The presence of an intraocular cilium is very rare and the response of the eye to the cilium is variable. We present the case of a patient with a cilium found in the vitreous cavity during vitrectomy for rhegmatogenous retinal detachment 40 years following penetrating eye injury. To our knowledge, this is the longest reported presence of a cilium in the vitreous cavity.A 70-year-old Caucasian woman presented to the emergency department of our hospital complaining of sudden visual impairment and floaters of her right eye initiated 2 weeks earlier. Ophthalmic history included a penetrating injury of the right eye with a sharp metallic object 40 years ago and an uncomplicated phacoemulsification surgery in the same eye 2 years earlier. Fundoscopy revealed an inferior macula off rhegmatogenous retinal detachment. No inflammation was present. During vitrectomy and under scleral indentation at 5-o’clock position, a cilium was found at far retinal periphery. One end of the cilium was embedded in the retina, whereas the other end floated freely in the vitreous. The cilium was removed through the pars plana sclerotomy with intraocular foreign body forceps. The procedure was completed without any complications.Penetrating eye injury is the most possible cause of cilium entrance in vitreous cavity in this case, which suggests that cilium can be well tolerated in vitreous cavity for as long as 40 years. The presence of cilia intraocularly has been rarely associated with penetrating eye injuries. Retained cilia have been reported in the anterior  and postWe present the case of a cilium found in the vitreous cavity of a 70 year old Caucasian female patient. We believe that the cilium in question entered in the vitreous cavity as a result of penetrating injury 40 years prior to the time of the vitrectomy. Other less likely ways of entry include phacoemulsification performed 2 years prior to beginning of symptoms or even during the pars plana vitrectomy.A 70-year-old Caucasian woman presented to the emergency department of our hospital complaining of sudden visual impairment and floaters of her right eye initiated 2 weeks earlier. Ophthalmic history included a penetrating injury of the right eye with a sharp metallic object 40 years ago and an uncomplicated phacoemulsification surgery in the same eye 2 years earlier. The left eye was normal and the medical history was unremarkable.At presentation, visual acuity was “hand motion” in the right eye and slit-lamp examination revealed an opacity at the inferior ¼ of the cornea due to past injury and a posterior chamber intraocular lens with an intact posterior capsule. Intraocular pressure was 12 mmHg. Fundoscopy revealed an inferior macula off rhegmatogenous retinal detachment. There was no evidence of intraocular inflammation. Two days later, the patient underwent 20G three-port pars plana vitrectomy in the right eye under retrobulbar anaesthesia. During vitrectomy and under scleral indentation at 5-o’clock position, a cilium was found at far retinal periphery. One end of the cilium was embedded in the retina, whereas the other end floated freely in the vitreous Figure . The proWe present the case of a patient with a cilium in the vitreous cavity and partly embedded in the retina discovered during pars plana vitrectomy for rhegmatogenous retinal detachment.Previous reports have described the presence of intraocular cilia secondary to penetrating trauma ,9,14, suPhacoemulsification is a possible way of foreign body introduction into the eye. Islam and Dabbagh  observedIn our case, the eyelash was found under scleral indentation at the far inferior retinal periphery. Moreover, an opacification was present in the inferior ¼ of the cornea adjacent to the area where the eyelash was detected. This is in favor of the hypothesis that the eyelash was embedded at the time of penetrating eye injury 40 years ago.Our patient also underwent an uncomplicated phacoemulsification surgery 2 years earlier. In reported cases of intraocular cilium related to phacoemulsification surgery, its location was limited to the anterior segment of the eye and most commonly in the anterior chamber ,3,12. ThThe prognosis of intraocular cilia is variable. It ranges from lack of any response to acute inflammation , endophtWe conclude that penetrating eye injury is the most possible cause of cilium entrance in vitreous cavity in this case, which suggests that cilium can be well tolerated in vitreous cavity for as long as 40 years.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.


DA) to the rectum in order to understand the relationship between dose and toxicity. The primary objective of this work was to quantify systematic (Σ) and random (σ) variation in the position of the rectum during a course of prostate radiotherapy.Radiotherapy for prostate cancer does not explicitly take into account daily variation in the position of the rectum. It is important to accurately assess accumulated dose  of means] between planning and treatment was 4.2 mm in the anteroposterior (AP) direction and 1.3 mm left–right (LR). σ (root mean square of SDs) was 5.2 mm AP and 2.7 mm LR. Superior–inferior variation was less than one slice above and below the planning position.Σ are in line with published data for prostate motion. σ, however, was approximately twice as great as that seen for prostate motion. This suggests that DA may differ from planned dose in some patients treated with radiotherapy for prostate cancer.Our results for Σ and σ of the rectum in prostate cancer. σ was found to be greater than published data, providing strong rationale for further investigation of individual DA.This work is the first to use daily imaging to quantify  This system delivers image-guided IMRT (IG-IMRT).Radiotherapy is a clinically effective and cost effective curative treatment for prostate cancer. The major dose-limiting organ at risk is the rectum, located posterior to the prostate. In our centre, inverse-planned intensity-modulated radiotherapy (IMRT) has been delivered to the prostate since 2007.1 At present, no allowance is made for the position of the rectum on the MV CT scan. If this were to be different at the time of treatment compared with the time of planning, then the dose delivered to the organ that day (“delivered dose”) might differ from the planned dose.For standard treatment, a kilo-voltage (kV) CT scan is acquired for radiotherapy planning. When the patient comes for treatment each day , a lower-resolution longitudinally shorter mega-voltage (MV) CT scan is acquired. The patient is then moved, so that the position of the prostate on the MV scan matches its position on the kV scan, and the treatment is delivered.9 These studies have been small and have tended to rely on a limited number of images acquired during treatment. Several studies have confirmed differences between planned and delivered doses to the rectum.11 These early data support the hypothesis that accumulated dose (DA) to the rectum over the course of treatment differs from the planned dose in some patients. Development of methods to accurately estimate DA is critical for a better understanding of the relationship between dose and effect. This would allow us to advance radiotherapy for the individual patient and is an important radiotherapy research priority.14A variety of studies have demonstrated rectal motion in patients treated with radiotherapy for prostate cancer.A major impediment to progress is the need for an automated system to track the material elements of the rectum from day to day, both in order to calculate delivered dose in a timely fashion and to do so for a significant number of patients. We carried out the present study in order to understand the location of rectal voxels during a course of prostate radiotherapy, by parameterizing this organ. We tracked the position of the rectum from day to day over the course of treatment and compared the position each day with that at the time of planning. It was important to describe the daily position and to quantify differences within and between patients.15 The ultimate aim of VoxTox is to establish DA and its relationship with toxicity in 1920 participants treated with IG-IMRT for head and neck cancer, prostate cancer or a central nervous system tumour. Ethical approval was granted on 4 February 2013. From those consented so far, 10 patients with prostate cancer treated with radical radiotherapy to the prostate gland and pelvic lymph nodes were identified. All 10 had been treated using helical tomotherapy with intensity modulation and daily MV image guidance to a dose of 74 Gy in 37 fractions over 7.5 weeks. Patients were asked to have a comfortably full bladder and empty rectum. Treatment was delivered in the supine position using knee and ankle immobilization. kV planning scans and MV image guidance scans were retrieved from the TomoTherapy archive using in-house software, converted into digital imaging and communications in medicine (DICOM) format and imported into the radiotherapy virtual simulation software ProSoma® .16This work is from the VoxTox study.18 A single clinician (JS) outlined the rectum and femoral heads on the kV and MV scans for the 10 patients; this eliminated interobserver variability. The entire circumference of the rectal wall was contoured on each slice of each MV scan where it was shown. For rectal contouring, the images were viewed at 1.4-times zoom with 83 HU centre and 520 HU width. The most superior slice to contour was defined as the rectosigmoid junction, the last slice before the bowel turns anteriorly and to the left, confirmed using both axial and sagittal planes. The inferior slice to contour was set as the last slice clearly demonstrating both ischial tuberosities.A clinical oncologist (JS) and radiologist (SF) adapted recent clinical trial protocols for contouring the rectum and femoral heads on kV scans to incorporate features consistently present and identifiable on MV scans.The entire circumference of each femoral head was contoured on each slice where it could be seen as separate from the femoral neck. For bone contouring, 1.4-times zoom, 300 HU centre and 1500 HU width were selected. The femoral heads were chosen as fiducials, as they could be reliably identified on both kV and MV scans, and the bones were known to be identical in size on all scans for individual patients. They therefore provided a reference that was consistent within patients across scans and could also be used to compare patients. Contouring of rectum and femoral heads following the same protocol was also performed for the kV scans using standard kV windowing.The rectosigmoid junction was set as slice 1 on kV and MV scans; this allowed matching of the kV and MV scans at the most superior slice level. kV scans had been acquired with 3-mm longitudinal slice thickness and MV scans with 6-mm thickness. The rectum was divided into lower, middle and upper thirds of equal length, and each slice was assigned to one of these thirds. If the total number of slices did not divide exactly by three, then an extra one or two slices were distributed first to the lower third and then to the middle third.The DICOM data were anonymized, in order to allow their transfer from the hospital network to the Cavendish Laboratory. They were then processed using an in-house application, written in the high-level programming language, Python, as manual measurement of distances on the scans was found to be extremely time consuming. A point midway between the centres of the femoral heads, estimated from the centroids of the associated outlines, was chosen as the axial reference point. The distance from this, to the most anterior, posterior, right and left extent of the rectum, was measured for each slice of each scan for each patient. The axial measurement system is illustrated in vs reducing the rectum to thirds. It was important to establish the proportion of rectal voxels that were evaluable by this methodology, in order to plan future imaging protocols. We also wanted to assess variability in contouring using MV scans.Subsequent analysis was performed in Microsoft Excel®  and SPSS® . The MV contours were compared with the kV contours, and methods to parameterize the rectum were developed. These included investigation of variation in rectal position in axial and sagittal directions and axial rectal size. We wanted to assess the merits of incorporating data from all slices We present detailed results here; a comprehensive summary is given at the end of the Results section in the Summary of key results section.kV planning CT scans were available for all 10 patients. Complete sets of MV image guidance scans were available for 9/10 patients. In 1 patient, 36/37 scans were available; 1 scan could not be found in the archive . After training, manual contouring of an MV scan took approximately 20 min. Complete contouring for a single patient therefore took 12 h, with 120 h needed for the 10-patient cohort. The Python application produced accurate distances for the contours for 368/369 MV scans. 1 output failed and was omitted; 368 scans were included in the analysis.17 The rectal lengths that were demonstrated on the MV scans are shown in On the kV scans, the rectum was demonstrated on a median of 30 slices , representing a median vertical rectal length of 10 cm. This is within the predicted range for this organ.The rectosigmoid junction was shown on all MV scans. Hence, each time the actual slice number was lower than that projected from the kV scan, it was slices relating to the lower rectum that were not available. The lower third was missing completely on at least one MV scan for each patient  and was therefore not able to be assessed by this methodology. Middle and upper thirds were shown on all MV scans, and these parts of the rectum could be analysed in detail. All results that follow relate to scan slices from the middle and upper thirds of the rectum.Σ]. It also allowed estimation of the random variation in position for each patient (SD of the within-patient daily differences) and for the group of 10 patients [root mean square (RMS) of these 10 between-patient SDs = σ]. Differences between variation in position in the AP and LR directions and between the upper and middle thirds of the rectum were assessed.The mean position of the centre of the rectum was calculated, in anteroposterior (AP) and left–right (LR) dimensions, for each of middle and upper thirds of the rectum, for each MV scan. These were compared with the corresponding position of these thirds on the kV scan. Differences in position between kV and MV scans were calculated for each day. This allowed estimation of the systematic variation in rectal position between planning and treatment for each patient (mean of the within-patient daily differences) and for the group of 10 patients  and a mean LR position of −0.2 mm . The SD in the AP direction was 6.5 mm and in the LR direction was 3.0 mm.Σ) was 4.2 mm in the AP direction and 1.3 mm in the LR direction.The mean position was then calculated for each patient in the AP and LR directions in the same way. These mean positions are shown as the centres of the ellipses and circles in σ) was 5.2 mm and of the 10 LR SDs was 2.7 mm. In order to visually compare random variation in position between patients, the SD in the AP direction multiplied by two and the SD in the LR direction multiplied by two were used as the axes to construct ellipses as shown in The SD of the AP differences in position between the kV and MV scans was calculated for each patient, along with the SD in the LR direction. The RMS of the 10 AP SDs  to the mean LR difference in position. For 8/10 patients, the ratio was greater than 1 . This gives an estimate as to the magnitude of difference in σ between the two directions.In the same way, ratios were calculated for each patient of SD in the AP direction to SD in the LR direction. AP SD was greater than LR SD for 9 of the 10 patients . This gives an estimate as to the size of difference in Σ and σ between different thirds of the rectum. The results from the Variation in position of the axial centre of the rectum section were separated into those for the upper and middle thirds. Ratios were calculated for each patient of mean differences in position between the middle and upper thirds. No clear patterns were seen, suggesting that Σ does not differ significantly between these thirds.We sought to evaluate whether differences could be detected in σ between the middle and upper thirds of the rectum in this direction. No clear differences were seen for AP SDs between thirds.Ratios were also calculated for each patient of the SDs between thirds. The LR SD for the upper third was greater than that for the middle third in all 10 patients, with a median ratio of 1.8 . This gives an estimate as to the size of difference in The SI position of the superior rectum on each MV scan was compared with the position on the kV scan. Positions that were more superior on the MV scan were defined as positive, and distances that were less superior on the MV scan were defined as negative. The median difference in position when all days and patients were combined was 3 mm, with an IQR of −1.5 to 7.5 mm. With an MV slice thickness of 6 mm, this meant that the IQR showed <1 slice variation above and below the superior position on the kV scan. The distribution at the individual patient level is shown in the supporting material in The ratio of AP to LR rectal size on each of the 37 MV scans was calculated for the upper and middle thirds for each patient. A histogram of these results for all patients and treatment days is shown in This meant that we were able to approximate the rectal circumference to a circle. The rectal radius was calculated as:The difference between the rectal radius on each of the 37 MV scans and the rectal radius on the kV scan was calculated for both thirds for each patient. These results are shown as a histogram in A data set was created of the kV scan radius for each of middle and upper thirds for the 10 patients. The median of this data set was 13.3 mm . This meant that the radius on the MV scan [(13.3 + 1.3)/13.3] was 1.1 times greater, on average, than the radius on the kV scan.Σ in rectal radius between patients. IQR varied between patients , corresponding to differences in σ between patients.The rectum was initially investigated with results for both upper and middle thirds combined. The median difference in radius between kV and MV scans was calculated for each patient by taking the median of all days and both thirds. The range was −1.4 to 4.2 mm for the 10 patients, reflecting We wanted to establish whether there were differences in axial size between the middle and upper thirds of the rectum. The median MV rectal radius was calculated for each third for each patient; no clear differences were found between thirds.We wanted to assess the rectum at the individual slice level, in order to understand whether reducing the rectum to thirds removed vital information or not. We chose to analyse a single point on the rectal wall, the furthest anterior point, in order to combine information about position and size in one metric.The change in position of this point was calculated for each slice of each MV scan for the upper and middle thirds of the rectum, for each patient, with reference to the position of that point on the matched slice of the kV scan. Positions that were more anterior on the MV than the kV scan were defined as positive and distances that were more posterior on the MV scan were negative. A histogram of these differences in MV position relative to the kV position was constructed for all slices for all patients. This showed near normal distribution (data not shown). The mean position for this histogram was 0.5 mm more anterior than the position on the kV scan . The overall SD was 8.6 mm.Σ) was 4.6 mm. The within-patient SDs of these differences in position ranged from 4.7 to 9.3 mm and are illustrated by the whiskers in σ) was 7.4 mm.These data are presented as a boxplot in 19 The results for these were 0.83 and 1.0 mm, respectively; these are consistent with data in the literature on contouring variation using kV scans.Repeat contouring was performed at a 3-month interval by JS on a random selection of 50 individual slices from these 369 MV scans. Contours were compared using conformity index and mean distance to conformity metrics.Σ and σ of the axial centre were greater in the AP than in the LR direction. Σ was found to be 4.2 mm AP and 1.3 mm LR. These results are consistent with previous work in the literature on prostate motion. σ was 5.2 mm AP and 2.7 mm LR. These values are higher than those previously found for prostate motion. SI variation was of the order of one slice above and below the position on the kV scan. The rectum could be approximated to a circle in the axial plane, with the median radius during treatment being 1.3 mm larger than on the kV scan. Analysis of the rectum in thirds provided a good approximation of Σ at the individual slice level . This method appeared to underestimate σ with values of 5.2 mm for thirds and 7.4 mm for individual slices. Intraobserver variability of contouring on MV scans was similar to that previously seen for kV scans.Manual contouring was time consuming and estimated as 12 h per patient. The MV scans did not reliably show the inferior rectum, and only the middle and upper thirds could be evaluated using this methodology. When the 10 patients were combined, the median position of the axial centre of the rectum was close to its position on the kV scan. Both 17 This suggests that our contouring protocol, optimized for the longitudinally shorter and lower resolution MV scans, produced contours for the whole rectal height when applied to kV scans. It also suggests that when applied to the MV scans, all slices showing rectum should have been identified. Where the number of contours was lower than that predicted from the kV scan, it was because the whole rectum had not been imaged at the time of the MV scan. We chose patients who were treated with radiotherapy to pelvic lymph nodes as well as the prostate, as our previous work had demonstrated that the image guidance scans for this group were longer in the SI direction than for patients having their prostate alone treated.20 The rectum was analysed in thirds, which is the traditional anatomical approach for this organ.22The median vertical height of the rectum on the kV scans was 10 cm, which is within the predicted range for this organ.For each of the 10 patients, at least one MV scan contained the projected number of slices required to demonstrate the entire SI extent of the rectum. However, the mean number of slices identified on the MV scans (11 slices) was 4 slices less than the length predicted from the kV scans (15 slices). The rectosigmoid was identified on all MV scans for all patients, and therefore where there were slices missing, they related to the inferior rectum. This reflects the fact that the priority for the image guidance scans was to show the position of the prostate and pelvic lymph nodes, which do not extend as far inferiorly as the rectum does.DA. We found that the prostate (high-dose region) was adjacent to the middle third of the rectum for approximately 80% of its length and adjacent to the lower third of the rectum for the remaining 20%. Movement of the middle third is therefore likely to have the greatest effect on DA. Our initial work suggests that the lower third has less variation than the other two-thirds, as also has been found in other studies.23 In order to prove this incontrovertibly, for the next cohort of patients recruited to VoxTox, we are extending the inferior border of the MV scans to below the ischial tuberosities, in order to ensure complete coverage of the inferior rectum. This will allow accurate evaluation of this third of the rectum.We were, therefore, able to analyse the position and size of the middle and upper thirds of the rectum, but not the lower third, using these MV scans. We also investigated which parts of the rectum, if they moved, would be most likely to affect Σ and σ.The centre was chosen as the part of the rectum to track from day to day, as it could be reliably and consistently identified on each slice of the MV scans, using the furthest extents in the anterior, posterior, right and left directions. It also permitted examination of movements in the AP and LR directions. Relating the rectum on all scans and all patients to a three-dimensional (3D) bone reference meant that set-up variation was eliminated from this system, allowing more accurate estimates of Σ between patients can be estimated from the SD of the individual patient mean positions.26 The SD for our patient group was 4.2 mm in the AP direction and 1.3 mm in the LR direction.The differences in Σ and σ in the rectal position during treatment for prostate cancer.23 Hoogeman et al4 performed 8–13 repeat CT scans during treatment for a group of 19 patients who were asked to have a full bladder and empty rectum. The rectum was unfolded and rectal wall displacements were quantified between the planning CT and treatment using co-ordinate maps. They found that AP Σ was greater than LR Σ for the rectum as a whole, consistent with our results for middle and upper thirds. Stasi et al23 looked at 10 patients, who received 2 CT scans per week, prior to their radiotherapy. They were treated supine and were asked to have a full bladder and empty rectum. The difference in position between the anterior, posterior and lateral contours at planning and the average positions of these contours during treatment were compared, with the rectum divided into cranial and caudal halves. The SD for the cranial half was 4.4 mm anterior, 3.0 mm posterior, 3.7 mm right and 2.7 mm left. For the caudal half, the SD was 1.0 mm anterior, 1.9 mm posterior, 1.2 mm right and 1.6 mm left. Our AP Σ was similar to the results of Stasi et al for the cranial half and our LR Σ was similar to their results for the caudal half. Differences may be owing to their scanning protocol being less frequent than ours.To our knowledge, two previous studies exist quantifying 31 There are 11 studies in the literature that have quantified Σ in prostate motion.37 The median AP variation from these studies was 3.5 mm  and LR was 1.7 mm ; these values from prostate motion are very similar to our rectal data. Three studies used daily MV scans to assess this motion. Bylund et al32 assessed prostate movements on daily cone beam MV CT scans in 24 patients. They found Σ of 4.9 mm AP and 2.6 mm LR. Fiorino et al33 assessed prostate movements on daily helical tomotherapy MV scans for 21 patients. Σ was found to be 3.4 mm AP and 1.6 mm LR. Engels et al3 found that a group of 18 patients treated using daily MV image guidance could be split into those with a small and stable rectal cross-sectional area (10 patients) and those with a significantly greater and unstable cross-sectional area. Σ of the prostate was 2.4 mm AP in the stable group and 6.1 mm in the unstable group; values for LR variation were not provided. Fiorino et al37 investigated patients treated using two different immobilization techniques, either of the pelvis or of the legs. They found that Σ was affected by this, with AP variation being 3.5 mm for pelvis immobilization and 2.1 mm for leg immobilization; LR variation was 2.8 and 1.7 mm, respectively.Most previously published work investigating this area has been based on prostate motion. This has been shown to relate to rectal filling and to a lesser extent, bladder filling and leg motion.4 who found that mean local AP displacements between planning and treatment ranged from −7.0 to 7.5 mm. In their study, if the planning rectum volume was ≥96 cm3, the upper anterior rectal wall shifted posteriorly during treatment, but if the planning volume was <96 cm3, the upper rectal wall shifted anteriorly during treatment. Lebesque et al5 found that a large rectum at planning was predictive of a large difference between planning and treatment rectal volumes. Rectal distension at planning has also been shown to correlate with an increased risk of biochemical and local relapse of prostate cancer.38The most extreme posterior change in our group was a patient with a mean position of −9.6 mm during treatment. This patient had a loaded rectum at planning , which h26 The RMS of the SDs of all patients is considered the correct way to determine the group mean of the SD of the random error.26 This provides an estimate of the differences in σ between patients over a course of treatment and for our group was calculated as 5.2 mm in the AP direction and 2.7 mm in the LR direction. The AP SD was greater than the LR SD for 9 out of the 10 patients, with a median AP:LR SD of 2.3. σ is most likely to result from differences in rectal filling and emptying from day to day. Hoogeman et al4 also found greater AP than LR σ.An individual patient's SD of daily positional differences provides an estimate of the random variation in position within that patient over a course of treatment (the SD of the random error).σ to be greater than Σ in both AP and LR directions. Stasi et al23 found the same. The converse was true for Hoogeman et al;4 however, this might have been caused by the method of analysis.We found σ in prostate motion during radiotherapy for prostate cancer.37 The median AP variation from these studies was 2.7 mm  and LR was 1.6 mm . Our results suggest that rectal σ is approximately twice prostate σ in both AP and LR directions. Fiorino et al37 found that σ was also affected by immobilization, with AP variation being 3.1 mm for pelvis immobilization and 1.8 mm for leg immobilization, and LR variation being 2.4 and 1.6 mm, respectively.There are six studies in the literature that have quantified σ was seen in the LR direction for the upper third of the rectum than the middle third, with a median ratio of 1.8 to 1.0. There were no clear differences in Σ variation in either direction or AP σ. These are in line with the results of Hoogeman et al.4Greater σ for this third is a result of variable filling of the sigmoid colon. Chong et al22 assessed rectal movement on weekly cone beam CT (CBCT) scans for 16 patients treated with chemoradiation for rectal cancer. In keeping with our results, they found that σ in left and right rectal wall movements was significantly greater for the upper rectum than for the mid rectum.The upper third of the rectum is attached to the rectosigmoid. We propose that the greater LR Σ and σ for this third than middle and upper thirds.4 The median SI position of the femoral head contours was chosen as the SI reference point, meaning that there was a minimum of 3 mm between possible median positions. We found that the most challenging aspect of MV contouring was identifying the superior slice of the rectum, as separate from rectosigmoid, mainly owing to the 6-mm slice thickness. Song et al39 looked at differences in kV and MV contours for prostate and seminal vesicles. They also found that the greatest increase in target localization uncertainty between the two scan types was in the SI direction.In addition to axial variation, it was important to assess SI variation in rectal position. We were unable to adequately view the inferior rectum on the image guidance scans; this will be tested with a new imaging protocol for the next cohort of participants recruited. Previous work found less SI These factors meant that our results for SI variation were much less exact than those for axial variation. The IQR was 4.5 mm above and below the kV superior position; this is equivalent to less than one MV slice. It is important to know whether this means that the rectum truly does not significantly vary SI or whether variation has not been adequately captured owing to inaccuracies in this system. Ongoing work is seeking to answer these questions.39 found that prostate volumes segmented on MV scans were on average 1.1 times larger than those on kV scans. They attributed this to the lower soft-tissue contrast of the image guidance scans, analogous to larger volumes contoured on CT than on MRI scans.41 This may not only be a feature of MV CT outlines. The study by Stasi et al23 used kV CT scans for contouring, and the average rectal volume during therapy was 8 cm3 larger than that at planning. They hypothesized that this may be either owing to reduced compliance with bowel preparation as treatment progressed or to acute proctitis with wall oedema, as also suggested by Stroom et al.28We found that the median rectal radius was 1.3 mm greater for contours drawn on the MV scans than those on the kV scans, making it 1.1 times as large. Data in the literature regarding this are conflicting. Song et al4 however, found that the mean rectal volume during treatment was smaller at 74 cm3 than at planning (84 cm3). Crook et al36 found a mean decrease in rectal diameter of 1.5 cm between planning and treatment, and Lebesque et al5 found that rectal volume during treatment was 16% smaller than that at planning.36 None of these studies used daily imaging. Investigation of time trends in our data is underway to try and clarify the reason for the apparently larger rectum we found during treatment.Hoogeman et al,Σ and σ over and above the mean thirds data. We also wanted to devise a single metric that would allow us to describe both rectal position and size. In order to achieve this, we selected a single point to track in a single direction, namely the most anterior point of the rectum and its AP movements. We chose the anterior rectum for a variety of reasons. Our work showed that the greatest Σ and σ of the centre of the rectum occurred in the AP direction. Others found that the largest variation in rectal wall movements was at the anterior side.4 The anterior rectum is also the part of the rectal circumference closest to the high-dose region; movement of this area is therefore likely to be the most relevant in terms of effects on delivered dose.It was important to examine rectal movement at the individual slice level to see whether this gave additional information about Σ incorporating anterior movements from all slices from middle and upper thirds was 4.6 mm. Σ calculated from AP movements using the thirds data only was 4.2 mm. σ for all slices was 7.4 mm and for the thirds was 5.2 mm. These results suggest that analysis of the rectum in thirds was a very good approximation of rectal behaviour at the individual slice level in terms of Σ. However, σ was greater when calculated using data from all slices. The higher value also represented movement of the anterior rectum, rather than the axial centre. This may indicate that condensing the results into thirds loses some detail about σ or may simply reflect the fact that the anterior rectum moves more than the posterior rectum. Hoogeman et al4 estimated the greatest σ for any part of the anterior side as 8 mm and for the posterior side as 2 mm.DA.The results suggest that, provided these factors are taken into account, either the axial centre or a point on the rectal circumference could be used to track rectal movement. This information will be important for future work on Σ and σ in the position of the anterior rectum between patients. The dosimetric implications of these variations, in terms of dose to the whole rectum, are not yet clear: future work will address this. We propose that DA to the anterior rectum for Patient 1 could be lower than the planned dose. In the same way, DA to Patient 10 could be higher than that planned.43The voxels within a patient who receives a dose each day depend on the position of the prostate that day; the MV scan is used to move this target into the same 3D position for each treatment fraction as it was in at the time of planning. Variation in rectal position calculated relative to prostate position, rather than our bone reference point, may therefore be less than suggested from our results. Pre-treatment scans were used to assess the rectal position. This does not take into account rectal movements during the actual treatment fraction, which may be significant and may depend on the overall treatment time.44A single clinician provided all contours for this study; this eliminated uncertainty owing to interobserver variability in contouring. Estimation of the contouring accuracy of the work is challenging: in this context, other clinicians not used to looking at MV scans would be less likely to provide useful interobserver measurements than would usually be the case with contouring on kV scans.46 Intraobserver conformity indexes were slightly higher at 0.82 for planning scans and 0.76 for CBCTs.46 Our intraobserver conformity index of 0.83 for individual slices was closest to the value previously seen for contouring on kV scans. This suggests that the soft-tissue resolution on the MV scans is certainly good enough to allow for reproducible rectal outlines. Further work is underway to assess whether this level of conformity is also seen for rectal volumes, rather than individual slices, on the MV scans.Previous studies have estimated interobserver conformity index for the rectum on kV planning scans as between 0.77 and 0.81, with the result for kV CBCT being slightly lower at between 0.70 and 0.75.47 Current work is to evaluate DA for these 10 patients. We are also developing an automatic method for MV contouring, which is necessary to be able to calculate DA for the projected 1200 prostate participants for VoxTox. We are seeking to combine anatomical rule-based finite element modeling with deformable image registration. The future aim, therefore, is to calculate dose differences between patients, rather than positional differences as quantified here.Variation in rectal position relative to the prostate is a corollary of delivered dose. We have developed our in-house method for calculating this, based on the MV contours.48 This found that acute toxicity was significantly associated with both rectal volume during treatment and with delivered dose. On average, dose is an excellent biomarker, both of tumour control in the target and toxicity in the normal tissues. This means that, at the population level, dose can be used as a surrogate for toxicity. Performance is not as good at the individual patient level, and more detail is needed. The results from VoxTox are expected to make a major contribution to our understanding of this area, with the potential to modify both toxicity and tumour control on an individual basis in the future.One small study (38 patients each with an average of 9 scans during treatment) has recently been published investigating the relationship between delivered dose to the rectum and toxicity.DA. Σ was similar to the published literature for prostate motion. σ of the rectum, however, was found to be approximately two to three times greater than that for the prostate, particularly in the AP direction. These results strengthen the evidence that DA may differ from planned dose in some patients treated with radiotherapy for prostate cancer. Development of systems for tracking at the voxel level is underway, in order to understand physical variation in dose between patients. This is essential before biological variation in radiation response can be understood, with the potential for true tailoring of radiotherapy to the individual.This work shows that the rectum could be tracked from day to day on the MV image guidance CT scans and is the first step towards building a model of this organ for calculation of JS is supported by Cancer Research UK through the Cambridge Cancer Centre. NGB is supported by the NIHR Cambridge Biomedical Research Centre. VoxTox is funded by Cancer Research UK.


A microfluidic device that is capable of trapping and sensing dynamic variations in the electrical properties of individual cells is demonstrated. The device is applied to the real-time recording of impedance measurements of mouse embryonic stem cells (mESCs) during the process of membrane lysis, with the resulting changes in the electrical properties of cells during this process being quantitatively tracked over time. It is observed that the impedance magnitude decreases dramatically after cell membrane lysis. A significant shift in the phase spectrum is also observed during the time course of this process. By fitting experimental data to physical models, the electrical parameters of cells can be extracted and parameter variations quantified during the process. In the cell lysis experiments, the equivalent conductivity of the cell membrane is found to increase significantly due to pore formation in the membrane during lysis. An increase in the specific capacitance of the membrane is also observed. On the other hand, the conductivity of the cytoplasm is observed to decrease, which may be explained the fact that excess water enters the cell through the gradual permeabilization of the membrane during lysis. Cells can be trapped in the device for periods up to several days, and their electrical response can be monitored by real-time impedance measurements in a label-free and non-invasive manner. Furthermore, due to the highly efficient single cell trapping capacity of the device, a number of cells can be trapped and held in separate wells for concurrent parallel experiments, allowing for the possibility of stepped parametric experiments and studying cell heterogeneity by combining measurements across the array. It has been recently expounded that individual cells, even those identical in appearance and type, would have different characteristics and have an unpredictable and heterogeneous behaviour in a given population Di Carlo . The celTo identify the cell-to-cell variability in a population, the analysis of individual cells is mandatory. Single cell analysis can effectively remove most uncertainties caused by bulk techniques such the loss of information inherent in data averaging  has seen much recent interest. Microfluidic techniques are often best suited to this purpose , and is related to the geometry of channels and properties of solution. Due to the length and geometry difference between the two paths  are released at the inlet of the channel and driven by the drag force of the fluid. According to the particle tracing simulation, the transmission probability of particles flowing into the trap is 52 %, which is greater than the probability for the particle to flow into the bypass channel, i.e., 48 %. These transmission probabilities indicate whether the trapping is efficient or not. The criteria for efficient single particle trapping is that the probability of particle flowing into the trap should be larger than that of particle flowing into the bypass  can be expressed as: PDMS (polydimethylsiloxane) rapid prototyping technique was employed for fabricating the microfluidic channels. PDMS was chosen due to its low cost and other advantages such as its good elasticity and conformity. Firstly, SU-8 2025 (MicroChem) was patterned on a 3″ silicon wafer by standard photolithography, serving as the master mould for microfluidic channels. Before being used for PDMS moulding, the master mould was treated with FDTS  by vapour deposition  was spun onto the master mould at 500 rpm for 8 s and 1000 rpm for 60 s, and then cured on a 65 °C hot plate for 2 min and on a 150 °C hot plate for 5 min. The reason for using the PDMS spin coating method rather than the conventional pouring method is to address the shrinkage-induced PDMS alignment problem. Pouring PDMS directly onto a master mould typically results in a thick PDMS layer (> 1 mm in thickness). However, it has been observed that moulded structures in a thick-layer PDMS will shrink when the PDMS sample is peeled away from its master mould, due to thermal expansion and contraction during the curing process , used in image reversal mode, was patterned on a 2″ Pyrex glass wafer by photolithography, serving as a sacrificial layer for lift-off process. Metal electrodes (20 nm Ti and 100 nm Au) were deposited on the wafer by electron beam evaporation. Lift-off was performed in AZ 100 remover  bath at 50 °C.The alignment and bonding of the PDMS channels and electrode patterns was done using a mask aligner. Prior to bonding, the bonding surface of PDMS was activated by oxygen plasma . The back of the PDMS sample was attached to a 1 mm-thick custom-made acrylic adapter, whose surface is coated with FDTS to avoid PDMS adhesion, and the front surface of the PDMS sample, containing trapping channel structures, is exposed and available for bonding with the glass substrate with electrode patterns. The acrylic adapter, together with the PDMS sample, were loaded into the mask aligner and held by the vacuum mask holder of the mask aligner. The glass substrate was loaded into the wafer chuck of the mask aligner. The alignment process is similar to the standard process of aligning photo-masks and wafers during photolithography. Once the alignment of the microchannels and electrode patterns was done, the PDMS sample and glass substrate were brought into conformal contact to realise permanent bonding. The alignment and bonding process was typically completed within 15 min after the oxygen plasma treatment. The alignment errors using this method were typically smaller than 5 μm. After alignment and bonding, the device was post baked in a 65 °C oven for 1 h to improve the bonding strength. The electrical connections between the on-chip electrodes and external measuring instrumentation  were made by using surface mount connectors that are bonded to the electrode pads on the chip using silver conductive epoxy.Mouse embryonic stem cells were cultured in standard serum and LIF (Leukemia Inhibitory Factor) conditions  is higher than the values mentioned in some literature (0.006 F/m2), which may be explainable by the differences in the morphology of cell membranes, such as the extent of folding or surface features of the membrane (Muratore et al. The cell volume is kept constant during the fitting procedure to further simply the analysis. The cellular size of mouse embryonic stem cells was estimated by optical measurements under a microscope and the nuclear size was demonstrated previously by high-resolution fluorescence microscopy (Pagliara et al. As shown in Table It should be noted that even though the cell volume is kept unchanged in the fitting procedure, this may not be the true in in practice where an increase in cell volume has been observed during lysis (Malleo et al. Nevertheless, the impedance-based single cell study quantitatively indicates how cell properties change during the lysis process. Multiple cells can be trapped and monitored simultaneously in the same device. Compared with traditional petri-dish based cell assays, the microfluidic device enables electrical impedance studies at the single cell level and monitoring their impedance spectra over a given period of time. Our preliminary studies reveal that cells can be trapped stably in the device over a significant time course. This would be beneficial to long-term culturing of single cells and analysis of cell dynamics over longer periods of time. In this work, we have demonstrated the usefulness of the device by monitoring single cell lysis. However, this device is not just limited to the measurement this particular process – it can also be used for real-time monitoring of other dynamic processes such as changes occurring during the cell cycle or during differentiation. Moreover, this device is also compatible with other detection methods such as fluorescence imaging techniques, opening up the possibility of integrating electrical and optical detection methods in a multiplexed format. Future work will incorporate the microfluidic device with external environmental control to investigate the dynamic changes in electrical properties of live cells.A PDMS-glass-based microfluidic device has been developed for single cell trapping and real-time impedance-based sensing. This platform enables the measurement of the actual frequency response of individual cells rather than the average among the cell population. Dynamic monitoring of mouse embryonic stem cells during cell lysis process has been demonstrated and quantitative analysis on the electrical properties of cells during this process is presented. Changes in cell membrane conductivity, specific capacitance and cytoplasm conductivity have been observed. The proposed device can be used to monitor and track time-dependent changes in electrical properties of individual cells, the analysis of which can shed light on the underlying mechanisms at a cellular level. This microfluidic platform also provides the possibility of performing analyses on large number of cells simultaneously to obtain data on statistical variability of the response. While a model system is presented here to validate device functionality, future work is expected to address real-time study of stem cell differentiation using the electrical impedance-based method including the quantitative analysis of changes in electrical properties during the cell cycle, as well as the investigation of how these changes can be correlated with specific biological mechanisms.


Treatment of cells with Protein X results in five times higher levels of cell death than those seen in untreated cells (wild type), as measured by Caspase-positive cells. Based on previous work, the authors identify Protein Y as the putative receptor for Protein X and here try to test whether this is indeed the case. They claim that in a  A common way to represent data comparing two conditions is to plot the relative change of the outcome that is being measured by normalising both data sets to the average of the control condition. This gives the control values as ‘1’ and the experimental condition as a fold-change over the control.In this example, the authors show that in a wild-type (WT) background, treatment with Protein X caused a clear increase of dying cells when compared with the untreated control Fig. . Figure geneY-/- samples are both shown with values of 1, they do not represent the same actual numbers. The authors compared the treated cells of one genotype with untreated cells of the same genotype: thus, the two untreated conditions represent two separate controls—one the untreated WT, the other the untreated mutant—each normalised to 1. To see how this can mislead, we can look at Fig. However, plotting only the fold-change values can mask a more complicated story. Although in Fig. Although treating cells with Protein X did not induce a noticeable increase in dying cells in the mutant background when represented as in Fig.


By controlling the traction between its body and the tube wall, a tube-dwelling polychaete can move efficiently from one end of its tube to the other, brace its body during normal functions , and anchor within its tube avoiding removal by predators. To examine the potential physical interaction between worms and the tubes they live in, scanning electron microscopy was used to reveal and quantify the morphology of worm bodies and the tubes they produce for species representing 13 families of tube-dwelling polychaetes. In the tubes of most species there were macroscopic or nearly macroscopic (∼10 μm–1 mm) bumps or ridges that protruded slightly into the lumen of the tube; these could provide purchase as a worm moves or anchors. At this scale (∼10 μm-1 mm), the surfaces of the chaetal heads that interact with the tube wall were typically small enough to fit within spaces between these bumps  or ridges (made by secretions on the interior surface of the tube). At a finer scale (0.01–10 μm), there was a second overlap in size, usually between the dentition on the surfaces of chaetae that interact with the tube walls and the texture provided by the secreted strands or microscopic inclusions of the inner linings. These linings had a surprising diversity of micro-textures. The most common micro-texture was a “fabric” of secreted threads, but there were also orderly micro-ridges, wrinkles, and rugose surfaces provided by microorganisms incorporated into the inner tube lining. Understanding the fine structures of tubes in conjunction with the morphologies of the worms that build them gives insight into how tubes are constructed and how worms live within them. The tubes of polychaete annelids have long been of interest to a variety of scientists. Paleontologists have examined them for insight into the early biosphere and the evolution of the annelids . The inner sheath is usually comprised of successive layers made of sheets  has glandular masses on the parapodia that secrete successive layers of fine threads forming an elastic tubular coating in which algae or other materials may be incorporated  to see if they would produce similar overall patterns. For issues having to do with practicality of viewing with scanning electron microscopy (SEM), all the individual worms examined had diameters from 0.5 to 5 mm.To gain a broad phylogenetic perspective, I examined species from across the spectrum of polychaete taxa Table. The phyAlvinella pompejana and Oasisia sp.), I collected live worms in their tubes by hand , uncini , or paleae (thickened or flattened chaetae) that clearly had distinct working surfaces that could be or were seen to be in contact with the tube wall or that had wear patterns that indicated regular contact with the tube wall  in the same region on the body. I was interested in measuring the portion of the dentition free to interact with the tube surface. On multi-dentate chaetae, the teeth may be arranged in a linear anterior–posterior row, or as an interdigitated field of teeth , I similarly measured the distance between the tops of the ridges  and the spaces between them were measured along the tube's long axis as perceived by the distortion and drape of the tube's inner lining Fig.A. When tdges Fig.B,C. Undedges Fig.D. These The measurements of the features on the bodies and tubes were used to define a range of sizes for that feature for a given worm. These ranges were then compared within a worm to see if there were areas of overlap that might suggest physical interaction between the worm and its tube. Lastly, comparisons among species that span the phylogeny of the group allowed me to define what constitutes the broader structural patterns and the exceptions to them.Mesochaetopterus taylori and Schistocomus hiltoni, Figs.Oasisia sp., Figs.Owenia collaris and Serpula columbiana Fig.M. taylori , inner tube topography came from the presence of external materials that had been incorporated into the outer layer of the tube . Alvinella pompejana regularly incorporated much smaller exogenous items (including bacteria) that became merged into the tube lining by successive layers of tube material deposition , all chaetae that were likely to interact with the tube wall had substantial micro-dentition  internal layers of secreted material that had coated and smoothed out bumps originating from exogenous material in the outer layers of their tubes , it suggests that this lineage of Errantia . If worms are allowed to reside in artificial tubes and lay down inner tube linings then they may maintain their position well . The general pattern in tube-dwelling polychaetes is that there are two scales at which there is a size match between morphological features of the bodies of the worms and the tubes they inhabit. At a macroscopic or nearly macroscopic scale (∼10 μm–1 mm), the chaetal heads that interact with the tube wall are small enough to fit within the spaces between inward projections of exogenous materials incorporated into the tube wall (bumps) or between ridges of secretions generated on the interior surface. At a finer scale (0.01–10 μm) there is a second overlap in size, usually between the dentition on the surfaces of chaetae that interact with the tube walls and the texture provided by the secreted strands and gaps of the inner lining and from microscopic inclusions. This textural overlap at two size ranges may be analogous to the way in which a ladder constructed by humans also has two size matches—one between the spacing of the rungs and the length of human leg bones, and a second between the anti-slip surfaces of the rungs and the tread of shoe soles. Each is necessary for us to climb up and down efficiently with relatively sure footing.


The accuracy of interdisciplinarity measurements is directly related to the quality of the underlying bibliographic data. Existing indicators of interdisciplinarity are not capable of reflecting the inaccuracies introduced by incorrect and incomplete records because correct and complete bibliographic data can rarely be obtained. This is the case for the Rao–Stirling index, which cannot handle references that are not categorized into disciplinary fields. We introduce a method that addresses this problem. It extends the Rao–Stirling index to acknowledge missing data by calculating its interval of uncertainty using computational optimization. The evaluation of our method indicates that the uncertainty interval is not only useful for estimating the inaccuracy of interdisciplinarity measurements, but it also delivers slightly more accurate aggregated interdisciplinarity measurements than the Rao–Stirling index.The online version of this article (doi:10.1007/s11192-016-1842-4) contains supplementary material, which is available to authorized users. Most quantitative measures of the output of InterDisciplinary Research (IDR) rely on bibliometric methods. Since such methods are commonly used to inform policy in science and technology, they require reliable indicators and results. While analytical indicators and tools have been refined over time, their results are in most cases not precise. The accuracy of such indicators depends on the quality of the bibliographic data, which should be correct and complete. Unfortunately, the gathering of a correct and complete bibliographic dataset is a complicated task due to the fact that not all scientific publications are indexed by digital libraries. Current bibliographic databases, such as the Web of Science (WoS) or Scopus, do not cover books, book chapters and many regional non-English journals in which some fields mainly publish. Even conference proceedings, which constitute the main publication venues in many applied fast-changing fields, are often not indexed. The gathering and comparison of records gathered from different bibliographic sources mitigates this problem to some extent. However, an additional problem affects top–down approaches to measure IDR such as the Rao–Stirling diversity index: the need for a predefined taxonomy of disciplines that classifies all publications in the dataset. This problem cannot be solved with the comparison of data gathered from different sources because not all libraries classify their publications into a taxonomy of disciplines nor use the same taxonomy, and even those that use a taxonomy might not classify all their indexed publications with it—as is the case of WoS. Manual classification of publications into disciplinary fields is also not viable for a large number of uncategorized publications. In consequence, top–down measurements of IDR usually deliver proxy results.In this paper we acknowledge the problem of dealing with incomplete data gathered from several libraries. We focus on the problem of uncategorized publications for the measurement of IDR with the Rao–Stirling index. We choose this index because it is a well-established bibliometric indicator that requires a complete categorization of all references into disciplinary fields; however this problem has not received adequate attention in the literature. We propose a theoretical extension of the Rao–Stirling index to account for the uncertainty resulting from references that remain uncategorized.The field of measuring IDR heavily relies on bibliometric methods and data due to the widely-held view that scientific research is disseminated via publications. Different types of approaches exist for measuring IDR, which have been accordingly endorsed for differing needs of analysis. For an extensive review of approaches, we refer to the work of Wagner et al. . Among tThe results of citation analyses are subject to the quality of bibliographic data in terms of completeness and accuracy. Well-established top–down methods used to analyze the number of disciplines cited by a publication or their degree of concentration such as Shannon entropy Shannon  and HerfConcerning references, verification mechanisms as discussed by van Raan  are crucA method that automatizes the assignment of disciplines was implemented by Ponomarev et al.  in orderIn the following we propose a method which acknowledges missing data and determines the associated uncertainties see “” sectioni in a given paper. In this section we briefly introduce the Rao–Stirling index and present as our main theoretical contribution an extension of it that encodes the uncertainty caused by missing bibliographic data as an uncertainty interval. The Rao–Stirling index is a distance-based indicator, inspired by the Stirling index Stirling , which ni-th discipline of The information on the disciplines of the categorized references of Stirling .Problems arise when the disciplines of one or more references are unknown. As a consequence, To capture the effects of missing data, we will compute the range in which the Rao–Stirling diversity categorized into disciplinary fields. Furthermore, u uncategorized documents, i.e., documents for which we have no information on their respective disciplines. We now aim to compute new sets u reassigned references. The last constraint indicates that we expect each uncategorized reference to be assigned to at least one discipline and at most Given a document mentclass2pt{minimmentclass2pt{minimall disciplines. Since this is not a realistic scenario, we limit the number of disciplines that each uncategorized reference could belong to. If we assume that each uncategorized reference cannot cover more than k disciplines, we can represent this as an additional constraint in optimization problem Eq. The full range of uncertainty in the Rao–Stirling diversity index regarding missing data is given as solutions to the optimization problems stated in Eqs. computer science that exclusively cites previous works from its own discipline but has two uncategorized references. A possible reassignment that would significantly increase its diversity can be realized by assigning them to the unrelated disciplines of, for example, zoology and slavic literature. While such an assignment is not invalid per-se, it is nevertheless prohibitively unlikely and in this section we present a method to exclude such improbable disciplines.A reassignment of an uncategorized reference to an arbitrary subset of disciplines can lead to highly improbable results even when the cardinality of the subset is bounded as described in “Our primary goal is to choose for each document a subset entclass1pt{minimaA simple straightforward solution would be to just eliminate all disciplines that are not already observed from the categorized references, i.e., to set the constraint In contrast, we take the mutual similarities of different disciplines into account for which we utilize the similarity matrix mentclass2pt{minimdiscipline neighborhood i given by all those disciplines that have a similarity higher than a given value CompletenessEach neighborhood should contain at least two observed disciplines. This ensures that each neighborhood includes at least all disciplines that are more similar than the next most similar known discipline.CohesionThe neighborhoods should form a single connected component to avoid having multiple disjoint discipline clusters. For documents with references in, for example, two dissimilar disciplines, an omission of this objective could lead to a set of permissible disciplines that are very similar to either of these two known disciplines without considering the disciplines in between them.ConcisenessThe neighborhoods should be chosen in such a way as to yield the smallest possible set of permissible disciplines that fulfills the previous objective. The actual meaningfulness of the upper bound of the uncertainty interval is ensured in this way.As we show in Appendix “Discipline pruning”, we can obtain a set of permissible disciplines tolerance parameter—modulating the similarity values Our method is based on the concept of a entclass1pt{minimapositive semidefinite to yield a non-negative diversity index for arbitrary discipline counts. The associated quadratic form convex function in concave. Thus, the Rao–Stirling diversity  faculty of a highly ranked European university between 2009 and 2014. Doctoral researchers are usually the main authors of their publications and have a thorough knowledge of the literature they reference. We focus on CS because this field emerged as a result of integrating disciplines and it continues to be one of the most interdisciplinary fields because of its diverse applications. Moreover, CS is an ideal field to use in evaluating our method because gathering publication data with a high percentage of categorized references is especially challenging. While in other fields conferences serve as venues for community building and maintenance, in CS they focus on selectivity, quality and fast dissemination—needed in such a fast-evolving field—which drives down conference acceptance rates Grudin . TherefoIn order to gather the most complete and accurate record of publications and their references, data was gathered from different sources. First, the publication database of the university was used to collect all the publications of doctoral students of the CS faculty published between 2009 and 2014. This database contains a very exhaustive list of publications authored by those affiliated to the university, as its records are used to compute the financial assignments to the different research groups. Because the publication database of the university does not keep records of references, in the next step we gathered more data from online bibliographic databases: (1) Scopus from Elsevier, which offers high coverage of articles; and (2) WoS from Thomson Reuters, which provides a comprehensive citation search and encompasses publications of multiple online databases, resulting in multidisciplinary coverage.Category Terms (CTs). It contains 249 CTs and is elaborated based on a combination of subject matter expert judgments and inter-journal citation patterns that together serve to cluster journals into topical groupings. Since there is no consensus on a perfect taxonomy of disciplines, the one of WoS was selected because its extensive use in the bibliometric analyses of previous related work, but other taxonomies could also be used. As a measure of similarity between CTs, we used the co-citation similarity matrix provided by Porter and Rafols  the proportion of categorized references among all references of a paper; and (2) the degree of interdisciplinarity of a publication, calculated using the Rao–Stirling index with the incomplete publication dataset that was previously gathered from the digital libraries WoS and Scopus see “” sectionIn order to evaluate the performance of our method, its results were compared with the measurement of IDR based on completed data. The ground-truth data provided by the interview participants was used to complete the missing categorization of references from their publications. We computed the Rao–Stirling index of these publications again, this time using the completed data. The results of the Rao–Stirling index with completed data are compared with the results of the Rao–Stirling index with incomplete data in Fig. Since the bounds of the uncertainty interval are an estimation of the possible highest and lowest Rao–Stirling index of a publication with incomplete data, its result is correct when the interval includes the Rao–Stirling index with completed data see Fig. . The accIn order to assess the performance of both our method and the Rao–Stirling index, where both use incomplete data, we compare the average of their results to the ones of the Rao–Stirling index with completed data Below is the link to the electronic supplementary material.


To determine the extent to which members of the general population have talked to their physician about their wishes regarding medical treatment at the end of life, to describe the prevalence of advance directives on euthanasia, and to identify associated factors.N = 9651) of the Belgian population.This study used data from the cross-sectional Health Interview Study (HIS) 2008 that collected data from a representative sample (Of all respondents, 4.4 % had spoken to their physician about their wishes regarding medical treatment at the end of life, while 1.8 % had an advance directive on euthanasia. Factors positively associated with discussions regarding wishes for medical treatment at the end of life were being female, being older in age, having poorer health status and having more GP contacts. People older than 55 years and living in Flanders or Brussels were more likely than the youngest age categories to have an advance directive on euthanasia.Younger people, men, people living in the Walloon region of Belgium, people without a longstanding illness, chronic condition or disability and people with few GP contacts could represent a target group for education regarding advance care planning. Public information campaigns and education of physicians may help to enable the public and physicians to engage more in advance care planning. Advance care planning (ACP) has gained international attention for its perceived benefits in enhancing patient autonomy, ensuring better quality of care and improving quality of life in the final stages of life , 2. ACP A recently published systematic review showed that interventions including communication about ACP improved the quality of communication and concordance between patient preferences and end-of-life care received . BecauseIn Belgium the Law on Patients’ Rights (2002) gives people the right to reject any medical treatment and to appoint a surrogate decision-maker to advocate for their rights if they are unable to make decisions or speak for themselves . RefusalThe aim of this study is firstly to determine to what extent members of the general population have talked to a physician about their wishes regarding medical treatments at the end of life and what the prevalence is of an AD on euthanasia in the general population and secondly to determine to what extent socio-demographic characteristics, health status and health service use are associated with the involvement in ACP.This study uses data from the cross-sectional Health Interview Study (HIS) that collects data from a large representative sample of the Belgian population. The HIS is organized by the Belgian Scientific Institute of Public Health (WIV-ISP) and was conducted for the fourth time in 2008–2009. Around 6000 private households are randomly selected from the National Population Register using a multistage stratified clustered sampling process. Of each selected household, a maximum of four members are eligible. The householder and partner are always selected, as well as two extra randomly selected members (or three if there is no partner). This study includes only participants older than 15 years.Involvement in ACP was analyzed based on two items: (1) Have you ever spoken to your physician about your wishes regarding medical treatments at the end of life? and (2) Do you have an advance directive requesting euthanasia?. Possible responses were Yes and No. Data collection is performed via a self-administered questionnaire filled in by each selected person aged 15 years or older. However, only respondents aged 18 years or older are included in the analysis, because an advance directive on euthanasia can only be drafted by people older than 18.Several procedures were used to ensure data quality: the content of the HIS questionnaire was discussed in workgroup sessions with academic experts, health government agencies and fieldwork experts. The questionnaires were pre-tested: firstly, questions from other European surveys that were added to the HIS 2008 questionnaire benefited from a large scale pre-test  and secoThe selection of the independent variables is based on their possible influence on involvement in ACP or the formulation of ADs, as shown in previous research –15. SociThe sample is weighted according to the stratified clustered sampling design of the survey to be representative of the Belgian population. Involvement in ACP is described using frequencies. The independent characteristics were tested for significant association with involvement in ACP using Pearson chi2 test (not shown in paper) and, when found significant, entered in multivariate logistic regression models in order to control for confounding effects and investigate their association with the dependent variables. Confidence intervals are calculated at the 95 % level. Analyses are conducted with SPPS 22.0 software using the complex samples procedure to account for the complex survey design.The protocol of the Belgian HIS 2008 is approved by the Superior Council of Statistics . SubmissThe participation rate among the contacted households was 55 % . Of the 9651 respondents, 52.1 % were female, 26.2 % were between the ages of 18 and 34, 37.5 % were between the ages of 35 and 54, 25.6 % between 55 and 74 and 10.7 % 75 years or older  and those with a longstanding illness, chronic condition or disability (OR = 1.5) Table . The proCompared with the youngest age category, people older than 55 years were more likely to have an AD on euthanasia. Those living in the Walloon region of Belgium were less likely to have an AD on euthanasia compared with those living in Flanders (OR = 0.5).This study shows that 4.4 % of a representative sample of the Belgian general public have spoken about their wishes regarding medical treatments at the end of life, while 1.8 % have an AD on euthanasia. Discussions with a physician regarding wishes for medical treatment at the end of life were more likely to have taken place among women, as people get older, among people with a poorer health status and those having more GP contacts. Having an AD on euthanasia was more likely for people older than 55 years and living in Flanders or Brussels.Discussions regarding wishes for medical treatment at the end of life with physicians are relatively rare among the Belgian general public. Even among those who have an AD on euthanasia only half of respondents (55.4 %) had discussed their wishes regarding medical treatment with a physician. However, an AD on euthanasia does not need to be discussed with a physician, something about which some people might be hesitant. An AD on euthanasia must be drafted in the presence of two adult witnesses and they are responsible for notifying the treating physician of its existence should the patient fall into an irreversible coma. People can choose either to deliver copies of their AD on euthanasia to a number of people (of whom their physician might be one) or to register it at the city hall in a federal database, but this is not mandatory. It is however also possible that people do visit their physician with the intention of discussing the completion of an AD on euthanasia, but that the physician omits to take up the opportunity to elaborate on their wishes for medical treatment at the end of life.A cross-sectional survey in the Netherlands  showed that 13 % of the general population had discussed issues related to medical decision-making at the end of life with a physician . Cross-cA number of characteristics associated with the public’s engagement in ACP are consistent with earlier studies. Women and those with a serious illness or increased dependency have been shown to discuss their end-of-life care preferences more often with physicians or have higher AD completion rates , 20, 25.Remarkably, people living in the Walloon region of the country were less likely to have an AD on euthanasia compared to people living in the Flemish part of Belgium. Unfortunately, reasons for the identified differences between the regions in Belgium could not be explored. Previous research on end-of-life care in Belgium has suggested a difference in medical culture between the Dutch-speaking and French-speaking community, with a stronger appreciation of curative, technological and specialist medicine in the French-speaking community . PerhapsEven though a previous study has shown that the majority of people in Belgium are open to discussions on end-of-life care , only a This is the first study on the general public’s involvement in ACP in Belgium. It is a population-based study founded on a representative sample of the Belgian population. Other important strengths include the large sample size, the robustness of the methodology and the quality of research procedures. We used data from the HIS, which has a long history of data collection in the Belgian population and is not based only on a specific interest in end-of-life care. However, this study also has some limitations. Firstly, the specific context of Belgium as one of the three countries where euthanasia is legal, might hamper the generalizability of our results to other settings. Secondly, because of the low response-rate (55 %), non-response bias cannot be excluded. The missing values for the outcome variables are around 23 % and non-response analysis showed that missing values were more likely to be male, older, have a lower educational level and live in Wallonia or Brussels. As a result, it is possible that some of our findings are biased because of non-response. Thirdly, because this study examined the respondent’s own report of their involvement in ACP, the results may be subject to recall bias.Few people in Belgium have discussed their wishes regarding medical treatment at the end of life with their physician or have completed an AD on euthanasia. Younger people, men, people living in the Walloon region of Belgium, people without a longstanding illness, chronic condition or disability and people with few GP contacts might represent a target group for education as they are less likely to engage in ACP. Public information campaigns and the education of physicians may encourage the public to engage in ACP and help to enable patients, families and physicians to have more conversations about care at the end of life.


AV300 uses near infrared laser light to improve visibility of peripheral veins and could help cannulating them. The aim of this study was to examine if use of AccuveinFrom January to March 2011, 238 consecutive pediatric patients (0–17 years) preceding surgical interventions were included. All participants including newborns, infants and children were allocated to groups [control group (124 patients) and intervention group (114 patients)] in a non-random way. Randomization was not feasible because data was acquired retrospectively from a clinical quality management project. In control group, peripheral IV cannulation was performed without supporting device, in intervention group with support of AV300. Time and number of attempts until successful venous cannulation were defined as primary end points.Median time until successful cannulation was 2 min  in the intervention group and 1 min  in the control group (p < 0.01). Median number of attempts was higher in the intervention group  than in the control group . Rate of cannulations successful at first attempt was 0.45  in the intervention group and 0.73  in the control group (p < 0.01).In our study we were not able to reduce neither time nor number of attempts until a successful venous cannulation in children using the vein viewer. Given certain limitations of our study as the lack of randomization and no control for inter-operator variability, the conclusions drawn from it are also limited, but by our results laser-supported cannulation cannot be recommended for standard procedures.Trial registration: ClinicalTrials.gov NCT01434537. Registered 29 July 2011 In many clinical situations a fast and effective venous access is essential for patient’s safety and care: for rehydration, in emergency situations, application of systemic drugs and for every anesthesiological procedure. While inhalational anesthesia induction in children has been standard care throughout the world for many years, the prerequisite of a peripheral venous access prior to the induction becomes more and more part of clinical practice, at least in elective procedures. The aim is to establish the venous access fast, with few attempts and without causing pain in the pediatric patients. It has been shown that there are effective ways to reduce pain  by apply® AV300 acts as one of the vein imaging techniques using near-infrared (NIR) light [In many pediatric patients the venous access is difficult to establish due to their thicker layer of subcutaneous tissue compared to adults, particularly in children younger than 3 years . In thesR) light –13. It i®, LLC, 40 Goose hill Rd, Cold Spring Harbour, NY) following the User Manual of AccuVein® model AV300 vein viewing system [The study was approved by the IRB of Charité (EA1/171/11) and registered at clinicalTrials.gov (ID: NCT01434537) on July 29th, 2011. The ethics committee waived the need for written informed consent for the intervention group, since this retrospective study was performed as an analysis of a project accompanying the introduction of an already approved device into clinical standard of our department. The project was initiated from the Department of Anesthesiology and Intensive Care CVK/CCM, Charité-Universitaetsmedizin Berlin, and not from the manufacturer of the device. No data were handed out to the manufacturer. Only because the project revealed information that seemed to be important to publish, the ethics committee was asked whether to retrospectively analyze and publish the anonymous data and agreed to do so. From January 2011 altogether 238 consecutive pediatric patients from 0 to 17 years of age preceding surgical interventions in the pediatric operating room of the Campus Virchow-Klinikum, Charité-Universitaetsmedizin Berlin, were included in the trial. All of the participants including newborns, infants and children were allocated to two groups in two timeframes of each 4 weeks: The first consecutive 114 patients were allocated to the intervention group, the next 124 into the control group. Randomization was not feasible because data was acquired retrospectively from a clinical quality management project. In the control group, peripheral IV cannulation was performed as usual without any supporting device. In the intervention group, the same intervention as in the control group was done but with support of AV300 vein viewer  was measured by a member of the research team. The end of the procedure was defined as the successful establishment of a vein access easily flushable by sterile 0.9 % sodium chloride solution.®, a mixture of lidocaine and prilocaine) or not, needle size, the time and number of attempts until successful cannulation for both groups.Data were collected on gender, age, weight, presence of general anesthesia or not, received local anesthesia . Results were given by rates (in %) with 95 % confidence limits as well as by median and 25–75 %-quartiles for continuous variables because of deviations from normal distribution. Chi square and nonparametric (Mann–Whitney) testing was used to access the differences in demographic data  between both groups. Explorative data analysis including checks for normal distribution (P–P plots) was applied. Time and number of attempts until successful venous cannulation were defined as primary end points. Differences in outcome variables were analyzed by nonparametric tests (Mann–Whitney-U-test). Rates were tested using the Chi square test. P-values <0.05 were considered statistically significant. All tests should be understood as constituting exploratory data analysis, such that no adjustments for multiple testing have been made.®) was higher (p = 0.003)  months. Differences between both groups were tested with Chi square-test as well as Mann–Whitney-tests and there were no statistically significant differences found in distribution of gender, age, weight and presence of general anesthesia. There were no differences found in the sizes of the used needles (p = 0.069). The only difference in this main group was that in the intervention group the proportion of patients with applied local anesthetics  in the intervention group and 1 min  in the control group (p < 0.01)  than in the control group   in the control and 2 min  in the experimental group (p < 0.01)  Fig. . The med01) Fig. . The rat® AV300 vein scanner was not able to reduce neither the time needed for establishing a peripheral venous access nor the needed number of puncturing attempts.The results of this trial indicate that in our study group use of the AccuveinOur findings are comparable to those of a trial examining a similar device in an emergency room setting where the use of the vein viewer could not facilitate the venipuncture either . Though These results differ substantially from a recent study showing that a vein viewing system similar to the device used in our study was able to facilitate venous cannulation of peripheral veins in difficult veins . A study® might have an influence on the results of these studies as it was reported that EMLA® could cause vasoconstriction of the peripheral veins and pallor or edema at the application site and therefore make vein cannulation more difficult [® were mild and transient, and might not have an influence on vein cannulation [® is still thought to be one of the potential confounders in our trial. In our study our results seemed to point in the same direction, with EMLA® being in a higher proportion in the intervention group, but when analyzing a subgroup of children of 72 months and younger there was no significant difference in the use of EMLA® , presented prominent value in facilitating venipuncture and IV catheterization [® in a randomized controlled trial [Another product designed on the basis of NIR (VeinViewerrization , 20, 21.ed trial . Recentled trial .In our study, errors in size and position between the vein shadow and the vein itself may have contributed to the outcome. In some cases, it was difficult to get an IV insertion due to the enlarged vein images with aid of the AV300; meanwhile, a failing detection of the target vein depth was thought to be an obvious disadvantage. In addition, the target site chosen for IV insertion was just exposed in the NIR beam and punctured directly, often leading to deformation of the vessel image by the needle pressing. So the endeavor to avoid the deformation of the vein image would offer one of the solutions to improve the first-attempt success rate as using the NIR devices . A recenThe main limitation of our trial is the lack of randomization which causes a bias. The sample size was large compared to similar studies but might have still been too small. The influence of the person practicing the venipuncture was limited by the fact that only experienced persons were in charge but this fact could be controlled better by stratifying the staff or switching after the half of the study into the other group. Observer bias could have been caused by the fact that the member of the research team measuring the time until successful cannulation was not blinded. A dummy vein viewer would need to have been used in the control group to control for. The comorbidities and ASA classification of the patients should also be taken into account in a future study to clarify the benefit and utility of these devices based on NIR.® Vein Viewer was not able to reduce neither time nor number of attempts until a successful venous cannulation. Thus, its use in standard procedures with easy cannulations cannot be recommended within the limitations of this study.In our study the use of the AccuveinEven if the findings of these studies including the present examining the benefit of vein viewing systems are inconsistent, there might be a place for using them in cases where peripheral veins are poorly visible or inexperienced medical staff performs the cannulation.


Lancet 1987;1:1192–4) pointed out that all fetuses alive at the start of the given week were at risk of antepartum stillbirth, not just those that were born. Hence, the risk of antepartum stillbirth was calculated by the ratio of the number of stillbirths during the given week to the number of ongoing pregnancies at the start of the week. Next it was proposed that antepartum stillbirths should be analysed by time‐to‐event methods, which take into account censoring due to birth . Now Naimi and Auger suggest that, when analysing cumulative risk of stillbirth using time‐to‐event methods, birth should be regarded not as censoring but as a ‘competing risk’ . There are, however, some important clinical issues that are not addressed by their analysis. First, they make no distinction between antepartum and intrapartum stillbirth. Second, it is not clear whether they have considered the fact that stillbirth of a dead twin may occur months after the actual in utero death. Third, 20–30% of births follow a medical or social decision (i.e. induction of labour or planned caesarean). The last of these points is a key issue in the analysis of post‐dates pregnancy and is best considered with an example of estimating stillbirth risk at 42 weeks.Approaches to estimating the risk of antepartum stillbirth at a given week of gestational age have developed over the last 30 years. Previously, researchers related the number of antepartum stillbirths to the number of births at the given week. Then Yudkin et al.  as the number of stillbirths in the 42nd week divided by the total number of pregnancies that were born at or after 24 weeks. Does it yield a valid answer? This depends on what the question was. The plot in Naimi and Auger's Figure 1 is the distribution of cumulative stillbirth risk across the range of gestational age when viewed at the start of the 24th week. The additional risk of stillbirth at 42 weeks is small, as most of the population will be delivered before then. However, what do we tell a woman who has reached the start of the 42nd week and wishes to know her risk of stillbirth if she postpones induction of labour until the start of the 43rd week? In this case we know that the woman did not deliver before 42 weeks. Hence, we need to calculate the subsequent risk of stillbirth The approach described by Naimi and Auger is important. However, to use this approach to inform clinical decision making, for example, in estimating the effects of inducing labour at term or postterm, competing risk models should analyse the subsequent cumulative risk conditional on achieving a given week of gestational age, and distinguish between spontaneous and elective deliveries.Full disclosure of interests available to view online as supporting information. Click here for additional data file. Click here for additional data file.