbuphine showed no efficacy. G protein activation by receptors has been predicted to occur by random encounter. In this model a reduction in the number of receptors will decrease the rate of G protein activation but not the maximum number of G proteins activated. To test this model C6 mu cells were treated with the irreversible mu-antagonist beta-funaltrexamine (10 nM) prior to permeabilization. This reduced the number of mu-opioid receptors determined with [3H]diprenorphine to 23 +/- 3% of control with no change in affinity. A commensurate reduction (to 29 +/- 10% of control) in the level of [35S]GTPgammaS binding stimulated by DAMGO was observed, but the t(1/2) for [35S]GTPgammaS binding remained unchanged. Thus, random encounters of receptor and G protein failed to occur in this permeabilized cell preparation. A model that assumes an organized association of G proteins with receptors better describes the activation of G proteins by opioid mu-receptors.

Exploring the unique pharmacology of a novel opioid receptor, ZFOR1, using molecular modeling and the 'message-address' concept.

Previous studies have probed the structural basis of ligand selectivity in the mu, delta and kappa opioid receptors through the application of molecular modeling techniques in concert with the 'message-address' concept. Here, this approach was used in an attempt to rationalize the unique pharmacological profile of a recently cloned novel opioid receptor, ZFOR1 (ZebraFish Opioid Receptor 1). Specifically, a model of the transmembrane domains of ZFOR1 was constructed and used to explore the binding modes of various prototypical opioid ligands. The results show that the 'message' portion of the binding pocket of ZFOR1 is highly conserved; hence, the binding modes of non-selective opioid ligands are well preserved. In contrast, a small number of variant residues at the extracellular end of the binding pocket, particularly Lys288 (VI:26) and Trp304 (VII:03), are shown to create adverse steric interactions with all delta and kappa selective ligands examined, thereby disrupting their binding modes. These results are consistent with, and serve as an explanation for, the observed pharmacology of this receptor, lending support to both the validity of the 'message-address' concept itself and to the use of molecular modeling approaches in its application.

Tetrapeptide derivatives of [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) lacking an N-terminal tyrosine residue are agonists at the mu-opioid receptor.

The Phe(1) cyclic tetrapeptide Phe-c[D-Cys-Phe-D-Pen]NH(2) (Et) (JH-54) has been shown previously to exhibit high affinity and selectivity for the mu-opioid receptor. To examine the role of the Phe(1) residue in the unexpected high affinity of this peptide, 11 analogs of JH-54 have been synthesized and evaluated for opioid ligand binding and for efficacy using the [(35)S]GTPgammaS assay. Alteration of the bridging groups between the D-Cys(2) and D-Pen(4) residues of JH-54 from dithioether to disulfide revealed the importance of the relative position of the aromatic rings of the first and third residues in determining mu- and delta-affinities. The one carbon distance between the alpha carbon and phenyl ring in the N-terminal residue was critical. Additional steric bulk in the N-terminal Phe(1) residue was accommodated without large reductions in affinity in two naphthyl analogs, but not with 3, 3-(diphenyl)alanine. Conformational restriction of the Calpha-Cbeta and/or Cbeta-Cgamma bonds had little effect on affinities in two peptides with 2-amino-2-carboxytetralin in position 1, but it abolished activity in an isoquinoline analog and differentially altered activity in four phenylproline(1)-containing peptides. Most surprisingly, replacement of the Phe(1) aromatic ring with cyclohexyl resulted in a peptide of moderate affinity (K(i) = 32.5 nM) and potency (EC(50) = 58.8 nM). Thus, the tyrosyl para-hydroxyl substituent and even aromaticity in the N-terminal amino acid of these tetrapeptides are shown to be important, but not critical, features for mu-opioid receptor affinity, agonist potency, and efficacy.

The steroid 17alpha-acetoxy-6-dimethylaminomethyl-21-fluoro-3-ethoxy-pregna-3, 5-dien-20-one (SC17599) is a selective mu-opioid agonist: implications for the mu-opioid pharmacophore.

The steroid SC17599 (17alpha-acetoxy-6-dimethylaminomethyl-21-fluoro-3-ethoxypregna -3, 5-dien-20-one) has mu-opioid actions in vivo. The ability of SC17599 to interact with opioid receptors has been studied using radioligand and [(35)S]guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) binding assays. SC17599 bound to mu-opioid receptors in SH-SY5Y neuroblastoma cells and to recombinant receptors expressed in rat C6 glioma cells and Chinese hamster ovary cells with good affinity and with greater than 100-fold selectivity for mu- over both delta- and kappa-opioid receptors. Binding was much reduced when aspartate 147 in the wild-type mu-opioid receptor was replaced with asparagine. The affinity of SC17599 for the mu-opioid receptor was decreased in the presence of sodium ions, indicating agonist activity. SC17599 stimulated the binding of [(35)S]GTPgammaS in a naloxone-reversible manner with good potency and maximal effect equivalent to that of the mu-opioid agonists fentanyl and [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin. In rat brain membranes, SC17599-mediated stimulation of [(35)S]GTPgammaS binding was reversed by the antagonist naltrexone. SC17599 lacks an aromatic ring and para-hydroxyl substituent considered critical in the pharmacophore for mu-opioids. The structural relationship between SC17599 and more traditional opioid ligands was investigated through genetic algorithm-based modeling techniques for pharmacophore generation (GASP) and ligand-receptor docking (GOLD). The relatively planar and electron-rich A ring of the steroid compensated for the lack of aromaticity. Modeling of ligand-receptor docking showed that both morphine and SC17599 occupy the same binding pocket within the transmembrane helix bundle of the mu-opioid receptor and that the relationship between their binding modes largely mimicked the pharmacophore alignment.

Characterization of ZFOR1, a putative delta-opioid receptor from the teleost zebrafish (Danio rerio).

ZFOR1 is a putative opioid receptor from zebrafish brain which has 66% homology with the mammalian delta-opioid receptor. When expressed in HEK293 cells ZFOR1 bound the non-selective opioid antagonist [(3)H]diprenorphine with high affinity. However, the binding of this ligand was not readily displaced by opioids selective for mu, delta or kappa opioid receptors (affinities>1000 nM). Rather non-selective ligands showed good affinity, as did the non-peptide delta-ligand BW373U86 (Ki 69 nM), the delta-antagonist naltrindole (Ki 28 nM) and the peptide beta-endorphin (Ki 37 nM). Agonist binding to the receptor encoded by ZFOR1 receptor stimulated the binding of [(35)S]GTPgammaS confirming coupling to G proteins. Study of the receptor should contribute to understanding of the evolution of the opioid system.

Modifications of the cyclic mu receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et): effects on opioid receptor binding and activation.

The previously described cyclic mu opioid receptor-selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]NH2 (Et) (JOM-6) was modified at residues 1 and 3 by substitution with various natural and synthetic amino acids, and/or by alteration of the cyclic system. Effects on mu and delta opioid receptor binding affinities, and on potencies and efficacies as measured by the [35S]-GTPgammaS assay, were evaluated. Affinities at mu and delta receptors were not influenced dramatically by substitution of Tyr1 with conformationally restricted phenolic amino acids. In the [35S]-GTPgammaS assay, all of the peptides tested exhibited a maximal response comparable with that of fentanyl at the mu opioid receptor, and all showed high potency, in the range 0.4-9nM. However, potency changes did not always correlate with affinity, suggesting that the conformation required for binding and the conformation required for activation of the opioid receptors are different. At the delta opioid receptor, none of the peptides were able to produce a response equivalent to that of the full delta agonist BW 373,U86 and only one had an EC50 value of less than 100nM. Lastly, we have identified a peptide, D-Hat-c[D-Cys-Phe-D-Pen]NH2 (Et), with high potency and > 1,000-fold functional selectivity for the mu over delta opioid receptor as measured by the [35S]-GTPgammaS assay.

A randomized double blind-cross over trial of soya protein for the treatment of cyclical breast pain.

Twenty patients with cyclical breast pain were enrolled in a double-blind cross-over trial in which either a soy protein drink or a flavoured cow's milk was taken orally each day for 3 months before crossing over to the alternate drink for a further 3 months. Records of pain scores were taken throughout the study. Blood was also taken before and after 3 and 6 months for the measurement of phytoestrogents to assess compliance. Two women withdrew from the study at the outset leaving 18 evaluable patients who completed the study. Of these 10 (56%) felt that soy protein improved breast pain (two of whom received soy as first treatment) and two (11%) felt that cow's milk alleviated symptoms (one receiving this as first preparation) and the remaining six (33%) experienced no relief of pain with either dietary preparation. Blood levels of diadzein and genistein were elevated after the ingestion of soy protein in only 13 patients (seven of whom felt that soy improved their breast pain); in the remaining five patients (three of whom suggested that soy protein improved breast pain) phytoestrogen levels were no higher than pretreatment values. Although the ingestion of soy protein may be associated with relief of breast pain, these results illustrate the problem of non-specific effects in studies of mastalgia in that 1) cow's milk also relieved breast pain in some patients and 2) that the benefits of soy protein were not always associated with evidence of elevated circulating levels of phyto-estrogens, indicating the difficulty of compliance in dietary intervention studies using soy foods.

Consequences for fetus and neonate of maternal red cell allo-immunisation.

AIMS: To study the distribution of clinically important red cell antibodies in pregnancy, and the associated fetal and neonatal morbidity and mortality. METHODS: The case notes of women with clinically important red cell antibodies identified in their serum during pregnancy were reviewed. RESULTS: During a 12 month period 22,264 women were referred for antenatal screening. Clinically important red cell antibodies were detected in 244 (1%). Of these, 100 were anti-D and 144 were non-RhD antibodies. There were three intrauterine deaths, three fetuses required intrauterine transfusion, 10 neonates were transfused, 27 others had phototherapy, and 27 with a positive direct antiglobulin test received no treatment. Early fetal losses occurred in the presence of both high and low levels of anti-D. CONCLUSIONS: Anti-D remains the most common clinically important antibody in pregnancy, and accounts for the greatest fetal and neonatal morbidity and mortality. Of the other antibodies detected, anti-c was associated with most neonatal morbidity. The production of many of the non-D antibodies detected could be avoided by the use of selected red cells when transfusing pre-menopausal women.

Fetal growth retardation and second trimester maternal serum human chorionic gonadotrophin levels.

Second trimester maternal serum human chorionic gonadotrophin (hCG) levels in women who remained normotensive but delivered an unexplained growth retarded infant were compared with those from a control group and a group of women who developed pre-eclampsia in a retrospective observational study. Our hypothesis was that the similar placental pathological changes shared by unexplained normotensive IUGR and pre-eclampsia would be reflected by elevated maternal serum hCG levels in the second trimester. Normotensive women delivering unexplained singleton growth retarded infants were identified (n=43) and their second trimester hCG levels, taken as part of antenatal screening for Down's syndrome, were obtained. These were compared with a control group of 625 women, and a group of 48 women who subsequently developed pre-eclampsia. There was no significant difference in the hCG levels expressed as multiples of the median (MOM) between the women who delivered growth retarded fetuses (median MOM 0.96) and the control group (median MOM 0.97). The levels of hCG in the women who subsequently developed pre-eclampsia were significantly higher (median MOM 1.3, P=0.008). There were no significant differences in AFP levels in the three groups; however, the trend was towards a higher level of AFP in the fetal growth retardation group. Maternal serum hCG in the second trimester does not appear to be elevated in normotensive women who later produce a growth retarded fetus, although human chorionic gonadotrophin levels are significantly higher in women who subsequently develop pre-eclampsia.

Design of a high affinity peptidomimetic opioid agonist from peptide pharmacophore models.

A pair of diastereomeric peptidomimetics based upon opioid receptor-binding pharmacophore models derived for a series of opioid tetrapeptides was synthesized. Both analogues display high opioid receptor affinity, moderate selectivity for the mu opioid receptor, and are potent, full agonists.

Histological study of decidual spiral arteries and the presence of maternal erythrocytes in the intervillous space during the first trimester of normal human pregnancy.

During the first trimester in normal human pregnancy, endovascular trophoblast migrate along the decidual spiral arteries and invade their walls to produce physiological change. There is controversy as to whether invading trophoblast plug the arteries and prevent blood flow into the intervillous space. Using light microscopy, placental bed sections from 25 first trimester gravid hysterectomy specimens were examined. From each specimen, one section was divided into equal central and peripheral compartments. Maternal red blood cells were present in the intervillous space in all specimens, in both central and peripheral areas. In total, 232 decidual spiral arteries were found, each of those represented by several cross sections, 136 in the central area and 96 in the periphery. Seventy-nine per cent had undergone physiological change (significantly more in the centre than in the periphery), 63 per cent contained scattered endovascular trophoblast, 20 per cent had plugs of trophoblast partially occluding the vessel and 17 per cent had plugs totally filling the vessel lumen. These data confirm that in the first trimester of normal pregnancy, maternal blood enters the intervillous space, total plugging of the arterial system by trophoblast is not common, and more spiral arteries undergo physiological change in the centre than in the periphery.