Genomic selection has become a standard tool in dairy cattle breeding. However, for other animal species, implementation of this technology is hindered by the high cost of genotyping. One way to reduce the routine costs is to genotype selection candidates with an SNP (single nucleotide polymorphism) panel of reduced density. This strategy is investigated in the present paper. Methods are proposed for the approximation of SNP positions, for selection of SNPs to be included in the low-density panel, for genotype imputation, and for the estimation of the accuracy of genomic breeding values. The imputation method was developed for a situation in which selection candidates are genotyped with an SNP panel of reduced density but have high-density genotyped sires. The dams of selection candidates are not genotyped. The methods were applied to a sire line pig population with 895 German Piétrain boars genotyped with the PorcineSNP60 BeadChip.Genotype imputation error rates were 0.133 for a 384 marker panel, 0.079 for a 768 marker panel, and 0.022 for a 3000 marker panel. Error rates for markers with approximated positions were slightly larger. Availability of high-density genotypes for close relatives of the selection candidates reduced the imputation error rate. The estimated decrease in the accuracy of genomic breeding values due to imputation errors was 3% for the 384 marker panel and negligible for larger panels, provided that at least one parent of the selection candidates was genotyped at high-density.Genomic breeding values predicted from deregressed breeding values with low reliabilities were more strongly correlated with the estimated BLUP breeding values than with the true breeding values. This was not the case when a shortened pedigree was used to predict BLUP breeding values, in which the parents of the individuals genotyped at high-density were considered unknown.Genomic selection with imputation from very low- to high-density marker panels is a promising strategy for the implementation of genomic selection at acceptable costs. A panel size of 384 markers can be recommended for selection candidates of a pig breeding program if at least one parent is genotyped at high-density, but this appears to be the lower bound. Genomic selection refers to the use of large numbers of single nucleotide polymorphisms (SNPs) spread across the genome for breeding value estimation and subsequent selection of individuals based on genomically enhanced breeding values ,2. This One way to reduce routine costs is to genotype selection candidates with an SNP panel of reduced density -10. MissMany SNPs of the available chips have unknown chromosomal positions. For example, the PorcineSNP60 BeadChip contains > 62 000 SNP, of which 30% have no known position on the porcine genome sequence (build 7 version) [The aim of the present study was to evaluate different strategies for genomic selection in a sire line pig population using low-density marker panels. The strategies included methods for the approximation of SNP positions, for the selection of SNPs to be included in the low-density panel, for genotype imputation, and for the estimation of the accuracy of genomic breeding values. The methods were validated using genotype imputation error rate, imputation accuracy, correlation between direct genomic values (DGV) and BLUP breeding values (EBV), and approximate accuracies of DGV.Genotypes and EBV of 895 German Piétrain boars were available from breeding organizations. Boars were genotyped with the PorcineSNP60 BeadChip [The boars were progeny tested with a varying number of offspring. Conventional EBV were available for 14 growth, carcass and meat quality traits from the routine animal evaluation centre  of every individual from the validation set was in the training set. The individuals of the validation set were chosen from the latest delivered genotypes. In order to avoid a possible bias due to overfitting the model, we excluded these 100 boars (i.e. their EBV and their genotypes) from all evaluations done during the development of the imputation method.Gm to be the vector of genotypes of the individuals for marker m and MAFm the MAF of this marker. We constructed equivalence classes of marker sets such that markers from the same equivalence class are expected to belong to the same chromosome. Two markers m′ and m″ belong to the same equivalence class if a chain m1,..., mn of markers exists, starting with marker m1 = m′ and ending with marker mn = m″, such that the absolute value of the correlation of the genotypes for adjacent markers in the chain is larger than a threshold value of 0.4. That is,In order to also use markers with unknown physical position for imputation, their positions were approximated using LD information, as described below. Let k = 2,..., n − 1. The threshold value 0.4 was chosen to avoid equivalence classes to cover multiple chromosomes. Correlations of genotypes  were used and not the LD measure r[m′ with unknown position on the identified chromosome was then set equal to the known position of a marker m from the same chromosome that maximized with measure r, becauselocm be the location in megabases (Mb) and Chrm the chromosome of SNP m. In the first step, we defined a distance measure d between two SNPs m′ and m″ as d = ∞ if Chrm′ ≠ Chrm″, and if Chrm′ = Chrm″ thenFrom the set of markers, four subsets consisting of 384, 2 · 384 = 768, 3 · 384 = 1152 and 3000 SNPs were selected based on equidistant location, high MAF, and low correlation of genotypes, as described in the following three steps. Let κ = 5. Following this, we have λ < 1 (λ = 1) if the markers were separated by less than (more than) κ = 5 Mb. Hence, for closely linked loci (λ < 1), the correlation between the genotypes contributed to the distance measure. This was done so that two markers at similar genomic positions could be included in the low-density panel if they were not in LD and, hence, the correlation between their genotypes was low.where m based on its MAF (MAFm):In the next step, a score was calculated for each marker um = 1 if marker m had a known physical position in build 10.2 and if the position did not change during the editing of the marker map, and um = 0.8 if the position of the marker was estimated as described in the previous section, i.e. the latter markers were penalised in the construction of the low-density panels. In the third step, markers were selected based on their scores and the distance measure d. If n markers were already included in the low-density panel, then marker mn+1 was chosen such that mn+1 was chosen from the largest gap, provided that a marker in the gap had a high score.where Scorem = 1), κ was close to zero, and only markers with known physical positions were included. This resulted in low-density panels with approximately equally spaced markers since they were subsequently chosen from the centre of the largest gap.For comparison, we also considered a naïve approach in which all markers had the same score . If the alleles have a different origin t between DGV and EBV was estimated for each trait t. The parameter of most interest, however, is the correlation between DGV and true breeding values (TBV), which will be referred to as the accuracy of the DGV. Since the breeding values for individuals in the training set and the validation set were taken from the same genetic evaluation, there is a substantial correlation of prediction errors among individuals for the EBV that were computed using the complete pedigree. Thus, the frequently used formula to derive the accuracy of DGV, i.e.The individuals were divided into a training set and a validation set as described above. For individuals in the validation set, the correlation is expected to provide estimates that are substantially biased upwards . Hence, n randomly chosen traits, the correlation cort has been estimated. These estimates have been obtained for different mean accuracies Suppose that for a0 and the regression coefficients a1 and a2 are fixed effects, and the errors et are normally distributed. Note that for where the intercept et on t can be estimated asFor simplicity we assumed that possible dependency of the error Table Table Figure Table Table Figure The results presented in this paper showed that imputation caused only a small decrease in accuracy of the DGV, even for very low-density marker panels (384 SNPs across the genome). This might be due to the performance of the genotype imputation method proposed in this study. The method uses both LD and family information. It is tailored to a situation in which at least one parent of the selection candidates is genotyped at high-density. This might be a typical situation in livestock breeding schemes that apply genomic selection with low-density panels. Compared to imputation error rates reported in most other studies, the error rates obtained in this study Tables  and 3 weHuang et al.  estimatem and the haplotype h with the largest score was used to impute the maternal haplotype i of the individual in the neighbourhood of m. The score of a haplotype h depends not only on the length of the interval in which h coincides perfectly with haplotype i, but also on the mismatches at nearby SNPs. This increases the robustness of the method with respect to sporadic haplotyping errors that occur from data phasing. Moreover, inclusion of the additive relationship into the score has the effect of favouring haplotypes of closely related individuals for imputation. This is an advantage because for unrelated individuals the low-density haplotypes can by chance coincide in the neighbourhood of m.For the imputation approach, all haplotypes of the haplotype library were scored for every low-density marker Other methods such as Beagle , LDMIP , IMPUTE2Imputation error rates could be reduced by genotyping at high-density more close relatives of the low-density genotyped individuals Table . A furthLm to be the length of the chromosome that contains marker m. The score may be multiplied with a factor of the form ((1 − λ)Lm + λ max (L))/Lm in order to ensure that more markers from the low-density panel are placed on short chromosomes. In some cases, it may be desirable that the markers from the low-density panel explain part of the additive variance. The approach can be generalized to this situation. For example, the score of a marker may be defined as its average contribution to the additive variance of traits that are standardized to have the same additive variance. That is, the score could be m, averaged over all traits. Another possibility is to let the score of a marker depend on the p-values obtained from an association study, such that markers with small p-values have a higher score. It is also possible to choose more markers from the chromosome ends by modifying the distance measure.Markers for the low-density panels were selected based on their scores and their distances to the markers already included in the low-density panel. The MAF of the marker was used as the score. An alternative procedure for marker selection that takes MAF and distances of adjacent markers into account was proposed by Wang et al. . Our appThe correlations between DGV and EBV Table  were subs could be obtained by splitting the data into a training set, a validation set and an omitted set. Care should be taken so that the mean accuracies of the EBV in the validation sets vary between replicates and that the mean accuracies in the training sets are approximately equal to the average accuracy of all EBV. For these replicates the linear model a2 could be omitted if only one trait is considered.The regression approach used a linear model to predict the regression function outside the range of the data. Since the linearity assumption might be violated, this approach should be evaluated in more detail with simulated data, where the true accuracies are known. The regression approach used results from multiple traits with heterogeneous accuracies of the EBV Table . This apMethods for genomic selection using low-density marker panels were introduced and applied to a dataset from a sire breeding line in pigs. It was shown that imputation from low- to high-density marker panels is a promising strategy, even if the low-density panel contains less than 1000 markers. A number of 768 markers can be recommended, but 384 markers may be sufficient if at least one parent is genotyped at high-density. Careful selection of low-density markers is essential. The proposed regression method for obtaining unbiased estimates of the accuracy of genomic breeding values in a cross-validation setting showed promising results but has to be evaluated in more detail.The authors declare that they have no competing interests.RW developed the methods and did the statistical analysis. RW and JB conceived and designed the experiment and wrote the paper. SP and KW generated the genotypes. JH and ET generated the conventional BLUP EBV. All authors read and approved the final manuscript.The table shows the genotype error rate and imputation accuracy per chromosome for the 384 marker panel.Click here for file


Salmonella. The aim of the present study was to evaluate the conditions under which human serum can be stored and manipulated while maintaining complement integrity. Serum bactericidal activity against Salmonella was maintained for a minimum of 35 days when stored at 4°C, eight days at 22°C and 54 hours at 37°C. Up to three freeze-thaw cycles had no effect on the persistence of bactericidal activity and hemolytic complement assays confirmed no effect on complement function. Delay in the separation of serum for up to four days from clotted blood stored at 22°C did not affect bactericidal activity. Dilution of serum resulted in an increased rate of loss of bactericidal activity and so serum should be stored undiluted. These findings indicate that the current guidelines concerning manipulation and storage of human serum to preserve complement integrity and function leave a large margin for safety with regards to bactericidal activity against Salmonella. The study provides a scheme for determining the requirements for serum handling in relation to functional activity of complement in other systems.The complement cascade includes heat-labile proteins and care is required when handling serum in order to preserve its functional integrity. We have previously used a whole human serum bactericidal assay to show that antibody and an intact complement system are required in blood for killing of invasive isolates of  Salmonella. We have found that these mechanisms of bacterial killing require both antibody and complement Complement comprises a set of plasma proteins that facilitate the killing of pathogens by antibody It has long been known that complement activity is heat-labile We have been able to uncover only limited objective data about the stability of the human complement components required to induce cell free and phagocyte-mediated lysis of bacteria in vitro. Hemolytic assays are normally used for such investigations of complement stability Salmonella in our cell-free bactericidal assays. In this study, we explored the longevity of bactericidal activity at different temperatures, effect of freeze-thaw cycles and effect of delayed separation of serum from blood. We were able to determine the conditions for preservation of serum complement activity for use in our assay system. The study also serves to provide a scheme for assessing serum handling in order to maintain complement function for other in vitro functional assay systems.We conducted the current study to determine acceptable conditions for manipulation of human serum that would not be detrimental to its ability to kill Ethical approval for the use of serum samples in this study was granted by the Life and Health Sciences Ethical Review Committee of the University of Birmingham. Informed written consent was obtained from all participants.Blood was venesected from four healthy adults  and left to clot at 4°C for 8 hours or at 22°C for from zero to four days in the delayed serum-separation experiment. Serum was separated by centrifugation at 4°C and frozen in aliquots at −80°C in sterile 8 ml polypropylene tubes (Sarstedt) or left at 4°C or 22°C (in the delayed serum-separation experiment). When required, frozen aliquots of serum were thawed on the bench at 22°C. Samples undergoing freeze-thaw cycles were immediately refrozen at −80°C after reaching 22°C, and this was repeated daily for up to three sequential days. Heat-inactivation of complement was performed, when needed, by incubating serum in a water bath at 56°C for 30 minutes.Salmonella enterica serovar Typhimurium D23580, a well-characterized invasive nontyphoidal Salmonella isolate from Malawi Salmonella were as described previously S. Typhimurium D23580 was grown at 37°C to log-phase from an overnight culture in LB medium for two hours and washed twice in PBS. 10 µl of washed bacteria resuspended in PBS, without additional Mg2+ or Ca2+, was added to 90 µl of serum in a microfuge tube to give a final concentration of 106 cfu/ml in 90% serum, and incubated on a rocker plate at 37°C and 20 rpm. Viable numbers of Salmonellae were determined for the washed bacterial inoculum and at 45, 90 and 180 minutes exposure to serum by serial dilution in PBS followed by overnight growth at 37°C on LB agar. Killing of Salmonellae was calculated by subtracting the concentration of viable Salmonellae at the start of the assay from the concentration of viable bacteria at each time point. Serum bactericidal assays were performed with heat-inactivated serum as a negative control. When required, for inhibition of alternative pathway activity, polyclonal antibodies to Factor B  were added to the assay at a final concentration of 0.92 mg/ml.Serum bactericidal assays against S. Typhimurium D23580 IgG, IgA and IgM levels were assessed by flow cytometry as previously described Anti-Classical and alternative pathway hemolytic complement assays were performed by radial immunodiffusion  according to the manufacturer’s instructions.The ANOVA test was used to compare groups of data within the study using Prism version 5.02 .Salmonella has previously been shown to depend on specific IgG or IgM antibody activating the classical complement pathway and the consequent deposition of membrane attack complex on the bacterial surface S. Typhimurium D23580 when diluted in PBS. We confirmed the finding that, when first thawed, serum concentrations of 20% or above are required to achieve a 1.0 log10 cfu/ml kill of Salmonella  at 180 minutes in the serum bactericidal assay , each serum killed D23580 by approximately 2.0 log10 cfu/ml  or 22°C (p = 0.19 to 0.99).Delayed separation of serum from blood often occurs due to delays in transportation of blood samples from clinic to laboratory. To investigate the effect of up to four days delay in separation of serum from blood on Salmonella killing assay. To test this, we took further samples of blood from the four donors and separated and froze serum on the day of venesection, and after 1, 2, 3 or 4 days at 4°C and 22°C for functional complement pathway assays. There was no significant difference in classical or alternative pathway hemolytic complement activity with serum that had been separated from blood after four days at 4°C or 22°C, compared with serum separated and frozen on the day of venesection (Loss of complement activity following four days of delayed separation of serum from blood could occur to a degree that would not be detectable by our esection .S. Typhimurium D23580 was dependent on the alternative pathway of complement, we performed the serum bactericidal assay with anti-properdin antibodies added to fresh serum from subject 1 at a final concentration of 0.92 mg/ml in order to block the alternative pathway. Killing of Salmonella was fully inhibited with net bacterial growth at all time points in the assay (In order to test whether killing of he assay .th century. Much of the data described in this literature relates to studies of animal, rather than human complement, and uses hemolytic complement assays that may not reflect the bactericidal assay against Salmonella or bacteria in general, which usually depend on the combined action of antibody and complement.Despite the importance given to careful handling of serum in order to preserve complement activity, the available scientific literature describing experimental studies on this activity dates from the first half of the 20Salmonella for 35 days. For three of the four sera, killing was still obtained after 70 days at 4°C. We have previously shown that classical pathway of complement is required for bactericidal activity against invasive African isolates of SalmonellaSalmonella in our serum bactericidal assay using blood that had been left for four days at room temperature prior to serum separation and use. It is possible that some loss of complement activity, undetectable by our serum bactericidal assay, which standardly uses undiluted serum, may have occurred during this time. However, the lack of change in functional complement activity assessed by the hemolytic assays indicates that this was not the case.A common assumption is that frozen aliquots of serum should be used on the day of thawing when required for bactericidal assays. Our findings indicate that this is not the case, since thawed serum stored at 4°C effects normal levels of killing of Salmonella, this is sufficient for the deployment of the alternative pathway which then becomes the critical determinant of bactericidal activity. When we performed the bactericidal assay with anti-properdin antibodies to block the alternative pathway, killing was fully inhibited confirming the critical role of alternative pathway in serum killing of Salmonella. It is surprising that serum from subject 1 had only half the duration of bactericidal activity of the other three sera when stored at 4°C. Our data do not provide an explanation for this, since longevity of classical and alternative pathway hemolytic complement activity for this serum was no less than that for the other three sera, and there was no evidence for the blocking activity which we have previously described in serum from some HIV-infected African adults Mechanistically, these data are compatible with the hypothesis that once the classical pathway has initiated C3b deposition on Salmonella was reduced with increased storage temperature post-thawing. The practical implication of this is that if thawed human serum is to be used over an extended number of days, it is important that it is kept refrigerated.Perhaps the most surprising finding of the study was the lack of any discernible effect on bactericidal activity of up to three freeze-thaw cycles, given the accepted view that freeze-thaw cycles are to be avoided in the context of preservation of complement function When considering the significance of the findings of the current study, it is important to consider that much of the non-variable blood and serum handling involved was conducted under optimal conditions. Different findings could be expected if, for example, frozen serum had been stored at temperatures higher than −80°C, or if during freeze-thaw cycles, serum had been left thawed for extended periods of time before refreezing. We have allowed blood to clot at both room temperature and 4°C, as described in the present study, and have found no difference in integrity of complement activity with either protocol. Blood clots more rapidly at room temperature and should be separated and frozen sooner than blood stored at 4°C. As expected, diluted serum loses bactericidal activity more rapidly than undiluted serum, so serum to be used for serum bactericidal assays and other functional complement assays should be stored undiluted. It is important to remember that human complement does not necessarily behave the same as animal complement in bactericidal assays It possible that serum from some individuals may perform less well that than that of others due, for example, to polymorphisms of the alleles encoding C4. Furthermore, serum from individuals with complement-consuming conditions such as autoimmunity or hepatitis C infection would be unsuitable for use. The current study only tested serum from four individuals which was due to the large number of assays required to determine the conditions for serum manipulation. Ideally, serum for each new donor should be tested in an established assay system prior to using it routinely.Salmonella, the subject’s own endogenous complement is used allowing assessment of the combined activity of the subject’s antibody and complement in the bactericidal process. This could provide a more accurate indication of the complement-mediated bactericidal activity that each individual has against a pathogen.Serum bactericidal assays, particularly against meningococcus, often use animal complement as a source of exogenous complement usually in the form of baby rabbit serum. While this can facilitate standardization, it has led to problems with assay sensitivity and specificity leading some to propose the use of human complement instead Salmonella, it is important to establish the conditions for serum handling to each particular in vitro assay system and complement source. This study provides a model for the testing of conditions of serum manipulation that can be applied to other assay systems and other sources of complement.While the current study was focused primarily on the preservation of complement activity in relation to bactericidal activity of human serum against


Three issues regarding sensor failure at any position in the antenna array are discussed. We assume that sensor position is known. The issues include raise in sidelobe levels, displacement of nulls from their original positions, and diminishing of null depth. The required null depth is achieved by making the weight of symmetrical complement sensor passive. A hybrid method based on memetic computing algorithm is proposed. The hybrid method combines the cultural algorithm with differential evolution (CADE) which is used for the reduction of sidelobe levels and placement of nulls at their original positions. Fitness function is used to minimize the error between the desired and estimated beam patterns along with null constraints. Simulation results for various scenarios have been given to exhibit the validity and performance of the proposed algorithm. In adaptive beamforming, null steering and beam steering are hot research areas. It has direct application in radar, sonar, and mobile communication –3. In thIn the last few decades Radar technology has developed very rapidly. The radar commonly used nowadays is known as phased array radar. In this radar the whole input array transmits the same signal with different delay and a beam is formed towards the area of interest . The advThe evolutionary computing technique has been doing well in solving numerous problems in search and optimization due to the impartial nature of their operations which can still be present in situations with no domain knowledge. The search method used by evolutionary algorithms (EAs) is impartial having no domain knowledge to guide the search method. Domain knowledge serves as a method to reduce the search space by pruning unnecessary parts of the solution space and by promoting required parts. Cultural algorithm is based on the principle to bias the search method with prior knowledge about the domain, as well as the knowledge during the evolution method.Among EC techniques, differential evolution (DE) is considered to be one of the powerful and reliable tools to optimize the problems in any engineering field –14. The In this paper, the proposed algorithm developed three issues in case of sensor failure. These are raised in sidelobe levels, displacement of nulls from their original positions, and diminishing of null depth. We propose a symmetrical sensor failure (SSF) method that provides better results in terms of null depth. Moreover, the SSF method has deeper first null which is another big improvement over single sensor failure. The first null depth in beamforming is of great importance. To address the other two issues, we have used a cultural algorithm with differential evolution (CADE) to reduce the sidelobe levels and positions of nulls reverse to their original positions by adjusting the current weights of active sensors. A hybrid method based on the memetic computing algorithm is proposed, which combines the cultural algorithm with differential evolution (CADE) for the reduction of sidelobes and placement of nulls. Different simulation results are provided to confirm the performance of the proposed approach. The rest of the paper is organized as follows. The problem formulation is discussed in N = 2M + 1. The array factor in this healthy set up with uniformly spaced sensors, nonuniform weight, and progressive phase excitation will be [wn is the nonuniform weight of nth sensor whereas n = 0, ±1, ±2,…, ±M. The spacing between the adjacent sensors is d, while θ is the angle from broadside. k = 2π/λ is the wave number with λ as wavelength. The progressive phase shift β = −kdcosθs and θs is steering angle for the main beam. The damage array factor for 7th sensor failure is given by the expression below:Consider a linear array of 17 sensors in which all the sensors are placed symmetrically about the origin. The total number of sensors is  will be (1)AF for the reduction of sidelobes and placement of nulls in the required positions.N decision variables; F and CR are parameters given by the user and given in DE is an EA and was developed by Storn and Price which is used to solve real valued optimization problems . The DE Differential evolution is used as a population space in the cultural algorithm. CAs have been developed to model the evolution of the cultural component of an evolutionary computational system over time as it accumulates experience. As a result, CAs can provide a clear method for global knowledge and a framework within which to model self-adaptation in an evolutionary system.Cultural algorithms consist of three components, a population space, belief space, and a communication protocol as shown in CAs model has two levels of evolution. One is the population level and the other is belief space level. In addition to a population space, CA has a belief space in which the beliefs acquired from the population's evolution can be stored and integrated. An acceptance function is used to generate beliefs by gleaning the experience of individuals from the population space. In return, this belief space can bias the evolution of the population component by means of the influence function. The belief space itself also evolves by the adjust function . In the P found along the evolutionary process. It represents a leader for the other individuals to follow. The variation operators of differential evolution are influenced in the following wayPi is the ith component of the individual stored in the situational knowledge. This way, we use the leader instead of a randomly chosen individual for the recombination, getting the children closer to the best point found. The update of the situational knowledge is done by replacing the stored individual P, by the best individual found in the current population, xbest only if xbest is better than P.Situational knowledge stores individuals from population space which provides the direction for other individuals. Situational knowledge consists of the best example ds1 to influence the mutation operator adopted in differential evolution. The following expression shows the influence of the normative knowledge of the variation operatorsli and ui are the lower and upper bounds, respectively, for the ith decision variable. The update of the normative knowledge can reduce or expand the intervals stored on it. An extension takes place when the accepted individuals do not fit in the current interval, while a reduction occurs when all the accepted individuals lie in the current interval, and the extreme values have an improved fit and are feasible. The values dsi are updated with the difference  found of the variation operators of the prior generation. Normative knowledge leads individuals to jump into the good range if they are not already there. The normative knowledge is updated as follows, let us consider xa1, xa2, xa3,…, xanaccepted be the accepted individuals in the current generation and ximin and ximax belong to  and the accepted individuals with minimum and maximum values for the parameter i:The normative knowledge contains the intervals for the decision variables where good solutions have been found, in order to move new solutions towards those intervals. The normative knowledge includes a scaling factor, li and ui are updated, the values of Li and Ui will be done in the same way. The dsi are updated with the greatest difference of |xi,r1 − xi,r2| found during the variation operators at the prior generation.If The flow chart and pseudocode for CADE is shown in θi, we want [wH is N × 1 vector which is defined asA jamming signal located at a particular angle wants to be eliminated, in case of satellite, radar, and mobile communication applications. For a uninformed array, to put a null at a particular angle  we want (8)AF represents the desired pattern and AFCADE(θi) is the pattern obtained by using CADE. The second term in  is used for the reduction of sidelobes and placement of nulls in the required positions.In the simulation, a classical Dolph-Chebyshev linear array of 17 sensors with Case a. At the first instant the w7 sensor is assumed to fail. After sensor failure the radiation pattern is destroyed, which results in an increase of the SLL and displacement of null positions. In order to regain the symmetry, its mirror sensor weight w−7 is forced to zero. We achieve the desired null depth level (NDL) and deeper first null depth level (FNDL) as compared to that of nonsymmetric case. The SLL rises to −32.32 dB due to the w7 sensor failure, while due to SSF of the w7 sensor, the SLL is −26.53 dB. The advantage of SSF is deeper nulls, especially, the first null. The SLL and FNDL for a damage array of single sensor failure and SSF are shown in w7 sensor failure are reduced to −32.99 dB while due to SSF, the SLL is reduced to −28.35 dB. The recovery of one null due to 7th sensor failure and SSF to its original position θ1 = 19.93° is shown in Figures After optimization by a cultural algorithm with differential evolution (CADE), the SLL of the θ1 = 19.93° and θ2 = 34.88°, respectively, for 7th sensor failure and SSF. The SLL and NDL for the corresponding nulls are given in Figures θ1 = 19.93°, θ2 = 34.88°, and θ3 = 45.44° for 7th sensor failure and SSF. The SLL and NDL for the corresponding nulls are given in Now we check the recovery of three nulls at the required positions. Figures Now the recovery of five nulls for 7th sensor failure and SSF originally at positions 19.93°, 34.88°, 45.44°,62.02°, and 68.94° is carried out and shown in Figures Case b. In this case, we discuss the failure of w4 sensor. If the sensor w4 fails due to any reason, the whole radiation pattern became damage. After optimization, the SLL reduces and nulls are steered back to their original positions as shown in w−4 equal to zero, to achieve the required null depth level. The advantage of symmetry sensor failure is to get deeper null depth level. The number of nulls achieved in 7th symmetry sensor failure is six, and in case of 4th symmetry sensor failure the number of nulls received are three. From the simulation results, it is clear that the number of nulls reduces by one as the sensors get damage near the centre sensor. After optimization by CADE, the SLL reduces and nulls are steered back to their previous positions at angles θ1 = 34.89°, θ2 = 54.31°, and θ3 = 68.9° as shown in Case c. In this section, we discuss the possibility of getting failure near the centre sensor, if the sensor w1 fails due to unforeseen reason. From w−1 equal to zero. The one advantage of symmetry sensor failure is to get the deeper null depth level and, on the other hand, due to w1 SSF its beamwidth also decreases. In case of 7th symmetry sensor failure, the nulls are six, and in 4th SSF the achievable nulls are three but we received only one null in case of w1 SSF as shown in Case d. The main beam can be steered at any desired angle. If the user changes their position than the main beam can be steered in the desired direction. θs = 110°. The main beam can be steered in the direction of the desired user at any particular angle. The array factor for 2M + 1 sensors in terms of main beam direction θs is given byθs is the main beam direction to which it can be steered to the desired angles.w1 SSF we received only one null with reduced beamwidth. The simulation result shows that as the faulty sensor gets near the central sensor the number of nulls reduces by one. The reduction in the corrected sidelobe level comes at the cost of broader main beam. The corrected pattern has beamwidth broader than that of the original one. Using the approach of symmetric sensor failure, with the reduction of the SLL, we can steer single, double, and multiple nulls in the direction of known interferences. This method can be extended to planar arrays.We have proposed symmetric sensor failure (SSF) technique along cultural algorithm with differential evolution for the correction of faulty arrays. The null depth of all nulls, especially the first one, has been achieved with the help of SSF technique. Null steering at their original positions and sidelobe reduction has been achieved by a cultural algorithm with differential evolution and using a proper fitness function demanding the sidelobe reduction and null constraints. Due to 7th SSF the number of nulls is six and in 4th SSF the achievable nulls are three but in case of


Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation.A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months.Organisation/Responsibility The ACUPEND - Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg.th 2009. The first patient was randomized on February 2nd 2010.The trial is registered at Germanctr.de (DRKS00000164) on December 10 More than 10 million gastrointestinal (GI) endoscopic procedures are performed every year in the United States only. The staRecently, the first S3-guideline for sedation in GI endoscopy in Germany was published to improve patient safety, which demands additional trained personnel and endoscopy equipment. TherefoAcupuncture has been used as a part of Traditional Chinese Medicine (TMC) for more than 2000 years. Many stIf the use of acupuncture could improve tolerance and examination quality of diagnostic EGDE without sedation it should be possible to increase the willingness of patients to undergo this examination without systemic sedation. Consequently, it would be possible to reduce the rate of serious adverse events due to systemic sedation and to lower the costs for personnel and material.Up to now, only one double-blind, controlled trial with 90 patients undergoing EGDE was performed in 1978, using real versus sham-acupuncture (1 cm away from the acupuncture point) with 10 needles and electrical stimulation and showing that upper endoscopy was much easier and better tolerated after real acupuncture. But thiThe objective of this trial is to compare the rate of successful EGDE  in patients receiving pharyngeal anaethesia as well as either real or placebo acupuncture.The sample size calculation is based on the two-sided chi-square test for difference with respect to the primary endpoint.A review of the previous literature identified a randomized controlled trial from Abraham et al. with a group of 419 patients comparing the rate of successful EDGE with and without sedation. In bothInclusion criteria• Age equal or greater than 18 years• Patients scheduled for elective diagnostic EGDE without systemic sedationExclusion criteria• Patients classified ASA V• Participation in another clinical trial which could interfere with the primary endpoint of this study• Expected lack of compliance• Impaired mental state or language problems• Patients with known allergy to lidocaine anaesthetic spray or acupuncture needle material• Necessity of systemic sedation• Emergency procedures• PregnancySubject withdrawal criteria• At their own request or at request of the legal representative• If, in the investigator's opinion (physician performing the acupuncture or physician performing the examination), continuation of the trial would be detrimental to the subject's well-being .All withdrawn patients will be reported in the final results to guarantee maximum transparency.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf. The protocol was approved by the Ethics Committee of the University of Heidelberg (S-273/2009). All patients scheduled for an elective diagnostic EGDE in the Interdisciplinary Center of Endoscopy (IEZ) of the Department of General, Visceral and Transplantation Surgery and the Department of Internal Medicine of the Universitiy of Heidelberg will be screened, informed about the ACUPEND trial and included by physicians of the IEZ supervising in this trial. The study procedure, risks, benefits and data management will be clarified in detail before the patients are asked to give their informed consent.The ACUPEND- Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki 1989 and GoodThe study protocol was designed according to the Standards for reporting Interventions in Clinical Trials Acupuncture (STRICTA).To achieve comparable groups for known and unknown risk factors, randomization will be performed as a block randomization with alternating block size. Allocation to treatment group will be performed by sealed consecutively numbered envelopes prepared by the Institute of Medical Biometry and Informatics of the University of Heidelberg (IMBI). Randomization will be carried out after the patient has signed the informed consent form and will be documented in the case report file of every patient. The allocation will be controlled by a monitor.All physicians who participate in this trial will be trained and updated every 3 month to improve comparable treatment of patients.Special manuals will be used in the Interdisciplinary Center for Endoscopy (IEZ) to reduce errors. Acupuncture will be performed by physicians of the department of the Interdisciplinary endoscopy center (IEZ) who were trained by experienced acupuncturists with level B diploma and who performed at least 20 acupuncture procedures explained in the intervention chapter under supervision. Furthermore the PS3 device will be used to support the localisation of the correct acupuncture points by measuring loss of skin resistance.A study nurse or physician will document and monitor the procedure in the endoscopy and recovery room. Before the endoscopic procedure is performed the acupuncturist will open the allocation envelope. The physician performing the EGDE and the assistant nurse will not be informed about the allocation. Once patients are randomized they will be included into the analysis according to the principle of intention to treat.Patients who are scheduled for EGDE will be screened and informed by a member of the IEZ about the trial before their EGDE procedure. After signing the informed consent form the patients will be prepared by staff nurses for the procedure as usual. A study nurse or physician will be present to monitor and document the procedures Table .2 and non-invasive blood pressure will be established. Pharyngeal anaesthesia will be performed with a topical xylocaine spray  in all patients by a nurse or physician.All patients will be positioned on a stretcher lying on their backs with 30 degrees reverse Trendelenburg's position. Standard monitoring with SaOWe based the acupuncture point selections on Traditional Chinese Medicine meridian theory to improve tolerance and examination quality of diagnostic EGDE.All patients will receive placebo acupuncture at the following points according to the procedure of the Streitberger placebo acupuncture needle system Figures  and 3 1:KG 24   Chengjiang   middle line (to reduce choking)Pericard 6   Neiguan   bilateral   Di 4   Yangxci   bilateral   (to reduce nausea and vomiting)Half to one inch 32G needles  will be placed and left in their position for five minutes prior and throughout the endoscopic procedure.After the described preparation patients will receive a real acupuncture at the following acupuncture points:KG 24   Chengjiang   middle line   (to reduce choking)Pericard 6   Neiguan      bilateral       Di 4   Yangxci      bilateral      (to reduce nausea and vomiting)Half to one inch 32G needles  will be placed into these points, stimulated for 1-2 seconds to induce de qi sensation and left in this position for five minutes prior and throughout the endoscopic procedure.To perform EGDE all patients in both groups will be turned on their left side still with a 30 degree reverse Trendelenburg's position.The primary endpoint will be the rate of successful diagnostic EGDE.Rate of successful elective diagnostic EGDE is defined as a composite score of patient satisfaction with the procedure as well as quality of the examination  as assessed by the examiner. These were determined by the administration of standardized Likert scales.Immediately after the elective diagnostic EGDE, the examiner scores the technical adequacy of the examination. Each anatomic area  that was adequately viewed receives a score of 1 versus 0 if inadequately viewed, for a maximum score (4/4) if all four main anatomic areas of the examination were well visualized. The result will be documented in the CRF with tick boxes by the physician who performed the examination.The patients are asked to rate their satisfaction with the examination after the completion of EGDE, prior to being told the results of their procedure and prior to discharge from the recovery room, on a Likert scale from 1 = acceptable to 5 = unacceptable. The results will be documented in the CRF with tick boxes by a nurse or physician. An EGDE will be counted as success if patients' satisfaction is 1 or 2 on the Likert scale and the examination quality score is 4/4,18-20.The willingness to repeat the procedure is defined as readiness of the patient to repeat the examination under the same conditions and will be recorded in the CRF with tick boxes (yes/no) by a nurse or physician. Heart rate (beats per minute), blood pressure (mmHg) and oxygen saturation (per cent) will be assessed before EGDE, after passage of the larynx and after removal of the endoscope. The results will be documented in the CRF by a nurse or physician. The duration of the examination in minutes from insertion to removal of the endoscope will be documented in the CRF. Furtheremore periinterventional complications as described and defined in Table The correct placement of the needles will be checked and if necessary replaced by the physician who performed the acupuncture right before the examination. After endoscopic examination the needles will be checked again. If some of the needles are not in place after examination it will be documented in the CRF.Every patient can be switched to systemic sedation at anytime to successfully complete the EGDE if necessary or at the patient's wish. The conversion will be documented in the CRF and the patient's satisfaction will be counted as 5/5 (unacceptable) on the Likert scale. Therefore, the need for systemic sedation is defined as unsuccessful EGDE for both intervention groups.Prior and concomitant illness of the patients will be documented in the CRF.AEs will be reported to the principal investigator in regular intervals during the course of the study. SAEs will be documented on a special SAE form in the CRF and will be reported to the principal investigator within 24h.Each patient's allocation to the different analysis populations  according to the intention-to-treat (ITT) principle, per protocol (PP) analysis set, safety analysis set) will be defined prior to the analysis. The allocation will be documented in the statistical analysis plan. During the data review, deviations from the protocol will be assessed as "minor" or "major". Major deviations from the protocol will lead to the exclusion of a patient from the PP analysis set.The null hypothesis H is assessed by testing the intervention effect in a primary analysis using a two-sided chi-square test. In a secondary analysis a binary logistic regression model that takes into account the covariates "intervention" (placebo/acupuncture), age  and gender will be used. A two-sided type I error rate of α = 0.05 will be applied to the primary and secondary analysis.Confirmatory analysis will be primarily based on the FAS which is consistent with the intention-to-treat (ITT) principle, by including all patients who were randomized into the two groups. This approach reflects the idea that the study should correspond to the conditions in clinical practice as closely as possible.In addition to the evaluation of the FAS, a PP analysis will be performed including all randomized patients without major protocol violations.st and 3rd quartiles as well as minimum and maximum or absolute and relative frequencies, respectively, will be reported. Descriptive p-values of the corresponding statistical tests comparing the treatment groups and associated 95% confidence intervals will be given.The secondary variables will be analyzed in a descriptive manner by tabulation of the measures of the empirical distributions. According to the scale level of the variables, means, standard deviations, medians, 1® software, Version 9.1 (or higher) of the SAS System for Unix .The homogeneity of the treatment groups will be demonstrated descriptively using the demographic data and the baseline values. All statistical analyses will be performed using SASAfter approval of the protocol by the local ethics committee of the University of Heidelberg, the trial was internationally registered at Germanctr.de (DRKS00000164). All patients scheduled for elective, diagnostic EGDE in the Interdisciplinary Endoscopy Center (IEZ) who refuse sedation will be referred to and screened by members of IEZ or the Clinical Study Center Surgery (KSC). The result of the screening will be recorded in the screening-log.Approximately 4300 patients per year undergo an EGDE including about 900 patients without systemic sedation in the Interdisciplinary Center for Endoscopy (IEZ) of the Universitiy of Heidelberg. The estimated time frame to randomize 354 patients is 20 months.Sponsor of the ACUPEND trial is the University Hospital of Heidelberg.The independent data management and statistical analysis will be carried out by the Institute of Medical Biometry and Informatics (IMBI) of the University of Heidelberg according to a prespecified Statistical Analysis Plan.The principal investigator has the right to terminate the trial and to remove all trial material from the trial centre at any time in consultation with the Clinical Study Team Leader and the Biostatistician. Reasons that may require a termination of the trial include the following:• The incidence or severity of adverse events in this trial indicates a potential health hazard caused by the study treatment• It appears that patient's enrolment is unsatisfactory with respect to quality or quantity or data recording is severely inaccurate or incomplete• External evidence that renders the necessity to terminate the trialThe trial will be sponsored by the regular research budget (State of Baden-Württemberg) of the Clinical Study Center Surgery (KSC), Department of General, Visceral and Transplantation Surgery of the University of Heidelberg and the IEZ.The authors declare that they have no competing interests.PK, CB, CMS, KP and AS are responsible for the study design, definitions of the primary and secondary endpoints and preparation of the protocol. TB is responsible for the sample size calculation. KS carried out the literature research.


The main emphasis of the work concerns the improvement of the techniques for the molecular simulation of these epoxies and specific attention is paid towards model construction techniques, including automated model building and prediction of glass transition temperatures (Tg). Typical models comprise some 4200–4600 atoms (ca. 120–130 monomers). In a parallel empirical study, these systems have been cast, cured and analysed by dynamic mechanical thermal analysis (DMTA) to measure Tg. Results for the three epoxy systems yield good agreement with experimental Tg ranges of 200–220°C, 270–285°C and 285–290°C with corresponding simulated ranges of 210–230°C, 250–300°C, and 250–300°C respectively.The construction of molecular models of crosslinked polymers is an area of some difficulty and considerable interest. We report here a new method of constructing these models and validate the method by modelling three epoxy systems based on the epoxy monomers bisphenol F diglycidyl ether (BFDGE) and triglycidyl- Epoxy resins are one of the more commonly encountered families of commercial thermosetting polymers and are widely used in a diverse range of industrial applications including coatings, adhesives, electronic devices, and as the matrix resin for advanced structural composites  and >90 g was cured following the scheme in ca. 5 mg) were taken for Differential Scanning Calorimetry (DSC) from the cured and uncured material. A cured and an uncured sample was taken from each formulation and scanned from −50°C to 350°C at a rate of 10 K/minute under nitrogen (40 cm3/min.). DMTA was carried out on cured neat resin samples (4×1.4×40 mm3) in air using an ARES LS 2K/2K FRT DMTA in torsion rectangular solicitation mode at 3 K/minute (0.1 Hz frequency and 0.1% strain). Specimens were dried prior analysis (100°C over night if Tg >180°C).The three epoxy formulations  were mixe.g. a Dell PowerEdge 1950, 2×Quad Core Intel Xeon E5140 2.33 GHz, 8GB RAM, 500 GB HDD). The Discover module was used for general simulation requirements, such as geometry optimisation and molecular dynamics as well as molecular mechanical analysis to predict values for tensile, bulk modulus, shear modulus, Poisson’s ratio and the Lamé constants. The Amorphous Cell module was used to build amorphous, homogenous 3D cells composed of molecules that were drawn in silico. It also has a number of protocols designed to make greater use of the Discover module, of specific interest is the temperature cycling protocol, which can be used for Tg prediction. All simulations were performed in the bulk state, i.e. without the addition of solvent as there is no added solvent in epoxy resin cure.The Materials Studio molecular modelling suite (Accelrys Inc.) was utilised in this work Formulations were made with BFDGE and Daminodiphenylsulphone (DDS) (Epoxy 1) and with TGAP and DDS (Epoxies 2 and 3). A summary of the epoxy formulations and atomistic models is given in ca. 150 K above the experimental Tg as determined by DMTA). Each temperature step was of 125 ps with the first 25 ps of data discarded.Each model was subjected to a Discover Molecular dynamics single run using the NPT Ensemble for a minimum of 500 ps, a timestep of 1 fs, using the Anderson Thermostat at a Pressure of 0.1 MPa under the Parrinello Barostat. The force field was the Polymer Consistent Force Field (PCFF) with Atomic vdW and Coulomb Summation with a cutoff of 10 Å, a spline width of 3 Å and a buffer width of 1 Å. The same procedure was then applied to the MD simulation over a predetermined temperature range, with decrements of 10 K from the starting temperature  = 162 g/mol and a purity degree of 96%. The impurities appear to be monofunctionalised and oligomers.” and from the specification of Triglycidylaminophenol (TGAP) “EEW = 96 g/mol and a purity degree of 96%. The impurities appear to be functionalised oligomers”. The simplest way to achieve the specified EEW is to include a proportion of functionalised dimer or trimer using With reference to 3).It would be simple to build the atomistic models using the pure monomer molecules in monomer should be equal to the purity of the monomer, it is a molar fraction, not to be confused with the mass fraction, which is usually quoted for purity. However this can be limiting as it requires a precise EEWoligomer to achieve the desired EEWmix. Calculation shows that 96% BFDGE monomer and 4% BFDGE dimer gives an EEWmix of 161.3  and 96% TGAP monomer and 4% TGAP octamer gives and EEWmix of 96.1 . It would be possible to represent exact purity and EEW by also including a small fraction of trimer to BFDGE and a small fraction of pentamer to the TGAP mix. This solution often requires fine tuning of fractions and requires a very large model to keep the ratios of molecules as integers. For practical purposes, the model size has to be kept in check, to do this, only BFDGE dimers and TGAP trimers were used to represent the impurity molecules. It was considered more important to maintain the EEW and it can be seen in For the best accuracy the Fractione.g. 4555 atoms, with 119 epoxy-amine pairs requiring bonding for a 70% cure, the desire for an automatic cure program became a requirement.Once a model has been planned and the types and quantities of each molecule, including monomers, isomers, oligomers and monofunctionalised monomers have been calculated, one of each type of molecule needs to be drawn out in the 3D modelling software manually. The Amorphous Cell Materials Studio includes the scripting language BTcL which allows deeper interaction and automation of the Discover and Amorphous Cell modules. BTcl is an extension of the open source tool command language (Tcl) developed by John Ousterhout in 1988 and carries all the Tcl operations with integration of the Discover control commands . This waThe periodic cell packed with uncured monomer created by Amorphous cell is taken as the starting point for the program. The user definable variables are set up to determine how the model will cure and the program is set to run its course to produce an atomistic model of cured epoxy resin, ready for further investigation. The additional advantages on top of the reduction in time to produce a model also become apparent, a program will build more amorphous nature into the unit cell, as human randomness in choosing which groups to bond is a weigh off between poor quality and excessive time consumption. Also, when curing manually, it is necessary to bond a reasonable number of groups at once before running a molecular dynamics simulation to save having to come back to the model too frequently. With a program however, if it was desired, this same molecular dynamics time could be divided up so the model can relax and move after every individual bond creation.In the current version, when the program looks through the model to find which epoxy – amine pairs to bond together, only the interatomic distance is considered, with the closest pairs taking priority and being bonded first. However it has been written so that other influences can be programmed in at a later date. For example, a more reactive primary amine could be offered higher bonding priority over secondary amines. Factors influencing bonding which would have been very difficult to include if the model was cured manually are simple to implement, for example atomic velocity or local energy could be included in the algorithm, perhaps giving priority to groups with greater mobility.During the automatic cure programme a 5 ps MD simulation was run after every new group was bonded. Observing the MD playback animation, it can be seen 5 ps is well in excess of the required time for the new bond and the vibrations in the surrounding structure to stabilise. When 70% of the amine groups had reacted the cure was halted after the final energy minimisation and 5 ps MD. A plot of the effect of varying the MD timestep on the degree of cure is given as The interatomic separation between the nitrogen and carbon atoms of the new bond was recorded before energy minimisation. These distances were plotted alongside the degree of cure for the 3 models in It is valuable to compare the interatomic bonding distances between the two TGAP based epoxies, Epoxy 2 and Epoxy 3. Epoxy 3 has an excess of epoxy groups compared to 2, so there is more choice for the amine groups, and so a greater possibility of finding bonding groups in closer proximity to any specific amine group. However care is needed when comparing stoichiometric with non-stoichiometric cures, as both models could have 70% of the amine cured, but they are not equivalent. All three models show the clear trend, as the degree of conversion increases it becomes less and less likely for an amine and epoxy to be in close proximity, with bonding distances increasing. As the cure progresses, molecular dynamics allows oligomers and chains to move, but the more bonding actions that take place, the less freedom amine and epoxy function groups have. Eventually the groups are too far away to bond and the epoxy model has cured to a degree where they do not have the freedom to diffuse closer together. When there are no functional groups within 5 Å (4.7 Å for Epoxy 3) that are capable of undergoing reaction, the model is subjected to further molecular dynamics to give the chains more time to diffuse. Work is currently underway to investigate whether it is possible to predict a maximum degree of cure for a given cure temperature by observing the point at which gelation happens, and the ensuing restriction in chain motion.At sufficiently low temperatures, polymers are in the glassy state, here the polymer chains are quite restricted in movement, with only small vibrations occurring. As the polymer is heated, there comes a point where there is sufficient energy for larger motions involving the polymer backbone, involving an estimated 20–50 chain atoms to take place g with little knowledge of the polymer chemistry involved with the glass transition. Molecular dynamics will simulate the location and velocity vector for each atom within the model over time at specified conditions. This method can be used to calculate Tg by running simulations at various temperatures and taking readings for density. These data can then be used to plot a graph, Tg can be estimated as the point of intersection between the thermal expansion gradients above and below the glass transition temperature Molecular dynamics can be utilized with a molecular model to estimate Tg determination because it allows for anisotropic deformation of the cell. This is acceptable because the cross linked epoxy is structurally sound. Parrinello allows more degrees of freedom, and a more natural simulation. The default thermostat and barostat values appear to be reasonably well tuned for our system, although with this system the Nosé thermostat failed to maintain a suitably stable temperature. This was not entirely surprising because the Nosé thermostat is known to have trouble maintaining equilibrium with stiff systems; a Nosé Hoover Chain would perhaps have offered some potential, but it was unavailable Berendsen and velocity scale thermostats were deemed not suitable for property determination molecular dynamics because they are too crude Increasing the simulation resolution from 1 fs to 0.5 fs generally improved stability, although the cost of processing time for the small improvement over 1 fs made this undesirable, as the same processing time could be spent extending the duration to more than double, which would improve the average, but not the standard deviation. Increasing the cell size dramatically improved standard deviation for variance in temperature and density, but if the cell units are multiplied by 8, the processing time will take longer than 8 times that of a single cell to cope with the demands of the larger cell.As an early improvement over previous techniques used in our group g.Data were taken from each temperature step for average and standard deviation of Temperature and Density, which were plotted graphically and analysed by an in-house program to determine the point of gradient change, which occurs at Ti.e. a program which could take a group of temperature and density data points and return the best fit, and a value quantifying it). This is quite complex, but returns the best possible results.As the best fit line is not simple, it is a ‘hinged line’, it was considered worthwhile to see whether the data interpretation could be improved and automated , due to the lower crosslink density generated by the difunctional epoxy monomers, whereas Epoxies 2 and 3 containing significant quantities of the trifunctional TGAP, show similar peak maxima (Tg), albeit with quite different damping behaviour .The thermomechanical data for the three cured epoxy systems  are presented in g values of 208, 276 and 281°C respectively .The DMTA results for Epoxies 1, 2 and 3 show Tectively . The preg. The ultimate aim is to validate the models by using them to predict Tg within reasonable accuracy of the values measured empirically. Preliminary results involving the three epoxy systems are very encouraging with simulated values falling within 10–20 K of the experimental values. It should of course be borne in mind that as Tg is not a first order thermodynamic parameter there is also an uncertainly in the experimentally determined values, so the systematic error in both experimental and simulated values is not greater than 20K.The methodology which has been developed for model design, construction and curing is now at a point where very high quality models are being produced. The process is now streamlined and mostly automated by using the Amorphous Cell module in Materials Studio and programs developed in-house. DMTA was performed on the three epoxy systems to determine the values of T


The study of the geographical distribution of disease has expanded greatly with GIS technology and its application to increasingly available public health data. The emergence of this technology has increased the challenges for public health practitioners to provide meaningful interpretations for county-based state cancer maps.One of these challenges—spurious inferences about the significance of differences between county and overall state cancer rates—can be addressed through a nonparametric statistical method. The Wilcoxon’s signed rank test (WSRT) has a practical application for determining the significance of county cancer rates compared to the statewide rate. This extension of the WSRT, developed by John Tukey, forms the basis for constructing a single confidence interval for all differences in county and state directly age-adjusted cancer rates. Empirical evaluation of this WSRT application was conducted using Minnesota cancer incidence data.The WSRT procedure reduced the impact of statistical artifacts that are frequently encountered with standard normal significance testing of the difference between directly age-adjusted county and the overall state cancer rates.Although further assessment of its performance is required, the WSRT procedure appears to be a useful complement for mapping directly age-adjusted state cancer rates by county. For many years, investigators have evaluated geographic patterns of cancer occurrence by county to generate etiologic hypotheses –3. For eEvaluation of cancer rates by county for etiologic hypothesis development and testing has limitations , 8. ThesDisplaying cancer incidence by county remains a valuable tool for describing the occurrence of cancer to the general public. County cancer rates are also important to community health assessments and allocation of public health resources . County In 1976, the eminent statistician Tukey  describeThe appropriate methodology to ensure that maps of health statistics inform and not mislead is the subject of much discussion and research , 18. StaDeveloping a map representing differences between county rates and the overall state rate involves many different geographic comparisons (eighty-seven in Minnesota). A table of eighty-seven differences provides the opportunity for simultaneously evaluating eighty-seven separate hypotheses. If there is a 5% chance that each of the individual confidence intervals does not contain the true difference in rates, the probability that all eighty-seven confidence intervals contain the true difference is considerably less than 95%. The distinction between a single statistical test of hypothesis that the county rate and state rate are not different and a test of all differences is referred to as the multiple inference or multiple comparison problem .87 = 0.99 [When the number of comparisons is large, the potential for error in the inferences increases. In Minnesota, the probability that at least one of the differences will be found to be statistically significant (at the 0.05 level) is 1 − (0.95)7 = 0.99 . CompariThe problem of multiple comparisons applies to cancer mapping as well. The graphical representation is based on the tabular values of differences between county and overall state rates. If the comparisons are mapped based on a single comparison test of statistical significance, then eighty-seven different comparisons are implied but not distinctly stated by the map itself. The high likelihood that one or more of the “statistically” different county rates is due to chance is integrated into the global representation of the map.The standard normal statistical test for the difference between two directly age-standardized cancer rates can be approximated by a formula that assumes that the covariance of the two rates is zero, that is, the two rates are independent. The estimate for the variance of the difference between two directly age-adjusted cancer rates is the sum of each cancer rate’s variance estimate . If the The assumption of independence is frequently violated when one of the rates is for a populous county. Cancer rates for populous counties are often positively correlated with the overall state rate since the county has a relatively large impact on the state rate. Assuming that the covariance is zero, when it is numerically positive, creates a loss of statistical power . Removing the county before calculating the overall state rate would mitigate this dependence to some degree but would result in a different overall state rate for each county—an undesirable outcome.A negative covariance can occur for sparsely populated rural counties. For example, if populous urban counties had a higher smoking prevalence (compared to some non-urban counties) as in Minnesota, then the overall state rate for smoking-related cancers would tend to be higher and the cancer rates for counties with lower smoking prevalence would be relatively lower for these cancers. The result of assuming that the numerically negative covariance is zero would be an over specification of significance .This paper describes a method to evaluate the significance of county cancer incidence rates compared to the overall state rate that is more resistant to the artifacts created by these statistical inaccuracies than are the frequently used standard normal tests of significance. This method is complementary to the graphical presentation of county cancer rates employed by states and larger governmental units when specification of significance is also desired.Tukey’s modification of the Wilcoxon’s signed rank test (WSRT) is a nonparametric procedure. A detailed description of the theoretical basis of the large sample approximation for the distribution-free confidence interval employed here is given in the text . This tem (number of counties) 95% standard normal confidence intervals. Six steps based on Tukey’s extension of the WSRT procedure are proposed to calculate a joint confidence interval for all differences between directly age-adjusted county cancer rates and the overall state rate.m 95% standard normal confidence intervals using the Keyfitz formula [m lower and upper confidence limits: ; i = 1, m.Form  formula  for the i = c ratei − s rate; i = 1, m , and sei = standard error of c ratei, is calculated as follows, for a given sex and 18 age groups, Nj is the number of specific cancers  in the ith county, Pj is the population of the jth age group for the given sex of the ith county, Wj is the US 2000 standard population weight for the jth age group, se = standard error of s rate,  and, the standard error of the difference between the county and state rate, i ± 1.96 se(diffi) =  [Let diffi, CIUi) .m 95% standard normal confidence intervals [W) averages.Form the ntervals . These am = 87 (Minnesota), For Rank (sort) both lower and upper sets of Walsh averages, so that:The 1 − α confidence interval for the lower limit is Cα rounded to the nearest integer determines the two elements of the ordered arrays of Walsh averages that serve as end points of the joint confidence interval, α is usually 0.05). does not contain zero, the significance of the diffi is then determined by the joint confidence interval derived in 5).If the  = 1.96, Cα = 1,451, M + 1 − Cα = 2,378; and 5) becomes If the diffThe WSRT procedure as applied here uses a measure of the average of all possible boundaries of the i, CIUi), are specific to each county for the null hypothesis H0: diffi  = 0.A detailed example of the calculations required for the application of this nonparametric procedure described by steps (1)–(6b) is given in “i, CIUi) whose statistical significance is less likely due to multiple comparisons and possible lack of the independence of the two rates. Therefore, the application of step 6b) requires that step 6a) first be satisfied. Any difference where zero lies inside the standard normal 95% confidence interval is judged as nonsignificant and is not compared to the joint interval The purpose of the analysis is to identify differences in cancer rates that lie outside  . SpecifiThe data used for these comparisons were from the Minnesota Cancer Surveillance System . The MCSFigure Figure The National Cancer Institute’s SEER*Stat software provides additional parametric methods, based on rate ratios, for determining statistical significance of county age-adjusted cancer rates compared to the overall state rate . The resTable The 95% standard normal test resulted in 882  differences between county and overall state rates being classified as significantly lower than zero and 170 (3.3%) as significantly larger than zero. In other words, there were 882 county rates significantly lower than the overall state rate and 170 significantly higher. This large proportion of significantly low rates is a measure of the spuriously significant differences that can result when comparing many county rates to the overall state rate and when the independence of the county rates and the overall state rate are an issue. Another indication of this artifact is provided by the 170 comparisons that were significantly high. Only 128 (2.5%) of the rates were expected to be significantly high.Results of the 99% standard normal test demonstrated the expected overall reduced numbers of statistically significant results. However, there was still evidence of spuriously significant differences, most notably for low rates (12% significant). The 90% Bonferroni test, designed to reduce the number of false positives, was more conservative, in that, it severely reduced the number of significantly elevated rates to 0.7%. The Bonferroni test was not as effective in mitigating the impact of low rates; 488 (9.5%) remained significant.Results from the WSRT procedure provided a different perspective. Only 2.5% of the county rates were significantly low and 1.5% were high. The number of significantly low rates was reduced, and the sensitivity for detecting elevated county rates did not appear to be greatly impaired. The 1.5% of the rates considered significantly high exceeded that estimate for both the 99% standard normal and the 90% Bonferroni tests. The only result that was larger (3.3%) was for the 95% standard normal test and that number was likely skewed too large by the multiple comparisons  that were made. For these data, the WSRT procedure greatly reduced the number of apparently spurious results generated by the three standard normal tests of significance.Figures Precision of the estimates for age-adjusted rates mapped in Figs. Figures For less common cancers, there were many zero occurrences in a county during the time period 1988–2007). Of the 882  for the incidence rate per 100,000 per year was  and the female 95% CI was . By this measure, any county with a zero occurrence had a statistically significant low bone cancer incidence. A zero occurrence resulted in a zero estimate for the county standard error that reduced the 95% CI for the difference between the county and the overall state rate to that of the 95% CI for just the state rate.There were 31 counties with zero occurrences for males and 50 counties with zero occurrences for females. Thus, 81 (46.6%) of the 174 comparisons were considered as significantly low by the 95% standard normal test of significance. None of the counties had significantly elevated rates. . The results for the 99% standard normal and the 90% Bonferroni significance tests were identical to the 95% standard normal test; 81 (46.6%) were significantly low, and none were significantly elevated.These evaluations could be used in two ways to create a cancer map. Maps  portraying almost half of the state’s counties as having significantly low rates of bone cancer could be created. Alternatively, a decision could be made that, except for a small number of larger counties, the rates were too unstable to warrant mapping cancer rates by county.Both of these approaches would be problematic. The first set of maps would create a misrepresentation of significance. The second approach would not take advantage of the county-specific data on cancer incidence and the composite information available from these observations.The WSRT procedure identified none of the county bone cancer incidence rates as unusually low or unusually high. Utilizing all the data on bone cancer incidence, there was no evidence of an unusual rate of this cancer for the period 2003–2007 in any of the counties. Two maps could be created that would provide the impression that there were no unusual occurrences of male or female bone cancer incidence for the period 2003–2007 in any of the counties. This would be the most appropriate representation of the MCSS data and the one supported by the WSRT procedure.Sensitivity for detecting unusual occurrences of cancer, especially for childhood cancers, is important. In Table The ALL data for Stearns County were examined by age groups  to evaluate the consistency of this elevated rate. None of the rates for males were statistically significant based on the 95% standard normal test. ALL rates for females were consistently higher than the state rate. For the period 1998–2002, the difference reached statistical significance: 12.2 per 100,000 per year vs. 2.8 per 100,000 for the entire state. The importance of an observation of elevated ALL in young females in Stearns County without a corresponding elevation in young males is hard to interpret. Nonetheless, from a public health surveillance perspective of identifying unusual occurrences of cancer through disease mapping, the Stearns County observation was an example of decreased sensitivity for the WSRT procedure. This was the only such example identified during the evaluation of the WSRT procedure.There have been several methods developed to account for the loss of specificity due to multiple statistical comparisons . ConventThis application of the WSRT procedure is another approach for assessing the significance of the difference between directly age-adjusted county cancer rates and the overall state age-adjusted rate. Traditional presentation of the pattern of county cancer rates occurs in several ways. Two of the most common are to portray the county rates as above or below the state average and to distribute the county rates by quartiles. These approaches have become a standard of practice . The WSRThe large amount of random variation associated with the analyses of rates based on a small number of cancers raises concern over the precision of the estimates . SeveralThe most common strategy to address the small number problem is to suppress analyses that are based on a number of occurrences judged to be too low to yield valid results. This number is not consistently defined. The Kentucky Cancer Registry uses 15  and the The evaluation of the performance of the WSRT procedure was empirical and based on cancer incidence data from Minnesota. Population-based cancer incidence data in the United States are collected under similar protocols , and it The computational algorithm for the WSRT procedure used in this evaluation was coded in FORTRAN—a mathematically based programing language. The translation of this extension of the Wilcoxon’s signed rank test into an executable algorithm was straightforward and can be incorporated as a FORTRAN (available from the first author upon request) or C subroutine, or it can be created within a SAS program. The simplicity of coding required for calculating the WSRT significance is an appealing attribute of this procedure.As the number of observations increase, the precision of the estimates increase, often resulting in small differences becoming statistically significant. The WSRT procedure was not as greatly impacted by the large number effect but it is not immune to it. Identification and interpretation of important differences in cancer rates will always require skill and judgment. The WSRT procedure is an ally in this process as it reduces the number of cancer rates that need to be evaluated.As illustrated throughout the evaluation of the WSRT procedure, the level of significance for differences in directly age-standardized rates, such as 0.05 or 0.01 is theoretical; each application will likely yield a computed significance that is different than the desired theoretical level of significance. For the purposes of cancer mapping, it is not the level of significance that is important, but the fact that the significantly different rates represent truly unusual occurrences. John Tukey recommended that for disease mapping, significant differences be described as “unusual occurrences.” The WSRT procedure provides a useful method to portray the differences in directly age-adjusted cancer rates occurring at the county level compared to the overall state rate as “unusually low,” “not unusual,” or “unusually high.”


Understanding how long-term abiotic and biotic processes are linked at a landscape level is of major interest for analyzing future impact on humans and the environment from present-day societal planning. This article uses results derived from multidisciplinary work at a coastal site in Sweden, with the aim of describing future landscape development. First, based on current and historical data, we identified climate change, shoreline displacement, and accumulation/erosion processes as the main drivers of landscape development. Second, site-specific information was combined with data from the Scandinavian region to build models that describe how the identified processes may affect the site development through time. Finally, the process models were combined to describe a whole interglacial period. With this article, we show how the landscape and ecosystem boundaries are affected by changing permafrost conditions, peat formation, sedimentation, human land use, and shoreline displacement.The online version of this article (doi:10.1007/s13280-013-0407-5) contains supplementary material, which is available to authorized users. During the Quaternary period (−2.5 million years to present), the earth has experienced up to 40 glacial cycles  was suggested by the National Academy of Science in the US Rechard . Since tDuring earlier study in Sweden, we showed the possibility to give a rather detailed description of site characteristics and the historical development of a site  Is it possible to use the major drivers identified for global glacial cycles on a specific local site to describe the main ecosystems during landscape development? (ii) Is it possible to mimic the historical landscape development in a model and extrapolate it to the future? and (iii) Can we build a model that dynamically describes the ecosystem and landscape information needed to calculate radiation dose  and that develops spatially in time at a landscape level?In steps, we describe the different features and processes involved in long-term environmental change and show how the processes change the landscape features during a whole glacial cycle. This is further discussed in terms of land use potential in future landscapes with different climates. Finally, we present a landscape development model for the Forsmark area in Sweden to be used as a base in assessments of calculating risks arising from a nuclear waste repository in relevant variants of future possible landscapes.The Forsmark study site is located 150 km north of Stockholm at the shoreline of the Baltic Sea in the county of Uppland, Sweden . The model area is delimited using a future catchment area containing present land and sea. Till is the dominant Quaternary deposit (QD), whereas granite is the dominant rock type. The annual precipitation and runoff are 560 and 150 mm, respectively. The lakes are small, <1 km−1 tot-N and 12 to 25 μg L−1 tot-P  showing the Forsmark landscape developing during the present interglacial starting from after the ice cap had disappeared (9500 bc) and into the far future (35 000 ad).A digital elevation model (DEM) was put together from various datasets described in Strömgren and Brydsten . This DEThe overall modeling strategy was to set up a chain of models that mimics the major processes involved in landscape development. In Fig. Electronic Supplementary Material), we further describe each module and the methods that finally lead to a combined landscape development model presented in a GIS.The task to integrate the defined processes involved a number of steps as described above. In Appendix S1 , whereas the lakes in the lake module were processed one by one. The data sets were merged in ArcGis to receive single raster data sets for each time step for the modeled lakes. In this process, the thickness of the postglacial clay (PGC) was split into a marine and a lacustrine stratum. A fourth raster data set referring to the thickness of fen peat was also produced. The result from the marine module at 10 500 The marine module results were overlain with the results from the lake module and the result was a set of raster maps that dynamically showed the topography/bathymetry, soil/sediment depth, and the sea/lake/land areas in time. In a time-lapse presentation, this set of data constitutes a model describing the landscape during a typical glacial/interglacial cycle.Picea abies) and Scots pine (Pinus sylvestris), and thinner soils on bedrock are dominated by Scots pine. Post-glacial clays were dominated by wetlands except when humans chose to ditch areas consisting of post-glacial clay, to create agricultural land. Glacial clay, which mainly is found in the future landscape, either was populated by forests or used for agricultural purposes. In a future periglacial landscape, where the underlying QDs are assumed to be the same, the vegetation pattern was generalized from a tundra biome  with emphasis on the interglacial and periglacial periods. The first period, just after an earlier glaciation, was characterized by sea. Land was submerged to a depth of approximately 150 m due to isostatic load from the previous ice sheet. Land emerged from the sea starting at 500 ad, and lakes and wetlands form. After 20 000 years (10 000 ad), the model area was above sea level and only a narrow bay can be seen in the northeastern part of the Forsmark landscape . The vegetation and the properties needed for potential agriculture were developing in response to the developing landscape.Climate change, shoreline displacement, and sedimentation/infilling were found to be the most important processes driving landscape development at Forsmark. The results show how the landscape develops during a glacial cycle , temperate conditions will persist in Forsmark until 10 000 ate Fig. . Initialad and turn into a bay. This will negatively affect the water circulation and, due to the continuing narrowing of the bay, further restricting the water turnover. However, at the beginning of the period, turnover times are not expected to be longer than a couple of days, except for closed bays which are near isolation  was dominated by transport and erosion. Finally, transport and accumulation in sheltered locations in the sea only occurred during a short period before the sea bottom became land, suggesting that only limited parts of the model shows continuous accumulation of sediments throughout the whole marine period. During the period from 3000 ad to 10 000 ad a large number of lakes will be isolated from the sea. Most of the new lakes were small and shallow, and will quickly transform into mires, although a few deeper lakes were projected to exist for several millennia. Around 10 000 ad, almost all lakes in the area will be infilled and only some initially relatively large and deep lakes near the island of Gräsö were expected to remain , a relatively short period of periglacial conditions will follow. The periglacial conditions will once again change back to temperate conditions that more or less will continue until 25 000 ad with a few periglacial interruptions. Another temperate period is expected around 40 000 ad that will last for about 5000 years. During far future temperate conditions, Forsmark will have characteristics that mimic the late parts of the initial temperate period. This means that there will be a landscape that comprises terrestrial ecosystems with few or no lakes and no sea. The terrestrial system will consist of forests, mires, and areas that could be used for agriculture. Higher altitude areas with outcrops of bedrock will possible be forested with pine.After the initial temperate period  and humans. The populations of vertebrates and humans are likely to migrate over large areas due to low food productivity or severe weather conditions. In most cases, a human population will probably comprise occasional visitors, due to the hostile environment and the variable ice-situation. It is possible that a human population could be present for longer periods close to the ice margin along the coast and live on fish.bc. The last areas in the Forsmark landscape that will become land are calculated to do so at around 11 500 ad. This means that the submerged conditions will have two phases, one first phase of ca 8000 years when the whole area is submerged, and one that continues for 12 000 years when the sea gradually withdraws and the land area accordingly expands. Submerged conditions are a landscape state when the processes and properties related to the marine or limnic system (aquatic ecosystem) totally dominate at Forsmark. These ecosystem types are not expected to change dramatically due to changes in climate, except for the effects of the long-term change in salinity. Therefore, the submerged future landscape could be treated as identical to the historical and present aquatic ecosystems at Forsmark.In the reference glacial cycle developed for Forsmark and described in Näslund (2013), two periods of submerged conditions are identified. During these periods, Forsmark is covered by sea. The submerged conditions always followed directly after the ice sheet has withdrawn and the ice load has depressed the Forsmark bedrock. After the Weichselian glaciation, the first terrestrial areas appeared around 500 bc (just after the ice cap left Forsmark during the latest deglaciation) until the present day (2000 ad), and the model was compared with the site characteristics. The first validation step, process handling for each input model, is described in references listed in Table To validate a model that describes the future is, for obvious reasons, not possible. However, the input models and the handling of the processes therein can be validated. It is also possible to compare the model output of present landscape with site features of today. The landscape development model was, therefore, validated in two steps: 1) the input processes were validated for each input model or dataset, (2) the final model was run using initiation data from 9500  the inpuad is merged with a map of Forsmark showing present conditions at the site. It is of importance to note that the model in many ways uses the present conditions as input. The shoreline displacement rate is one example of a process that builds upon understanding of historical conditions. Therefore, the validation of the landscape development model shown here is not to be taken for a validation of the capability to model the future, but rather of its capability to mimic the historical landscape development at Forsmark. However, as long as the processes do not change dramatically, we should have a good tool for also modeling a future of relevance for the questions at issue.The second validation step is only qualitative and visualizes the model’s ability to mimic process rates at landscape level. In Fig. ad (a) is compared with the present map (b) using similar land classes as in the model. The figure shows that agricultural land use is overestimated and that wetland is underestimated in the model. One explanation for this is that the model interprets all mires with a deeper peat layer than 1 m as areas suitable for agricultural land use. Also glacial clay and fine-grained moraine are modeled as suitable for agricultural use even though today only parts of areas covered with these soils are used for cultivation. The model also slightly overestimates the infilling of lakes, but the areas covered by forest and sea is in good agreement with present conditions.In Fig. The landscape development model shows that the main processes of climate change, shoreline displacement, infilling, and sedimentation are drivers that well explain the landscape development seen at Forsmark today. Although our model cannot be fully validated, we argue that the processes and features we rely upon are scientifically sound and well understood. Using the physical constraints on the Forsmark future landscape, we have narrowed down landscape variants and data from these futures and present a model that is relevant and realistic. Thus, we stress that applying the same processes to the Forsmark landscape into the future is potentially appropriate during a whole glacial cycle and beyond; especially since the confidence in the ecosystem pattern in the landscape is high. Although human activities often is regarded as having a major impact on ecosystems, we conclude that in the time frames discussed within this work, no change in long-term landscape succession is caused by human activities at the site. Nevertheless, human land use is part of the landscape development, and the type of possible land use during a glacial cycle is depending on the processes discussed in this study.Using the present differences in elevation at Forsmark as an analog for time (due to shoreline displacement), we can argue that the current sea–lake–mire succession is a good representation of future development of areas presently submerged under the sea. This dynamic and multi-discipline approach, based on robust sedimentation and succession models, gives us a useful tool to explain the results, not only to the scientific community but also to the public as well as to practitioners searching for information on how site-specific data and understanding are extracted and used, e.g., in dose calculations. The modeling done within the framework described here is the state of the art supporting tool for predicting risks to humans and the environment, valid to use in the context of potential future releases of radionuclides from a repository for spent nuclear fuel as well as other long-term risk assessments.Supplementary material 1 (PDF 16281 kb)Below is the link to the electronic supplementary material.