Systematic development and validation of a predictive model for major postoperative complications in the Peri-operative Quality Improvement Project (PQIP) dataset.

Complications are common following major surgery and are associated with increased use of healthcare resources, disability and mortality. Continued reliance on mortality estimates risks harming patients and health systems, but existing tools for predicting complications are unwieldy and inaccurate. We aimed to systematically construct an accurate pre-operative model for predicting major postoperative complications; compare its performance against existing tools; and identify sources of inaccuracy in predictive models more generally. Complete patient records from the UK Peri-operative Quality Improvement Programme dataset were analysed. Major complications were defined as Clavien-Dindo grade ≥ 2 for novel models. In a 75% train:25% test split cohort, we developed a pipeline of increasingly complex models, prioritising pre-operative predictors using Least Absolute Shrinkage and Selection Operators (LASSO). We defined the best model in the training cohort by the lowest Akaike's information criterion, balancing accuracy and simplicity. Of the 24,983 included cases, 6389 (25.6%) patients developed major complications. Potentially modifiable risk factors (pain, reduced mobility and smoking) were retained. The best-performing model was highly complex, specifying individual hospital complication rates and 11 patient covariates. This novel model showed substantially superior performance over generic and specific prediction models and scores. We have developed a novel complications model with good internal accuracy, re-prioritised predictor variables and identified hospital-level variation as an important, but overlooked, source of inaccuracy in existing tools. The complexity of the best-performing model does, however, highlight the need for a step-change in clinical risk prediction to automate the delivery of informative risk estimates in clinical systems.

Development and internal validation of a model for postoperative morbidity in adults undergoing major elective colorectal surgery: the peri-operative quality improvement programme (PQIP) colorectal risk model.

Over 1.5 million major surgical procedures take place in the UK NHS each year and approximately 25% of patients develop at least one complication. The most widely used risk-adjustment model for postoperative morbidity in the UK is the physiological and operative severity score for the enumeration of mortality and morbidity. However, this model was derived more than 30 years ago and now overestimates the risk of morbidity. In addition, contemporary definitions of some model predictors are markedly different compared with when the tool was developed. A second model used in clinical practice is the American College of Surgeons National Surgical Quality Improvement Programme risk model; this provides a risk estimate for a range of postoperative complications. This model, widely used in North America, is not open source and therefore cannot be applied to patient populations in other settings. Data from a prospective multicentre clinical dataset of 118 NHS hospitals (the peri-operative quality improvement programme) were used to develop a bespoke risk-adjustment model for postoperative morbidity. Patients aged ≥ 18 years who underwent colorectal surgery were eligible for inclusion. Postoperative morbidity was defined using the postoperative morbidity survey at postoperative day 7. Thirty-one candidate variables were considered for inclusion in the model. Death or morbidity occurred by postoperative day 7 in 3098 out of 11,646 patients (26.6%). Twelve variables were incorporated into the final model, including (among others): Rockwood clinical frailty scale; body mass index; and index of multiple deprivation quintile. The C-statistic was 0.672 (95%CI 0.660-0.684), with a bootstrap optimism corrected C-statistic of 0.666 at internal validation. The model demonstrated good calibration across the range of morbidity estimates with a mean slope gradient of predicted risk of 0.959 (95%CI 0.894-1.024) with an index-corrected intercept of -0.038 (95%CI -0.112-0.036) at internal validation. Our model provides parsimonious case-mix adjustment to quantify risk of morbidity on postoperative day 7 for a UK population of patients undergoing major colorectal surgery. Despite the C-statistic of < 0.7, our model outperformed existing risk-models in widespread use. We therefore recommend application in case-mix adjustment, where incorporation into a continuous monitoring tool such as the variable life adjusted display or exponentially-weighted moving average-chart could support high-level monitoring and quality improvement of risk-adjusted outcome at the population level.

Probing the seismic cycle timing with coseismic twisting of subduction margins.

Assessing the timing of great megathrust earthquakes is together crucial for seismic hazard analysis and deemed impossible. Geodetic instrumentation of subduction zones has revealed unexpected deformation patterns at subduction segments adjacent to those that hosted recent mega-earthquakes: coastal sites move landward with faster velocities than before the earthquake. Here, we show observations from the largest and best-monitored megathrust earthquakes, and from a scaled analog model, to reveal that these events create coseismic and postseismic deformation patterns typical of a complete gear-like rotation about a vertical axis, hereafter called twisting. We find that such twisting alters the interseismic velocity field of adjacent subduction segments depending on the time since the last earthquake. Early interactions accelerate while late interactions decelerate local kinematics. This finding opens the possibility of using megathrust earthquakes, the characteristics of the twisting pattern, and the ensuing geodetic velocity changes, as a proxy for estimating the timing of the seismic cycle at unruptured segments along the margin.

Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.

Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and ß) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-ß-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.

Assessment of MLC tracking performance during hypofractionated prostate radiotherapy using real-time dose reconstruction.

By adapting to the actual patient anatomy during treatment, tracked multi-leaf collimator (MLC) treatment deliveries offer an opportunity for margin reduction and healthy tissue sparing. This is assumed to be especially relevant for hypofractionated protocols in which intrafractional motion does not easily average out. In order to confidently deliver tracked treatments with potentially reduced margins, it is necessary to monitor not only the patient anatomy but also the actually delivered dose during irradiation. In this study, we present a novel real-time online dose reconstruction tool which calculates actually delivered dose based on pre-calculated dose influence data in less than 10 ms at a rate of 25 Hz. Using this tool we investigate the impact of clinical target volume (CTV) to planning target volume (PTV) margins on CTV coverage and organ-at-risk dose. On our research linear accelerator, a set of four different CTV-to-PTV margins were tested for three patient cases subject to four different motion conditions. Based on this data, we can conclude that tracking eliminates dose cold spots which can occur in the CTV during conventional deliveries even for the smallest CTV-to-PTV margin of 1 mm. Changes of organ-at-risk dose do occur frequently during MLC tracking and are not negligible in some cases. Intrafractional dose reconstruction is expected to become an important element in any attempt of re-planning the treatment plan during the delivery based on the observed anatomy of the day.

Human spermatozoa and temperature: the elephant in the room.

Men are notable for low sperm production, relative to that of other large mammals, and often inferior morphology and motility of their spermatozoa. The extent to which temperature plays a role in this picture has been a moot point. However, animal experiments suggest that an increased scrotal temperature of approximately +4°C brought by inguinal clothing has a negative impact on the germinal epithelium and on the epididymis in man. In two animal species with inguinal testes, their transposition to the abdomen, raising the testis temperature by a modest approximate 1.5°C brought reduced sperm production and abnormalities of spermiogenesis (distorted sperm nuclei, shared acrosomes), a picture seen commonly in man alongside morphologically normal spermatids. Reflection of the scrotal epididymis to the abdomen in laboratory animals did not inhibit sperm maturation there, but the consequences of this for other epididymal parameters are mirrored in several features seen in man. In addition to the typically puny form of the human cauda, these include often rapid epididymal sperm transit, rapid capacitation in vitro, a poor sperm reserve (as reflected in the steep decline in sperm numbers in successive ejaculates), and not least, the cauda's failure to maintain the viability of spermatozoa there (reflected in both their mixed potential for motility and the negative outcome of abstinence). Because the number of competent spermatozoa inseminated relates to prompt fertilization and/or incidence of pregnancy in some animal models, the negative effects of scrotal temperature may be an important factor in the need for an average of approximately five cycles of unprotected intercourse in order to establish pregnancy in human females.

The epididymis re-visited: a personal view.

The sperm maturation and storage functions of the epididymis are important determinants of ejaculate quality, and perhaps provide an avenue to male contraception. In the last 50 years, the creation of epididymal fertility profiles in laboratory animals was followed by recognition of new sperm maturation-related parameters (organization of the acrosome, of the sperm plasmalemma, and -S-S- -based structural change) which made it possible to confirm that a similar pattern of sperm maturation obtains in man. The novel sperm storage function of the cauda epididymidis in therian mammals is regulated by androgen, usually in conjunction with the low temperature of the scrotum. The temperature-dependence of the scrotal cauda is reflected in the secretory and ion transport functions of the epithelium, in its duct dimensions and so in sperm storage capacity. Moreover, a variety of indirect evidence suggests that an elevated temperature of the cauda created by clothing may be compromising its function in man. The pattern of change in the sperm plasmalemma involving sterols, and also glycosylphosphatidylinositol-linked macromolecules as spermatozoa enter the cauda region, may underlie the need for their capacitation subsequently in the female tract. Further, in a variety of taxa the anatomy of the scrotum, together with the U-shaped configuration of the epididymis/vas deferens, suggests that the cauda's storage function may also underlie the evolution of the scrotum. Finally, despite the still relative paucity of comparative evidence, we can consider now why the epididymis has come to be organized as it is.

Singular features of fertilization and their impact on the male reproductive system in eutherian mammals.

Therian (marsupial and eutherian) mammals have evolved a suite of novel reproductive features - seen variously in their gametes, the steps of fertilization and the male reproductive tract - whose adaptive significance remains unclear. Present evidence for the better-understood eutherian mammals suggests that the 'prime mover' in their evolution has been the character of the egg coat, with other such features being adaptations to the consequences of this. Its elastic thickness allows the zona pellucida to stretch to a variable degree and yet remain around the blastocyst during much or all of its expansion before implantation, but its character represents an unusual challenge for spermatozoa. Novel aspects of the acrosome related to this challenge enable it to maintain a relatively prolonged binding after the onset of the acrosome reaction, and the structure, shape and behaviour of the sperm head point to physical thrust as a major element of zona penetration - with the unique configuration of gamete fusion as a sequela of this strategy. In the male, such adaptations are reflected in sperm head formation in the testis and in sperm maturation in the epididymis involving at least the sperm head's structure, plasmalemma and acrosome. This complexity allied to a slow epididymal sperm transport, a relatively modest sperm production and the brief life span of mature spermatozoa kept above the cauda epididymidis could account for the evolution of the sperm storage function - a development seemingly linked, in turn, to the need for sperm capacitation and scrotal evolution.

An experimental evaluation of the Agility MLC for motion-compensated VMAT delivery.

An algorithm for dynamic multileaf-collimator (dMLC) tracking of a target performing a known a priori, rigid-body motion during volumetric modulated arc therapy (VMAT), has been experimentally validated and applied to investigate the potential of the Agility (Elekta AB, Stockholm, Sweden) multileaf-collimator (MLC) for use in motion-compensated VMAT delivery. For five VMAT patients, dosimetric measurements were performed using the Delta(4) radiation detector (ScandiDos, Uppsala, Sweden) and the accuracy of dMLC tracking was evaluated using a gamma-analysis, with threshold levels of 3% for dose and 3 mm for distance-to-agreement. For a motion trajectory with components in two orthogonal directions, the mean gamma-analysis pass rate without tracking was found to be 58.0%, 59.0% and 60.9% and was increased to 89.1%, 88.3% and 93.1% with MLC tracking, for time periods of motion of 4 s, 6 s and 10 s respectively. Simulations were performed to compare the efficiency of the Agility MLC with the MLCi MLC when used for motion-compensated VMAT delivery for the same treatment plans and motion trajectories. Delivery time increases from a static-tumour to dMLC-tracking VMAT delivery were observed in the range 0%­20% for the Agility, and 0%­57% with the MLCi, indicating that the increased leaf speed of the Agility MLC is beneficial for MLC tracking during lung radiotherapy.

From DNA damage to chromosome aberrations: joining the break.

Despite many years of experimental studies on radiation-induced chromosomal aberrations, and the recent progress in elucidating the molecular mechanisms of the DNA damage response, the link between DNA double-strand break repair and its expression as microscopically visible chromosomal rearrangements remains, in many ways, obscure. Some long standing controversies have partially been resolved to the satisfaction of most investigators, including the linearity of the dose-response for DNA double-strand break induction, the necessity of pairwise interaction of radiogenic damaged sites in the formation of exchange aberrations, and the importance of proximity between lesions in misrejoining. However, the contribution of different molecular DNA repair mechanisms (e.g., alternative end-joining pathways) and their impact on the kinetics of aberration formation is still unclear, as is the definition of "complex" radiogenic damaged sites - in either the chemical or spatial sense - which ostensibly lead to chromosome rearrangements. These topics have been recently debated by molecular biologists and cytogeneticists, whose opinions are summarized in this paper.

Assessment of the robustness of volumetric-modulated arc therapy for lung radiotherapy.

Volumetric-modulated arc therapy (VMAT) is increasingly popular as a treatment method in radiotherapy owing to the speed with which treatments can be delivered. However, there has been little investigation into the effect of increased modulation in lung plans with regard to interfraction organ motion. This is most likely to occur where the planning target volume (PTV) lies within areas of low density. This paper aims to investigate the effect of modulation on the dose distribution using simulated patient movement and to propose a method that is less susceptible to such movement. Simulated interfraction motion is achieved by moving the plan isocentre in steps of 0.5 cm and 1.0 cm in six directions for five clinical VMAT patients. The proposed planning method involves optimisation using a density override of 1 g cm(-3), within the PTV in lung, to reduce segment boosting in the periphery of the PTV. This investigation shows that modulation can result in an increase in the maximum dose of >25%, an increase in PTV near-maximum dose of 17% and a reduction in near-minimum dose by 46%. Unacceptable organ at risk (OAR) doses are also seen. The proposed method reduces modulation, resulting in a maximum dose increase of 10%. Although safeguards are in place to prevent the increased dose to OARs from patient movement, there is nothing to prevent the increased dose as a result of modulation in lung. A simple planning method is proposed to safeguard against this effect. Investigation suggests that, where modulation exists in a plan, this method reduces it and is clinically viable.

Comparison of deliverable IMRT and VMAT for spine metastases using a simultaneous integrated boost.

OBJECTIVE: To effectively treat spine metastases, significant dose must be delivered to regions surrounding the spinal cord. We present a study comparing both step-and-shoot intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) techniques to deliver a concomitant hypofractionated prescription dose to the diseased region and to the involved vertebrae. METHODS: Seven-field IMRT and a single arc VMAT were inversely planned on five (two cervical and three thoracic) spinal metastatic patients. Planning target volumes PTVm (macroscopic) and PTVe (elective involved vertebrae) and associated organs at risk were localised. Mean doses of 35 Gy to PTVm and 20 Gy to PTVe were prescribed in five fractions. Dose statistics, estimated delivery time and results of verification using Delta(4) (ScandiDos, Uppsala, Sweden) were compared. RESULTS: Deliverable plans were achieved with both IMRT and VMAT. The coverage to PTV was similar for both IMRT and VMAT (p=0.5) and the dose to the regions adjacent to the spinal cord was 1% higher with VMAT (p=0.04). The mean delivery time for VMAT was 3.5 min compared with 10.5 min for IMRT. Fewer monitor units were required to deliver IMRT than to deliver VMAT. The median (range) percentage of measured points with a γ-index <1 with 3%/3 mm was 100 (99.9-100)% for IMRT and 100 (88.5-100)% for VMAT. CONCLUSION: Both VMAT and IMRT can deliver the concomitant hypofractionated regime proposed, and both offer different benefits in dose delivery. IMRT is currently preferred for its superior pre-treatment verification results and shorter planning times. ADVANCES IN KNOWLEDGE: This study explores the feasibility of delivering tumouricidal doses of radiation to metastatic spine disease in the vicinity of the spinal cord.

Paraspinal volumetric modulated arc therapy.

OBJECTIVES: The processes involved in the treatment of paraspinal tumours by volumetric modulated arc therapy (VMAT) are described here by means of an illustrative case. METHODS: Az single anticlockwise arc from gantry angle 179° to 181° was constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 2°. The dose prescription was 60 Gy in 30 fractions to cover the planning target volume (PTV) as uniformly as possible while sparing the 0.3-cm planning risk volume (PRV) around the spinal cord. The plan was verified before treatment using a diode array phantom and radiochromic film. Treatment delivery was on a Synergy linear accelerator with a beam modulator head (Elekta Ltd, Crawley, UK). RESULTS: Homogeneous dose coverage of the PTV was achieved with a D(2%) of 62.0 Gy and D(98%) of 55.6 Gy. Maximum spinal cord dose was 49.9 Gy to 0.1 cm(3) and maximum dose to the spinal cord PRV was 55.4 Gy to 0.1 cm(3). At pre-treatment verification, the percentage of the high-dose region receiving a dose within 3% and 3 mm of the planned dose was 98.8% with the diode array and 93.4% with film. Delivery time was 2 min 15 s and the course of treatment was successfully completed. CONCLUSIONS: VMAT was successfully planned, verified and delivered for this challenging tumour site. VMAT provides a very suitable method of treating complex paraspinal tumours, offering a high-quality conformal dose distribution with a short delivery time.

Volumetric modulated arc therapy planning for distal oesophageal malignancies.

OBJECTIVES: Volumetric modulated arc therapy (VMAT) is a novel form of intensity-modulated radiation therapy that allows the radiation dose to be delivered in a single gantry rotation using conformal or modulated fields. The capability of VMAT to reduce heart and cord dose, while maintaining lung receiving 20 Gy <20%, was evaluated for chemoradiation for oesophageal cancer. METHODS: An optimised forward-planned four-field arrangement was compared with inverse-planned coplanar VMAT arcs with 35 control points for 10 patients with lower gastro-oesophageal tumours prescribed 54 Gy in 30 fractions. Conformal (cARC) and intensity-modulated (VMATi) arcs were considered. Plans were assessed and compared using the planning target volume (PTV) irradiated to 95% of the prescription dose (V95), volumes of lung irradiated to 20 Gy (V20), heart irradiated to 30 Gy (V30), spinal cord maximum dose and van't Riet conformation number (CN). The monitor units per fraction and delivery time were recorded for a single representative plan. RESULTS: VMATi provided a significant reduction in the heart V30 (31% vs 55%; p=0.02) with better CN (0.72 vs 0.65; p=0.01) than the conformal plan. The treatment delivery was 1 min 28 s for VMAT compared with 3 min 15 s. CONCLUSION: For similar PTV coverage, VMATi delivers a lower dose to organs at risk than conformal plans in a shorter time, and this has warranted clinical implementation.

Optimising stereotactic body radiotherapy for non-small cell lung cancer with volumetric intensity-modulated arc therapy--a planning study.

AIMS: The potential advantages of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC) over conventional fractionated radiotherapy include a higher biological effective dose, a reduction in accelerated repopulation, greater patient convenience and reduced demand on radiotherapy resources. Before introducing SBRT in our department, a review of planning and delivery was undertaken, starting with an assessment of optimum beam number and arrangement. MATERIALS AND METHODS: Radiotherapy planning computed tomography scans for five patients previously treated for T1 peripheral NSCLC were selected. In each the contoured tumour had planning target volume (PTV) margins of 1cm in all directions. Forward-planned three-field coplanar and non-coplanar plans and a seven-field coplanar plan were produced and optimised. In-house inverse-planning software (AutoBeam) was used to generate three-, five-, seven- and nine-field coplanar and non-coplanar plans and two volumetric intensity-modulated arc therapy (VMAT) plans. The resulting V(20), V(11), PTV(90), PTV(95) and mean lung dose were compared. RESULTS: Analysis of variance showed non-coplanar plans to have lower V(11) and higher PTV(90) and PTV(95) than coplanar plans. VMAT showed equivalent V(20) and target coverage when compared with the best non-coplanar plans, but with a faster delivery time (2min 8s versus 12min 40s). CONCLUSIONS: Inverse-planned five-field non-coplanar plans and VMAT improve target coverage while minimising the higher dose to normal lung tissue for SBRT of NSCLC compared with coplanar beam arrangements. VMAT is preferable because of significantly shorter treatment delivery times.