The hyperreactive malarial splenomegaly (HMS) represents a chronic, potentially fatal complication of malaria. Case definition includes: gross splenomegaly, high level of anti-malarial antibody and IgM, response to long-term anti-malarial prophylaxis. In this study, a large series of patients not fully meeting the case definition was tentatively classified as early hyperreactive malarial splenomegaly (e-HMS). The main research questions was: does “e-HMS” tend to evolve to the full-blown syndrome? And if so, what are the main factors influencing this evolution?Retrospective, longitudinal study. The patient database was searched to retrieve all potentially eligible patients. e-HMS was defined by splenomegaly of any size (with or without raised IgM), high anti-malarial antibody titre and exclusion of other causes of splenomegaly. The clinical outcome at following visits was analysed in relation to re-exposure to malaria, and to treatment . The association of the outcome with the main independent variables was first assessed with univariate analysis. A stepwise logistic regression model was then performed to study the association of the outcome with the main independent variables.One hundred and twenty-six subjects with e-HMS were retrieved. Eighty-one had at least one follow-up visit. Of 46 re-exposed to malaria for a variable period, 21 (46 %) had progressed, including 10/46 (22 %) evolving to full-blown HMS, while of 29 patients not re-exposed, 24 (93 %) had improved or cured and five (7 %) progressed (p < 0.001). At logistic regression re-exposure was confirmed as a major risk factor of progression  while treatment at initial visit was protective .e-HMS should be regarded as a clinical condition predisposing to HMS. Although the case definition may include false positives, e-HMS should be treated just as the full-blown syndrome. A single anti-malarial treatment is probably adequate, followed by effective prophylaxis for patients exposed again to malaria transmission.The online version of this article (doi:10.1186/s12936-015-1015-6) contains supplementary material, which is available to authorized users. Plasmodium falciparum is by and large the predominant species in the countries where the syndrome has been described [The hyperreactive malarial splenomegaly (HMS), previously referred to as tropical splenomegaly or tropical splenomegaly syndrome (TSS) is a chronic complication of malaria. Patients have high levels of anti-malarial antibody , 2, as aescribed . A histoescribed , 6 diffeAt the very beginning patients might not have any symptoms. If HMS is not cured most patients report unspecific symptoms like asthenia, abdominal discomfort and other. Patients adapt physiologically to chronic anaemia, which develops due to hypersplenism , 8 and bAfter excluding other known causes of splenomegaly, “tropical splenomegaly syndrome” (the former name of HMS) was defined as a separate entity and Fakunle set clear diagnostic criteria in 1981 , that weAt the centre for tropical diseases (CTD), in the last 25 years, a relevant number of cases have been observed, both in immigrants from malaria endemic areas and in Italian citizens who had lived for a prolonged period in such areas. Furthermore, over the years it has been also observed that some patients, who initially had only some of the case definition criteria of the HMS , once examined again after a further stay of variable duration in endemic areas, developed all the HMS criteria. It was, therefore, supposed that it is possible to identify and diagnose an early stage of HMS, here below defined as “early HMS” (e-HMS). As the latter was not considered in medical literature, these patients were usually not treated, unless malaria parasites were identified in blood . Once the early syndrome was hypothesized, a number of patients considered potentially affected were then treated for malaria and advised to follow an effective prophylaxis in case they had to go back to endemic areas.to assess if e-HMS, that has not been so far considered as a nosological entity, tends to evolve to the full-blown HMS;if so, if the evolution of e-HMS is significantly different between patients re-exposed and not re-exposed to malaria transmission, andif the evolution of e-HMS is significantly different between patients who are treated for malaria versus those who are not.The main objectives of this research were:anti-malarial antibody titre (IFAT-Biomérieux) > 1/160, PLUS:splenomegaly  AND/ORhigh IgM level (≥2.5 g/L), ANDno other identified causes of splenomegaly or of raised IgM, such as: schistosomiasis, HBV, HCV, HIV, brucellosis, leishmaniosis, autoimmune disease, cirrhosis, haemoglobinopathies, and other haematological conditions, such as leukemia, lymphoma, Waldenstrom disease.Retrospective, longitudinal study aiming to identify patients with e-HMS observed from 1 January 1990 to 31 January 2014 and subsequently visited at follow-up . The population included in the analysis had to be selected according to the following case definition of e-HMS:Patients with splenomegaly or with raised IgM, observed during the study period, and without any of the mentioned alternative diagnoses, were retrieved from the CTD patient database as indicated below. Those with anti-malarial antibody titer ≥160, and/or with history of ≥3 years stay in malaria-endemic areas and reporting ≥10 acute malaria episodes, were initially included. Patients meeting the case definition of full-blown HMS as outlined above were excluded. The remaining subjects, meeting the tentative case definition of e-HMS, were retained for further analysis. The main epidemiological, clinical and laboratory findings were recorded at baseline. From baseline, patients were then traced prospectively for any further visit and, in case any follow-up contacts were recorded, follow up data was included in the study file. For all patients having at least a follow-up visit after initial observation, the last follow-up visit was considered for the outcome assessment in relation with re-exposure or not to malaria-endemic areas and to treatment or not at initial visit, as well as with the other main independent variables.CTD patient database . Echography of the upper abdomen, as well as immunoglobulin dosage and anti-malarial antibody testing, were part of the routine screening of patients with a history of a long stay (>1 year) in a malaria endemic country and reporting several malaria episodes.(T1) baseline;(T2) short-term follow up visits (1–6 months after first observation);(T3) long-term follow up visits (≥6 months after first observation).Data was exported to a pre-structured Excel file  titre ≥ 1:160. In the few cases of missing serology, a prolonged stay in an endemic area (≥3 years) and over 10 malarial episodes reported, was considered equivalent to a high anti-malarial antibody titer.Serum IgM level, two standard deviations above the local mean, corresponding to ≥2.5 g/L.Cured: absence of splenomegaly and normal IgM titer;Improved: ≥0.5 cm decrease of the spleen diameter, or unchanged spleen diameter and ≥0.5 g/dL decrease of IgM level;Unchanged: <0.5 cm or no variation of the spleen diameter and <0.5 cm or no variation of IgM level;Progressed: ≥0.5 cm increase of the spleen diameter, or unchanged spleen diameter and ≥0.5 g/dL increase of IgM level;HMS: patients with e-HMS at initial visit, meeting the case definition of full-blown HMS (as resumed in Introduction) at follow-up.Plasmodium using one of the following methods: QBC Malaria Test  or Malaria antigen Rapid Detection Test (RDT) . For all positive results, confirmation with microscopy was also carried out.Patients were screened for 2 test. The Fisher exact test was used if appropriated. A stepwise logistic regression model with forward selection was performed to study the association of the main dependent variable (outcome at follow-up) with the independent variables such as: sex; ethnicity; re-exposure to malaria; presence/absence of symptoms and of malaria parasites at first visit; treatment or not at first visit; age; time elapsed between the first observation and follow-up. Potential interaction among the variables was also studied with the same model. Significance values for entry in (pe)/removal from (pr) the model were set at 0.10 and 0.15, respectively.Data was analysed using the software STATA IC 14  . For catSubjects were anonymously coded in the database, unlinked from any information identifying the source individuals. Although the study was retrospective and no action on patients was involved, the study protocol was nevertheless submitted to the Ethics Committee of the Coordinating Site  for approval. The latter acknowledged the study protocol and formally authorized the study .The patient flow is resumed in Fig. Most of the subjects included met the main case definition criteria as outlined in “Table Most subjects (46/78 or 59 %) were re-exposed to malaria transmission before follow-up (this data was missing for three patients). Table 6/µL, p = 0.042), but the Hb value was similar in the two groups.The median age of re-exposed subjects was higher: 54 years versus 37.5 years (p = 0.003). Most patients re-exposed were Caucasian . There was no significant gender difference. The average duration of exposure to malaria before observation was similar and so were most clinical and laboratory findings. The median diameter of the spleen was higher in not re-exposed subjects  and so was the median RBC count .The characteristics of the e-HMS subjects who received/did not receive an anti-malarial treatment are summarized in Table Most of the patients were symptomatic at first observation. Asthenia was the most frequently reported symptom, present in 44/97 Caucasians (45 %) and in 7/29 non-Caucasians (24 %). Fever (most often low-grade) was present in 37/97 Caucasians (38 %) and in 8/29 non-Caucasians (28 %).Plasmodium was searched in 87 subjects out of 126 (59.2 %), with a positive result  in 36/87 (41.4 %). P. falciparum was the species involved in all cases, but for one case of Plasmodium malariae and one of Plasmodium vivax, both in Caucasians. Among Caucasians, positive results were 27/67 overall, of which 3 (11 %) had only a positive RDT or QBC (with negative blood film), and of the remaining 24, 12 (50 %) had a parasite density <1000/µL (of which 3 with <50/µL). The highest value of parasite density was 10,500/µL, roughly corresponding to 0.25 %. Among non-Caucasians, positive results were 9/20 overall (45 %), of which 2 (22 %) had only a positive RDT or QBC, and of the remaining 7, 5 (71 %) had a parasite density <1000/µL (of which 2 with density <50/µL). The highest value of parasite density was 21,500/µL, roughly corresponding to 0.5 %.Overall, The results of univariate analysis are reported in Table 2 = 0.2137) suggesting the need of confirming the results with a higher number of observations and/or with the association of other possible predictors, if any. Variables significantly associated with outcome in the final model . Patients were more likely to be treated if malaria parasites were found in blood, which is by no mean unexpected. All potentially confounding variables were included in the log regression model.As 1/3rd of the study subjects were lost at follow-up, it was first assessed if this group was similar for the main baseline characteristics to the group of subjects with follow-up, which was indeed the case Table , with a This retrospective, longitudinal study aimed to describe the clinical evolution of subjects presenting a history of long term exposure to malaria transmission and a splenomegaly (any spleen size), with or without a raised IgM level in blood. After excluding other possible causes of splenomegaly, a tentative definition of e-HMS was devised, as described in the “It has been reported that the development of HMS can be influenced by various aspects, including genetic predisposition –18, but Returning to an endemic area for malaria proved to be a risk factor for the evolution of the syndrome. Almost half of all the subjects re-exposed to malaria progressed, versus none of those who remained in Italy until follow-up. Even more importantly, almost a quarter of the re-exposed group evolved to a full-blown HMS. Therefore, although the case definition of e-HMS may not be specific and may include patients with other  causes of splenomegaly, the risk of evolution to HMS, a severe disease with high mortality, justifies in itself the recognition of the early stage of the disease, that should be properly treated. Treatment appeared to be independently protective against evolution of e-HMS to full-blown HMS.loss at follow-up of several patients: the follow-up data was obtained retrospectively from the patients returned  to the observation after the first contact; anyway for about 2/3rd of the study subjects follow-up data was available, moreover as mentioned above the baseline characteristics of the two groups were in all similar;not uniform follow-up time, for the same reasons outlined above; however, this variable was duly included in the log regression model;differences between the two main groups of re-exposed/not re-exposed and of treated/not treated for some characteristics as discussed above;on logical grounds, for treatment at initial observation to be really effective, long term prophylaxis and/or frequent/intermittent anti-malarial treatment are also necessary , 20. UnfThe main limitations of this study are inherent to the retrospective study design, in particular:However, at multivariate analysis including most potential predictors, the main findings  was robust. Asthenia was the only symptom seemingly influencing the risk of evolution, although it cannot be excluded a chance association.It’s possible to identify an early stage of HMS, which has been defined as e-HMS, that tends to evolve into a full-blown HMS if malaria antigenic stimulus persists and if subjects are not treated for malaria. e-HMS is characterized by a spleen size ≥12 cm, even in the absence of high values of IgM level, or by raised IgM without splenomegaly, in subjects with a history of long term exposure to malaria transmission, and with high titre of anti-malarial antibodies. The case definition of the syndrome should be updated in order to include criteria to diagnose e-HMS, that should be recognized and treated. Although the diagnostic criteria of e-HMS may not be highly specific and include false positive subjects , treatment is warranted even if diagnostic certitude is lacking, considering the risk of evolution to HMS and its complications.A randomized controlled trial would be the best way to rigorously assess the efficacy of initial anti-malarial treatment, followed by prophylaxis or possibly by intermittent anti-malarial treatment in case of re-exposure, on the evolution e-HMS. However, undertaking a similar trial may prove difficult in the field, also considering the necessarily long follow-up time. On the other hand, a multicentre retrospective study on a larger series of patients observed in non-endemic countries could corroborate the findings of this research and lay a more robust basis for its conclusions.


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There has been a rapid increase in the retail availability of e-cigarettes in the UK and elsewhere. It is known that exposure to cigarette point-of-sale (POS) displays influences smoking behaviour and intentions in young people. However, there is as yet no evidence regarding the relationship between e-cigarette POS display exposure and e-cigarette use in young people.This cross sectional survey was conducted in four high schools in Scotland. A response rate of 87 % and a total sample of 3808 was achieved. Analysis was by logistic regression on e-cigarette outcomes with standard errors adjusted for clustering within schools. The logistic regression models were adjusted for recall of other e-cigarette adverts, smoking status, and demographic variables. Multiple chained imputation was employed to assess the consistency of the findings across different methods of handling missing data.Adolescents who recalled seeing e-cigarettes in small shops were more likely to have tried an e-cigarette (OR 1.92 99 % CI 1.61 to 2.29). Adolescents who recalled seeing e-cigarettes for sale in small shops (OR 1.80 99 % CI 1.08 to 2.99) or supermarkets (OR 1.70 99 % CI 1.22 to 2.36) were more likely to intend to try them in the next 6 months.This study has found a cross-sectional association between self-reported recall of e-cigarette POS displays and use of, and intention to use, e-cigarettes. The magnitude of this association is comparable to that between tobacco point of sale recall and intention to use traditional cigarettes in the same sample. Further longitudinal data is required to confirm a causal relationship between e-cigarette point of sale exposure and their use and future use by young people. There is increasing concern about the rising prevalence of e-cigarette use among children and young people in particular, that e-cigarette use is increasing among young people who have never smoked (never smokers) . AlthougIt has been clearly demonstrated that increased availability of cigarettes is associated with higher consumption. For example, a higher tobacco retail outlet density in a young person’s home environment increases the probability of current smoking and ever smoking  and the The e-cigarette market is undergoing a period of substantial growth internationally  and the The regulatory environment for e-cigarettes is very different to that for tobacco. While most tobacco advertising and promotion is prohibited in the UK  and saleYoung people are not only exposed to e-cigarette adverts through POS displays but also from TV, billboards, print media and the internet. Experimental research has shown that exposure to e-cigarette TV adverts increases the likelihood that adolescents will intend to try e-cigarettes in the future .This Scottish study examines the relationship between the recall of e-cigarette POS displays and children’s use and future intention to use e-cigarettes controlling for exposure to online advertising of e-cigarettes, e-cigarette advertising via other media, smoking status and demographic factors. In order to compare the size of effects we also examine the relationship of cigarette point of sale exposure to intention to smoke cigarettes in the same sample. To our knowledge information on young people’s recall of e-cigarettes in retail outlets and use and intention to use e-cigarettes has not been collected in any other survey to date so this is the first and currently the sole source of information on this important and policy relevant topic.The data presented here were collected as part of an ongoing 6-year multi-modal study designed to assess the impact of Scottish legislation banning tobacco POS displays on young people’s smoking-related attitudes and behaviours . The infThe results reported here are based on data collected between January and March 2015 after the implementation of the tobacco point of sale ban in large supermarkets but before its implementation in small shops. Questionnaires were administered to pupils in Secondary 1 through to Secondary 6  by teachers during class time under examination conditions. Information regarding the survey was sent out to parents two weeks prior to the survey date. Parents could withdraw their child from the survey by returning the opt-out form to the school. Young people could decline to take part in the survey or withdraw from the survey at any point. Ethical approval for the study, including the consent procedures, was obtained from the University of St Andrews, School of Medicine Ethics Committee.This study aimed to examine the relationship between e-cigarette point of sale recall  and e-cigarette use. Previous e-cigarette use and intention to use e-cigarettes in the next 6 months were the dependent variables. E-cigarette POS recall in large supermarkets and small shops were the explanatory variables. Recall of other sources of e-cigarette advertisement was included in the adjusted models to control for the potentially confounding effects of exposure to other types of e-cigarette advertisement. In addition, demographic factors such as age, sex, and family affluence were included as control variables. Tobacco smoking is known to be a predisposing factor to e-cigarette use therefore previous tobacco use was also included in the adjusted models as a control variable in order to test whether e-cigarette POS sale influenced e-cigarette uptake in never smokers (never tried tobacco cigarettes).Respondents were asked their gender, ethnic group, and date of birth. Ethnic group was dichotomised to white ethnic group versus other responses. Individual family material well-being was assessed through the Family Affluence Scale (FAS)  which isRespondents were asked whether they had heard of e-cigarettes and could respond ‘yes’, ‘no’, or ‘don’t know’. Respondents who answered ‘yes’ were directed to the question ‘which ONE of the following is closest to describing your experience of e-cigarettes?’, to which they could respond ‘I have never used them’, ‘I have tried them once or twice’, ‘I use them sometimes (more than once a month)’, or ‘I use them often (more than once a week)’. This variable was dichotomised to ‘ever tried-1’ versus ‘never tried-0’. The next question was ‘Do you think that you will try e-cigarettes in the next 6 months?’ to which they could reply ‘yes I do’, ‘no I don’t’ or ‘don’t know’. This response was also dichotomised to ‘yes’ -1 versus ‘no’ or ‘don’t know’-0. In the original coding of the e-cigarette variables participants who responded that they did not know what an e-cigarette was or missed this question were coded as ‘missing’ on all other e-cigarette questions. Another alternative coding method was employed to minimise missing data where participants who did not know what an e-cigarette was, were assumed not to have tried one and not to intend to try one. Results are presented for both versions of the e-cigarette dependent variables.Ever smoking was assessed with the question: ‘Have you ever smoked cigarettes, even if it is just one puff?’ to which they could respond ‘yes’ or ‘no’. Negative responses were used as our variable for ‘never smoked’. To assess intention to smoke respondents were asked ‘Do you think you will smoke a cigarette or hand-rolled cigarettes (roll-ups) at any time during the next year?’ To which they could answer ‘definitely yes’ ‘probably yes’ ‘probably not’ ‘definitely not’. This was dichotomised to ‘yes’-1 or ‘no’-0.Respondents were asked ‘During the past 30 days, have you noticed any adverts  for (a) cigarettes or hand rolled cigarettes (roll-ups), or (b) electronic cigarettes (e-cigarettes)?’ To which respondents could answer ‘Yes’, ‘no’ or ‘don’t know’. This response was also dichotomised to ‘yes’-1 versus ‘no’ or ‘don’t know’-0.Respondents were asked ‘When you are using the internet, how often do you see adverts for (a) tobacco products or pictures of people smoking, or (b) electronic cigarettes (e-cigarettes) or people smoking them?’ To this pupils could respond ‘I don’t use the internet’, ‘most of the time’, ‘some of the time’, ‘hardly ever’, ‘never’. Responses of ‘I don’t use the internet’ were recoded as ‘never’. All responses were dichotomised to ‘never’ -0 versus other responses-1.Respondents were asked whether in the past 30 days, when they had been in (a) large supermarkets and (b) small shops, they could remember seeing (i) cigarette or tobacco packs or (ii) electronic cigarettes displayed for sale. To this they could respond ‘yes’, ‘no’ or ‘don’t know’. This response was also dichotomised to ‘yes’ -1 versus ‘no’ or ‘don’t know’-0.Data analysis and imputation was conducted in Stata version 14. Analysis was by logistic regression with standard errors adjusted for clustering by school. Where the prevalence of the outcome was low  was not a significant predictor of previous e-cigarette use or intention to use in the adjusted models. This indicates that once recall of point of sale and internet e-cigarette adverts is included in the models, recalling seeing adverts in billboards, newspapers or magazines or on TV does not account for any additional variance in uptake of e-cigarettes by adolescents. Recall of e-cigarettes in small shops and supermarkets contributes independently to the prediction of intention to use e-cigarettes. Recall of e-cigarette displays in small shops and on the internet is associated with previous e-cigarette use. Thus, e-cigarette advertising may be influencing adolescents from two sources – the physical spaces in which they live their lives and their online experience.Small shops may be important as a source of e-cigarette point of sale exposure because they are frequently visited by young people. They also represent part of young people’s formative environment. Display of e-cigarettes in local small shops may indicate normality and social acceptability to young people . The preThe other key source of e-cigarettes advert exposure is the internet. A recent report on children’s use of online technologies in Europe highlights ‘how embedded the internet has become in young people’s lives’ and that ‘most young people find the internet to be a necessity for life in modern society’ . The data, in this study, are cross-sectional so no firm conclusions can be drawn regarding causality. Therefore, we do not know whether young people plan to try e-cigarettes because they have noticed e-cigarette displays in shops or on the internet, or whether they notice e-cigarette displays because they are favourably disposed towards trying e-cigarettes. However, even if e-cigarette experimentation makes users more likely to notice displays, seeing displays in the local environment may well further reinforce that inclination . FurtherAnother limitation is that the sample is not representative of the population of Scotland, as a fully randomised sampling process was not employed and there was 13 % non-response to the survey. However, demographic variables have been included in the adjusted models to control for these factors.This is the first study to suggest that there is an association between young people’s exposure to and recall of POS displays for e-cigarettes and their stated intentions to use e-cigarettes. Longitudinal data, which will be provided by this study in the future, will allow us to establish whether this relationship is causal. The possibility that e-cigarette POS displays may be linked to likelihood of uptake by young people is of concern, given that forthcoming EU legislation will state that e-cigarettes should be an adult-only product. There is some evidence, from animal models, that nicotine has long term effects on the adolescent brain including permanent changes to connectivity and neurotransmitter receptivity in neural reward-systems. These are the brain circuits associated with addictive behaviours , 33. TheOur findings suggest that young people’s recall of e-cigarettes POS displays in small shops is associated with use of, and intention to use, e-cigarettes. Further research is required on how to balance the promotion of e-cigarettes as a cessation aid while preventing the initiation of e-cigarette use among young people who have never smoked.


This usually causes the sparse problem and reduces the classification accuracy. To solve this problem, we add gaps into k-mer and introduce a new feature called gapped k-mer (GKM) for identification of recombination spots. By using this feature, we present a new predictor called SVM-GKM, which combines the gapped k-mers and Support Vector Machine (SVM) for recombination spot identification. Experimental results on a widely used benchmark dataset show that SVM-GKM outperforms other highly related predictors. Therefore, SVM-GKM would be a powerful predictor for computational genomics.Recombination is crucial for biological evolution, which provides many new combinations of genetic diversity. Accurate identification of recombination spots is useful for DNA function study. To improve the prediction accuracy, researchers have proposed several computational methods for recombination spot identification. The k-mer feature is one of the most useful features for modeling the properties and function of DNA sequences. However, it suffers from the inherent limitation. If the value of word length  Recombination plays an important role in genetic evolution, which describes the exchange of genetic information during the period of each generation in diploid organisms23et al.et al.181920et al.23To improve the predictive accuracy, researchers have proposed several computational methods for recombination spot identification, which are based on some well known machine learning techniques, such as support vector machine (SVM)579111213k neighboring residues. By using this feature, the local sequence composition information can be extracted. Typically, the value of k is set to 6 or 7, and the length of their corresponding feature is 46 = 4096 or 47 = 16384. Actually, larger k values are preferred, because more sequence composition information can be incorporated. However, large k values (k > 6) will lead to extremely sparse feature vectors, which may cause a severe over-fitting problem. In order to find a tradeoff between the sparse feature space problem and more sequence composition information, the gapped k-mer has been proposed, and successfully applied to enhancer identification33All these computational methods could yield quite encouraging results, and each of them did play a role in stimulating the development of recombination spot identification. However, further study is needed due to the following reason. Among the aforementioned features, k-mer628293031In this study, we apply the gapped k-mer to recombination spot identification, and propose a new computational predictor called SVM-GKM via combining GKM with Support Vector Machines. Experimental results on a widely used benchmark dataset show that SVM-GKM outperforms the two state-of-the-art methods in the field of recombination spot identification, and some interesting patterns can be discovered by analyzing the discriminative features in SVM-GKM.et al.Here, we employ a benchmark dataset taken from Liu + contains recombination hotspots, negative subset ∑− contains recombination coldspots, and symbol ∪ represents the “union” in the set theory. There are 490 hotspots in ∑+ and 591 coldspots in ∑−. The codes of the 1081 DNA samples as well as their detailed sequences are given in the where positive subset ∑k, the method based on k-mers could cause the sparse problem. This is because many k-mers are not appeared in one DNA sequence, and thus its feature vector may contain a large amount of zero values. To overcome this disadvantage caused by k-mers, Ghandi et al.With the increase of word length m to stand for is the length of matches, so the length of gaps is k−m. Then feature vector f S of a given sequence S can be defined asFirst, each training sample is represented as a series of k-mers, where k is the length of subsequence. The key to calculate the GKM kernel matrix is to compute the number of mismatches between each pair of sequences for all pairs of k-mers. Here, we define a variable i−th gapped k-mer in the sequence S, b is the alphabet size. For DNA sequence, b = 4. Then the kernel function between two sequences S1 and S2 can be defined aswherem increases, direct calculation of Since the number of all possible gapped k-mers grows extremely rapidly as n(n ≤ k − m) is the number of mismatches between two k-mers x1 and x2. x1 is from S1 and x2 is from S2, Nn is the number of pairs of k-mers with n mismatches in sequences S1 and S2, hn is the corresponding coefficient. hn is defined as follows:where hn when calculating the mismatch for two sequencesIn order to reduce the error caused by corresponding coefficients, the following equation is used to get n1is the mismatch number that k-mer x1 contains, n2is the mismatch number that k-mer x2 contains, and t is the mismatches number, which exists at the k − n mismatch positions for both x1 and x2. The remaining mismatches r = n2 − t − (n − n1 − t) are among the the n mismatch positions for k-mer x2.where In this paper, a tree structure is employed to count mismatchesti) stands for the path from the root to node ti with depth d. d means that the corresponding sub-sequence has a length of d. For a tree, its maximum depth is k, i.e. the length of the k-mer. Therefore, for a terminal leaf node of the tree, the leaf node represents a k-mer. A terminal leaf node can also hold the list of training sequence labels, which contains the information of appeared k-mers and the number of these k-mers in each sequence. We use depth-first search (DFS)35ti at depth d and also store the number of mismatches between two paths s(ti) and s(tj). Differing from this method, our method only needs to store the values of the terminal leaf nodes and does not need to store the information of all nodes. Thus, at the end of one DFS traversal of the tree, the mismatch profiles for all pairs of sequences are completely determined. k = 3. The tree is generated by sequences S1, S2, and S3. We can see that for node t6, s(t6) = ‘AAA’. Sequence S1 contains two counts of substring s(t6), but sequence S2 and sequence S3 do not contain this substring. For our experiments, we used the gkm-SVM software v1.3http://www.beerlab.org/gkmsvm/.The tree is generated by training samples and we construct it by adding a path for every k-mer. Assume that s(The support vector machine (SVM) method is a widely used method for classification problems3438394041434445K-fold cross-validation is a widely used method for evaluating the performance of a computational predictor47Here, we use four metrics, sensitivity (Sn), specificity (Sp), accuracy (Acc), and Mathew’s correlation coefficient (MCC) to test the predictor485051N+ is the total number of the tested recombination hotspots sequences, N− is the total number of the tested recombination coldspots sequences, where k (see method section for details) on the performance of SVM-GKM. k from 8 to 15 with match length m set as 7. The performance of SVM-GKM increases significantly with the growth of k values, and SVM-GKM achieves the best performance when k = 13. These results are not surprising, because for larger k values, more sequence order information can be incorporated into the predictor, contributing to higher performance for recombination spot identification.The SVM-GKM predictor is constructed by only using the gapped k-mer as a feature. We first evaluate the impact of the parameter word length n is set as 0, and the tree structure is also employed so as to reduce the computational cost. The performance of these two methods on the benchmark dataset with different parameters is shown in The k-mer is a widely used feature considering the local sequence order information along the DNA sequences. GKM is an improvement of k-mer by introducing the gaps into k-mers. For comparison, a predictor called kmer-SVM is constructed based on k-mers. The kmer-SVM can be viewed as a special case of GKM-SVM without gaps. Therefore, the implementation of kmer-SVM is the same as that of SVM-GKM except that the gap number k > 9). We can also see that parameter k does not have significant impact on the performance of SVM-GKM, and SVM-GKM achieves its highest accuracy (86.57%) when k = 13. In contrast, kmer-SVM achieves its highest accuracy (82.31%) when k = 10 and then its performance decreases significantly. This is because when k is larger than 10, the dimension of the feature vectors is very large and many values are zeros, leading to extremely sparse problem. For example, when k = 13, the dimension of the feature vectors generated by kmer-GKM is 413 ≈ 6.7 × 107. In contrast, for the same word length, the length of feature vectors generated by SVM-GKM is only 6, which is much smaller than that of kmer-SVM, and therefore, GKM can efficiently avoid the sparse problem. As shown in et al.We also compare SVM-GKM with other two highly related methods, including iRSpot-PseDNCIt is interesting to explore if the gapped k-mers can reflect the characteristics of the recombination spots or not. Therefore, the discriminative power of different gapped k-mers in SVM-GKM are calculated by using the Principal Component Analysis (PCA)5455As a widely used feature in the field of recombination spot identification, k-mer only incorporates the local sequence composition information of DNA sequences. In order to overcome this disadvantage, gapped k-mer (GKM) has been proposed to incorporate the long range sequence order information and reduce the length of the feature vectors. GKM successfully overcomes the sparse problem caused by k-mers via introducing the gaps into the k-mers, and has been successfully applied to enhancer identification. In this study, we apply the concept of GKM to the field of recombination spot identification, and demonstrate that this approach can obviously improve the predictive performance. These results are not surprising, because previous studies485859Besides k-mer and gapped k-mer, palindrome structure, relatively high GC content, dinucleotides bias, and consensus DNA motifs have been showed useful for recombination spot identification. Our future study will focus on exploring various feature combinations to construct a computational predictor. Performance improvement can be expected by using some neural-like computing strategies, such as spiking neural models611616263How to cite this article: Wang, R. et al. Recombination spot identification Based on gapped k-mers. Sci. Rep.6, 23934; doi: 10.1038/srep23934 (2016).


F = 2.28, p = 0.10. In addition, the results demonstrated that both groups were immersed and present in the environment. The results on posttreatment measures of CH  demonstrate the efficacy of IBT in terms of symptom reduction. Overall, these results suggest that the creation of a virtual environment may be effective in the treatment of CH by helping the compulsive hoarders take action over their clutter.The present study evaluated the efficacy of adding a virtual reality (VR) component to the treatment of compulsive hoarding (CH), following inference-based therapy (IBT). Participants were randomly assigned to either an experimental or a control condition. Seven participants received the experimental and seven received the control condition. Five sessions of 1 h were administered weekly. A significant difference indicated that the level of clutter in the bedroom tended to diminish more in the experimental group as compared to the control group  Though classified in DSM-V as a distinct disorder, compulsive hoarding (CH) was long considered a subtype of OCD. Also new in DSM-V is that OCD is no longer considered an anxiety disorder. CH and OCD are now considered separate disorders, part of the Obsessive Compulsive and Related Disorders category. Regardless, the experience of intense anxiety when required to get rid of personal objects and difficulty in taking action are part of the diagnostic criteria for CH . The majn = 13) corroborates the results of the other meta-analysis and reports an average effect size of 1.11 for VR, as compared to a control condition  validated in an individual format 1-There will be a statistically significant difference between the experimental and control conditions on measures of clutter, such as the Clutter Image Rating scale.2-The participants in the experimental condition will experience clinically greater levels of anxiety than participants in the control condition during the sessions with immersion in the VR environment.3-The non-immersive virtual environment will elicit a state of presence and immersion in all of the participants.4-IBT will lead to clinically and statistically significant improvement in symptoms of (a) CH, (b) anxiety, and (c) depression.The hypotheses:Participants were recruited using advertisements posted in universities, hospitals, CLSC’s, and community organizations in the region of Montréal, as well as Fernand Seguin research centre’s website. Twenty-five participants were evaluated in the context of this project. Of these, nine were excluded following the initial evaluation, and two dropped out over the course of treatment, one in each group. Of the 14 participants who took part in the project, 2 were males and 12 were females. Demographic data are reported in Table neuroVR 2.0 platform (www.neurovr.org) was used to create the environments. A digital camera was used to take photographs of the CH’s home environments and Corel Paint Shop Pro Photo X2 software was used to treat the images. This procedure was validated at the Université du Québec en Outaouais (UQO) in a sample of six participants , which is freely accessible online. In the experimental condition, objects that belong to the hoarders were inserted into the apartment environment created using this platform. In the control condition, images depicting objects were selected from the internet and inserted into the apartment environment. To create the experimental virtual environments, approximately 30 photos taken by participants of their homes were selected. The objects in these images were cut out using Corel Paint Shop Pro Photo X2 and inserted in the apartment environment. The objective was to recreate the participant’s apartment, mainly their living room, kitchen, and bedroom. The objects were placed in piles as represented in their pictures. The objects that were eventually selected to be used in VR procedure were cut out individually so that the participant could select them.All of the virtual environments were created using the neuroVR 2.0 platform , post-IBT treatment, and post-VR. The clinical interviews were administered by an evaluator trained in the administration of CH measures. The evaluation lasted for 4 h.Structured Clinical Interview for DSM-IV for Axis I disorders [SCID-I; French version; Ref.   .Overvalued Ideas Scale (OVIS) (r = 0.86), and inter-rater reliability (r = 0.88).The e (OVIS)  is an 11Evaluation of Primary Inferences Scale (EPIS) (The e (EPIS)  was deveEvaluation of Secondary Inferences Scale (EPIS) (The e (EPIS) . With thSaving Inventory-Revised (SIR)  , is compSaving Cognitions Inventory (SCI) (The ry (SCI)  is a queClutter Image Rating (CIR) (The ng (CIR)  is a serBeck Depression Inventory (BDI-II) (r = 0.93).The (BDI-II)  is a 21-Beck Anxiety Inventory (BAI) (r = 0.63) (The ry (BAI)  contains = 0.63) .Inferential Confusion Questionnaire – Expanded Version (ICQ-EV) (r = 0.90).The (ICQ-EV)  is compr(ICQ-EV) . This meImmersive Tendencies Questionnaire (ITQ) (The Canadian adaptation of the re (ITQ)  is comprre (ITQ)  demonstrre (ITQ) .Presence Questionnaire (PQ-F) (The French Canadian adaptation of the e (PQ-F)  consistsThe French Canadian translation of the Simulator Sickness Questionnaire (SSQ-F)  was alsoFinally, the therapist asked the participants to rate their level of anxiety and discomfort during the VR tasks. For example, when the client had to discard a virtual object, the therapist asked the client to rate their level of anxiety and discomfort on a scale from 0 to 10 and took note of the rating. This allows for measure of the difficulty of the task and also to verify if the VR elicited the expected emotions.Fourteen participants with a diagnosis of CH took part in this project. The participants were randomly assigned to one of two of the following conditions: active control condition and experimental condition.All of the participants received IBT administered by psychologists trained in this approach. The treatment protocol used was developed by O’Connor et al.  and adapAfter receiving IBT, five sessions of 1 h were given to participants in both conditions. These sessions were administered by psychologists trained in the use of neuroVR 2.0 and the established treatment protocol. These sessions were also audio recorded and verified by an independent person involved with the project to ensure the integrity of the steps of the VR sessions was respected. In addition, the participants had no contact with one another between VR sessions. The first session allowed participants in the experimental condition to familiarize themselves with the virtual environment and to change elements of the environment to make them resemble, as much as possible, their actual environment at home. The second session was aimed at helping participants begin to sort through their homes by establishing a plan of action based on the elements present in the virtual environment. In the last three sessions, participants took action virtually by disposing of objects already selected based on the degree of subjective distress they reported. Once an object was selected, the participants were supposed to put it in a virtual, 3D garbage can. They were then asked to re-evaluate their degree of anxiety and discomfort on a scale of 0 to 10. At the beginning of each session, the therapist evaluated if some objects were sorted or taken out from home by the participant. The last session was also used to discuss relapse prevention and to establish a plan of action for the coming months. The client was asked to identify at-risk situations for relapse and to write a plan of action with the therapist as a way to ensure the client had all of the tools that may be needed in the future. Finally, measures of presence and VR sickness were completed at the end of each VR session.For control participants, the steps of treatment were the same. The only difference was that the objects selected when sorting and discarding did not belong to them. Their level of anxiety and discomfort on a scale from 0 to 10 was still evaluated to determine the presence of any emotions toward these objects. With regards to the task completed at home, participants were asked to discard one object, without specifying which one. The point of this exercise was to see if they would dispose of an object that was similar to the one discarded in the virtual environment.T-test were conducted on all normal variables. Non-parametric analyses were conducted when variables did not meet the assumptions of normality or had a small sample size. The variables for which non-parametric analyses were conducted are the following: the subscale “control” of the SCIR and the “acquisition” and clutter subscales of the SIR. The non-parametric analyses of these variables will be presented following the presentation of the parametric analyses. Additionally, a significance level of 0.10 was chosen because of the small sample size. Even though we used a cut-off point of 0.10, we nonetheless corrected for multiple comparison analysis.Normality was verified for all variables and the analyses were conducted by taking into consideration whether the assumptions were met or not. Analysis was conducted on completers. Repeated measures ANOVAs and p > 0.05). Also, there were no significant differences between the groups at pretreatment on clinical measures.Univariate (age) and chi-square  analyses did not find any significant differences between the groups  = 2.28, p = 0.10. It is possible to qualify this interaction because of the significance level. Contrasts indicated a linear interaction between the two groups for the pre-VR and post-VR F = 7.80, p < 0.001. This interaction demonstrates that the participants’ results for the series of images of the bedroom in the experimental group had a tendency to decrease over time as compared to the control group. There were no interactions observed for the other rooms depicted in the CIR, the kitchen F = 0.16, p = 0.85 and the living room F = 0.90, p = 0.42.Repeated measures ANOVAs were conducted on the main measure of clutter, the CIR. With regards to the images of the bedroom, a significant interaction was observed t-tests were conducted in order to determine if there was a difference between the mean level of anxiety before and after action was taken in the two groups. A significant difference was observed for the experimental group t(6) = 17.67, p < 0.001 as well as for the control group t(6) = 8.00, p < 0.001. An independent t-test was conducted, and a significant difference was found between the groups before action was taken in VR t(12) = 3.36, p < 0.05 and after the VR task t(12) = 3.35, p < 0.05.Paired sample F = 5.32, p < 0.05, but no interaction effect, for the “emotional” subscale of the SCIR F = 0.97, p = 0.39. There was also a main effect of time for the “responsibility” subscale of the SCIR F = 4.20, p < 0.05 and the “memory” subscale F = 7.76, p < 0.05, but no significant interaction effects between groups (p > 0.05). A Greenhouse–Geisser correction was applied to these variables. Finally, a main effect of time was observed for the SCIR total score F = 9.46, p < 0.001, but there were no interaction effects.A repeated measures ANOVA demonstrated a main effect of time F = 2.38, p = 0.15 or for the SIR total score F = 1.68, p = 0.22. As the “clutter” and “acquisition” subscales did not meet the assumptions of normality, non-parametric analyses were conducted. There is no test equivalent to a 2 × 2 repeated measures analysis. As such, a composite score between post-RV and pre-IBT was calculated and a Mann–Whitney U test was conducted in order to determine if there was a significant difference between groups. No difference was observed for the “clutter” subscale for the experimental group  and the control group , U = 20.00, z = −0.58, p = 0.56, r = 0.14. Also, there was no difference for the “acquisition” subscale for the experimental group  and control group , U = 14.00, z = −1.35, p = 0.18, r = 0.36.As previously mentioned, a main effect of time from pre-IBT to post-RV was found for the SIR total score and its three subscales. A repeated measures ANOVA did not find an interaction between the groups for the “discarding objects” subscale F = 3.56, p < 0.05, and no interaction effect F = 0.16 p = 0.85. A main effect of time was also observed for the “obsessions” subscale F = 4.19, p < 0.05 but not for the “compulsions” subscale F = 1.13, p = 0.31. No interaction was observed between the groups for either subscale. A repeated measures ANOVA found no main effect F = 2.39, p = 0.11 or interaction F = 0.24, p = 0.24 for the OVIS. There was, however, a linear trend across time for both groups. Essentially, the total score demonstrated a tendency to decrease for the two groups. The results do not demonstrate a main effect for the BDI F = 0.02, p = 0.98 or the BAI F = 0.22, p = 0.80. There was also no interaction observed for the BDI F = 1.81, p = 0.19. There was, however, an interaction found for the BAI F = 3.17, p < 0.10. The BAI scores for the control group had a tendency to decrease over time, while that of the experimental group increased from pre-IBT to post-IBT, and decreased at post-VR. A Mann–Whitney U test did not find any difference between the groups on the ICQ-EV at post-VR: experimental group  and control group , U = 19.5, z = −0.22, p = 0.83, r = 0.06. See Table A repeated measures ANOVA found a main effect of time for the total score on the YBOCS between pre-IBT, post-IBT, and post-RV F,24 = 3.5t-tests found no significant difference between groups on any of the subscales of the presence questionnaire. The scores demonstrated a high degree of presence for both groups according to the French-language norms of the questionnaire; experimental group M = 90.96, SD = 3.07; control group M = 86.98, SD = 20.94. The SD is much larger for the control group than for the experimental group. An independent t-test did not find any difference between the two groups for the Simulator Sickness Questionnaire. Furthermore, each group obtained scores that were below the average reported in the norms for the questionnaire .Independent We also compared the results of this study with a non-concurrent data collected from another group. Five participants were recruited in the same way as the participants in the present study’s sample and participated in the first therapy group given at the Fernand Seguin research center, before the virtual environments were created. They received the same treatment protocol (IBT), and it was the same therapist who animated the sessions.z = 0.00, p = 1.0; kitchen: z = −1.00, p = 0.32; living room: z = 0.00, p = 1.00. This was also the case for measures from post-IBT to 6-month follow-up: bedroom: z = 0.00, p = 1.0; kitchen: z = −1.41, p = 0.20; living room: z = 0.00, p = 1.00. The results for the three rooms decreased.Measures were taken at pretreatment, posttreatment, and at 6 months following completion of the treatment. The results demonstrate no clinical or statistical difference on measures of clutter (CIR) from pre-IBT to post-IBT; bedroom: z = −1.6, p < 0.10, with a large effect size (r = 0.57). The median score decreased from pre-IBT (Md = 21.50) to post-IBT (Md = 17.00). The “obsessions” subscale decreased significantly z = −1.83, p < 0.10, with a large effect size (r = 0.65). The median score decreased from pre-IBT (Md = 11.00) to post-IBT (Md = 8.50). No change, however, was observed for the “compulsions” subscale z = −0.38, p = 0.71. There was no significant difference for the total YBOCS score from post-IBT to 6-month follow-up z = −0.00, p = 1.00.With regards to the secondary measures, scores on the YBOCS decreased significantly from pre-IBT to post-IBT z = −0.37, p = 0.72 and BDI: z = −0.92, p = 0.36. There was a significant difference on the ICQ-EV z = −1.60, p < 0.10, with a large effect size (r = 0.60). The median score decreased from pre-IBT (Md = 76.00) to post-IBT (Md = 65.50).There was no significant difference from pre-IBT to post-IBT on the OVIS: z = −1.83, p = 0.06, with a large effect size (r = 0.65). The median score decreased from pre-IBT (Md = 16.50) to post-IBT (Md = 7.00). There was no significant difference on any of the questionnaires from post-IBT to 6-month follow-up.A significant difference on the BAI was also observed z = −1.63, p < 0.10, with a large effect size (r = 0.62). The median score decreased from pre-IBT (Md = 2.00) to 6-month follow-up (Md = 0.00). No measures were taken at post-IBT in this sample, as they were in the present study.With regards to the secondary CH measures, no significant decrease on the SIR total score and the “clutter” and “discarding objects” subscales was observed between pre-IBT and 6-month follow-up. A significant difference was observed on the “acquisition” subscale z = −1.63, p < 0.10, with a large effect size (r = 0.62). The median score decreased from pre-IBT (Md = 2.00) to post-IBT (Md = 0.00). No significant difference was observed from post-IBT to the 6-month follow-up for the SCIR and its subscales.With regards to the SCIR, no significant difference was observed from pre-IBT to post-IBT for the total score or for its three subscales: “emotional,” “responsibility,” and “memory.” A significant difference was observed for the “control” subscale from pre-IBT to post-IBT t-tests were conducted to measure change on measure of CH from pre-IBT to post-IBT. Unfortunately, the SIR was not completed at post-IBT because of an omission in the questionnaire package given to participants. As such, the only measures available for the SIR are at pre-IBT and post-VR. A significant difference was observed from pre-IBT to post-VR for the SIR total score t(13) = 4.79, p < 0.001 and the “discarding objects” subscale t(13) = 5.44, p < 0.001. A Wilcoxon test of signed-rank showed a statistically significant decrease on the “acquisition” subscale from pre-IBT to post-VR z = −2.64, p < 0.005, with a large effect size (r = 0.50). The median score on the “acquisition” subscale decreased between pre-IBT (Md = 21) and post-VR (Md = 15). No significant difference was observed for the “clutter” subscale between pre-IBT and post-VR z = −1.03, p = 0.31.Paired sample t(13) = 4.59, p < 0.001, and for its three subscales: “emotional” t(13) = 2.82, p < 0.05; “responsibility” t(13) = 3.07, p < 0.05; and “memory” t(13) = 6.07, p < 0.001.A significant difference was found for the SCIR total score from pre-IBT to post-IBT, z = −2.80, p < 0.005, with a large effect size (r = 0.53). The median score decreased between pre-IBT and post-TBI (Md = 15.46).A Wilcoxon signed-rank test demonstrated a statistically significant decrease for the subscale “control” of the SCIR from pre-IBT to post-IBT t(13) = 1.14, p = 0.27; kitchen: t(13) = 1.30, p = 2.22; living room: t(13) = 0.54, p = 0.60).No significant difference was found between the different images on the CIR between pre-IBT and post-IBT (bedroom: p > 0.05).A repeated measures ANOVA was conducted comparing the two groups  for all measures of CH from pre-IBT to post-IBT and no significant interaction was observed between the two groups  = 3.21, p < 0.05, and for the “obsessions” subscale t(13) = 2.77, p < 0.05. Also, a significant difference was observed for the “compulsions” subscale t(13) = 3.21, p < 0.06. There was no significant difference on the OVIS t(13) = 1.37, p = 0.20, BDI t(13) = 1.00, p = 0.34, or BAI t(13) = −0.09, p = 0.93. To better understand these results, a repeated measures ANOVA was conducted and the results demonstrated that for the BAI, an interaction effect was present between the two groups F = 8.64, p < 0.05. The scores of the experimental group increased, whereas those of the control group decreased. As the assumption of sphericity was not met, the Greenhouse–Geisser correction was applied. As the ICQ-EV was not normally distributed and also not transformable, a Wilcoxon signed-ranked test was conducted. There was no significant difference from pre-IBT to post-IBT for the ICQ-EV z = −0.72, p = 0.47.Paired sample As expected, the results on measures of VR demonstrated a good state of presence during the experimentation, good immersion, and very little VR sickness. These results confirm the hypothesis that non-immersive virtual environments allow for the creation of a feeling of presence and immersion, which can contribute to the eliciting of emotions, when using the virtual environment.It was observed that both groups experienced anxiety during the VR sessions, a finding that is contrary to the initial hypothesis that stipulated that the control group would not experience significant anxiety. A significant difference, however, was found between the groups. Specifically, the participants in the experimental group experienced significantly more anxiety than the control group during the action taking task completed in the virtual environment. Following the VR task, the control group was significantly less anxious than the experimental group. This may be explained by the fact that the virtual environment in the experimental condition used participants’ personal objects, whereas the virtual environments in the control condition did not. For this reason, the feeling of attachment toward the objects was not the same for participants in each condition.Following VR sessions, there was an interaction between the groups on the main measure of clutter, that is, for the images of the bedroom. The level of clutter in the experimental group showed a tendency to decrease, as compared to a tendency to increase in the control group. This may signify that taking action in VR allowed participants in the experimental group to discard significantly more objects in their bedroom. It does not seem that action taken in the control group allowed participants to discard objects in the same room, as their scores actually increased. It should be noted, however, that for participants in the experimental group, the majority of selected pictures were of their bedroom.Following VR, there was also a decrease over time in cognitions related to the CH symptoms “responsibility,” “emotional,” and “memory” as well as for the total score. The SIR total score as well as the “acquisition” and “discarding objects” subscales also decreased over time, as well as the “obsessions” subscale of the YBOCS. Overvalued ideas also evinced a tendency to decrease over the three time points, pre-IBT, post-IBT, and post-VR. Finally, a significant interaction was observed between the groups on a measure of anxiety. The results of the experimental group increased slightly at post-IBT and decreased at post-VR, whereas anxiety in the control group consistently decreased over time. This may be explained by the fact that individuals in the experimental group had to submit pictures of their home so that their virtual environment could be created. This may have caused anxiety as many of the participants in this group reported worries about what was going to happen in the VR sessions.Finally, the comparison of the experimental group with the control group and non-concurrent comparison group suggest that the VR condition is an accessible and interesting tool that may help the participant take action at home. The results also demonstrate that IBT is a promising approach in the treatment of CH as it was possible to observe improvements in CH symptoms in the participants. It may also be possible to use VR as a preventative measure to impede the development of compulsive behavior .After receiving IBT, participants in all three groups evinced a significant improvement in their CH-related cognitions. The same can be said for the measures of obsessions and compulsions, as these scores significantly decreased as well for both groups included in the present study. No differences were observed, however, on measures of depression or inferential processes. Also, no differences were observed on the measure of clutter (CIR). These results are in line with other studies that have reported that hoarders have difficulty in taking action when it comes to their clutter. With regards to the measure of depression, the participants expressed that they would have appreciated additional sessions. The majority of them reported feeling discouraged regarding the clutter of their homes and did not see any progress in this respect. With regards to overvalued ideas, even though the scores on the OVIS did not significantly decrease, the clinical scales demonstrated a decrease of 40% in the primary doubt. This pattern of results may be attributable to the fact that the OVIS considers only one overvalued idea, whereas the clinical scales are more exhaustive, taking into account all of the overvalued ideas reported by the participant.The limitations of the present study are mainly the small sample size and the absence of a passive control group. Also, it would have been preferable to have additional time points, such as at 3- and 1-year follow-up. Following the clinical evaluations post-VR, some participants indicated they had experienced difficulties during the IBT and the VR. As such, it would have been of interest to have included qualitative measures and analyses. For example, participants reported problems, such as bankruptcy, sickness or death of a loved one, eviction, and loss of employment. These elements were also corroborated by the participants’ psychologists. The participants as well as the psychologists identified these events as obstacles to progress in treatment. It is, therefore, important to consider these life events as they can have a considerable impact on the success of treatment.Other elements should also be considered for future research. Indeed, it would be interesting to compare the experimental condition to a passive control condition or a wait list. Though the results were compared to a non-concurrent control group that did not receive VR, these participants were not randomly assigned to this condition. Also, as many studies include home visits, it would be of interest to have an active control condition comparing VR to home visits. In addition, it may be that five sessions of VR is insufficient to observe significant results on CH measures. As the home environments are extremely cluttered, they require a lot of work to achieve satisfactory results.In conclusion, it seems that non-immersive VR is accessible and elicits a state of presence and immersion in participants suffering from CH. VR also elicits emotions during sorting tasks and when virtually discarding objects. Personalization of the virtual environment seems to help hoarders clean out their environment, as was the case in the bedroom in the context of this study. Only two participants dropped out of treatment, which is very little compared to the majority of studies conducted with this population. It may be that VR is less overwhelming. Finally, the participants reported that virtually sorting and discarding objects helped them to take action and experience less distress and anxiety at home. They were also generally satisfied with the IBT and VR.The present article was part of M-E St-P-D’s thesis. Dr. KO was supervising the entire research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dear Editor,Hepatitis E virus (HEV), a member of the genus Hepevirus, is a non-enveloped virus with a positive stranded RNA genome that is approximately 7.2 kb in length . It has


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Microscale soft-robots hold great promise as safe handlers of delicate micro-objects but their wider adoption requires micro-actuators with greater efficiency and ease-of-fabrication. Here we present an elastomeric microtube-based pneumatic actuator that can be extended into a microrobotic tentacle. We establish a new, direct peeling-based technique for building long and thin, highly deformable microtubes and a semi-analytical model for their shape-engineering. Using them in combination, we amplify the microtube’s pneumatically-driven bending into multi-turn inward spiraling. The resulting micro-tentacle exhibit spiraling with the final radius as small as ~185 μm and grabbing force of ~0.78 mN, rendering itself ideal for non-damaging manipulation of soft, fragile micro-objects. This spiraling tentacle-based grabbing modality, the direct peeling-enabled elastomeric microtube fabrication technique, and the concept of microtube shape-engineering are all unprecedented and will enrich the field of soft-robotics. Spiraling tentacles are widely utilized in nature for grabbing and squeezing objects. There have been continuous soft-robotic efforts to mimic them with pneumatic tube actuators325121431Our approach is two-stepped. In the first, we fabricate easily deformable elastomeric microtubes as the platform structure. High deformability is ensured by the thinness of the microtube itself (100−125 μm in inner diameter) and its tube-wall (8−32 μm). Making such a subtle structure at a length exceeding several millimeters has been deemed unfeasible. We accomplish it with a new, direct peeling-based soft-lithographic technique. It also allows significant asymmetrization of the microtube’s cross-sectional shape which leads to bending up to a single-turn. In the second step, we apply shape-engineering to the microtube to amplify the bending into multi-turn spiraling. Using a semi-analytical model, we establish a design rule which enables such a spiraling with a simple hump . The outin situ thermal solidificationPast reports testify that the biggest issue in using liquid-phase poly(dimethylsiloxane) (PDMS) for building long and thin structures, such as pillars or wires, is its tendency to beadL reaching 5−8 mm. The main factor limiting L was the inevitable increase in the friction and wrinkling during the peeling process. Despite their high aspect-ratios  and thin walls, the microtubes did not sag or collapse, even when no air pressure was applied.The completed PDMS microtube is robust enough to be peeled directly from the template with a polymer jacket remover, a standard tool in fiber-optics . The pro38t1 and t2 of 31.8 ± 4.9 (s.d.) and 7.9 ± 1 (s.d.) μm, respectively. The coating thickness can also be made uniform by rotating the template during curing.The solidification process can also be controlled for additional tailoring of the microtube’s cross-sectional shape. Slowing it down prolongs gravitational impact on the coating, resulting in an increase in the tube’s cross-sectional asymmetry, as shown in As shown in We connected the microtubes directly to blunt syringe needles for pneumatic actuation. Owing to their high aspect-ratio, thin tube-wall, and inherent softness of PDMS, the microtubes bent significantly upon applying air pressure, as shown in L, di, t1, and t2 at 5600, 104, 35.6, and 7.7 μm, respectively. As the characterization sample, we used the one in Regardless of the pressure or cross-sectional asymmetry, plain microtubes with no cross-sectional change along in the axial direction failed to achieve spiraling. Conventionally, such an insufficient bending has been amplified into spiraling through the use of bi-material composite structures34Instead, we enabled the spiraling motion in the PDMS microtube actuator by adding a simple hump to it as shown in x, y) of the deformed base curve can be described by an integration:s ∈  is the natural coordinate of the beam of length L, and f is a cosine (sine) function for u = x (u = y). E is the material’s Young’s modulus, and I is the second moment of area. At this specific instant, it is plausible to assume that a plain microtube has a constant I along its length, and that a humped microtube has a step-wise distribution of I, as shown in I with increasing pressure would call for analyses of hyperelastic deformations and plasticity at extreme cases, which is beyond our scope. The bending moment Mo ≡ π·r2·p·de wherer is the radius, p the current pressure, and de the distance between the microtube's neutral axis and void hole's center. y > 0. In light of the simple harmonic functions in x and y to 0, thereby impeding the desired spiraling.We investigated the hump’s role in promoting the spiraling motion using the Euler-Bernoulli beam theory3141I as shown in I, the integration in I1 and I0 are the values of I in the hump and non-hump sections, respectively, as shown in I0 < I1. By adjusting the levels of the phase-shifts in x and y, we can control re-entry point to the first quadrant. A simple criterion can be derived by assuming With the hump, we can modulate the microtube’s geometry and, hence, the values of L) affects the level of bending as a function of its position. We used a microtube model with its characteristics approximately matching those of MT1. With I0 and I1 at 5.1 × 10−16 and 8.6 × 10−15 m4, respectively, the inward spiraling can be obtained when 0.024 < α < 0.524. We set the α value of Hump B at an improper value of 0.55 while setting that of Hump A to the proper value of 0.21, as indicated by arrows in Hump A did achieve inward spiraling with the final y > 0. Hump B, on the other hand, performed even worse than the plain, un-humped microtube, resulting in y < 0.L, di, t1, and t2 at 5800, 104, 33, and 7.4 μm, respectively, and compared its bending behaviors before and after adding a hump at an obviously improper position of 0.78·L. To experimentally confirm the prediction above, we fabricated another PDMS microtube with structural characteristics very similar to those of MT1 with L, di, t1, and t2 at 5470, 105, 34.6, and 8.2 μm, respectively, and its hump installed at 0.17·L point exhibited spiraling with two full turns, achieving the final RoC of 210 μm. RoC as low as 185 μm has been obtained.hg to the optical fiber cantilever. The standard beam deflection theory relates the force F and the deflection δc at hg as41I = πr4/4, r the radius of the optical fiber cantilever, and E the Young’s modulus of fused silica.The spiral formed by the PDMS micro-tentacle is ideal for grabbing and holding microscale objects. To estimate its grabbing force, we configured it to deflect a cantilever as shown in the inset of L, di, t1, and t2 at 5000, 107, 39.1, and 7.2 μm, respectively. Its minimum spiraling diameter was 370 μm and the corresponding maximum achievable deflection δc,max was 200 μm. c as a function of hg at the pressure level of 9.8 psi. Each represents the average of five measurements. We omitted the error bar since the standard deviations were <1% of the average values. The force F, estimated through curve-fitting, was approximately 0.78 mN. We retained only the first four points in the curve-fitting since δc approached its maximum possible value and began to saturate beyond hg ~ 7.5 mm.For this measurement, we used a micro-tentacle with L, di, t1, and t2 at 5000, 104, 31.5, and 6.9 μm, respectively. Our first target was the egg of Mallotus villosus which deforms and bursts easily when manipulated with hard tweezers. We initially placed multiple eggs on a glass slide and then used the micro-tentacle’s bending motion to separate one egg. Then we grabbed the egg by winding the micro-tentacle around it. The optical micrographs in Thanks to the softness of PDMS and the spiraling motion, the micro-tentacle can function as a soft-robotic grabber of micro-objects that can easily be deformed or damaged under hard material-based grippers. As practical examples, we attempted to grab biological objects. We utilized a micro-tentacle with et al. exhibited 10−50 mN of forceet al. and Wakimoto et al. also exhibited force levels of 3 mN11 and 2.2 mN3, respectively. The force-volume ratio of our micro-tentacle is 8.4 mN/mm3 which is higher or comparable to those listed above. It indicates that our micro-tentacle produced force very efficiently with a simple and small structure. In fact, our micro-tentacle can be regarded as the bridge between the conventional, larger micro-actuators producing mN-level force and biological micro-organisms such as C. elegans capable of producing 62 μN of forceThe cantilever deflection measurement revealed that the spiraling micro-tentacle’s grabbing force is in the vicinity of 0.78 mN at 9.8 psi pneumatic pressure. In absolute sense, this force is weaker than those of existing elastomer-based pneumatic micro-actuators. For example, the PDMS/polyimide-based pneumatic balloon actuator by Konish in situ thermal solidification of PDMS dip-coated around a cylindrical template and direct peeling of the cured structure. Its capability to asymmetrize the microtube’s cross-sectional shape enabled the microtube to bend up to a single turn. But we went further to amplify the bending into a life-like, multi-turn spiraling motion. To that end, we established a semi-analytical model to shape-engineer the microtube and turn it into a micro-tentacle. The optimized micro-tentacle exhibited a spiraling motion with two full turns and ~200 μm inner radius, which is ideal for grabbing micro-objects.To conclude, we have demonstrated elastomer-based soft-robotic micro-tentacles capable of winding around and holding microscale objects. To realize the thin, highly deformable microtubes, we established a new fabrication technique based on in vivo biomedical manipulation or surgery714Experimental confirmation of the feasibility of such a winding motion in elastomer-based microscale pneumatic actuators is another of this work’s contribution. The spiraling capability will render the micro-tentacle particularly useful for manipulating fragile or easily deformable objects since it will allow the micro-tentacle to grab and hold a delicate object either by winding around it conformally or by forming a ring that can scoop up the object without squeezing. Thanks to the use of PDMS for its construction and also to its microorganism-level force, our micro-tentacle is fully compliance-matched to biological structuresAs depicted in For grabbing force measurement, we utilized a 15 mm-long section of 125 μm-diameter communication-grade fused silica optical fiber  as the cantilever. As the support for applying the grabbing force, we also installed a 155 μm-diameter stainless steel wire  in parallel with the fiber. Then we measured the deflection of the fiber under an optical microscope  as the micro-tentacle wound around both the metal wire and optical fiber.How to cite this article: Paek, J. et al. Microrobotic tentacles with spiral bending capability based on shape-engineered elastomeric microtubes. Sci. Rep.5, 10768; doi: 10.1038/srep10768 (2015).


Z-numbers based formalization of information (Z-information) represents a natural language (NL) based value of a variable of interest in line with the related NL based reliability. What is important is that Z-information not only is the most general representation of real-world imperfect information but also has the highest descriptive power from human perception point of view as compared to fuzzy number. In this study, we present an approach to decision making under Z-information based on direct computation over Z-numbers. This approach utilizes expected utility paradigm and is applied to a benchmark decision problem in the field of economics.Real-world decision relevant information is often partially reliable. The reasons are partial reliability of the source of information, misperceptions, psychological biases, incompetence, and so forth.  Decision making is one of the attractive research areas in the last decades. The complexity and uncertainty are persistent phenomenon in the real world, and the fuzzy set –3 is widZ-number is a sufficient formalization of real-world information that should roughly be considered in light of its reliability. The critical issue is that the reliability of information is not considered properly. Zadeh has proposed a new notion Z-number which is more appropriate to describe the uncertainty. Z-number takes both restraint and reliability. In comparison with the classical fuzzy number, Z-number has more ability to describe the real information of human   Z-numberdered in . Z-numbeested in , 9. In  is a discrete fuzzy number if its support is finite; that is, there exist x1,…, xn ∈ ℛ with x1 < x2 < ⋯<xn, such that supp(A) = {x1,…, xn} and there exist natural numbers s, t with 1 ≤ s ≤ t ≤ n satisfying the following conditions:(1)μA(xi) = 1 for any natural number i with s ≤ i ≤ t;(2)μA(xi) ≤ μA(xj) for any natural numbers i, j with 1 ≤ i ≤ j ≤ s;(3)μA(xi) ≥ μA(xj) for any natural numbers i, j with t ≤ i ≤ j ≤ n.A fuzzy subset A be a discrete fuzzy number. A probability measure of A denoted by P(A) is defined asLet ested in –14, 16, α-cut is given as  as a mental factor which influences a choice of a preferred Z-number. The degree of pessimism is submitted by a human observer who wishes to compare the considered Z-numbers but does not completely rely on the results obtained by the above mentioned fuzzy optimality approach. In this viewpoint, given do(Zj) ≤ do(Zi), we define for two Z-numbers Z1 and Z2 [The suggested approach may be considered as basis of a human-oriented ranking of  and Z2 (19)rZi,Zi = Zj otherwise [Thentherwise .β is submitted by a human being and adjusts ranking of Z-numbers to reflect human attitude to the computed do. This attitude may result from the various importance of Z-numbers for a human being and other issues [The degree of pessimism r issues .Real-world decision relevant information is imprecise, uncertain, and partially reliable. Therefore, results of decision analysis based on such information are also partially reliable. This fact should prevent decision makers relying much on decision analysis results even when a very careful mathematical modeling was used.Z-information may help achieve a more realistic decision analysis technique and, at the same time, use a simple form of the utility function.A well-known approach to decision making under uncertainty is the use of expected utility function . However𝒮 = {S1, S2,…, Sn} be a set of states of nature and let 𝒳 = {X1,…, Xl}, k = 1,…, l, be a set of Z-valued outcomes. Denote by ℱ𝒮 a σ-algebra of subsets of 𝒮. Then consider 𝒜 = {f ∈ 𝒜∣f : 𝒮 → 𝒳}, the set of Z-valued actions, as the set of all ℱ𝒮-measurable Z-valued functions from 𝒮 to 𝒳35,32.Let ZPl of the states of nature is represented by Z-valued probabilities Si:Linguistic information on likelihood 𝒳 are Z-valued outcomes; elements of 𝒜 are Z-valued acts; elements of 𝒮 are states of nature; elements of ℱ𝒮 are events.In the suggested framework, we extend a classical neo-Bayesian nomenclature as follows: elements of Z-information can be formalized as a 4-tuple . The problem of decision making with Z-valued information on the basis of EU consists in determination of an optimal act f* ∈ 𝒜: find f* ∈ 𝒜 for which ZU(f*) ≥ ZU(f), ∀f ∈ 𝒜.A framework of decision making with ZU(f) is a Z-valued expected utility defined asHere Z-numbers, without converting them to fuzzy and/or crisp numbers. This allows preserving available imprecise and partially reliable information and using it in the final comparison of alternatives.The suggested approach is based on direct computations with In this application section, we intend a problem of decision making in the field of economics. The analyzed data are obtained from Techware Incorporated in . Two newZ-numbers. The set of alternatives isf1 denotes introducing product 1, f2 denotes introducing product 2, and f3 denotes introducing both products (1 and 2).Let us proceed to formal description of the considered decision problem. The partially reliable linguistic decision relevant information in the considered problem will be described by S1 denotes strong national economy, S2 denotes fair national economy, and S3 denotes weak national economy. The probabilities of states of nature are ZP(S1) = , ZP(S2) = .The set of states of nature isThe set of outcomes isThe partially reliable linguistic information for the probabilities of states of nature and the utilities of each alternative taken at different states of nature is shown in Z-number based representation is shown in The corresponding decision matrix with Z-numbers for probabilities and utilities from The membership functions of the first and the second components of Z-number based probability ZP(S3) = Z43 =  on the basis of ZP(S1) = Z41 and ZP(S2) = Z42. As ZP(S3) is completely determined by ZP(S1) and ZP(S2), its reliability B43 will be the same as reliabilities B41 and B42. Therefore, to complete determination of Z43 =  it is needed to compute A43 on the basis of A41 and A42. For computation of A43 we used the approach suggested in [Z43 =  is shown in Let us proceed to solving the problem. First it is needed to determine unknown ested in . The detZ-number based data we compute the expected utility for each of the alternatives f1, f2, f3 as follows:Z-numbers described in Based on the previous The results of computation of expected utilities for all the alternatives are shown in Figures Z-number valued utilities is needed. For comparison we will use the approach suggested in Now determining the best alternative by comparing the computed β = 0.3.As one can see, the second alternative is not Pareto optimal. Now it is needed to compare the first and the third alternatives. Suppose that the pessimism degree in comparison of these alternatives is Then we havef1.Therefore, the best action is Z-numbers opens a door for applications in many areas, especially in decision making theory. The goal of the present study is to develop an approach for decision making under Z-information described in NL. The suggested approach utilizes the paradigm expected utility based on a direct computation of Z-numbers. The advantage of the approach is its ability to account for imprecision and partial reliability of information and relative simplicity of computations. The approach is applied to solve a benchmark decision problem in the field of economics. The obtained results show validity of the approach.The concept of


A serial femtosecond crystallography based method has been proposed, which enables simultaneous X-ray phase identification and structure solution for multiphase polycrystalline samples. Test results from simulating calculations are encouraging. CrystFEL. Identification according to the primitive unit-cell volume determined from individual snapshots was able to separate the whole set of snapshots into two subsets, which correspond to the two zeolites in the sample. Monte Carlo integration in CrystFEL was then applied to them separately. This led to two sets of three-dimensional single-crystal diffraction intensities, based on which crystal structures of the two zeolites were solved easily by direct methods implemented in the program SHELXD.Serial femtosecond crystallography (SFX) is capable of collecting three-dimensional single-crystal diffraction data using polycrystalline samples. This may dramatically enhance the power of X-ray powder diffraction. In this paper a test has been performed using simulated diffraction patterns. The test sample is a mixture of two zeolites with crystal grain sizes from 100 to 300 nm. X-ray diffraction snapshots by SFX were simulated and processed using the program suite  For those snapshots that passed through the indexing, their primitive unit-cell volume was calculated. Then numbers of snapshots were plotted against the unit-cell volumes as shown in Fig. 23. In addition to these two peaks, there are a number of much smaller peaks with their unit-cell volumes equal to N times or 1/N (N is a simple integer) of either 3800 or 5500 Å3. Peaks related to the volume of 3800 Å3 are coloured in red, while those related to the volume of 5500 Å3 are in blue. As seen, the red and blue peaks form the majority of peaks in Fig. 1indexamajig in CrystFEL near the unit-cell volume at 3800 and 5500 Å3 are as follows:In this section, no preliminary knowledge concerning either chemical composition or crystal structure of the sample was assumed. The critical step here is to find out how many different crystalline phases are contained in the sample. First, indexing of each diffraction snapshot was tried by the program a = 13.67, b = 14.25, c = 22.37 Å, α = 89.90, β = 89.89, γ = 61.81°.Red phase: a = 17.29, b = 17.33, c = 19.49 Å, α = 88.02, β = 88.02, γ = 70.85°.Blue phase: et al., 2010CrystFEL was applied to these two data sets separately and produced two sets of three-dimensional diffraction intensities of the red and the blue phases. Finally the program XPREP  was applied to the two sets of three-dimensional diffraction intensities separately. The space groups were thus determined and the unit-cell parameters were converted according to crystallographic conventions. The results are as follows:The whole set of test data was re-indexed by specifying the primitive unit-cell parameters of the red phase. 164 571 snapshots among the total 1 000 000 passed through the indexing. They were then separated to form the diffraction data set of the red phase. Similarly a set of 714 025 snapshots was separated to form the diffraction data set of the blue phase. Monte Carlo integration  are shown in Figs. 3From the previous section we now have two sets of three-dimensional diffraction intensities and the corresponding space group and unit-cell parameters. Based on these, the crystal structure of the red and the blue phases can be easily solved by standard single-crystal methods. The only additional information we need is the chemical composition of the two phases  technique based on a third-generation synchrotron radiation source can do the same, since Stellato  al. 2014 and Both al. 2014 showed t


In order to acquire radiation-tolerant characteristics in integrated circuits, a dummy gate-assisted n-type metal oxide semiconductor field effect transistor (DGA n-MOSFET) layout was adopted. The DGA n-MOSFET has a different channel shape compared with the standard n-MOSFET. The standard n-MOSFET has a rectangular channel shape, whereas the DGA n-MOSFET has an extended rectangular shape at the edge of the source and drain, which affects its aspect ratio. In order to increase its practical use, a new aspect ratio model is proposed for the DGA n-MOSFET and this model is evaluated through three-dimensional simulations and measurements of the fabricated devices. The proposed aspect ratio model for the DGA n-MOSFET exhibits good agreement with the simulation and measurement results. According to a recent report , the dumW and length L. Furthermore, this simple geometry enables easy calculation of its aspect ratio. The current density of the standard n-MOSFET is constant along its length [W by L. When the integrated circuit is designed using standard MOSFETs, the circuit characteristics are determined using adjustments of each aspect ratio of W/L in the MOSFETs. Circuit designers can adjust only the aspect ratios in order to obtain specified circuit characteristics because the other parameters are determined in the device fabrication process. Therefore, the aspect ratio of the MOSFET is the most important parameter in the circuit design.The standard n-MOSFET, which is shown in s length . TherefoThe channel shape of the DGA n-MOSFET is presented in According to previous reports , 4, the For the practical use of the DGA n-MOSFET in circuit design, this study proposes a simple aspect ratio model by adopting several reasonable approximations. It is expected that the proposed simple aspect ratio model simplifies the estimation of the aspect ratio of the DGA n-MOSFET. The proposed aspect ratio model is evaluated using a three-dimensional simulation with the SILVACO ATLAS simulation tool. Furthermore, the proposed aspect ratio model is also evaluated through device fabrication and its measurement.LT, WT, and  θ are the channel length, half of the source side channel width, and corner angle, respectively [θ was specified in order to determine whether to place an additional rectangle between the two trapezoid transistors. Thus, it was determined that if (LD · tanθ)/2 > D, a rectangle is added between the two trapezoid transistors. LD, D, and θ are the channel length, extended width, and corner angle, respectively. This approximation was developed based on two assumptions. The first assumption is that the current density at the corner regions of the DGA n-MOSFET channel can be negligible. It is intuitively known that the electric field will not reach the corner regions; consequently, the series association of the two trapezoidal structures substitutes the DGA n-MOSFET channel region. The second assumption is that the corner angle θ of the substituted trapezoid structure will be constant regardless of the length LD, extended width D, and width WD, because the spreading angle of the current at the edge of the source is expected to be constant. The behavior of the current spreading is determined by the contact shape between the electrodes and channel region. In the DGA n-MOSFET, the source and drain edges are always positioned in the middle of the upper and lower sides of the channel region.The channel region of the DGA n-MOSFET is approximated using the series association of two trapezoidal transistors. Moreover, the value of the corner angle WD, extended width D, and corner angle θ have the same values; however, the length LD has different values and it increases in order of the figure number. LD · tanθ)/2 < D.The final approximated channel shapes are presented in LD, WD, and  θ are the channel length, channel width, and corner angle, respectively.In this case, the series association of the two trapezoidal transistors replaces the channel area of the DGA n-MOSFET. Moreover, a space exists between the bottom vertexes of the upper trapezoid and both left and right sides of the original channel area. The effective aspect ratio for the approximated structure shown in LD · tanθ)/2 = D. In this case, the series association of the two trapezoidal transistors also replaces the channel area of the DGA n-MOSFET. However, the bottom vertexes of the upper trapezoid encounter both left and right sides of the original channel area. The effective aspect ratio for the approximated structure shown in LD( = 2Lcri), WD, and  θ are the channel length, channel width, and corner angle, respectively.LD · tanθ)/2 > D. In this case, the series association of the two trapezoidal transistors and one rectangle replaces the channel area of the DGA n-MOSFET. The rectangle is added between the two trapezoidal structures. The effective aspect ratio for the approximated structure shown in LD, WD, D, and  θ are the channel length, channel width, extended width, and corner angle, respectively. Moreover, A and B indicate the aspect ratio formula for the trapezoidal structure and rectangle, respectively, as shown in μm process technology using the SILVACO ATLAS simulation tool. For both the standard and DGA n-MOSFETs, the gate oxide thickness, body thickness, and body doping density were 7 nm, 6 μm, and 8e16 #/cm3, respectively. For the DGA n-MOSFET, the side p+ doping density was 1e19 #/cm3. Moreover, the isolation structure was adapted using local oxidation of silicon (LOCOS). Five different widths  and three different lengths , which resulted in fifteen different structures, were simulated. For the DGA n-MOSFET, the extended width D was fixed to 2 μm.The standard n-MOSFET structure and DGA n-MOSFET structure were designed to be compatible with the commercial 0.35 WD and extended width D were 2 μm. The length LD increased in order of the figure number as 0.5 μm, 1 μm, and 3 μm. In order to evaluate the proposed effective aspect ratio model for the DGA n-MOSFET, the current densities are presented using rainbow colors in a linear scale relative to each maximum current density. From θ was determined using comparisons of the proposed effective aspect ratio model with the simulation results. When the corner angle  θ was 0.977, the proposed effective aspect ratio model had the best agreement with the simulation results. The approximated channel area with a corner angle  θ of 0.977 is indicated in The corner angle  Wdrawn,  Weff,  Ldrawn,  Leff, μn, Cox, and  λ are the drawn width, effective width, drawn length, effective length, electron mobility, gate oxide capacitance per unit area, and channel length modulation parameter, respectively. Moreover, the superscripts “DGA” and “STD” refer to the DGA n-MOSFET and standard n-MOSFET, respectively. When calculating the effective aspect ratios, it was assumed that the DGA n-MOSFET and standard n-MOSFET have the same electrical parameters for the μnCox and channel length modulation parameter  λ. The transconductance gm was adopted at a Vds of 0.05 V in order to minimize the effects induced by the channel length modulation parameter  λ difference between the DGA n-MOSFET and standard n-MOSFET. Furthermore, the transconductance gm was used at a Vgs of 1.5 V in order to use a saturated gm.In the simulation, the effective aspect ratios for the DGA n-MOSFETs were extracted using the following equations: Weff and effective length Leff, the ΔW and ΔL were extracted from the simulation results of the standard n-MOSFETs. From the simulation results, the extracted ΔW and ΔL were 0.05 μm and 0.005 μm, respectively.Moreover, in order to acquire the effective width μm technology with a gate oxide thickness of 7.3 nm and LOCOS for the isolation of the active areas. Three different widths  and three different lengths , which resulted in a total of nine structures, were fabricated. For the DGA n-MOSFET, the extended side channel width D was fixed to 2 μm.The standard n-MOSFET and DGA n-MOSFET were fabricated using the MagnaChip and Hynix 0.35 Vg-Id curves were measured and were then differentiated by Vg in order to acquire the transconductance gm curve. When measuring the Vg-Id curves, the Vds was set to 0.05 V. Moreover, all transconductance values gm used to extract the aspect ratios were chosen at a Vgs of 1.5 V.The fabricated devices were measured using an Agilent 4156A semiconductor parameter analyzer. The W and ΔL were 0.15 μm and 0.05 μm, respectively.As in the simulation case, in order to extract the effective aspect ratios for the DGA n-MOSFETs,  were alsLD · tanθ)/2 > D, the rectangular structure was added between the two trapezoidal structures.For practical use of the radiation-tolerant DGA n-MOSFET in designing a radiation-tolerant integrated circuit, an effective aspect ratio model of the DGA n-MOSFET was proposed. In the proposed effective aspect ratio model, the channel area of the DGA n-MOSFET was approximated using a trapezoidal structure and a rectangular structure. When (The proposed effective aspect ratio model was evaluated using a three-dimensional simulation and through measurement of the fabricated devices. Compared with the simulation results, the proposed effective aspect ratio model had an error range between −0.4% and 1.4%. Moreover, compared with the measurement results, the proposed effective aspect ratio model had an error range between −3% and 5.4%. Therefore, it can be concluded that the proposed effective aspect ratio model is well matched with the simulation and measurement results.