The case-cohort study design combines the advantages of a cohort study with the efficiency of a nested case-control study. However, unlike more standard observational study designs, there are currently no guidelines for reporting results from case-cohort studies. Our aim was to review recent practice in reporting these studies, and develop recommendations for the future. By searching papers published in 24 major medical and epidemiological journals between January 2010 and March 2013 using PubMed, Scopus and Web of Knowledge, we identified 32 papers reporting case-cohort studies. The median subcohort sampling fraction was 4.1% (interquartile range 3.7% to 9.1%). The papers varied in their approaches to describing the numbers of individuals in the original cohort and the subcohort, presenting descriptive data, and in the level of detail provided about the statistical methods used, so it was not always possible to be sure that appropriate analyses had been conducted. Based on the findings of our review, we make recommendations about reporting of the study design, subcohort definition, numbers of participants, descriptive information and statistical methods, which could be used alongside existing STROBE guidelines for reporting observational studies. The case-cohort study design was originally proposed by Prentice .To make inferences from a case-cohort study, it is necessary to account for the over-representation of cases in the sample. Cox proportional hazards (PH) regression models need to be weighted, with cases outside the subcohort only included in the risk set at the time of their event The STROBE  Statement is a checklist of 22 items We used the electronic search engines PubMed, Scopus and Web of Knowledge to identify papers reporting analyses of case-cohort studies published between January 2010 and March 2013. We restricted the search to 24 major general medical and epidemiological journals/databases . We searFor each paper, we identified the original cohort from which the case-cohort study was constructed, and recorded the number of individuals in the following groups: original cohort, subcohort, total cases, subcohort cases and subcohort non-cases. Where the information was available, we recorded these numbers both before and after exclusion of individuals due to application of specific eligibility criteria for the analysis . We recorded whether or not the subcohort was selected by stratified sampling and the stratification factors if it was. For papers where the information was available, we calculated the subcohort sampling fraction as the ratio of the reported size of the subcohort to that of the original cohort, using values before any exclusion criteria were applied. We noted which of the groups of individuals (as defined above) were described using summarized baseline characteristics. We recorded the statistical methods used , whether statistical modelling assumptions were tested, and how missing data were handled in the analysis.Initial assessment of all papers was carried out by one assessor (MP) and a random selection of 20% of the papers was appraised independently by a second assessor (AW). All discrepancies were resolved by discussion between the two assessors.We identified 47 published papers using our search strategy. Fifteen papers were excluded from the review for the following reasons: used the term “case-cohort” incorrectly to describe the study they were reporting (N = 9 papers), reported a meta-analysis of published case-cohort and case-control studies (N = 1), used case-cohort analysis methods even though the data included were not from a case-cohort study (N = 1), discussed specific methods for the design and analysis of case-cohort studies (N = 3), described the protocol for a planned case-cohort study (N = 1). The remaining 32 papers , EPIC-Potsdam (one of the centres within EPIC), MONICA/KORA and the Netherlands cohort study were each the original cohort for more than one paper . Three iThe median subcohort sampling fraction was 4.1% (interquartile range 3.7% to 9.1%) . The subAll papers provided a reference to another publication describing the original cohort, and stated that the subcohort was a random sample from the cohort. Nine of the 17 original cohorts used stratified sampling to select the subcohort. The stratifying variables were age, gender, race, centre or a combination of these.The papers varied in the groups within which baseline characteristics were summarized, and also whether results of statistical comparisons of characteristics between groups were presented . There wAll except one paper used some form of Cox regression model to estimate the association between the exposure and disease ; the othThe four papers based on the EPIC (8 countries) cohort and two papers based on other groupings of EPIC centres, where the subcohort sampling was stratified by centre, described a two-stage approach to reflect the stratified design: first centre-specific models were fit to the data, and second meta-analysis methods were applied to combine the estimates of association across centres. For this second step, five papers used random effects and one used fixed effects meta-analysis.All the case-cohort studies had individuals with missing values of baseline covariates which were relevant to the analysis being performed; in 27 papers these individuals were excluded from the analysis, while in five papers there was an attempt to include them. In one paper, individuals with missing baseline covariates had their baseline redefined as the first visit with complete data. Four papers described imputation approaches either for the primary or sensitivity analysis.In this paper we have identified important variability and areas for improvement in the reporting of case-cohort studies in major general medical and epidemiological journals, all of which would be expected to have rigorous statistical review policies. It seems likely that there could be a greater degree of variability and lower quality of reporting in journals with less intensive statistical scrutiny. As with all reviews of this type, deficiencies in reporting do not necessarily imply that the analysis approaches used were inappropriate; however, the findings suggest that some guidance on minimum requirements for reporting these studies could be helpful to authors, journal reviewers and editors. Below, we highlight key aspects of the design and analysis of these studies which should be reported to enable readers to assess the appropriateness of the analyses; these recommendations could be used alongside existing STROBE guidance for reporting observational studies Having indicated that a paper is reporting results from a case-cohort study, the original cohort study on which the case-cohort study is based should be described and/or referenced. The case definition, methods of case ascertainment, and dates of start and end of follow-up should be provided. The method for selecting the random subcohort and any exclusion criteria that were applied to the analysis, should be stated. If the sampling was stratified, the stratification factor(s) and rationale for using a stratified design should be provided.The numbers of ascertained cases and individuals in the random subcohort should be stated both before and after any exclusion criteria have been applied. The number of individuals in the original cohort should also be provided, ideally both before and after application of the same exclusion criteria. If the size of the original cohort after applying exclusion criteria is unknown because the criteria include, for example, excluding individuals with missing data on a variable that is only measured in the case-cohort sample, then this should be stated explicitly. The subcohort sampling fraction should be presented. If the design was stratified, all the above information should be provided within each stratum. The rationale for choosing a particular sampling fraction should be explained, and reasons given if it differs between strata.Characteristics of study participants, including information on exposures and potential confounders, should be summarized in the usual way using either means and standard deviations, medians and interquartile ranges, or numbers and proportions depending on the type and distribution of the variable. There are various possible groupings of individuals in a case-cohort study for which characteristics could be summarized. If the purpose is to identify variables that are associated with the outcome (i.e. being a case), then characteristics should be summarized in (1) all cases and (2) either all subcohort individuals or all non-cases (i.e. the subcohort excluding cases). If the purpose is to identify variables that are associated with the exposure of interest, then characteristics should be summarized in the subcohort within groups defined by the exposure (groups based on either standard pre-defined cut-offs or quantiles of the exposure distribution in the subcohort). Descriptive information should be presented for the sample included in the analysis after application of exclusion criteria. Consistent with existing STROBE guidance for observational studies It can be helpful to present some descriptive information (where available) for participants in the original cohort from which the random subcohort was sampled, to enable readers to judge the generalizability of the findings and also to assess the extent to which the subcohort used in the analysis is truly representative of the original cohort.The statistical methods used to estimate the association between exposure and outcome should be stated; for a case-cohort study, methods should appropriately account for the oversampling of cases in the study design. If weights have been used (e.g. for weighted Cox regression), then the weighting method and rationale for its choice should be given. In particular, if Barlow weights have been used, the subcohort sampling fraction should be stated explicitly, since the inverse of the sampling fraction is used to weight subcohort non-cases and cases in the subcohort before they become a case If some form of Cox regression model has been used, the proportional hazards assumption should be assessed for each covariate in the analysis. Appropriate methods for assessing this assumption include fitting and testing interactions between covariates and the underlying analysis timescale, or using a correlation test based on Schoenfeld residuals If a stratified sampling design has been used, then a description of how the stratifying factor(s) was accounted for in the analysis should be given. Potential approaches include stratifying the baseline hazard function by the relevant factor(s), fitting separate analysis models within each stratum and combining stratum-specific estimates of association using meta-analysis Existing STROBE guidance Most of the papers identified in our review excluded individuals with missing covariate data. This approach results in a loss of efficiency and only gives unbiased estimates if missingness can be assumed to be independent of outcome, conditional on observed covariates The main focus of our review was on the use of case-cohort studies to estimate associations between an exposure and an outcome, rather than to develop and evaluate risk prediction models . Following recent publication of two papers describing adaptations to the case-cohort setting of standard measures of risk prediction Despite the fact that the case-cohort design was first proposed nearly 30 years ago, it is still relatively uncommon compared with other observational study designs, and specific issues related to design and analysis are likely to be less well known to the majority of researchers. Our review suggests that in recent years the use of case-cohort studies appears to be increasing, and therefore we hope our recommendations, which are summarized in Appendix S1List of journals/databases included in the literature search.(DOCX)Click here for additional data file.Appendix S2References of 32 papers included in review.(DOCX)Click here for additional data file.


In either scenario, these cavities have a transmembrane mode of access and may be partially bordered by lipid moieties. Their physicochemical nature is amphiphilic. Anesthetic binding may alter the overall motion of a ligand-gated ion channel by a “foot-in-door” motif, resulting in the higher likelihood of and greater time spent in a specific channel state. The overall gating motion of these channels is consistent with that shown in normal mode analyses carried out both in vacuo as well as in explicitly hydrated lipid bilayer models. Molecular docking and large scale molecular dynamics calculations may now begin to show a more exact mode by which anesthetic molecules actually localize themselves and bind to specific protein sites within LGIC’s, making the design of future improvements to anesthetic ligands a more realizable possibility.For over 160 years, general anesthetics have been given for the relief of pain and suffering. While many theories of anesthetic action have been purported, it has become increasingly apparent that a significant molecular focus of anesthetic action lies within the family of ligand-gated ion channels (LGIC’s). These protein channels have a transmembrane region that is composed of a pentamer of four helix bundles, symmetrically arranged around a central pore for ion passage. While initial and some current models suggest a possible cavity for binding within this four helix bundle, newer calculations postulate that the actual cavity for anesthetic binding may exist  For over 160 years, general anesthesia has been provided for the safety and comfort of a myriad of otherwise painful procedures, most notably surgery. Early investigations into the mechanisms of anesthetic action by Meyer and Overton . . 30]. This was thought to be composed of a polar extracellular domain involved in native ligand binding (LBD), a hydrophobic transmembrane domain (TMD) where mutations alter anesthetic modulation, and a somewhat mysterious intracellular domain involved in various cytoplasmic interactions. An ion channel pore traverses this entire protein for the passage of ions specific to the channel type. Within this class of LGIC’s, there are both cationic and anionic conducting channels. To form these regions, the overall schematic called for the axially symmetric placement of five protein subunits into a pentameric arrangement around the central ion pore . Within For most proteins of interest, the typical sequence of study involves the purification of the protein material for crystallization and analysis by means of x-ray crystallography. This is especially important when one desires exact atomic coordinates for purposes of studying protein structure activity relationships and possible receptor-based drug design. However, the difficulty with the vast majority of membrane spanning proteins, especially the LGICs, lies in the destruction of relevant protein structure when removed from their native transmembrane environment.This has prompted the use of computer-based theoretical techniques with the incorporation of a variety of experimental constraints, so as to build realistic, physically relevant models of the ion channel proteins within the family of LGICs. Specifically, with modern techniques of bioinformatics, computational chemistry, and molecular modeling, we have built models of the transmembrane subunit region within human glycine alpha one receptors (GlyRa1) and gamma amino butyric acid receptors (GABAR) that account for a large body of the physicochemical and experimental data that characterizes these proteins. ,36,37,38Our initial work concerned the nature of the “rod-like” structures that composed the transmembrane tetrameric portion of the individual protein subunits . To studhttp://www.rcsb.org). The next step was to use the principles of homology modeling in order to find a protein with a known three-dimensional structure and that looked in some way similar  to the sequence and predicted fold of the LGICs ,33,35. OThe SeqFold algorithm identified a relatively high-scoring modeling template in the coordinates of chain C of a bovine cytochrome oxidase (PDB ID 2OCC). This is a four-helix bundle of the up-down topology. The sequence of our LGIC was then aligned with this template using multiple scoring criteria. Manual refinement of the alignment closed sequence gaps to produce agreement with experimental labeling studies that had been carried out by many groups on the homologous receptors of the superfamily. Since the large intracellular cytoplasmic loop between TMD 3 and 4 had little resemblance to any template, the model was then edited so as to contain an abbreviated version of the loop composed of only nine native residues from the loop region itself along with a chain of five glycine residues substituted for the central remaining bulk of the loop. Structural assignment and refinement was achieved using the Modeler program . The finOnce the four-helix bundle nature of the individual transmembrane domains had been identified, the subunit models had to be combined into their pentameric arrangement, so as to produce the entire transmembrane domain of the ion channel. For this purpose, a new template for a different form of alignment involving only the pore lining helices was found in the analogous bacterial mechanosensitive channel (PDB ID 1MSL). Only the channel-lining helices were used as the pentameric template around which to organize the channel-lining helices of our LGIC tetrameric subunit, so as to build a pentamer of tetramers for the entire TMD construct .For the extracellular LBD, a homology model was built based upon the acetylcholine binding protein  of Sixma and coworkers . Here, tThe LBD and TMD were then mated , accordiUsing molecular mechanics forcefields, hydrogens were then added to the homology model structure and an automated conformation check performed to obtain a low energy state of the amino acid side-chains. After initially tethering the protein backbone, the entire complex underwent a series of restrained optimizations to eliminate any additional high energy conformations. In the end, final energy optimization was obtained without restraints and without gross distortion of tertiary structure. This produced a final construct that was reasonably similar to the intermediate resolution structure of the homologous nAChR derived from cryoelectron microscopy .Erwinia chrysanthemi (ELIC) has been crystallized at 3.3Å resolution . We. Wein vaThese calculations demonstrate a great many characteristics of LGIC motion and have many implications for future study. It can be shown that one of the most fundamental motions of our LGIC models is characterized by an “iris-like” wringing motion .This motion produces an alteration in pore diameter in the general direction of ion channel opening. The frequency of such motion appears to occur on the subnanosecond time scale. While this seems a bit faster than the experimentally derived time constant for ion channel gating, this time scale implies that the ion channel is vibrating in the general direction of channel gating on a virtually continuous basis. However, it is probably not open long enough, on the average, for actual ion transduction. It would not be until a large enough random thermal event occurred that an increase in amplitude or time spent in the open state would cause spontaneous channel opening to occur. This likelihood of opening is apparently increased by the presence of native ligand. It is further modulated by the presence of general anesthetics. In the case of the cation conducting nAChR, general anesthetics inhibit the excitatory currents due to acetylcholine binding. On the other hand, general anesthetic binding in GlyRa1 and GABAR potentiates the anionic inhibitory currents induced by glycine or GABA binding respectively.A plot of the backbone deviations during motion of the residues known to modulate anesthetic effects when mutated demonstrates that putative anesthetic binding pockets from any of the aforementioned models seem to be consistently located in a region of intermediate motion. This may prove to be some critically important “hinge point” within the complex. These cavities may also have a transmembrane/boundary mode of access. Anesthetic binding may actually alter the overall motion of a ligand-gated ion channel by a “foot-in-door” motif, resulting in the altered likelihood of and/or time spent in the open channel state. Finally, it appears that the transduction of native ligand binding from the extracellular LBD to the TMD occurs via two methods of coupling: The first method is by way of the protein backbone, as the amino acid sequence transitions from the LBD to the TMD. The second is through the intercalation of the TMD2-3 loop with loops 2 and 7 from the LBD. For the last one and a half decades, anesthetics have been given both safely and effectively for the relief of patient suffering. While a great many theories have been put forth, it has become increasingly apparent that a significant focus of anesthetic action lies within the family of ligand-gated ion channels (LGICs). These channels have a transmembrane region that is composed of a pentamer of four-helix bundles along with their putative amphiphilic anesthetic binding sites. This amphiphilic nature may help to explain the need for hydrophobicity expressed in the Meyer-Overton correlation, as well as the need for hydrophilicity required by the exceptions to the Meyer-Overton rule. The overall motion of these channels is consistent with the natural harmonic vibrations demonstrated by normal mode analyses. While still the goal of future pursuits, anesthetic binding may alter the overall motion of a ligand-gated ion channel by a “foot-in-door” motif, resulting in the altered likelihood of ion channel conductance when in the presence of the native ligand. Despite the great distance from the native ligand binding site to the gating elements of the pore, such analysis also demonstrates a ready means of information transduction over a large span. In the future, such calculations may allow for the analysis of subtle effects from mutations and small ligand binding. In addition, such a model may also be used to illustrate actual protein dynamics and more complete gating cycles elucidated via large-scale molecular dynamics and normal mode calculations. These latter calculations will become ever more possible as the huge computing horsepower requirements become more readily attainable. Especially in the case of molecular dynamics simulations, more realistic analyses will likely include the direct effects of explicit lipid moieties, water, and the binding of ligands in multiple portions of the ion channels. Furthermore, dynamic analyses will also allow the potential simulation of ion channel flux parameters. Finally, the ion channel motion that is associated with gating may actually one day serve as additional endpoints for future drug design.


The objective of this study was to develop and validate a reliable We defined the radiodensity ranges for trabecular tibia bone, polymethylmethacrylate (PMMA) cement and cement-penetrated trabecular bone and measured the percentages of cement penetration at various depths after cementing two tibia prostheses onto redundant femoral heads. One prosthesis was subsequently removed to examine the influence of the metal tibia prostheses on the quality of the CT images. The percentages of cement penetration in the CT slices were compared with percentages measured with photographs of the corresponding transversal slices.Trabecular bone and cement-penetrated trabecular bone had no overlap in quantitative scale of radio-density. There was no significant difference in mean HU values when measuring with or without the tibia prosthesis. The percentages of measured cement-penetrated trabecular bone in the CT slices of the specimen were within the range of percentages that could be expected based on the measurements with the photographs (p = 0.04).in vivo and to compare the results of different cementing methods in TKA.CT scan images provide valid results in measuring the penetration and distribution of cement into trabecular bone underneath the tibia component of a TKA. Since the proposed method does not turn metal elements into artefacts, it enables clinicians to assess the width and density of the cement mantle  In total knee arthroplasty (TKA), up to ninety percent of the orthopaedic surgeons use cement to fixate the tibia component. Despitein vivo remains a challenge. In current clinical practice, cement penetration is measured in vivo by means of conventional radiographs[While these studies have demonstrated the importance of optimal cement penetration, measuring the cement mantle surrounding implants iographs. Howeverin vivo. CT images, on the other hand, can be used in vivo. The disadvantage of using CT images used to be that the metal prosthesis produced artefacts in the images, which made a good interpretation difficult. In 2009, Lui et al.[.Various authors used Computed Tomography (CT) imaging to examine the cement mantle around implants,10-14. Gi et al. attemptein vivo by means of CT imaging. Hence, the objective of this study was to develop and validate an in vivo measuring technique which provides a truthful indication of the percentage distributed and penetrated cement in the total scanned surface underneath a tibia prosthesis. We assessed the accuracy of using CT scan images to measure cement distribution, i.e. the amount of cement on a cross section of the bone, and cement penetration, i.e. the amount of cement in the depth of the bone just underneath the tibial tray, and we evaluated the influence of metal elements on the depiction of cement on the CT reconstruction.So far no measuring technique has been validated for measuring tibia cement penetration in TKA in situ and no silicone was required, therefore we did not use it, as it is not used in the regular procedure of cementing, either. Finally, we controlled the findings on cement penetration by sawing the bones off at the measured depths and taking photographs of the sawed-off surface.To be able to discriminate between cement-penetrated cancellous bone and non-penetrated cancellous bone, we first defined the radiodensity  ranges for trabecular tibia bone, polymethylmethacrylate (PMMA) cement and cement-penetrated trabecular bone. The calibration of the HU levels was checked by scanning a phantom with water, teflon and nylon compartments. The scan of this phantom was analyzed to determine uniformity between the measured HU levels of water, teflon and nylon. If a parameter exceeded its criteria, corrective measures were taken. Next, we measured cement penetration at various depths after cementing two tibia prostheses, one of which was subsequently removed again to examine the influence of the metal tibia prostheses on the quality of the CT images. This tibia prosthesis had been covered with a silicone layer to enable removal of the prosthesis after the first measurements without damage to the bone-cement interface. The other prostheses remained For this study, we used 3 femoral heads which had been removed during total hip arthroplasty. All patients consented to the use of the redundant femoral heads. We prepared these femoral heads on the day of the resection. One femoral head was used to measure the radio-density range of pure PMMA cement and of cement-penetrated trabecular bone, as well as to validate the measured percentage of penetrated cement by comparing it to photographs of the femoral head slices sawed off at the required depth. The other two femoral heads were used as cadaver models for measuring cement penetration depth after cementing a tibia prosthesis into each of them, and one of these two femoral heads was used again for examining the influence of metal tibia prosthesis on the CT images.The CT slices were analyzed with Osirix® (version 3.2.1 32-bit). OsiriX® is an image processing software dedicated to DICOM images produced by a CT scan and has been specifically designed for navigation and visualization of multimodality and multidimensional images. The photographs of the sawed-off slices were analysed with Adobe Photoshop® CS2 (version 9.0), a graphics editing program that can select an area of an image and sample it for future use.To measure the radio-density range of trabecular tibia bone, we used CT images of 4 patients who had undergone a diagnostic CT scan of the knee. The radio-density range of the area 1 to 6 mm beneath the lowest point of the tibia plateau was defined as the clinically relevant area of trabecular tibia bone. The HU value of this area was measured in transversal and coronal slices.To measure the radio-density range of pure cement, we used a slice of one of the femoral heads. From the middle of the cut surface of this slice, 1.0 cubic centimetre of trabecular bone was removed and the hole was filled with cement. Several CT scans were made , using the NexGen® implantation tools. To cement the tibia prosthesis, the PMMA cement was only applied to the underside of the tibia component and not to the keel. Good compression was achieved by thrusting the tibia prosthesis into the femoral head with a tibial impactor, in line with the way a TKA is usually performed during surgery.Spiral CT scans were taken of both femoral heads, scanning parallel to the cut surface of the femoral head. The spiral CT scanner (Philips® Gemini GXL 16 slice) produced 0.8 mm slices. The slices were analyzed with Osirix®. Osirix® calculated the mean HU value of the selected areas as well as the standard deviations (SDs) of the mean HU values in the selected areas. These SDs provided an indication of the homogeneity of the scanned material in the selected areas and were identified as the homogeneity values of the selected areas.By measuring the amount of cement in the cross-sections of every 0.8 mm slice below the underside of the tibial tray, we calculated the penetration depth of the cement in percentages of the trabecular bone surfaces.in situ and once again after removal of the tibia prosthesis. Measurements were taken in the transversal slices parallel to the tibial tray. To measure the cement distribution in trabecular bone with the prosthesis in situ and without the prosthesis, three areas were selected, two beside and one posterior to the prosthesis  were defined, they were used to measure the percentage penetrated cement in the total scanned surface in transversal slices 3 to 6 mm beneath the cut surface. A femur head was cut into halves, both cut surfaces were pressurised with cement and a tantalum bead of 0.5 mm was placed 3 mm beneath the cut surface to facilitate orientation in the CT scans. CT scans were taken of both halves, and the total surface of the transversal slices was measured with Osirix®. Then the radio-density ROI of cement-penetrated trabecular bone was marked to be able to measure the surface of the cement-penetrated trabecular bone area. Next, the radio-density ROI of cement-penetrated trabecular bone was indicated as a percentage of the total scanned surface.After the CT scans were made, we controlled the findings by means of photographs. A transversal slice was sawed off each half of the femoral head at 3 mm below the cut surfaces, just above the tantalum beads. Both slices were photographed, and the photographs were analysed with Adobe Photoshop® CS2. First the pixels of the total slices were measured, then the colour range of the cement was marked and all pixels in this range were measured. Next, the surface of the cement area was calculated as a percentage of the total slice. The percentages measured in the photographs of the slices were compared with the percentages measured in the corresponding transversal CT slices.T-test). P-values less than 0.05 were considered significant.Analyses were performed using SPSS® Statistics for Windows Version 21, Chicago, IL, USA. Differences between the mean percentages of penetrated cement measured in the photographs of the femoral head slices and the percentages measured in the corresponding transversal CT slices were analyzed using the independent t-tests , with a mean homogeneity value of 152 HU (SD 14). In the coronal slices, the selected areas had a mean value of 162 HU (SD 24), with a mean homogeneity value of 123 HU (SD 16).The mean radio-density value in the selected areas of pure cement was 1328 HU (SD 27), with a mean homogeneity value of 66 HU (SD 12).The mean radio-density value of cement-penetrated trabecular bone in the selected areas was 1363 HU (SD 30), with a mean homogeneity value of 71 HU (SD 17).The mean value of the selected areas was 1384 HU (SD 53), with a mean homogeneity of 81 HU (SD 30).Table Table Table in vivo after cementing a total knee arthroplasty. The results showed that trabecular bone and cement-penetrated trabecular bone had no overlap in quantitative scale of radio-density, indicating that this method of measuring cement penetration may be useful in a clinical setting. In addition, there was no significant difference in quantitative radio-density values when measuring with or without the metal prosthesis, indicating that modern CT imaging technology no longer has the disadvantage of turning metal elements into artefacts that confound the interpretation of the images.The objective of this study was to assess whether CT images can be used to accurately measure the percentage of penetrated cement in the total scanned surface underneath a tibia prosthesis, and to develop and validate a measuring technique that can be used Our findings confirm the assumptions of other studies which used CT-scans for femoral implants and defined the Hounsfield Units for (cancellous) bone, PMMA and prosthesis in the same region as we found with our study,14.Our results showed no overlap in the radio-density ROIs of trabecular bone, cement-penetrated trabecular bone and the prostheses. This indicates that when the radio-density ROI of cement-penetrated trabecular bone was registered, there was no trabecular bone or prosthesis in the areas under investigation. Thus it is possible to see the differences between trabecular bone, cement-penetrated trabecular bone or prosthesis in every CT-slice underneath the tibia prosthesis. This enables clinicians to get a good impression of the three-dimensional extent of cement penetration into the trabecular bone after cementing the tibia component of a TKA.A comparison between the CT slices and the corresponding optical pictures showed different percentages of penetrated cement of the total surfaces of the transversal slices Table . NeverthA limitation of this study was that we used human femoral heads instead of the proximal part of a tibia. The femoral heads were much easier to acquire and we could use them on the same day after the resection during surgery of a total hip arthroplasty. Moreover, there are no big differences between the HU values of cancellous bone in tibia and femoral heads. According to Scheerlinck et al. the HU vAnother limitation was that our findings showed an overlap in the radio-density ROI of cement-penetrated trabecular bone and the radio-density ROI of cortical bone. However, this overlap had only a small influence on the measured percentages of penetrated cement, because only the thin edge on the transversal CT slices consists of cortical bone. Furthermore, all transversal slices had almost the same percentage of cortical bone, and, consequently, the final effect of this overlap in radio-density ROIs was the same in all slices. Therefore we do not expect this to affect the clinical use of the proposed method.A third limitation is that we compared the cement area to the total scanned surface, without subtracting the metal. However, this did not influence our measurements, since the prosthesis constituted nearly the same percentage of the cross-sectional surface over the measured depth of 3 to 6 mm.A fourth limitation is that we did not examine the radio-density ROI directly beside the prosthesis. Still, the CT technique we used showed nearly no effect of the metal prosthesis on the surrounding bone/cement. In addition, there was no significant difference in quantitative radio-density values when measuring with or without the metal prosthesis, indicating that modern CT imaging technology no longer has the disadvantage of turning metal elements into artefacts that confound the interpretation of the images.in vivo. We therefore accepted this drawback as a limitation, since this study aimed to develop and validate a measuring technique that can be used in vivo in clinical practice.A final limitation of our study is that with this CT technique, it is impossible to differentiate between bulk cement, like filled bony defects or cysts, and trabecular bone that is interlocked with cement. When cement is pressurized into trabecular bone, the cement fills up the space between the trabecals, which enlarges the density and improves the homogeneity. As a result, the homogeneity value of cement-penetrated trabecular bone is almost the same as the homogeneity value of pure cement. With this result we can make the assumption that the density of cement-penetrated trabecular bone equals the density of pure cement. To differentiate between them, we would have to use micro-CT, which cannot be used In this study we established that CT imaging can be used to measure the amount of cement at different depths beneath the cutting surface of the femoral head and to calculate the percentage of cement penetrated into the cancellous bone versus the percentage of cancellous bone without penetrated cement. We presented this percentage at a depth of 3 mm beneath the cutting surface, but the same technique can be used to establish the percentage at a depth of 5 mm. Further research might focus on the optimal percentage of cement-penetrated bone that is required at these depths to prevent loosening of the TKA.In conclusion, the trabecular cement penetration in TKA can be measured reliably by means of transversal CT slices in combination with the automatically marked radio-density ROI of cement-penetrated trabecular bone and Osirix® computer software. The metal prostheses had no significant effect on the measured radio-density values in the CT images, and there was no overlap between the automatically marked radio-density ROIs of trabecular bone and cement-penetrated trabecular bone. The percentages of cement penetration measured in the CT slices were within the range of percentages that could be expected based on the measurements in the optical pictures. This reproducible technique is, until now, the only way to measure the three-dimensional extent of cement penetration into the trabecular bone after cementing the tibia component of a TKA. Moreover, this technique will make it easier to compare the results of different cementing methods in TKA.TKA: Total knee arthroplasty; CT: Computed tomography; HU: Hounsfield unit; PMMA: Polymethylmetacrylate; SD: Standard deviation; ROI: Range of interest.The authors declare that they have no competing interests.All authors made substantive intellectual contributions to this research study. HV, LR and PP conceptualized the primary research questions and constructed the study design. LR performed the implantations of the prosthesis and LR and WV assessed the CT scans. HV and LR are responsible for writing this article. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2342/14/29/prepub


At the heart of ever growing demands for faster signal processing is ultrafast charge transport and control by electromagnetic fields in semiconductors. Intense optical fields have opened fascinating avenues for new phenomena and applications in solids. Because the period of optical fields is on the order of a femtosecond, the current switching and its control by an optical field may pave a way to petahertz optoelectronic devices. Lately, a reversible semimetallization in fused silica on a femtosecond time scale by using a few-cycle strong field (~1 V/Å) is manifested. The strong Wannier-Stark localization and Zener-type tunneling were expected to drive this ultrafast semimetallization. Wider spread of this technology demands better understanding of whether the strong field behavior is universally similar for different dielectrics. Here we employ a carrier-envelope-phase stabilized, few-cycle strong optical field to drive the semimetallization in sapphire, calcium fluoride and quartz and to compare this phenomenon and show its remarkable similarity between them. The similarity in response of these materials, despite the distinguishable differences in their physical properties, suggests the universality of the physical picture explained by the localization of Wannier-Stark states. Our results may blaze a trail to PHz-rate optoelectronics. The interest in electron dynamics in solids in strong fields has been long standing. Bloch34568102 under a strong field of ~1 V/Å underwent semimetallization2020Due to the recent advance of laser technology, there has been a revived interest in optoelectronic phenomena in solids in strong fields1318Here we show the semimetallization to be a general phenomenon for wide-bandgap insulators subjected to intense optical fields. We have investigated the semimetallization in wide-bandgap dielectric crystals such as quartz, sapphire, and calcium fluoride. They exhibit a remarkable resemblance in their responses to intense optical fields despite notable dissimilarities in their composition, structure, and electronic and optical properties.The physical properties of a solid are determined by its constituents and structure. In particular, the response of a medium to a weak external electric field is characterized by its dielectric permittivity. In this respect, quartz, sapphire and calcium fluoride are very different from each other. In fact, quartz belongs to rhombohedral lattice system with unit cell sizes of 8 times via a current amplifier, converted into a voltage signal, and fed to a lock-in amplifier for frequency filtering. Even though attention has been paid to make the shapes of the electrodes as identical as possible, there are still slight differences microscopically between the electrodes and unequal numbers of electrons are photoemitted from the electrodes so that there is a CEP-independent charge flow. In order to remove the CEP-independent components from the transferred charge, we introduced a modulation to CEP at half repetition rate and used a lock-in amplifier referenced at the CEP modulation frequency. In this way, the CEP-independent components were eliminated and only CEP-dependent components survived. A pair of motorized wedges was included in the setup so that arbitrary CEP could be introduced. Since the comparison between materials is an important aspect in the current study, we have paid attention to deal with the purist sample. The purity is greater than 99.999% in case of quartz. As this study deals with the light intensity close to the breakdown, we were careful of laser-induced damageFor the sake of comparison and data representation, we introduce the criticality parameter, The maximum transferred charge Since quartz and sapphire have almost the same band gap but different lattice systems, the good agreement between quartz and sapphire indicates that the structural factors may not play a major role in this phenomenon. Another question is whether it is the different band gap that really matters. To answer this, the comparison with the data from calcium fluoride sample is made: as mentioned earlier, the calcium fluoride has a different lattice system (cubic lattice) and a larger band gap (12.2 eV). st order of Fourier expansion for periodic potential, field strength was assumed to be small. Hence we attempted to better fit a lower-Zener has studied interband charge transfer, in terms of electrical breakdown in an insulator under strong field and derived an analytical formulaTo theoretically describe the measured data at high fields, i.e., in the higher To compare theory and experiment, According to the computation, the largest charge transfer is predicted for calcium fluoride at a given By multiplying proper Even though the microscopic description presented above provides good description of the experimental data, we would like to build a physical picture of the phenomena observed, especially to explain qualitatively why the very dissimilar dielectric crystals exhibit very similar behavior in strong fields suggesting universality of this phenomenon and underlying physics.We interpret this universality as a result of the WS localizationThe condition of adiabaticity is that the optical frequency, All WS states are localized within localization radius In conclusion, we have shown experimentally that wide-bandgap insulators, quartz, sapphire and calcium fluoride, undergo semimetallization in strong optical fields: there is charge transfer along the field direction, which is dependent on the maximum instantaneous field and is controlled by the CEP of the pulse. For these crystals, the semimetallization occurs in a very similar way, although their chemical compositions, crystallographic, and linear-optical properties are quite dissimilar. These observations can be understood in view of the WS localization of electrons. Since under our conditions, fields of We assume that the electron dynamics in external electric field of the optical pulse is coherent (which means that the duration of the laser pulse is less than the characteristic electron scattering time) and can be described by the time dependent Schrödinger equationwhere the Hamiltonian where The free-electron Hamiltonian whereThe Houston functions are solutions of time-dependent Schrödinger equation The expansion coefficients where Here It is easier to calculate the dipole matrix elements in terms of the interband matrix elements of the velocity operator,Then the dipole matrix elements are defined aswhere -point, system of equations System of equations From these electron distributions we can find the current generated in the system in the field of the pulse,The current is determined by the matrix elements of the velocity operator. The generated current results in the charge transfer through the system, which is determined by an expression2O3), the primitive unit cell has 15 atoms (three Al2O3 units). We take into account the s- and p-orbitals for each atom and use the corresponding parameters of the tight-binding Hamiltonian reported in Ref. For corundum  is modeled in a virtual crystal approximation with the corresponding tight-binding parameters given in The quartz  the applied field is not too strong that the energy change for displaced electrons in the crystal is rather still small. The field strength in which Zener’s approximation is valid is, considering typical lattice constants, estimated to be on the order of a few volts per nanometer, or Zener’s formula was derived based on assumptions and approximations. For example, (1) a lattice is simplified to one dimension, (2) the periodicity of potential is considered up to the 1The data for small How to cite this article: Kwon, O. et al. Semimetallization of dielectrics in strong optical fields. Sci. Rep.6, 21272; doi: 10.1038/srep21272 (2016).


Since their introduction in 2009, the BioNLP Shared Task events have been instrumental in advancing the development of methods and resources for the automatic extraction of information from the biomedical literature. In this paper, we present the Cancer Genetics (CG) and Pathway Curation (PC) tasks, two event extraction tasks introduced in the BioNLP Shared Task 2013. The CG task focuses on cancer, emphasizing the extraction of physiological and pathological processes at various levels of biological organization, and the PC task targets reactions relevant to the development of biomolecular pathway models, defining its extraction targets on the basis of established pathway representations and ontologies.Six groups participated in the CG task and two groups in the PC task, together applying a wide range of extraction approaches including both established state-of-the-art systems and newly introduced extraction methods. The best-performing systems achieved F-scores of 55% on the CG task and 53% on the PC task, demonstrating a level of performance comparable to the best results achieved in similar previously proposed tasks.The results indicate that existing event extraction technology can generalize to meet the novel challenges represented by the CG and PC task settings, suggesting that extraction methods are capable of supporting the construction of knowledge bases on the molecular mechanisms of cancer and the curation of biomolecular pathway models. The CG and PC tasks continue as open challenges for all interested parties, with data, tools and resources available from the shared task homepage. The BioNLP Shared Task (BioNLP ST), organized for the third time in 2013, presents open challenges in biomedical natural language processing to all interested parties. The shared task organizers provide task definitions, manually annotated data for method development and evaluation, and tools for the assessment and comparison of information extraction approaches proposed by the community ,5.knowledge base construction, the over-arching theme of the 2013 BioNLP ST. That is, both tasks are motivated by the need to develop better methods for automatically analyzing the literature at large scale in order to support the creation, maintenance and further development of structured representations of domain knowledge. However, the specific representations and subdomains of biomedical knowledge targeted by the tasks differ substantially, leading to two different information extraction task settings.Both the CG and PC tasks aim to support cancer" in the PubMed literature database [The CG task targets the automatic analysis of the literature on cancer, a complex group of genetic diseases that is one of the most common causes of death worldwide. Despite decades of focused research and an ever-increasing body of knowledge on its causes and mechanisms, cancer remains imperfectly understood ,7. Part database  finds meBy contrast to the disease-oriented focus of the CG task, the goals of the PC task are defined by a specific category of knowledge representation, namely formal models of biomolecular pathways such as the Systems Biology Markup Language (SBML) ,10 and tAlthough cancer knowledge base construction and pathway model curation both face challenges stemming from the enormous size and rapid growth of the biomedical literature, existing tools for the automatic analysis of that literature have not fully addressed the needs of these important tasks. In particular, in biomedical information extraction there has long been considerable focus on the recognition of biomolecular entities and binary relations such as protein-protein interaction involving these entities -20, largWhile previous BioNLP ST events have been instrumental in promoting the extraction of more expressive representations in the form of event structures ,22, theyWe believe that the event extraction approach can substantially benefit both cancer knowledge base construction and the curation of biomolecular pathway models, and the BioNLP ST'13 Cancer Genetics and Pathway Curation tasks aim to close the gaps hindering the realization of these benefits. Specifically, the CG task introduces novel extraction targets covering all levels of biological organization ranging from the molecular to the whole organism, further extending the scope of previous tasks in the series through the inclusion of pathological processes and events representing experimenter action. The PC task bases both its representation and its semantics directly on major pathway model standards such as SBML, BioPAX and the Systems Biology Ontology ,26 to asIn the following, we first present the applied event representation and its application in the CG and PC task settings in detail. We next introduce the corpora for the two tasks and the criteria for evaluating the predictions submitted by task participants against their annotation. We then present the task participants and systems, the primary evaluation results and additional analyses of these results, and finally discuss the overall findings of these tasks and present conclusions.event structures (or events for short) [entities of interest. In addition to entities and events, the representation applied in the tasks involves relations between entities and event modifications that identify additional aspects of extracted events such as speculation and negation. We next present these annotation primitives, and then proceed to present the specific types and their definitions applied in the CG and PC tasks.The BioNLP ST main tasks are information extraction tasks targeting r short)  followinr short) . Events CELL or SIMPLE CHEMICAL from a closed set of entity types defined for the task. Figure Each mention of a relevant physical entity is annotated as a contiguous span of text that is assigned a type such as The recognition of mentions of physical entities in free text is a very well-studied task both in general-domain and biomedical natural language processing ,30, and Equiv. Equiv is a symmetric, transitive binary relation that identifies entity mentions as being equivalent in the sense of referring to the same real-world entity. Equiv relations are used to mark local aliases such as abbreviations. Figure The CG and PC tasks both define a single relation type, Equiv annotation is applied also for the test data. The Equiv annotations are used in evaluation when determining if two events match: for event matching, any entities connected by an Equiv relation (directly or transitively) are interchangeable.The relation annotations are not an extraction target in the task, and gold standard event trigger). As for entity annotations, event types are drawn from a closed, task-specific set, and the event trigger is a contiguous span of characters. Event participants can be either entity or event annotations, the latter allowing complex event structures where one event is identified as e.g. causing or preventing another. For each event participant, the role that the participant plays in the event is further identified. The number of role types is small and mostly generic, but some moderately task-specific roles are also defined. The following roles are used in the CG and PC tasks:Events, the primary extraction target in BioNLP ST main tasks, are structured annotations, each of which has a type, zero or more participants, and an associated statement in text that expresses the event  or expressed in a speculative context . Event modifications are not associated with a text "trigger", unlike in some related task settings [NEGATION and SPECULATION.Both the CG and PC tasks involve the modification types settings ,33. The start, end) character offsets and marked text for physical entity annotations and event triggers. Figure The information introduced above is represented in the tasks using the simple data format first introduced for the BioNLP ST'09. This is a standoff format where the annotated texts are stored separately from their annotations, with annotations referencing relevant spans of text via character offsets. The annotations are further split so that the physical entity annotations that are provided to the task participants also for the test data are stored in one file, and the annotations corresponding to extraction targets in another. Each document thus involves three files: the text, the given annotations, and the extraction targets. The annotations are stored in a line-oriented format where each line contains a single annotation, consisting of a unique identifier, the annotation type, and fields specific to the annotation primitive, such as the trigger and event arguments for event annotations, or the  are annotated. We refer to Ohta et al. [patients") are annotated as ORGANISM, as in a number of previous tasks.Anatomy-level entities, a notable novel aspect of the CG task, are subdivided primarily by granularity, and their type labels and definitions mainly follow the Common Anatomy Reference Ontology (CARO) , which ia et al.  for moreRGANISM annotations are created with reference to the NCBI taxonomy [To assure consistency, resources identifying entities of each relevant type were used for reference during the entity annotation. Mentions of biomolecules are annotated with reference to databases of genes, proteins, their families, and related entities such as Entrez Gene , UniProttaxonomy .The CG event types and their arguments are summarized in Table GROWTH to extend their scope so as to include also pathological entities, so that e.g. "cancer development" is annotated with the GROWTH type. Second, for intrinsically pathological processes such as METASTASIS that lack a close physiological analogue, we introduce a small number of representative high-level event types such as Metastasis. Finally, we introduce the single upper-level event type PLANNED PROCESS to mark processes explicitly involving experimenter action [However, there are some categories of processes that are critical for comprehensive analysis of the cancer literature but fall outside of the scope of GO. Most importantly, GO systematically excludes from its scope pathological processes such as carcinogenesis. We address this limitation in two ways. First, we reinterpret GO types such as r action . We refer action  for furtIMPLE CHEMICAL, GENE OR GENE PRODUCT, and COMPLEX, and the CELLULAR COMPONENT type , and the two tasks share the definitions of these types. The remaining type, COMPLEX, is used to mark the names of molecular entities of non-covalently linked components, which are particularly relevant to the PC task extraction targets.Four entity types are defined in the PC task: the molecular level entity categories Spe Table . Of thesstructures to complex pathway reactions (and vice versa).Table Theme is used to annotate participants corresponding to reactants, and Cause is applied together with regulation event types to capture modifiers and their effects . Finally, we introduce the new role Product specifically for the purpose of representing the product role in pathway models.Popular pathway model standards such as SBML and BioPAX differentiate between three basic categories of reaction participants: reactants, products, and modifiers. The former two correspond roughly to reaction inputs and outputs, while the last category identifies entities that have a regulatory effect, such as inhibiting or catalyzing the reaction. While this categorization of pathway reaction participants has some close analogies to the event structures applied in previous shared tasks, some aspects of the event representation require adjustments to assure a systematic and consistent mapping. In the PC task, we interpret event role types as follows: first, p38γ as a reactant would have phospho-p38γ as a product. However, as the combination of reactant, reaction type and product is redundant, authors rarely express all three, instead using more concise forms such as "p38γ is phosphorylated". Figure The use of SBO types and event roles defined with respect to the participant categories in pathways makes events and pathway reactions fully isomorphic in theory. However, natural language text does not necessarily explicitly state all participants, so in practice event representations that adhere to the principle that all annotations are bound to specific expressions in text may not always map to complete reaction representations. For example, in a pathway model, a phosphorylation reaction that takes Both the Cancer Genetics and Pathway Curation tasks use corpus resources based in part on relevant previously released corpora. Nevertheless, most of the annotations in the shared task versions of the training, development and test corpora of both tasks were newly introduced specifically for these tasks. The following sections present these resources and their preparation.The annotation of the CG and PC task corpora followed the same overall process: document selection, automatic pre-annotation of entity mentions, manual finalization of entity annotations, and manual event annotation.SIMPLE CHEMICAL tagging, we used the OSCAR4 system, which was trained on the chemical entity mention recognition corpus of Corbett and Copestake [ENE OR GENE PRODUCT mention detection, we used BANNER[CULLULAR COMPONENT only for the PC task). For these tagging tasks, the general machine learning-based system was trained on the Anatomical Entity Mention (AnEM) corpus [GENE OR GENE PRODUCT annotation and dictionary-based tagging to create the initial annotations for the PC task COMPLEX type. Finally, LINNAEUS [ORGANISM mentions. The overall processing used the pipeline first introduced for similar analysis for the BioNLP ST'11 [While some of the aspects of the entity annotation are novel, many of the annotated entity types are in scope of established domain tools and resources. To reduce the overall annotation effort, we thus created preliminary annotation using a selection of automatic named entity and entity mention taggers. For opestake . For GENed BANNER for the ed BANNER for the ed BANNER. NERsuit) corpus  followin) corpus . As no bLINNAEUS  was applLP ST'11 . These tLP ST'11  to suppoWe acknowledge that automatic annotation is not only far from perfect, but also carries a risk of introducing systematic errors, some of which may persist through subsequent manual revision. As entity annotations were not a target of extraction in either of the tasks, the possibility of some remaining bias from such errors was considered acceptable. By contrast, we wished to assure that the quality of the event annotations was as high as possible and to avoid any possibility of introducing systematic errors that might call into question whether the evaluation provides a fair representation of the comparative performance of different extraction approaches. For this reason, the event annotation of both tasks was created manually from scratch, forgoing any initial automatic annotation.BRAT annotation tool [All manual annotation, including the revision of the initial automatic entity mention annotations as well as the primary event annotation, was performed using the open source ion tool .The task-specific annotation process details are presented below.The CG corpus consists of 600 PubMed abstracts selected on the basis of their relevance to established hallmarks of cancer, such as the evasion of apoptosis, tissue invasion, and sustained angiogenesis , which cThe CG corpus was annotated by Tomoko Ohta, a PhD biologist with a cancer molecular biology background and extensive experience in event annotation. The creation of the anatomical entity annotation is described in , and theBRAT to find text strings that were annotated as entity mentions in some cases but not in others and annotations that shared the same surface form but were assigned different semantic types. Automatically detected potential inconsistencies were subjected to further manual examination and correction when necessary. As only a single annotator was trained to perform the CG corpus annotation, we did not directly measure inter-annotator agreement during the annotation of this corpus. However, our previous IAA evaluation using the same annotation protocol [After the completion of the initial manual annotation, we performed some iterations of automatically supported revisions to further improve annotation quality and consistency. For example, we used the consistency check options of the search.py script included with protocol  indicateAs for the CG task, the texts of the PC task corpus are also drawn from PubMed abstracts. For the CG corpus, we aimed to assure that each included abstract provides evidence for the annotation of some reaction found in at least one selected pathway model Table . To seleFor the first approach, we selected the BioModels pathways that had the most manually annotated references identifying a document in PubMed. We then retrieved the abstracts of a random sample of these documents and filtered them manually to assure their relevance to the task. The second strategy was required as the majority of pathway models do not include any references to evidence documents. To select documents providing evidence for reactions in other pathways, we entered selected PANTHER DB models into PathText , a systeThe PC task annotation effort was carried out in collaboration between the UK National Centre for Text Mining (NaCTeM) and the Korea Institute of Science and Technology Information (KISTI). The entity annotation followed the automatically supported approach described above, and event annotation was performed fully manually by three biologists. The effort was organized by a coordinator with experience from several event annotation projects, but the individual annotators had no previous experience with the annotation of natural language texts. After a brief introduction to event annotation and training with the annotation tool and guidelines, the primary annotation was performed otherwise independently, but with a random 20% of documents provided to all three annotators to evaluate consistency, identify points of disagreement, and measure inter-annotator agreement. Following the completion of the primary manual annotation, consistency checking using automatic methods to detect potentially inconsistent annotations was performed similarly as in the CG task data preparation (described above).An evaluation of the redundantly annotated documents after consistency checking indicated an inter-annotator agreement of 61.0% F-score for the event annotation using the primary task evaluation criteria. This level of agreement is somewhat low given the comparative simplicity of the task annotation targets. This can likely be attributed in substantial part to the facts that the annotators were working in a different country from the annotation coordinators, communicating primarily over email, and that only a relatively short period of annotator training could be included due to the overall project schedule. This serves to emphasize that while it is necessary to involve domain experts in annotation efforts targeting specialized texts, such expertise must be accompanied by thorough annotator training that provides sufficient experience on the use of the annotation formalism and tools as well as detailed understanding of the annotation guidelines. Finally, the redundantly annotated documents were assessed by the annotation coordinator to select the best of each set of annotations for the final corpus. This selection implies that the measured inter-annotator agreement of 61% F-score is a lower bound on the quality of the released PC task event annotation.Both the CG and PC task corpora were divided into training, development and test sets representing approximately 50%, 17%, and 33% of the documents, respectively. Table The evaluation of both the CG and PC tasks is instance-based and uses the standard precision, recall and F-score metrics. The primary criteria for determining if an event (or event modification) predicted by a participating system matches a gold standard event (modification) follow those first introduced in the initial BioNLP ST. In brief, these criteria require that a predicted and gold event are identical with two possible exceptions: the boundaries of predicted events may differ from those of the corresponding gold event by up to one word on each side, and the events that are referred to as arguments of the predicted and gold events under consideration may differ in their non-core arguments  tasks [We consider here also two variants of the primary evaluation setting: evaluation on s Tables  and 5 asD) tasks , focusinD) tasks , aims toFinal results for the two tasks were submitted by six teams, with all six submitting to the CG task and two submitting also to the PC task. Table Table A range of different methods was applied also in support of the individual processing stages. The methods used for basic word-level processing are generally comparatively simple, domain-independent approaches, with only the NCBI system using a lemmatization method developed specifically for domain texts (BioLemmatizer) . By contAlthough event modifications were included as an extraction target in both tasks, three of the six systems involve no event modification component at all. Of the three that do, two apply a machine learning approach and one a rule-based approach. The choice of the three participants to exclude event modification from their methods may reflect at least in part the rarity of modifications compared to event annotations  excepting for that between the NCBI and RelAgent systems.The Cancer Genetics task primary evaluation results are presented in summary in Table The TEES-2.1 system achieved the best performance at the task, averaging an F-score of 55%. A version of the same system ranked first also in the original 2009 BioNLP ST, then achieving an F-score of 52% , as wellOf the three newly introduced systems, the rule-based system of RelAgent achieves the best performance, averaging an F-score of 46% and thus performing within 10 percentage points of the top-ranking system. This shows that the CG task targets are not so complicated as to make the task inaccessible to rule-based approaches and that newly introduced systems can achieve a level of performance that is broadly competitive with the established state-of-the-art systems. The parsing-based systems achieve less competitive results, with F-scores of 30% for UET-NII and 24% for ISI. The results for both systems are primarily limited by low levels of recall, suggesting that better F-scores could perhaps be achieved by trading off some of the comparatively high precision.We thus observe that the top three positions are taken by previously established systems - perhaps not a surprising finding - and, more importantly, that each of these systems achieves a level of performance at the CG task that is broadly comparable or better than the performance of the same system at previous related and narrower tasks such as GE. This is highly encouraging as it indicates that the state-of-the-art systems generalize to meet all of the novel challenges of the CG task, including the substantially increased number of entity and event types, the cancer domain, as well as the inclusion of higher levels of biological organization.anatomical and pathological event categories are not particularly challenging for the event extraction methods; indeed, the best results for anatomical category events are better than the best results for molecular events (F-score of 77% versus 73%). The best results for pathological processes are only slightly lower at an F-score of 68%. By contrast to the broad new categories of events, the specific newly introduced event type Planned process PLANNED PROCESS proved challenging to extract (best result was an F-score of 41%), perhaps in part due to the fact that it frequently involves multiple arguments.Table general and regulation remain as challenging here as in previous related challenges, likely reflecting at least partly the known challenges in the extraction of events with multiple arguments (e.g. BINDING) and those that recursively include other events (regulation types). Results are comparatively low also for the modification types, with a best F-score of 40% for NEGATION and 30% for SPECULATION. The extraction of these types involve challenges similar to those for regulation events in that their correct extraction requires also the correct extraction of the events that they apply to [The previously established event categories apply to .The overall results of the PC task are given in Table simple modification events such as PHOSPHORYLATION that frequently take only a single Theme argument are comparatively easy extraction targets (a better result of an F-score of 66%), while structures that require the correct extraction of events that they apply to are challenging (40% F-score for regulation and 29% for modifications). Interestingly, the general category of events, and in particular the previously often particularly demanding BINDING type show comparatively high results here, perhaps reflecting some special characteristics of the domain.Table It is interesting that the ranks of the two systems are inverted here compared to the CG task, where the TEES-2.1 system achieved 3 percentage points higher performance than EventMine. The only notable difference in the way that the systems were applied in the two tasks is that the EventMine system was trained using a large number of previously introduced resources for the PC but not the CG task . AlthougAs discussed in detail above, both EventMine and TEES are well-established, support vector machine-based pipeline systems that have demonstrated state-of-the-art performance across many previous event extraction tasks ,83. ThusIt is perhaps somewhat surprising that the best results for this purely molecular-level task are lower than those for the considerably broader CG task despite the same systems achieving the best results in both. However, it is nevertheless a positive finding that this newly introduced task employing a novel reference ontology and aligned with a representation that has not previously been directly applied in event extraction task can be addressed with established technology without clear decreases in performance compared to established tasks .We next present evaluation results under different variants of the evaluation criteria. Note that the supplementary evaluation results presented in this section do not supersede the primary evaluation results Tables  and 14, EGATION or SPECULATION annotations, and 6% involve non-core arguments. The greatest benefit is observed for the NCBI system, which unlike the highest-ranking two systems does not attempt to predict event modifications.Table Table Table The Pathway Curation task results with single partial penalty are shown in Table We next summarize some of the main findings of the CG and PC task evaluations, consider specific challenges and possible ways of addressing these, and discuss the significance of the task results. Overall, we find that the best results in both the CG and PC tasks broadly parallel those achieved in similarly structured event extraction tasks in the BioNLP ST'09  and '11 Similarly, complex extraction targets such as events involving multiple arguments, events that recursively involve another event, and event modifications that often involve non-local "triggers" that are not explicitly annotated Figure  represenpart-of. Despite supporting tasks organized to address some of these challenges as part of the BioNLP ST'11 [Previous detailed analyses of system errors ,36 identLP ST'11 ,86 and sLP ST'11 , no systIt must also be noted that measured extraction performance is limited by the quality and consistency of the gold standard annotation: even domain experts trained to perform event annotation may reach no more than 60% F-score in cases, and 80% F-score remains a difficult target even for highly trained human annotators. The evaluation criteria can also be questioned: results using different criteria showed relative reductions in F-score error of 10% or more for most systems Tables  and 19. We have presented the Cancer Genetics and Pathway Curation tasks, two event extraction tasks that were newly introduced in the BioNLP Shared Task 2013. Both tasks are motivated by the needs of maintaining comprehensive and up-to-date information in the face of the enormous size and rapid growth of the biomedical domain scientific literature. For the CG task, such information can be used to develop knowledge bases on the molecular mechanisms underlying cancer; for the PC task, for developing, evaluating and maintaining molecular pathway models using representations such as SBML and BioPAX.The two tasks both involve a number of aspects not previously considered in BioNLP ST settings. For the CG task, the most notable novel points are that the task addresses entities and events at all levels of biological organization from the molecular to the whole organism and involves pathological as well as physiological processes. The PC task stands out in particular in defining the structure of its extraction targets explicitly with reference to major pathway model representations and their types on the basis of the Systems Biology Ontology, thus aligning the extraction task closely with the needs of pathway curation efforts. Each of the tasks introduces a new, manually annotated corpus substantially extending on previously available resources. Both corpora draw their texts from PubMed abstracts, with the CG corpus containing annotations of over 17,000 events in 600 documents and the PC corpus over 12,000 events in 525 documents.Six groups participated in the CG task, applying a broad range of extraction approaches including machine learning-based pipelines, a joint pattern matching-based approach, a rule-based approach and two parsing-based approaches. Two groups participated in the PC task, both applying well-established pipeline systems using support vector machines. All participating systems applied detailed analysis of sentence structure, most commonly in the form of full dependency parses. The best result achieved in the CG task was an F-score of 55.4% by the TEES-2.1 system, and the best result in the PC task was an F-score of 52.8% by the EventMine system. Both of the top-ranking systems are machine learning-based pipeline systems that have achieved state-of-the-art results in many previously proposed event extraction tasks.The performance of the top-ranking systems at the two tasks is broadly in the range of the best results achieved at similar previously proposed event extraction tasks, indicating that current event extraction methods generalize well to meet the novel challenges represented by the CG and PC tasks.http://2013.bionlp-st.org/.Following the convention established in the first BioNLP Shared Task, both the Cancer Genetics and Pathway Curation tasks will continue as open challenges available to all interested participants. The corpora, evaluation tools, and supporting resources are available under open licenses from the BioNLP Shared Task homepage The authors declare that they have no competing interests.SP and TO conceived of the tasks. SP coordinated the CG task organization, drafted the manuscript, and implemented evaluation and support tools. TO coordinated the PC task organization and led the CG and PC annotation efforts. RR and AR contributed to preparation of tools for the PC task. HC, SJ and SC contributed to the design and manual annotation of the PC task. SA participated in the design and coordination of both tasks and JT participated in the coordination of the overall shared task.


The aim of this study was to design a navigation system composed of a human-controlled leader vehicle and a follower vehicle. The follower vehicle automatically tracks the leader vehicle. With such a system, a human driver can control two vehicles efficiently in agricultural operations. The tracking system was developed for the leader and the follower vehicle, and control of the follower was performed using a camera vision system. A stable and accurate monocular vision-based sensing system was designed, consisting of a camera and rectangular markers. Noise in the data acquisition was reduced by using the least-squares method. A feedback control algorithm was used to allow the follower vehicle to track the trajectory of the leader vehicle. A proportional–integral–derivative (PID) controller was introduced to maintain the required distance between the leader and the follower vehicle. Field experiments were conducted to evaluate the sensing and tracking performances of the leader-follower system while the leader vehicle was driven at an average speed of 0.3 m/s. In the case of linear trajectory tracking, the RMS errors were 6.5 cm, 8.9 cm and 16.4 cm for straight, turning and zigzag paths, respectively. Again, for parallel trajectory tracking, the root mean square (RMS) errors were found to be 7.1 cm, 14.6 cm and 14.0 cm for straight, turning and zigzag paths, respectively. The navigation performances indicated that the autonomous follower vehicle was able to follow the leader vehicle, and the tracking accuracy was found to be satisfactory. Therefore, the developed leader-follower system can be implemented for the harvesting of grains, using a combine as the leader and an unloader as the autonomous follower vehicle. Multiple autonomous vehicles can improve the efficiency of agricultural operations by performing labor-intensive tasks such as transporting, plowing, sowing, fertilizing, spraying, and harvesting ,2. The s(1)To establish an autonomous vehicle as a follower vehicle able to conduct tracking tasks.(2)To construct a robust and accurate monocular vision system able to estimate the relative position between a leader and a follower.(3)To develop a control algorithm able to realize accurate leader vehicle trajectory-tracking for multiple agricultural machinery combinations, with a human-driven leader and an autonomous follower.In any event, the follower vehicle needs to continually update its relative position with respect to the leader to fulfill the tracking task. Regarding safety, absolute sensors such as those employing GPS are not suitable for the tracking task because they may lose the satellite signal and are subject to multipath interference. Local sensors, such as cameras and laser range finders (LRF), are considered to be better approaches and have been successfully applied for tracking under both indoor and outdoor conditions ,13,14,15i.e., the follower vehicle. Both the leader and the follower vehicle had a 60 cm wheel base length and 49 cm drawbar length. Major subsystems of the autonomous vehicle included steering control, speed control, power and sensor units. The sensory data and control status were transmitted to an upper level controller through parallel communication. The basic instrumentation system for the autonomous vehicle is depicted in An electronic vehicle  was modified into an autonomous vehicle, D, and orientation angle H and the interval between square centers L were 0.2 m and 0.4 m, respectively. In the leader-follower system, the following steps were followed to develop the relative positioning system: camera servo systems, marker detection, marker positioning, and estimation of offset of the roll angle between camera and marker.r system b, in whiLosing the target was a severe problem during the tracking of the leader vehicle; it potentially occurred owing to the limitations of the camera view field, especially on a large-curvature path. To overcome this problem, a camera servo system was designed to keep the marker in the center of the camera view field. The camera servo system comprised a GWS servo motor and a rotary encoder with a camera c. By resThe marker was detected based on its pre-known geometry information, including its square shape features and relative spatial relationship between squares in the marker plane. The image processing flow comprises the following four steps: transforming an original RGB image into a grayscale image and then enhancing the contrast ratio, extracting contours, finding rectangles from the contour images, and determining the marker .Pre-known geometry information could reduce the computational cost and benefit real-time detection. Additionally, the high contrast ratio between the black squares and the white background enabled the generation of acutance contours and created stability for the detection of the marker. However, contour extraction was still influenced by illumination conditions. Low illumination conditions or strong sunlight under an outdoor environment would reduce the contrast ratio of the image and corrode the contour of squares, causing failure of marker detection. To expand the scope to adapt to various illumination conditions, a commonly used normal distribution of the image histogram method was utilized to enhance image contrast. Affected by posture changes of the vehicles, squares projected on the image plane would show the shapes of rectangles. Thus, rectangles were recognized and selected in the contour image. Relying on the relative spatial relationship between the three squares, false targets with rectangular shapes, such as rooms and windows, could be filtered, and only squares formed by the marker could be extracted.h is the height of squares in the image plane.Given that the vision data were obtained from a single camera and the relative position between the marker and the camera was estimated based on the known side length of the marker squares, the position of each square in the marker plane could be described by its center point. The pitch angle of the vehicle body was neglected, meaning that the sides of squares in the vertical direction would not be affected by the posture changes of the leader and follower vehicles when projected onto the image plane. For this reason, the centerline of the squares in the vertical direction could be used to estimate the relative position between the camera and marker plane. Utilizing the geometric relationship between similar triangles under a perspective model , the posOn uneven farm ground, rolling of the camera or the marker plane would occur and affect the leader-follower relative position observation accuracy. The calculation of the leader-follower relative position should offset the rolling effect of the camera or the marker plane. For example, suppose the leader vehicle is driven on a horizontal surface, while the follower vehicle forms a roll angle  surface . PCN can be rewritten as:Because the relative position between the leader and the follower vehicle only corresponds to the D and relative angle The transformation of coordinates between the camera and the follower vehicle could be expressed as follows c:(9)XVNThen, the relative position between the leader and the follower vehicle could be written asD and the relative heading angle n points of observation data to a quadratic curve using the least-squares method. In this study, the quadratic curve could be written as:n denotes observation times used to store and fit the data, and Limited by the monocular vision method, the observed leader-follower relative position was noisy under the worst farm conditions. In some cases, large observed errors would occur or there was even a failure to detect the marker plane. The estimation and smoothing of the observation data were necessary to ensure the accurate tracking of the leader vehicle and also to improve the motion stability of the follower vehicle. Because the motion of the two vehicles was continuous, the variation of relative distance and angle between the leader and the follower vehicle was also continuous. The commonly used method of least-squares was introduced to estimate and smooth the relative distance To ensure the fitting effect, avoid collapse of the least-squares method and maintain the original transfer tendency of the leader-follower relative position, the data stored for fitting required appropriate handling. The estimation and smoothing process was realized through two steps: first, once a new camera observation was available, the sequence of the stored observation data would be updated and the latest stored data after updating was temporarily determined as follows:n times of observation data, Second, after fitting to the quadratic curve using the least-squares method, the latest stored data and the current leader-follower relative position could be determined as follows:In this study, only the leader-follower relative position information was used by the follower vehicle to track the leader trajectory. The absence of information exchange and absolute reference positions made the leader trajectory thoroughly uncertain for the follower vehicle, and the tracking position for the follower vehicle was ambiguous. A feedback control method based on the leader-follower relative position was proposed to track the trajectory of the leader. As described in C, located on the centerline of the follower vehicle, was introduced. Moreover, the distance from the rear wheel axial center to the control point C was defined as:l is the length from the front wheel axial center to the rear wheel axial center; C; the parameter C. The position of the control point C in leader-based local coordinates could be written as:To improve the control freedom of the follower vehicle to realize the tracking of the uncertain leader vehicle trajectory, a control point C-based position tracking error between the follower vehicle and its requirement position could be calculated as:Combined with Equations (13)–(15) and (24)–(26), the control point A simple steering strategy for responding to longitudinal and heading tracking error is given as:A PID controller was designed to maintain the required distance between the leader and the follower vehicle; control of the follower velocity could be given as:Experiments for verifying the stability and accuracy of the camera-marker sensing system and leader trajectory tracking accuracy were conducted at the Agricultural and Forestry Research Center, University of Tsukuba . The camera-marker sensing system evaluation experiments included both a static and a dynamic evaluation experiment. The static evaluation experiment was intended to verify the stability and accuracy of the designed observation method and optimize the camera coefficients. The dynamic evaluation experiment was designed to determine the threshold values for data estimation and smoothing, analyze the observation stability and accuracy, and verify the effectiveness of the least-squares method-based data estimation and smoothing solution. A SICK LMS 511 LRF was used to provide reference data, and the relative position from the LRF to the marker plane was used as reference data to evaluate the camera observation accuracy a. In the tracking accuracy evaluation experiments, linear and parallel tracking experiments were conducted on straight, turning, and zigzag paths. Cylindrical markers were mounted above the rear wheel centers of the leader and follower vehicles b to faciIn the static evaluation experiment, the maximum distance from the camera to the marker was approximately 6 m and the relative angle that formed between the marker and the camera axis ranged from −40° to 40° . Using tThe RMS errors of the leader-follower relative distance, relative angle, and orientation angle observation were calculated. When the distance between the camera and the marker was 6 m, the RMS errors of the leader-follower relative distance, relative angle and orientation angle observation were 5.8 cm, 5.07° and 0.228°, respectively. At 4 m, the RMS errors of the leader-follower relative distance, relative angle and orientation angle observation were 3.63 cm, 3.01° and 0.239°, respectively. Considering that the orientation angle obtained from the camera-marker system was stable and had high accuracy, data estimation and smoothing was only conducted for the distance and relative angle observed. In the dynamic evaluation experiment, the leader vehicle was driven along a zigzag path and the follower vehicle was controlled in remote mode to follow the leader. The camera observation data before estimation and smoothing, the estimated and smoothed data obtained through least-squares-based curve fitting, and the LRF observation data were recorded during driving.The results showed that both the camera data before estimation and smoothing and the estimated and smoothed camera data closely matched the LRF data . The RMSTracking accuracy was evaluated using the interval space between the leader and follower vehicle trajectories; the trajectory segments AB and CD were used to calculate this interval space. The follower vehicle could adjust its state and arrive at its required position relative to the leader rapidly and smoothly .The tracking error between the leader and follower vehicle trajectories is shown in The driverless follower is the key of this research, which confirmed the high accuracy in following the human driven leader and the performance of the control system. Experiments were conducted using a specially built robot as follower to confirm the accuracy of tracking and develop a control system without any built-in communication between the leader and the follower. The travelling courses were chosen according to standard agricultural operations, such as straight, turning and zigzag paths. The tracking performance between the leader and the follower was satisfactory under regular field conditions. Undulating terrain and adverse climatic conditions were ignored in the field experiments. The experiments were conducted mostly under daytime conditions. The camera marker system was assisted with the LRF for cross checking the accuracy of the marker positions both in static and dynamic conditions. The LRF was utilized as an assist device to provide reference data and recorded the trajectories during tracking. The contour extraction was influenced by illumination conditions. Low illumination conditions or strong sunlight under an outdoor environment would reduce the contrast ratio of the image and affect the contour of squares, causing marker detection failure. To expand the scope to adapt to various illumination conditions, the image contrast was enhanced using a histogram method that ensured stable observation under various light conditions while conducting experiments during the daytime. The vertical vehicle’s movement or pitch angle of the vehicle body was not considered, as there was not much effect of posture changes of the leader and follower vehicles when projected onto the image plane while travelling on regular ground. This was one of the limitations of this research. However, to overcome such limitations, the centerline of the squares in the vertical direction was used to estimate the relative position between the camera and marker plane. The experiments were conducted with the prototype robot to confirm the accuracy and develop suitable control systems. The validation was done with a human driven small vehicle as leader and the autonomous prototype robot as follower. Definitely in an agricultural environment an actual size autonomous unit can be used as follower by implementing the proposed camera marker sensing and control systems. The productivity would definitely be higher, by reducing labor through enabling the human driven leader and autonomous follower system. In this study, a human-driven leader and automatic follower trajectory-tracking system was developed. A low cost camera servo system, comprising a web camera, encoder and a servomotor, was implemented. An effective camera–marker detection method was developed to follow the leader, which was controlled by an operator. A solution for enhancing image contrast that involved using the histogram method, offsetting vehicle roll angle, and estimating and smoothing the camera observation using the least-squares method ensured a stable and accurate monocular vision system that was able to estimate the relative position between the leader and the follower vehicles with high accuracy. A feedback control rule and a PID controller were also developed and exhibited good performance for linear and parallel leader trajectory tracking. The estimation and smoothing of the camera observation data reduced camera noise and yielded relative positional information between the leader and the follower vehicle with high accuracy. As a result, a stable velocity and steering angle of the follower vehicle and high accuracy of the trajectory tracking was established. Thus, a low-cost, reliable navigation system for a leader and follower vehicle tracking system was demonstrated. In further research, the leader should be converted to a remote control unit to make it unnecessary for the operator to be on-board the leader vehicle. Additionally, to overcome the limitations of the prototype leader-follower system, such as guidance in the adverse climatic conditions are required to consider for agricultural operations.