Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Comment on "Local accumulation times for source, diffusion, and degradation models in two and three dimensions" [J. Chem. Phys. 138, 104121 (2013)]

In a recent paper, Gordon, Muratov, and Shvartsman studied a partial differential equation (PDE) model describing radially symmetric diffusion and degradation in two and three dimensions. They paid particular attention to the local accumulation time (LAT), also known in the literature as the mean action time, which is a spatially dependent timescale that can be used to provide an estimate of the time required for the transient solution to effectively reach steady state. They presented exact results for three-dimensional applications and gave approximate results for the two-dimensional analogue. Here we make two generalizations of Gordon, Muratov, and Shvartsman’s work: (i) we present an exact expression for the LAT in any dimension and (ii) we present an exact expression for the variance of the distribution. The variance provides useful information regarding the spread about the mean that is not captured by the LAT. We conclude by describing further extensions of the model that were not considered by Gordon,Muratov, and Shvartsman. We have found that exact expressions for the LAT can also be derived for these important extensions...

Establishment and characterisation of an open mini-thoracotomy surgical approach to an ovine thoracic spine fusion model

Background A large animal model is required for assessment of minimally invasive, tissue engineering based approaches to thoracic spine fusion, with relevance to deformity correction surgery for human adolescent idiopathic scoliosis. Here we develop a novel open mini–thoracotomy approach in an ovine model of thoracic interbody fusion which allows assessment of various fusion constructs, with a focus on novel, tissue engineering based interventions. Methods The open mini-thoracotomy surgical approach was developed through a series of mock surgeries, and then applied in a live sheep study. Customized scaffolds were manufactured to conform with intervertebral disc space clearances required of the study. Twelve male Merino sheep aged 4 to 6 years and weighing 35 – 45 kg underwent the abovementioned procedure and were divided into two groups of six sheep at survival timelines of 6 and 12 months. Each sheep underwent a 3-level discectomy (T6/7, T8/9 and T10/11) with randomly allocated implantation of a different graft substitute at each of the three levels; (i) polycaprolactone (PCL) based scaffold plus 0.54μg rhBMP-2, (ii) PCL-based scaffold alone or (iii) autograft. The sheep were closely monitored post- operatively for signs of pain (i.e. gait abnormalities/ teeth gnawing/ social isolation). Fusion assessments were conducted post-sacrifice using Computed Tomography and hard-tissue histology. All scientific work was undertaken in accordance with the study protocol has been approved by the Institute's committee on animal research. Results. All twelve sheep were successfully operated on and reached the allotted survival timelines, thereby demonstrating the feasibility of the surgical procedure and post-operative care. There were no significant complications and during the post-operative period the animals did not exhibit marked signs of distress according to the described assessment criteria. Computed Tomographic scanning demonstrated higher fusion grades in the rhBMP-2 plus PCL-based scaffold group in comparison to either PCL-based scaffold alone or autograft. These results were supported by histological evaluation of the respective groups. Conclusion. This novel open mini-thoracotomy surgical approach to the ovine thoracic spine represents a safe surgical method which can reproducibly form the platform for research into various spine tissue engineered constructs (TEC) and their fusion promoting properties.

Biological performance of a polycaprolactone-based scaffold plus recombinant human morphogenetic protein-2 (rhBMP-2) in an ovine thoracic interbody fusion model

Introduction. We develop a sheep thoracic spine interbody fusion model to study the suitability of polycaprolactone-based scaffold and recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute within the thoracic spine. The surgical approach is a mini- open thoracotomy with relevance to minimally invasive deformity correction surgery for adolescent idiopathic scoliosis. To date there are no studies examining the use of this biodegradable implant in combination with biologics in a sheep thoracic spine model. Methods. In the present study, six sheep underwent a 3-level (T6/7, T8/9 and T10/11) discectomy with randomly allocated implantation of a different graft substitute at each of the three levels; (i) calcium phosphate (CaP) coated polycaprolactone based scaffold plus 0.54µg rhBMP-2, (ii) CaP coated PCL- based scaffold alone or (iii) autograft (mulched rib head). Fusion was assessed at six months post-surgery. Results. Computed Tomographic scanning demonstrated higher fusion grades in the rhBMP-2 plus PCL- based scaffold group in comparison to either PCL-based scaffold alone or autograft. These results were supported by histological evaluations of the respective groups. Biomechanical testing revealed significantly higher stiffness for the rhBMP-2 plus PCL- based scaffold group in all loading directions in comparison to the other two groups. Conclusions. The results of this study demonstrate that rhBMP-2 plus PCL-based scaffold is a viable bone graft substitute, providing an optimal environment for thoracic interbody spinal fusion in a large animal model.

The effect of testing protocol on immature bovine thoracic spine segment stiffness

Introduction. In vitro spine biomechanical testing has been central to many advances in understanding the physiology and pathology of the human spine. Owing to the difficulty in obtaining sufficient numbers of human samples to conduct these studies, animal spines have been accepted as a substitute model. However, it is difficult to compare results from different studies, as they use different preparation, testing and data collection methods. The aim of this study was to identify the effect of repeated cyclic loading on bovine spine segment stiffness. It also aimed to quantify the effect of multiple freeze-thaw sequences, as many tests would be difficult to complete in a single session [1-3]. Materials and Methods. Thoracic spines from 6-8 week old calves were used. Each spine was dissected and divided into motion segments including levels T4-T11 (n=28). These were divided into two equal groups. Each segment was potted in polymethylemethacrylate. An Instron Biaxial materials testing machine with a custom made jig was used for testing. The segments were tested in flexion/extension, lateral bending and axial rotation at 37 degrees C and 100% humidity, using moment control to a maximum plus/minus 1.75 Nm with a loading rate of 0.3 Nm per second. Group (A) were tested with continuous repeated cyclic loading for 500 cycles with data recorded at cycles 3, 5, 10, 25, 100, 200, 300, 400 and 500. Group (B) were tested with 10 load cycles after each of 5 freeze thaw sequences. Data was collected from the tenth load cycle after each sequence. Statistical analysis of the data was performed using paired samples t-tests, ANOVA and generalized estimating equations. Results. The data were confirmed as having a normal distribution. 1. There were significant reductions in mean stiffness in flexion/extension (-20%; P=0.001) and lateral bending (-17%; P=0.009) over the 500 load cycles. However, there was no statistically significant change in axial rotation (P=0.152) 2. There was no statistically significant difference between mean stiffness over the five freeze-thaw sequences in flexion/extension (p=0.879) and axial rotation (p=0.07). However, there was a significant reduction in stiffness in lateral bending (-26%; p=0.007) Conclusion. Biomechanical testing of immature bovine spine motion segments requires careful interpretation. The effect of the number of load cycles as well as the number of freeze-thaw cycles on the stiffness of the motion segments depends on the axis of main movement.

Segmental torso masses and coronal plane joint torques in the adolescent scoliotic spine

Introduction. Calculating segmental (vertebral level-by-level) torso masses in Adolescent Idiopathic Scoliosis (AIS) patients allows the gravitational loading on the scoliotic spine during relaxed standing to be determined. This study used CT scans of AIS patients to measure segmental torso masses and explores how joint moments in the coronal plane are affected by changes in the position of the intervertebral joint’s axis of rotation; particularly at the apex of a scoliotic major curve. Methods. Existing low dose CT data from the Paediatric Spine Research Group was used to calculate vertebral level-by-level torso masses and joint torques occurring in the spine for a group of 20 female AIS patients (mean age 15.0 ± 2.7 years, mean Cobb angle 53 ± 7.1°). Image processing software, ImageJ (v1.45 NIH USA) was used to threshold the T1 to L5 CT images and calculate the segmental torso volume and mass corresponding to each vertebral level. Body segment masses for the head, neck and arms were taken from published anthropometric data. Intervertebral (IV) joint torques at each vertebral level were found using principles of static equilibrium together with the segmental body mass data. Summing the torque contributions for each level above the required joint, allowed the cumulative joint torque at a particular level to be found. Since there is some uncertainty in the position of the coronal plane Instantaneous Axis of Rotation (IAR) for scoliosis patients, it was assumed the IAR was located in the centre of the IV disc. A sensitivity analysis was performed to see what effect the IAR had on the joint torques by moving it laterally 10mm in both directions. Results. The magnitude of the torso masses from T1-L5 increased inferiorly, with a 150% increase in mean segmental torso mass from 0.6kg at T1 to 1.5kg at L5. The magnitudes of the calculated coronal plane joint torques during relaxed standing were typically 5-7 Nm at the apex of the curve, with the highest apex joint torque of 7Nm being found in patient 13. Shifting the assumed IAR by 10mm towards the convexity of the spine, increased the joint torque at that level by a mean 9.0%, showing that calculated joint torques were moderately sensitive to the assumed IAR location. When the IAR midline position was moved 10mm away from the convexity of the spine, the joint torque reduced by a mean 8.9%. Conclusion. Coronal plane joint torques as high as 7Nm can occur during relaxed standing in scoliosis patients, which may help to explain the mechanics of AIS progression. This study provides new anthropometric reference data on vertebral level-by-level torso mass in AIS patients which will be useful for biomechanical models of scoliosis progression and treatment. However, the CT scans were performed in supine (no gravitational load on spine) and curve magnitudes are known to be smaller than those measured in standing.

Inter-vertebral rotational deformity after endoscopic anterior scoliosis correction may contribute to rib hump recurrence after two years

Introduction. Endoscopic anterior scoliosis correction has been employed recently as a less invasive and level-sparing approach compared with open surgical techniques. We have previously demonstrated that during the two-year post-operative period, there was a mean loss of rib hump correction by 1.4 degrees. The purpose of this study was to determine whether intra- or inter-vertebral rotational deformity during the post-operative period could account for the loss of rib hump correction. Materials and Methods. Ten consecutive patients diagnosed with adolescent idiopathic scoliosis were treated with an endoscopic anterior scoliosis correction. Low-dose computed tomography scans of the instrumented segment were obtained post-operatively at 6 and 24 months following institutional ethical approval and patient consent. Three-dimensional multi-planar reconstruction software (Osirix Imaging Software, Pixmeo, Switzerland) was used to create axial slices of each vertebral level, corrected in both coronal and sagittal planes. Vertebral rotation was measured using Ho’s method for every available superior and inferior endplate at 6 and 24 months. Positive changes in rotation indicate a reduction and improvement in vertebral rotation. Intra-observer variability analysis was performed on a subgroup of images. Results. Mean change in rotation for vertebral endplates between 6 and 24 months post-operatively was -0.26˚ (range -3.5 to 4.9˚) within the fused segment and +1.26˚ (range -7.2 to 15.1˚) for the un-instrumented vertebrae above and below the fusion. Mean change in clinically measured rib hump for the 10 patients was -1.6˚ (range -3 to 0˚). The small change in rotation within the fused segment accounts for only 16.5% of the change in rib hump measured clinically whereas the change in rotation between the un-instrumented vertebrae above and below the construct accounts for 78.8%. There was no clear association between rib hump recurrence and intra- or inter-vertebral rotation in individual patients. Intra-rater variability was ± 3˚. Conclusions. Intra- and inter-vertebral rotation continues post-operatively both within the instrumented and un-instrumented segments of the immature spine. Rotation between the un-instrumented vertebrae above and below the fusion was +1.26˚, suggesting that the un-instrumented vertebrae improved and de-rotated slightly after surgery. This may play a role in rib hump recurrence, however this remains clinically insignificant.

Postoperative pain relief using intermittent intrapleural analgesia following thoracoscopic anterior correction for progressive adolescent idiopathic scoliosis

Background Thoracoscopic anterior scoliosis instrumentation is a safe and viable surgical option for corrective fusion of progressive adolescent idiopathic scoliosis (AIS) and has been performed at our centre on 205 patients since 2000. However, there is a paucity of literature reporting on or examining optimum methods of analgesia following this type of surgery. A retrospective study was designed to present the authors’ technique for delivering intermittent local anaesthetic boluses via an intrapleural catheter following thoracoscopic scoliosis surgery; report the pain levels that may be expected and any adverse effects associated with the use of intrapleural analgesia, as part of a combined postoperative analgesia regime. Methods Records for 32 patients who underwent thoracoscopic anterior correction for AIS were reviewed. All patients received an intrapleural catheter inserted during surgery, in addition to patient-controlled opiate analgesia and oral analgesia. After surgery, patients received a bolus of 0.25% bupivacaine every four hours via the intrapleural catheter. Patient’s perceptions of their pain control was measured using the visual analogue pain scale scores which were recorded before and after local anaesthetic administration and the quantity and time of day that any other analgesia was taken, were also recorded. Results 28 female and four male patients (mean age 14.5 ± 1.5 years) had a total of 230 boluses of local anaesthetic administered in the 96 hour period following surgery. Pain scores significantly decreased following the administration of a bolus (p < 0.0001), with the mean pain score decreasing from 3.66 to 1.83. The quantity of opiates via patient-controlled analgesia after surgery decreased steadily between successive 24 hours intervals after an initial increase in the second 24 hour period when patients were mobilised. One intrapleural catheter required early removal due to leakage; there were no other associated complications with the intermittent intrapleural analgesia method. Conclusions Local anaesthetic administration via an intrapleural catheter is a safe and effective method of analgesia following thoracoscopic anterior scoliosis correction. Post-operative pain following anterior thoracic scoliosis surgery can be reduced to ‘mild’ levels by combined analgesia regimes. Keywords: Adolescent idiopathic scoliosis; Thoracoscopic anterior spinal fusion; Anterior fusion; Intrapleural analgesia; Endoscopic anterior surgery; Pain relief; Scoliosis surgery

Gay men, Gaydar and the commodification of difference

Purpose – The purpose of this paper is to investigate information communications technologies (ICT)-mediated inclusion and exclusion in terms of sexuality through a study of a commercial social networking web site for gay men. Design/methodology/approach – The paper uses an approach based on technological inscription and the commodification of difference to study Gaydar, a commercial social networking site. Findings – Through the activities, events and interactions offered by Gaydar, the study identifies a series of contrasting identity constructions and market segmentations that are constructed through the cyclic commodification of difference. These are fuelled by a particular series of meanings attached to gay male sexualities which serve to keep gay men positioned as a niche market. Research limitations/implications – The research centres on the study of one, albeit widely used, web site with a very specific set of purposes. The study offers a model for future research on sexuality and ICTs. Originality/value – This study places sexuality centre stage in an ICT-mediated environment and provides insights into the contemporary phenomenon of social networking. As a sexualised object, Gaydar presents a semiosis of politicised messages that question heteronormativity while simultaneously contributing to the definition of an increasingly globalised, commercialised and monolithic form of gay male sexuality defined against ICT

The Convergence Review and the principle of Australians' access to and opportunities for participation

The recent Australian Convergence Review’s second principle states: “Australians should have access to and opportunities for participation in a diverse mix of services, voices, views and information”. However, in failing to define its own use and understanding of the terms ‘access’ and ‘participation’ the Convergence Review exposes itself to criticism. These terms would no doubt be made unambiguously clear should the Review’s recommendations move towards policy, and this paper contributes to this discussion by framing access and participation, from the perspective of the ‘produser’ (Bruns, 2008), around three separate but related issues: the failure to frame the discussion that will be undertaken by the Australian Law Reform Commission’s 2012 2013 Copyright Inquiry; the prioritising of the market over and above media accountability and the health of the public sphere; and the missed opportunity to develop a national framework for digital literacy and advanced digital citizenry.

Is intermittent intrapleural analgesia safe and effective following thoracoscopic anterior scoliosis correction surgery?

Introduction: Thoracoscopic anterior instrumented fusion (TASF) is a safe and viable surgical option for corrective stabilisation of progressive adolescent idiopathic scoliosis (AIS) [1-2]. However, there is a paucity of literature examining optimum methods of analgesia following this type of surgery. The aim of this study was to identify; if local anaesthetic bolus via an intrapleural catheter provides effective analgesia following thoracoscopic scoliosis correction; what pain levels may be expected; and any adverse effects associated with the use of intermittent intrapleural analgesia at our centre. Methods: A subset of the most recent 80 patients from a large single centre consecutive series of 201 patients (April 2000 to present) who had undergone TASF had their medical records reviewed. 32 patients met the inclusion criteria for the analysis (i.e. pain scores must have been recorded within the hour prior and within two hours following an intrapleural bolus being given). All patients received an intrapleural catheter inserted during surgery, in addition to patient-controlled opiate analgesia and oral analgesia as required. After surgery, patients received a bolus of 0.25% bupivacaine every four hours via the intrapleural catheter. Visual analogue pain scale scores were recorded before and after the bolus of local anaesthetic and the quantity and time of day that any other analgesia was taken, were also recorded. Results and Discussion: 28 female and four male patients (mean age 14.5 ± 1.5 years) had a total of 230 boluses of local anaesthetic administered intrapleurally, directly onto the spine, in the 96 hour period following surgery. Pain scores significantly decreased following the administration of a bolus (p<0.0001), with the mean pain score decreasing from 3.66 to 1.83. The quantity of opiates via patient-controlled analgesia after surgery decreased steadily between successive 24 hours intervals after an initial increase in the second 24 hour period when patients were mobilised. One intrapleural catheter required early removal at 26 hours postop due to leakage; there were no other associated complications with the intermittent intrapleural analgesia method. Post-operative pain following anterior scoliosis correction was decreased significantly with the administration of regular local anaesthetic boluses and can be reduced to ‘mild’ levels by combined analgesia regimes. The intermittent intrapleural analgesia method was not associated with any adverse events or complications in the full cohort of 201 patients.

Segmental torso masses and gravity-induced coronal plane joint moments in adolescent idiopathic scoliosis

Introduction: Calculating segmental (vertebral level-by-level) torso masses in Adolescent Idiopathic Scoliosis (AIS) patients allows the gravitational loading on the scoliotic spine during relaxed standing to be estimated. This study used supine CT scans of AIS patients to measure segmental torso masses and explored the joint moments in the coronal plane, particularly at the apex of a scoliotic major curve. Methods: Existing low dose CT data from the Paediatric Spine Research Group was used to calculate vertebral level-by-level torso masses and joint moments occurring in the spine for a group of 20 female AIS patients with right sided thoracic curves. The mean age was 15.0 ± 2.7 years and all curves were classified Lenke Type 1 with a mean Cobb angle 52 ± 5.9°. Image processing software, ImageJ (v1.45 NIH USA) was used to create reformatted coronal plane images, reconstruct vertebral level-by-level torso segments and subsequently measure the torso volume corresponding to each vertebral level. Segment mass was then determined by assuming a tissue density of 1.04x103 kg/m3. Body segment masses for the head, neck and arms were taken from published anthropometric data (Winter 2009). Intervertebral joint moments in the coronal plane at each vertebral level were found from the position of the centroid of the segment masses relative to the joint centres with the segmental body mass data. Results and Discussion: The magnitude of the torso masses from T1-L5 increased inferiorly, with a 150% increase in mean segmental torso mass from 0.6kg at T1 to 1.5kg at L5. The magnitudes of the calculated coronal plane joint moments during relaxed standing were typically 5-7 Nm at the apex of the curve, with the highest apex joint torque of 7Nm. The CT scans were performed in the supine position and curve magnitudes are known to be 7-10° smaller than those measured in standing, due to the absence of gravity acting on the spine. Hence, it can be expected that the moments produced by gravity in the standing individual will be greater than those calculated here.

Modeling electricity price events as point processes

Energy prices are highly volatile and often feature unexpected spikes. It is the aim of this paper to examine whether the occurrence of these extreme price events displays any regularities that can be captured using an econometric model. Here we treat these price events as point processes and apply Hawkes and Poisson autoregressive models to model the dynamics in the intensity of this process.We use load and meteorological information to model the time variation in the intensity of the process. The models are applied to data from the Australian wholesale electricity market, and a forecasting exercise illustrates both the usefulness of these models and their limitations when attempting to forecast the occurrence of extreme price events.

A closed-form approximation for pricing temperature-based weather derivatives

This paper develops analytical distributions of temperature indices on which temperature derivatives are written. If the deviations of daily temperatures from their expected values are modelled as an Ornstein-Uhlenbeck process with timevarying variance, then the distributions of the temperature index on which the derivative is written is the sum of truncated, correlated Gaussian deviates. The key result of this paper is to provide an analytical approximation to the distribution of this sum, thus allowing the accurate computation of payoffs without the need for any simulation. A data set comprising average daily temperature spanning over a hundred years for four Australian cities is used to demonstrate the efficacy of this approach for estimating the payoffs to temperature derivatives. It is demonstrated that expected payoffs computed directly from historical records are a particularly poor approach to the problem when there are trends in underlying average daily temperature. It is shown that the proposed analytical approach is superior to historical pricing.