An important issue of psychological research is how experiments conducted in the laboratory or theories based on such experiments relate to human performance in daily life. Immersive virtual reality (VR) allows control over stimuli and conditions at increased ecological validity. The goal of the present study was to accomplish a transfer of traditional paradigms that assess attention and distraction to immersive VR. To further increase ecological validity we explored attentional effects with daily objects as stimuli instead of simple letters. Participants searched for a target among distractors on the countertop of a virtual kitchen. Target–distractor discriminability was varied and the displays were accompanied by a peripheral flanker that was congruent or incongruent to the target. Reaction time was slower when target–distractor discriminability was low and when flankers were incongruent. The results were replicated in a second experiment in which stimuli were presented on a computer screen in two dimensions. The study demonstrates the successful translation of traditional paradigms and manipulations into immersive VR and lays a foundation for future research on attention and distraction in VR. Further, we provide an outline for future studies that should use features of VR that are not available in traditional laboratory research. We experience this each time we are distracted and unable to focus. Understanding the mechanisms that underlie distraction is of interest to cognitive psychology but also many applied disciplines, including engineering, software development and therapeutic interventions, to name a few. Seminal research has shown that the detection of targets among distractors and the efficiency of ignoring distracting items are affected by features that stimuli share e.g. ,2). To a. To a2])An important issue critical to all psychological research is how experiments conducted in the laboratory and theories based on such experiments relate to human performance in daily life. After all, it is ‘daily’ human cognition and performance that psychologists wish to understand and explain. Ecological validity is a timely topic e.g. –11) and  and 11])immersive VR are beneficial because the sense of ‘presence’ within the environment is increased compared to other virtual environment technologies )nologies . Althougnologies ,20) studnologies . We therAlthough experiments in which images are presented in an immersive three-dimensional (3D) environment differ in various aspects from experiments in which stimuli are presented on a computer monitor in 2D , we expeIn our second experiment (Experiment 2), the 2D presentation was done on a standard CRT monitor in the laboratory. This provided us with the additional opportunity to track the eye movements of our participants. Eye tracking is a very sensitive method to measure the allocation of overt attention and can reveal attentional effects that are not apparent by only measuring RT and accuracy. Therefore, we decided to use this method in addition to manual RT measurements in Experiment 2 to verify typical search effects with our novel stimuli. Overall, we expected that participants should make more fixations until they reach the target when target discrimination is harder than easier, reflecting the more difficult and demanding visual search process with low target–distractor discriminability. Further, the assessment of fixations on the flanker was of interest to investigate ‘overt’ distraction, i.e. whether participants would look at the flanker at all or whether the flanker effect is rather mediated by covert attention. We also assessed whether target–distractor discriminability would modulate how often, when and for how long participants would look at the flanker.2.Experiment 1 was carried out in immersive VR. The design of the experiment followed typical experiments for the investigation of distraction, using the flanker paradigm. Participants were situated in a full virtual kitchen, looking at one of the countertops, located in front of them. They had to indicate by button press on a handheld device which one of two target stimuli (red/white yoghurt or red soda can) was present in a circular array consisting of six stimuli. Target–distractor discriminability was varied. In one condition targets and distractors were shown in a different colour, e.g. the targets were red or red/white and distractors were presented in green and green/white, and thereby easy to discriminate from each other. In another condition, both targets and distractors were red and red/white, and thus shared colour and were difficult to discriminate. In accordance with previous research, we predicted that search should be harder and RT should be higher when targets and distractors share colour. Further, a flanker item—congruent or incongruent with the target—was presented to the left or right of the circular array  and had 2.1.2.1.1.M = 34 years, s.d. = 13.8), gender , handedness (21 right-handed) and vision . After testing, participants filled out the CFQ [M = 41.32, s.d. = 9.16). Participants received $8. The protocol was approved by the Institutional Review Board of Duke University.Twenty-two participants, recruited via e-mail at Duke University, gave informed consent, and filled out a survey, providing information on age . Head tracking with 6 degrees of freedom was provided by an Intersense IS-900 tracker. The hand controller was an Intersense IS-900 wand controller, used only for its button capability. Participants wore Crystal Eyes CE3 shutter glasses synced to projectors running at 110 Hz. An active-stereo alternated between left and right displayed frames, which led to an effective frame rate of 55 Hz for the user. A cluster of computers (1 computer per projector) plus one computer as a master computer powered the system. All computers had NVIDIA Quadro FX 5600G graphics cards. The Simulation was created in the Unity3D game engine and used the MiddleVR plugin to facilitate running in our CAVE-type system.We used a six-sided active stereo CAVE-type system , two target or flanker objects that were easy to discriminate from each other  and 10 distractor objects . Colours were defined by the following RGB values: red = 191, 24, 24; white = 255, 255, 255; green = 29, 119, 47. The height of all objects was scaled to the height of the soda can . The apple was slightly smaller  because a larger apple appeared unnatural. Width and depth varied slightly to keep objects looking natural . Six stimuli  were arranged in a circular array (diameter 0.2 m). Distractor location was randomized. The target  appeared equally often at each location. A flanker  was displayed on the left or right of the circle (0.175 m distance between centre of the circle and flanker).The experiment contained four conditions, between which target–flanker congruency and target–distractor discriminability were varied. On congruent trials target and flanker were the same; on incongruent trials target and flanker differed. On trials with high target–distractor discriminability targets and distractors were of different colour , while on low target–distractor discriminability trials targets and distractors shared colour (both red and red/white). The experiment consisted of 192 trials, separated into two blocks. The conditions were randomized within a block. Participants completed 16 practice trials. Example displays are illustrated in Participants were shown example displays on paper to explain the task. To familiarize themselves with the VR environment, they went into the environment with the experimenter and were allowed to move and look around the entire virtual kitchen. During testing they stood on a pre-determined carpet tile in the centre of the VR environment, facing the countertop on which the stimuli appeared. The distance between eye level and location of the objects was approximately 1.1 m, varying slightly depending on the height of a participant.A trial started with the presentation of an upright or upside down cup in the centre that had to be fixated at the beginning of each trial. After 1000 ms the stimulus array and flanker were shown for 2000 ms. Participants pressed one of two response buttons on the wand to indicate which target was presented in the circle. Half of the participants pressed the top button for soda and the bottom button for yoghurt, half of the participants vice versa. Pressing a button elicited a dart sound effect (i.e. the moment the dart is thrown into the board) to provide feedback that a button was pressed but not whether the response was correct or incorrect. Participants were instructed to ignore the flanker. The inter-trial interval was set at 2000 ms. Participants were offered to take a break, to take off the shutter glasses and leave the VR environment between blocks. The end of a block was indicated by the Microsoft windows ‘tada’ sound. After the experiment, participants filled out the CFQ. An entire testing session took 35–45 min.2.2.Mean RTs of correct response trials were calculated per condition. Trials with no (0.4%) or incorrect responses (1.8%) and outliers  were discarded from the analysis. As error rate was very low, it was not analysed further.2.2.1.F1, 21 = 37.96, p < 0.001, F1, 21 = 61.23, p < 0.001, F1, 21 = 0.04, p = 0.845, A 2 (congruency: congruent versus incongruent) × 2 (discriminability: high versus low) analysis of variance (ANOVA) with repeated measures revealed that participants were slower on incongruent than congruent trials, 2.2.2.r = −0.302, N = 22, p = 0.172, two-tailed; nor under low discriminability, r = 0.037, N = 22, p = 0.871, two-tailed. We further divided participants into a high-CFQ (more distracted) and a low-CFQ (less distracted) group, using a median split of the CFQ scores (Mdn = 41). A 2 (congruency: congruent versus incongruent) × 2 (discriminability: high versus low) × 2  ANOVA with repeated measures confirmed the main effects of congruency, F1, 20 = 36.19, p < 0.001, F1, 20 = 59.23, p < 0.001, p > 0.214. In our high target–distractor discriminability condition, if anything, the extent of the flanker effect was numerically smaller for participants with high CFQ scores (25 ms) than for participants with low CFQ scores (56 ms). Participants with low CFQ scores responded in general numerically faster, in particular when target and flanker were congruent in the high target–distractor discriminability condition, resulting in a large difference between congruent and incongruent trials.We explored whether there is an association between the flanker effect and CFQ scores. High CFQ scores should reflect high distractibility in daily life. We determined the flanker effect (RT incongruent minus congruent) for high and low target–distractor discriminability trials per participant and calculated Pearson correlations. CFQ scores did not correlate with the flanker effect neither under high target–distractor discriminability, r = 0.444, N = 22, p = 0.039, two-tailed, but not for low target–distractor discriminability trials, r = 0.044, N = 22, p = 0.845, two-tailed.We had not restricted the sample to the usual age group of young adults. Thus we were able to explore potential age effects. Indeed, age correlated positively with the flanker effect for high target–distractor discriminability trials, 2.2.3.a), intermediate 1: position at the lower middle of the circular array (i.e. apple and soda can in figure 1a), intermediate 2: at the upper middle of the circular array (i.e. milk carton and tea box in figure 1a) and far: position furthest away from the observer/at the top of the circular array (i.e. coffee jar in figure 1a)). A 2 (congruency: congruent versus incongruent) × 4  ANOVA with repeated measures revealed, apart from a significant congruency effect, F1, 21 = 27.85, p < 0.001, F3, 63 = 12.57, p < 0.001, t21 = 2.61, p < 0.05; far versus intermediate 2 (810 ms), t21 = 5.64, p < 0.001; far versus near (783 ms), t21 = 2.92, p < 0.01). Responses were slowest to targets in the position intermediate 2 . There was no difference between the intermediate 1 and the near distance, t21 = 1.26, p = 0.223. Further, an interaction between distance and congruency was observed, F3, 63 = 3.99, p < 0.05, t21 = 2.85, p < 0.05, for the intermediate 2 than for the near distance, t21 = 3.18, p < 0.005, and there was a trend for a larger effect for the intermediate 1 compared to the near distance, t21 = 2.02, p = 0.057.To assess whether the distance between the observer and the target affected RT and distraction, we parsed the display into four areas (near: position nearest to the observer/at the bottom of the circular array (i.e. peanut butter jar in figure 12.2.4.a), intermediate  and far . A 2 (congruency: congruent versus incongruent) × 3  ANOVA with repeated measures showed, apart from a congruency effect, F1, 21 = 37.4, p < 0.001, F2, 42 = 8.51, p < 0.005, t21 = 4.19, p < 0.001. The differences between close (780 ms) and far and between close and intermediate showed only a trend, t21 = 2.03, p = 0.055; t21 = 2.07, p = 0.052, respectively. There was no interaction between distance and congruency, F2, 42 = 1.24, p = 0.301, To assess whether the distance between target and flanker affected RT and distraction, we defined three distances: close  than in previous studies that showed such an interaction (50 or 100 ms) , in lighWe further explored associations between distraction, i.e. flanker effects, and CFQ scores since the latter should reflect distractibility in daily life. CFQ scores did not correlate with the flanker effect. This lack of a correlation between flanker effect and CFQ scores cannot simply be attributed to a potentially small sample size because the correlational analysis considering age yielded significant effects. Results of our analysis using a median split of CFQ scores showed that in the high target–distractor discriminability condition participants with high CFQ scores, who should be more distracted, showed a numerically smaller flanker effect, indicating less distraction in the experiment, than participants with low CFQ scores. The observation that participants with low CFQ scores seemed to respond faster, especially when targets and distractors are easier to discriminate and target and flanker were congruent, is of interest. Such faster responses may indicate a tendency for a superior ability of the low CFQ group to focus in the present task. Investigation of CFQ scores was not a central part of our study but we suggest that including this instrument in future studies would be of interest to elucidate potential associations between distraction and performance in an experimental set-up. Interestingly, with respect to age effects we observed that the older the participants were, the more distracted they were in the high target–distractor discriminability condition. This finding agrees with reports that older adults show larger distraction effects under low load than younger adults  and shouThe analysis of spatial effects showed that when targets were located at the far position in relation to the observer responses were faster than for all other distances and responses were slowest to targets in the position intermediate 2. This result may indicate that objects further away may be processed earlier. However, it is possible that the objects in the far location are also coded as being presented at the top of the display and may thus be processed earlier than other objects, in line with a visual search strategy that begins search at the top of a display, and may, in addition, be more salient than objects in the intermediate positions because there is only one far object present compared to multiple objects at the intermediate position. The finding that flanker effects were significantly larger when the target was located further away from the observer may also indicate that even if responses are faster, processing of the targets at the far location may be less meticulous, leading to more distraction than for targets presented nearby. With respect to the distance between target and flanker, participants responded the fastest to targets when they were located at an intermediate distance from the flanker and slowest when they were located far from the flanker. In line with the previous analysis targets located at the intermediate position are those of which some are also located far from the observer (at the top of the display) where they may be responded to faster. Thus, the coding of distance from the observer as well as distance between target and flanker may not be independent.3.Experiment 1 showed that typical effects of congruency and target–distractor discriminability were observed during testing in an immersive VR environment, which confirms that our materials and set-up were suitable to elicit the basic effects. For further assessing the potential of immersive VR for this line of research, it is important to address hypothetical effects of the testing environment and to investigate whether the effects observed in VR would be stable and similar to effects in a 2D environment using the same stimuli and task. In order to do so, we replicated the experiment in a more ‘typical’ laboratory situation, using a computer monitor. Also, as outlined above, testing in the laboratory in front of a CRT monitor enabled us to track eye movements of our participants and led to the addition of this measurement in Experiment 2. As outlined above, we expected more fixations until a target is reached when target discrimination is harder. Moreover, we assessed whether the flanker would be fixated and if so, how often, when and for how long.3.1.3.1.1.M = 21.95 years, s.d. = 1.95), gender , handedness  and vision . After testing, participants filled out the CFQ [M = 38.96, s.d. = 15.57). All participants were compensated with 5 euros. The experiment was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.Twenty-six participants, recruited via e-mail at Jacobs University, gave informed consent, and filled out a survey, providing information on age ( the CFQ . Scores 3.1.2.″ CRT monitor (ViewSonic G220F). Experiment Builder software was used to run the experiment and eye movements were recorded with a head-mounted EyeLink II eye tracker (SR Research Canada). Testing was preceded by a 9-point grid calibration and validation for which participants were instructed to saccade to a black circle (0.5°) on a white background, which appeared sequentially and randomly at nine points in a square array. Eye movements were recorded at 500 Hz sample rate. Saccade onset was defined as a change in eye position with a minimum velocity of 30° s−1 or a minimum acceleration of 8000° s−2. Head movements were minimized using a chin rest.Displays were presented on a computer with a 213.1.3.The stimulus set, conditions and procedure were the same as in Experiment 1 with the exception that testing did not take place in VR but in the laboratory in front of a computer monitor. Screenshots of the 3D displays of Experiment 1 were used. The size of the objects varied slightly depending on the position of an item in the circular array. For instance, when the soda can was shown on the left its height was 9.8 cm (5.61°), in the back 8.8 cm (5.04°), and in the front 10.2 cm (5.84°), thus on average (5.5°) of the same size as in Experiment 1. The diameter of the circular array was 23 cm and the distance between the centre of the circle and the flanker was about 17 cm. The distance between the eyes of the participants and the screen was 100 cm. The experiment consisted of 192 trials, separated into two blocks. The conditions were randomized within a block. Participants completed 16 practice trials and pressed one of two response buttons on a standard keyboard located in front of them to indicate which target was shown in the circle. Half of the participants pressed the ‘arrow up’ button for soda and the ‘arrow down’ button for yoghurt, half of the participants vice versa. Pressing a button elicited a dart sound effect to provide feedback that a response was made but not whether the response was correct or incorrect. Participants were instructed to ignore the flanker. They did not obtain any instructions with respect to eye movements. After the experiment, the participants filled out the CFQ. An entire testing session took 35–45 min.3.2.Trials on which the initial fixation was not in the centre (0.1%), fixations were off screen (1.4%), the response was incorrect (4%) and outliers  were discarded from the analysis. As error rate was very low, it was not analysed further.3.3.3.3.1.F1, 25 = 12.56, p < 0.005, F1, 25 = 91.4, p < 0.001, F1, 25 = 0.373, p = 0.547, Mean response times of correct response trials were calculated per condition. The results are depicted in 3.3.2.F1, 46 = 44.03, p < 0.001, F1, 46 = 149.62, p < 0.001, F1, 46 = 0.314, p = 0.578, p > 0.181.In order to compare the effects between both experiments, a 2 (experiment: E1 versus E2) × 2 (congruency: congruent versus incongruent) × 2 (discriminability: high versus low) ANOVA with repeated measures was carried out. Congruency, 3.3.3.r = −0.237, N = 24, p = 0.264, two-tailed; nor with low target–distractor discriminability, r = 0.267, N = 22, p = 0.204, two-tailed. We further divided participants into a high-CFQ (more distracted) and a low-CFQ (less distracted) group, using a median split of the CFQ scores (Mdn = 38.5). A 2 (congruency: congruent versus incongruent) × 2 (discriminability: high versus low) × 2  ANOVA with repeated measures confirmed the main effects of congruency, F1, 22 = 12.36, p < 0.005, F1, 22 = 84.10, p < 0.001, p > 0.178. In the high discriminability condition the extent of the flanker effect was numerically smaller for participants with high CFQ scores (22 ms) than for participants with low CFQ scores (32 ms). Participants with low CFQ scores responded in general numerically faster, especially when target and flanker were congruent in the high target–distractor discriminability condition.We explored whether there was an association between the flanker effect and CFQ scores. We determined the flanker effect (RT incongruent minus congruent) for high and low target–distractor discriminability trials per participant and calculated Pearson correlations. As the CFQ was not assessed for two participants, we used the data of the remaining 24 participants for the analyses. CFQ score neither correlated with the flanker effect with high target–distractor discriminability, 3.3.4.F1, 25 = 13.18, p < 0.005, F3, 75 = 15.48, p < 0.001, t25 = 5.64, p < 0.001; far versus intermediate 2 (851 ms), t25 = 5.14, p < 0.001; far versus near (830 ms), t25 = 3.16, p < 0.005). Responses were slower to targets for the distance intermediate 1 than near, t25 = 3.18, p < 0.005, and there was a trend for the comparison between intermediate 2 versus near, t25 = 1.91, p = 0.067. There was no significant difference between the two intermediate distances, t25 = 1.64, p = 0.114. Further, an interaction between distance and congruency was observed, F3, 75 = 18.03, p < 0.001, t25 = 5.06, p < 0.001, the far than the intermediate 1 position, t25 = 4.65, p < 0.001; and numerically larger for the far compared to the intermediate 2 position, t25 = 2.05, p = 0.051. Further, flanker effects were larger for the intermediate 1 than for the intermediate 2 position, t25 = 2.44, p < 0.05; for the intermediate 1 than for the near position, t25 = 3.58, p < 0.005; and the intermediate 2 than the near position, t25 = 5.03, p < 0.001.To assess whether the distance between the observer and the target affected RT and distraction, we again parsed the display into four areas as in Experiment 1. A 2 (congruency: congruent versus incongruent) × 4  ANOVA with repeated measures revealed, apart from a significant congruency effect, 3.3.5.F1, 25 = 11.03, p < 0.005, F2, 50 = 45.7, p < 0.001, t25 = 7.81, p < 0.001, and when located far (821 ms) compared to close, t25 = 8.41, p < 0.001. There was an interaction between distance and congruency, F2, 50 = 3.3, p < 0.05, t25 = 2.26, p < 0.05. There was a trend for a larger flanker effect for the far compared to the close distance, t25 = 1.99, p = 0.057.The data were analysed analogous to Experiment 1. A 2 (congruency: congruent versus incongruent) × 3  ANOVA with repeated measures showed, apart from a congruency effect, 3.4.3.4.1.For the analyses of fixations, the display screen was parsed into areas of interest including one of the objects each. The analysis showed that in 70.9% of the trials the area of interest of the target was fixated at least once per trial. However, two participants maintained central fixation throughout the experiment. When those two were removed from the fixation analyses, 76.9% of the trials contained fixations on the target.F3, 69 = 22.35, p < 0.001, F1, 23 = 39.5, p < 0.001, F3, 69 = 6.39, p < 0.005, t23 = 4.85, p < 0.001, although there were also significant differences for the intermediate 1 , and the near  positions as well, and a trend for the far position , t23 = 1.82, p = 0.082. An additional analysis showed that, apart from discriminability, F1, 23 = 40.91, p < 0.001, F2, 46 = 18.26, p < 0.005, t23 = 4.04, p < 0.005, or far distance (4.0), t23 = 7.69, p < 0.001. For this latter analysis there was no interaction between distance and discriminability, F2, 46 = 0.054, p = 0.947, Analogous to the manual RT data, we carried out a 2 (congruency: congruent versus incongruent) × 2 (discriminability: high versus low) ANOVA with repeated measures to analyse the average number of fixations that were made before participants looked at the target. The statistical results of this analysis are reported in 3.4.2.We conducted three separate 2 (congruency: congruent versus incongruent) × 2 (discriminability: high versus low) ANOVAs with repeated measures to analyse (i) whether participants looked at the flanker, (ii) if so, with which fixation and (iii) for how long. The results of the three analyses are reported in 1 on the duration of the fixations on the flanker did not return any significant effects.The first analysis showed that overall, participants looked at the flanker only rarely, i.e. in 11.5% of all valid trials with a correct response. The percentage of trials in which participants looked at the flanker was modulated neither by target–distractor discriminability nor by congruency and the factors did not interact. The second and third analyses were, due to the rare percentage of trials with fixations on the flanker, based on the data of 14 participants only who showed fixations on the flanker in each combination of the factors target–distractor discriminability and congruency. The second analysis showed that participants looked at the flanker earlier when target–distractor discriminability was high compared to low. The earlier fixation of the flanker for high compared to low target–distractor discriminability was not modulated by congruency. There was neither a main effect of congruency nor an interaction. The third analysis3.5.The manual RT data replicated the results of Experiment 1. Flanker effects were observed, i.e. participants responded more slowly when flankers were incongruent compared to congruent. This result indicates that flankers could not be ignored and that a conflict occurred. Further, effects of target–distractor discriminability between targets and distractors occurred. Participants responded slower in lower compared to higher target–distractor discriminability trials. Similar to Experiment 1, no interaction between the two factors occurred. The analyses of correlations between flanker effects and CFQ scores also replicated the results of Experiment 1. This outcome is important because it demonstrates that our novel materials and the procedure elicit reliable effects. The spatial analyses showed that when targets were located far from the observer responses were faster than for all other distances and the flanker effect was largest for the far location. Also, participants responded significantly faster to targets when they were located at an intermediate distance to the flanker, i.e. at the top or bottom of the circular array, a result similar to Experiment 1 but were now faster to respond to targets far from the flanker than close. Experiment 2 showed an interaction between distance and congruency, i.e. there was no significant flanker effect in Experiment 2 when target and flanker were located close by, which was not apparent in Experiment 1. This result suggests that there can be subtle differences between assessments in 2D and 3D that justify further investigation.Taken together, the results of Experiments 1 and 2 were largely the same, in particular regarding effects of congruency and target–distractor discriminability. In our view, this fact does not undermine the usefulness of assessing attention and distraction in immersive VR, i.e. assuming that testing in VR would not be necessary because the same effects can be observed in 2D. To us, the results show that the materials and procedure are ‘safe’ to use also in VR, i.e. that the VR environment does not have any side effects that may undermine the effects. Our findings are in line with previous studies that also reported similar results in 2D and 3D. We used VR as a medium for visual presentation of stimuli and the next important steps would be to include further options that VR has to offer that are not available when testing with 2D presentations in front of a computer screen such as interaction with the environment. It is well possible that differences in results would occur under such conditions. Previous work has shown that, for example, exposure-related experience with the environment has larger effects in 3D than 2D and that memory may be used more in 3D than 2D .We included eye tracking in Experiment 2 and overall, we expected that participants should make more fixations until they reach the target when target–distractor discriminability is low compared to high. The analyses of the trials on which the target area of interest was looked at confirmed this prediction. The analysis of fixations on the target further showed that it was in fact possible to determine the target and complete the task without eye movements to the target but that most participants chose to move their eyes and to also look at the target in the majority of the trials. Further, the spatial analyses showed that the target was looked at earlier for the far than the intermediate 2 position when distance between observer and target was considered, partly in line with the RT results where RT was fastest for the far distance. Considering the distance between target and flanker, the RT analyses had shown the fastest RT for targets at an intermediate distance from the flanker. This result is underlined by the eye movement patterns as fewer fixations were made until the target was reached when the distance between target and flanker was intermediate.Regarding the assessment of fixations on the flanker, we asked whether the flanker would be looked at, i.e. whether distraction would be ‘overt’ and whether target–distractor discriminability would impact how often, early and for how long the flanker would be looked at. We observed that, overall, participants looked at the flanker only rarely and that whether participants looked at the flanker or not was modulated neither by target–distractor discriminability nor by congruency. This finding—that the flanker was not fixated in many trials and that participants completed the task without many fixations on the flanker—is novel as there is, to our knowledge, no study that assessed the effects of target–distractor discriminability in the flanker paradigm by measuring eye movements. The finding likely reflects that participants are effective at inhibiting eye movements to the flanker , irrespTo summarize, the RT results of Experiment 2 replicated Experiment 1. The fixation data reflected the more difficult search process when targets and distractors share colour and are hard to discriminate, since there were more fixations until the target was reached with lower than higher target–distractor discriminability and more fixations until the flanker was looked at for low than high target–distractor discriminability trials. The analyses of fixations on the flanker revealed that the flanker was fixated only rarely and thus, considering the strong congruency effect in the RT data, it appears that the flanker effect is largely driven by covert allocation of attention to the flanker. For future work it would be of high interest to assess eye movements in a similar task also in a VR environment as it may be possible that saliency of targets may play a smaller role in attracting gaze in more natural environments  and that4.The goals of our study were to accomplish a transfer of traditional paradigms used for assessing attention and distraction to an immersive VR environment and to explore the attentional effects when daily objects are being used as stimuli. We wished to take a first step in the direction of investigating distraction and response competition in a VR environment and to this end, we ensured contact with previous studies that have been carried out in the laboratory but at the same time increased ecological validity.Our two experiments showed that participants took more time to indicate which one of two target objects was present in a search array when targets and distractors shared the feature colour and were harder to discriminate than in a condition in which colour is distinct. Further, the manual RT data also showed significant congruency effects, indicating that typical congruency effects can be observed during testing in VR and when using daily objects as stimuli. This indicates that the assessment of attentional effects that have usually been investigated in the laboratory, in particular the implementation of a flanker paradigm, is feasible in immersive VR, accomplishing the desired transfer. This conclusion is also supported by the replication of the effects observed in Experiment 1 by Experiment 2.By using this technology and presenting daily items we made a significant step towards increasing ecological validity and we are hoping that our study will encourage the use of immersive VR for future studies. Here we used a combination of visual search and the flanker paradigm similar to previous research in order to make contact with the literature and the described effects. We employed VR as a medium for visual presentation of stimuli and the next important steps would include taking advantage of the more ecologically valid context that VR offers for studying cognition. We would like to suggest that future studies may wish to devise even more realistic settings and tasks, and could also include other response modalities than a simple button press. Assessments in immersive VR provide many options such as reaching, pointing and moving in the environment. Future work could thus make use of those exciting possibilities that cannot be applied using traditional methods. In addition, manipulating cognitive and motor demands, e.g. by asking participants to complete additional cognitive or motor tasks in VR, as is often the case in daily life (e.g. moving towards or grasping some object while searching for others) would be an interesting avenue to take. Further, the array of target objects could be extended to assess which features of everyday objects and also in how far semantic guidance may affect search performance. For instance, one study  showed tExperiment 1 showed a correlation between age and the flanker effect for high target–distractor discriminability trials. While our analyses were of a rather explorative nature we would like to point out the importance of assessing effects of ageing on attention in VR (see ).Taken together, VR offers a new and interdisciplinary perspective and a wealth of possibilities to investigate attention and distraction. We hope that our experiments will motivate such work.


Oxygenation is one of the most important physiological parameters of biological systems. Low oxygen concentration (hypoxia) is associated with various pathophysiological processes in different organs. Hypoxia is of special importance in tumor therapy, causing poor response to treatment. Triaryl methyl (TAM) derivative radicals are commonly used in electron paramagnetic resonance (EPR) as sensors for quantitative spatial tissue oxygen mapping. They are also known as magnetic resonance imaging (MRI) contrast agents and fluorescence imaging compounds. We report the properties of the TAM radical trismethyl, (PTMTC), a potential multimodal (EPR/fluorescence) marker. PTMTC was spectrally analyzed using EPR and characterized by estimation of its sensitivity to the oxygen in liquid environment suitable for intravenous injection . Further, fluorescent emission of the radical was measured using the same solvent and its quantum yield was estimated. An in vitro cytotoxicity examination was conducted in two cancer cell lines, HT-29  and FaDu (squamous cell carcinoma) and followed by uptake studies. The stability of the radical in different solutions  was determined. Finally, a primary toxicity test of PTMTC was carried out in mice. Results of spectral studies confirmed the multimodal properties of PTMTC. PTMTC was demonstrated to be not absorbed by cancer cells and did not interfere with luciferin-luciferase based assays. Also in vitro and in vivo tests showed that it was non-toxic and can be freely administrated till doses of 250 mg/kg BW via both i.v. and i.p. injections. This work illustrated that PTMTC is a perfect candidate for multimodal (EPR/fluorescence) contrast agent in preclinical studies. Low oxygen concentration (hypoxia) is associated with various pathophysiological processes in different organs, e.g., stroke or cancer. In solid tumors, fast angiogenesis of the cancer cells stimulates the creation of chaotic and poorly organized vasculature that in turn results in deprivation of both oxygen (pO2 < 5 mmHg) and nutrients supply to the tissue that further stimulates even faster angiogenesis of the pathological cells − (70%), 743.60 [M − CO2]− (100%), 698.82 [M − 2CO2]− (60%). HRMS (ESI): calcd. for C22H4Cl12O6 [M + H]+ 789.618; found 789.618.Trismethyl radical , 20  spectrum. The spectral displacement was achieved by applying magnetic field gradient 5 G/cm. The radical amplitudes were measured and normalized by the standard amplitude. The line width measurements were performed with 10,000 points resolution in the field of 2 G around the maximum of the radical absorption signal. Automatic fine tuning after each scan  was enabled. Microwave power was 3.6 mW, frequency 1.09 GHz, modulation amplitude 0.01 G, modulation frequency 10 kHz. No saturation effects were visible.Bruker ESP 380 FT/EPR X-band spectrometer in room temperature (23 oC). To estimate the spin–spin (T2*) and spin–lattice (T1) relaxation times, free induction decay (FID) sequence was used. Parameters used for T2* assessment were as followed: pulse (p1) of 24 ns, delay time (d0) of 96 ns and acquisition in steps of 8 ns. Recorded number of points was 128. Parameters for T1 assessment from FID were p1 = 80 ns, d1 = 96 ns, and the sequence was (p1d1)x8 dx (8 ns) p0 (24 ns) d0 (104 ns) and acquisition in steps of 8 ns  = 0.0148 (±10−4) pO2[%] +0.395 (±10−2), in the range of 0–18.5% of pO2. Using chemical methods of deoxygenation (saturation with Na2SO3 powder), a line width of 0.37 G was achieved. The maximal line width observed after O2 saturation was 0.79 G . As an important index, the fluorescent quantum yield (QY) of PTMTC radical solution (14.2 µM) in PBS was determined by applying the following equation:I is the measured integrated emission at the excitation wavelength 488 nm, A is the absorbance at the excitation wavelength 488 nm, n the refractive index of the solvent. Rhodamine 6 G solution in ethanol served as standard (QY = 95%). In order to minimize the reabsorption effect, the absorbance of rhodamine standard and radical solution was kept below 0.1 at 488 nm excitation wavelengths. The fluorescence quantum yield of the PTMTC radical solution in PBS was calculated to be 5.7%. This is a very low QY when comparing to standard fluorescence dyes such as Rhodamine 6 G with QY of 94%, quinine sulfate (57.7%) and zinc phthalocyanine (30%). On the other hand, there are organic fluorescent dyes with similarly low QY e.g., chlorophyll b (7.4%). Also currently intensively investigated inorganic quantum dots do not reach high QY values, and yet they are successfully applied as fluorescent markers, e.g., dodecanethiol-capped CuInZnxSx2+ (25%) [A PTMTC radical solution sample on excitation at 410 nm exhibited the strongest fluorescence emission peak with the maximum at 632 nm , with a Stokes shift of 1.06 eV   or un-mo+x (25%) .Fig. 5aFigure After exposing HT-29 and FaDu cells to PTMTC, the cell viability was measured. It was observed that viability of HT-29 was high and stable, even at the highest dose (2.5 mM) and at the longest time of incubation (72 h) Fig. . The viaThe uptake and luciferase–luciferin assays were performed using the IVIS Spectrum system, which allows simultaneous measurement of both luminescence and fluorescence. The excitation and emission filters were selected experimentally to measure the fluorescence of PTMTC and exclude autofluorescence background of the cells itself. The experiment showed that PTMTC was not absorbed by cells and its presence had no impact on the fluorescence intensity produced by oxidation of luciferin in luciferase expressing LNCaP cells (data not shown).In order to unequivocally identify the fluorescent species, the images of the cell and of a PTMTC suspension were taken in the lambda mode with excitation at 405 nm, thus obtaining spectra in the range of 560–685 nm for every pixel in the images Fig. . The blaAfter administration of tested compound via both i.p. and i.v. routes, animals did not show any signs of pain or distress. Their behavior, motoric activity, food and water intake did not differ from the control group. After 3 days, the animals were sacrificed and their livers and kidneys were examined: no macroscopically visible lesions were found. In blood samples a significant increase of AlAT was measured in mice receiving PTMTC via intraperitoneal injection. The activity of other enzymes in both tested groups was slightly increased, however these changes were not significant.13C nuclei. Relaxation times of PTMTC in PBS, namely T2* of (21 ± 1) ns and T1 of (63 ± 7) ns, were obtained from saturation recovery of the FID. The linewidth sensitivity to O2 concentration was estimated. The temporal stability of the compound was tested in PBS, cell medium, full rat blood, and blood plasma. The molecule is stable in PBS solution, but decomposes immediately in blood. However, this does not prevent to use the PTMTC for in vivo studies. Therefore, the fluorescence properties of this marker were preliminarily investigated. The fluorescence quantum yield of the PTMTC radical solution in PBS was calculated to be 5.7%, which was rather low, but allows attempts to use this radical as a bimodal EPR/fluorescence imaging marker. In vitro time-dependent and dose-dependent cytotoxicity studies revealed the low toxicity of PTMTC against HT-29 and FaDu cell lines. Further tests showed that the compound was not absorbed by cancer cells and did not interfere with luciferin–luciferase based assays. PTMTC was also tested in vivo. It was administered to Balb/c mice at 250 mg/kg BW via both i.v. and i.p. administration. The radical caused only slight but statistically significant elevation of alanine aminotransferase in the i.p. group, while levels of AsPAT, ALP, and LDH remained unchanged. Mice receiving PTMTC after 3 days did not exhibit any signs of pain or distress nor did we notice any differences in food and water intake between control and test groups. The poor stability of PTMTC in blood indicates that it will not be stable in vivo for 3 days. However, such long-term stability is not needed for the planned combined EPR-fluoresence imaging, but it was important to show PTMTC did not interfere negatively with the host physiology.The EPR spectrum of PTMTC was recorded in an L-band spectrometer and analyzed. The signal of the radical displayed four different hyper and super-hyperfine coupling constants of different intensities which were assigned to interactions of the electron spin with In summary, PTMTC is a non-toxic oxygen sensor exhibiting fluorescent properties. Thereby, it is a perfect candidate for multimodal imaging with the prospect of quantitative information about oxygenation of the tissue (EPR) and distribution of the marker in the body (fluorescence).


Gastrointestinal histoplasmosis (GH) is a well-described albeit uncommon disease. It is found almost exclusively in the immunocompromised host, especially those with untreated HIV and low CD4 counts. Presentation with intestinal perforation is seen mostly commonly in the colon. We present a patient with jejunal perforation, and there have been only 3 previous cases reported in the literature.  A 39-year-old male with known, untreated HIV presented to the ED with an acute abdomen after experiencing worsening intermittent abdominal pain for 2 months before that was associated with nausea, vomiting, diarrhea, and weight loss. CT of the abdomen and pelvis revealed evidence of gas in the mesentery, small bowel thickening, edema, and free fluid in the abdomen. Emergency exploratory laparotomy was conducted. Intraoperative findings included a perforated jejunum that was studded with nodular lesions as well as mesenteric masses. Histopathologic exam of these mesenteric masses and jejunal lesions were positive for histoplasmosis.  Disseminated histoplasmosis is a life-threatening disease that occurs nearly exclusively in immunocompromised hosts. Untreated, mortality is as high as 80%. This rare presentation with jejunal perforation highlights the need for awareness of histoplasmosis involvement throughout the entirety of the GI tract. Gastrointestinal histoplasmosis is a well-described phenomenon, occurring almost exclusively in immunocompromised patients. An estimated 70–90% of patients with disseminated histoplasmosis have GI involvement. Of these, only 3–12% are believed to have GI-related symptoms , 11. We A 39-year-old HIV-positive male presented to the Emergency Department complaining of severe, sharp pain diffusely across the abdomen that had awoken him from sleep at 01 : 30 AM. He had been experiencing milder, intermittent abdominal pain for 2 months before. Additionally, he admitted to chills, weight loss, loss of appetite, nausea, and occasional diarrhea and vomiting for 1 month. There was no reported hemoptysis, hematochezia, melena, or fevers. He had a cough with green sputum for 2 months as well.He had a past medical history significant for HIV due to IV drug use diagnosed 10 years earlier that he had neglected to treat. He has hepatitis C as well. He previously has abused alcohol but had quit 2 months ago, and quit IV drug use 11 years ago. He has less than 10 pack/year smoking. He has been in a monogamous relationship with his girlfriend for multiple years and denies any history of risky sexual behaviors including having polygamous or homozygous relationship. He has lived in southern Texas his whole life, an area of the US known to be mildly endemic with histoplasma species. He had no significant travel history.3/μL. Absolute CD4 count was 26, and viral load was 162,000. His remaining initial lab work  was as follows: WBC 2.95 × 103/microliter (4.8–10.8 × 103), absolute neutrophil count 2.57 × 103/microliter (1.8–7.7 × 103), absolute lymphocyte 0.20 × 103/microliter (1.0–4.8 × 103), absolute monocytes 0.18 × 103/microliter (0.0–0.8 × 103), eosinophils 0.00 × 103/microliter, and basophils 0.00 × 103/microliter. Hemoglobin was 11.4 g/dl (12.0–16 g/dl), hematocrit was 35.4%, and platelet count was 248 × 103/microliter (150–450 × 103/microliter).He was afebrile with a temperature of 98.2° Fahrenheit, stable blood pressure, tachycardia, and tachypnea with a heart rate of 110/bpm and respiratory rate of 22/min. Physical exam revealed a malnourished man in distress due to abdominal pain. On abdominal exam, he was very tender with diffuse guarding and rigidity in all quadrants. Initial lab work revealed white blood cell count of 2.95/10CT of the abdomen and pelvis  revealedAn exploratory laparotomy was performed. This revealed numerous nodular implants throughout the small bowel as well as numerous masses in the mesentery. There was an obvious perforation in the mid to proximal jejunum associated with a nodular lesion that had caused a stricture. The perforated segment was resected along with a representative mesenteric mass. Primary anastomosis was performed noting that the extent of disease involvement in the small bowel prohibited complete resection of all lesions.Histological examination of surgical specimens showed necrotic tissue with yeast consistent with histoplasmosis Figures –3. UrineIn regard to his pulmonary nodule seen on the CTA, the patient underwent bronchoscopy. Minimal diffuse inflammatory changes and thick whitish secretions were seen in the right lower lobe and right upper lobe. Bronchoalveolar lavage (BAL) was performed from left upper and right lower lobe. Gram stain of the BAL fluid showed 3 + WBCs with rare Gram negative rods, 1+ Gram positive cocci, and few coryneform Gram positive rods which was felt to be consistent with normal upper respiratory flora. Cultures grew rapid growing candida species. Pathological examination of the BAL fluid revealed inflammatory debries with yeast forms seen on the silver stain. No biopsies were performed.The patient was started on oral itraconazole, 200 mg orally TID for 3 days, and then changed to 200 mg orally BID anticipating 12 months of treatment. In addition to prophylactic, trimethoprim/sulfamethoxazole 800 mg/160 mg one tablet orally and azithromycin 1500 mg orally once per week were started. He was not immediately started on antiretroviral therapy due to lack of inpatient access to these medications.His hospitalization was complicated by high output drainage from his surgical JP drain. This eventually decreased to a more manageable level, and the patient was discharged home with his JP drain in place on day 17 of hospitalization. On discharge, he was referred to a local clinic for treatment of AIDS. He failed to follow-up there, citing financial hardship.The patient returned to the hospital 1 week after discharge with fever, chills, constipation, and abdominal discomfort with partial small bowel obstruction, which was managed conservatively and good resolution was achieved. Repeat bronchoscopy with BAL was negative except for growing yeast in the BAL. Patient was changed to liposomal amphotericin B intravenously with good clinical response. After 2 weeks of intravenous liposomal amphotericin B, he was switched back to itraconazole 200 mg orally BID, anticipating 12 months of therapy with close follow-up. He was discharged home with an instruction to follow-up at the HIV clinic to be started on antiretroviral therapy and follow-up CT scan of chest in 4 weeks.Histoplasma capsulatum is a dimorphic fungus endemic to the Midwestern and Southeastern United States as well as Central and South America. It is found most readily in soil contaminated with bird or bat guano [at guano . It is tGastrointestinal histoplasmosis (GIH) is uncommon, manifesting symptomatically in 3–12% of patients with DH. Much higher rates of GI histoplasmosis have been reported on autopsy review indicating the presence of disease which is asymptomatic . NeverthThe most common symptoms in those with GIH are weight loss, abdominal pain, fever, and diarrhea. The disease manifests variably as intestinal ulcers, bleeding, strictures, and, rarely, perforation. Several published cases and case series report ileal and colonic perforation. In 2000, Gumbs et al. reported what they believed to be the first report of jejunal perforation . A 2006 This rare presentation of a jejunal perforation due to disseminated histoplasmosis highlights the need for heightened awareness of this disorder in immunocompromised individuals. The majority of patients of GIH are AIDS patients with low CD4 counts who have not received therapy. The mortality in these patients without therapy is high, approaching 80%. With antifungal therapy, mortality improves to 30%. Our patient was initially treated with itraconazole, but was later changed to liposomal amphotericin B when his pulmonary lesions advanced. With this regimen, he has remained stable, although noncompliance with antiretroviral therapy remains an issue.


Among those without previously diagnosed diabetes, each 1 mmol/L higher usual RPG was associated with a HR of 1.12 (1.04‐1.21). In meta‐analysis of CKB and 22 other studies, previously diagnosed diabetes was associated with a 52% excess risk . Among those without diabetes, each 1 mmol/L higher blood glucose was associated with a 15%  excess risk. In Chinese and non‐Chinese populations, diabetes and higher blood glucose levels among those without diabetes are associated with an increased risk of PC.Diabetes is associated with an increased risk of pancreatic cancer (PC) in Western populations. Uncertainty remains, however, about the relevance of plasma glucose for PC among people without diabetes and about the associations of diabetes and high blood glucose with PC in China where the increase in diabetes prevalence has been very recent. The prospective China Kadoorie Biobank (CKB) study recruited 512,000 adults aged 30‐79 years from 10 diverse areas of China during 2004‐2008, recording 595 PC cases during 8 years of follow‐up. Cox regression yielded adjusted hazard ratios (HRs) for PC associated with diabetes (previously diagnosed or screen‐detected) and, among those without previously diagnosed diabetes, with levels of random plasma glucose (RPG). These were further meta‐analysed with 22 published prospective studies. Overall 5.8% of CKB participants had diabetes at baseline. Diabetes was associated with almost twofold increased risk of PC , with excess risk higher in those with longer duration since diagnosis ( What's new?Diabetes is associated with increased risk of pancreatic cancer (PC) in Western populations, but uncertainty remains about the relevance of plasma glucose among people without diabetes. In this first prospective study investigating the association of diabetes with PC risk in China, where the increase in diabetes prevalence has been very recent, diabetes was associated with an almost twofold increased risk of PC, with random plasma glucose being positively associated with PC risk among participants without prior diagnosis of diabetes. In meta‐analysis, the results were consistent with previous evidence in Western populations, highlighting diabetes as a potential aetiological factor of PC. BMIbody mass indexCIconfidence intervalCKBChina Kadoorie BiobankDSPDisease Surveillance PointsFBGfasting blood glucoseFPGfasting plasma glucoseHRhazard ratioICD‐10International Classification of Diseases, 10th RevisionIHDischemic heart diseaseMETmetabolic equivalent of taskPCpancreatic cancerRBGrandom blood glucoseRPGrandom plasma glucoseRRrelative riskSBPsystolic blood pressureSDstandard deviationAlthough pancreatic cancer (PC) is ranked as the 12th commonest cancer globally,In recent decades, there has been a substantial increase in diabetes incidence in China,Details of the CKB design, survey methods and population characteristics have been described elsewhere.At local study assessment clinics, participants completed an interviewer‐administered laptop‐based questionnaire on socio‐demographic characteristics, smoking, alcohol consumption, diet, physical activity, personal and family medical history and current medication. A range of physical measurements were recorded by trained technicians, including height, weight, hip and waist circumference, bio‐impedance, lung function, blood pressure and heart rate, using calibrated instruments with standard protocols.TM, USA). Immediate on‐site testing of random plasma glucose (RPG) level was undertaken using the SureStep Plus System (Johnson & Johnson), regularly calibrated with manufacturer quality control solution. Participants with glucose levels ≥7.8 mmol/L and <11.1 mmol/L were invited to return for a fasting plasma glucose (FPG) test the next day. RPG data were unavailable for 8,306 participants (because of a delay in making the on‐site test available in certain regions).A 10‐ml non‐fasting (with the time since the participant last ate recorded) blood sample was collected from participants into an EDTA vacutainer  and cardiovascular diseases  was collected. Among those without previously diagnosed diabetes, screen‐detected diabetes was defined as RPG ≥7.0 mmol/L and time since last eating ≥8 h, or ≥11.1 mmol/L with time since last eating <8 h, or a FPG ≥7.0 mmol/L on subsequent testing.From August to October 2008 (∼2.6 years after the baseline survey) a resurvey was done on 19,788 (∼5%) randomly selected surviving participants. The data collection and survey procedures were much the same as in the baseline survey. RPG data were available for 19,712 (99.6%) participants.The vital status of each participant was determined periodically through China CDC's Disease Surveillance Points (DSP) systemn = 2,577), leaving 510,314 for the main analysis.This study excluded participants with a prior history of cancer at baseline , sex and area structure of the CKB population.n = 486,189). RPG was categorised into three groups , selected to include the FPG thresholds for impaired fasting glucose and diabetes. RPG was also modeled as a continuous variable to estimate risk associated with a 1 mmol/L increase in RPG. The analysis for RPG was additionally adjusted for fasting time. For analyses involving more than two categories, all HRs are presented with 'floating' standard errors to facilitate comparisons between groups.Cox regression models were used to obtain adjusted hazard ratios (HRs) of PC incidence associated with diabetes and RPG levels, stratified by age at risk (5‐year groups), sex and study region (10 regions) and adjusted for education (4 groups), smoking  and alcohol . Duration of diabetes was categorised into four groups . The analysis for RPG was conducted in participants without previously diagnosed diabetes . Log HR estimates (and corresponding standard errors) per 1 mmol/L higher plasma glucose were divided by this correlation to obtain regression dilution‐adjusted estimates.We followed PRISMA guidelines for conducting a systematic review and meta‐analysis.I2 and Cochran's Q test. Publication bias was assessed visually by inspecting the funnel plots for asymmetry and tested with Egger's test,p <0.05.We calculated relative risks (RR) for diabetes using fixed effects modeling and fitted random effects models as a sensitivity analysis (Supporting Information Table 1). The main subgroup analyses included study design, geographical region, diagnostic method , different adjustment in the statistical models, whether or not studies excluded initial years of follow‐up and duration of diabetes. Meta‐regression analyses were conducted to assess heterogeneity between subgroups. Heterogeneity between studies was assessed using As we could not identify any prospective studies on blood glucose and PC that have been published since the most recent systematic review and meta‐analysis on this topic,Among the 510,314 participants in CKB, the mean (SD) age was 51.5 (10.7) years, and 59% were women. The prevalence of previously diagnosed and screen‐detected diabetes was 3.1% and 2.7%, respectively. The mean (SD) RBG was 5.7 (1.1), 13.3 (5.4) and 11.8 (5.7) mmol/L among participants without any diabetes, with screen‐detected diabetes and with previously diagnosed diabetes, respectively. Individuals with diabetes were older, and, after adjustment for age, sex and region, more likely to have higher BMI, higher SBP, lower physical activity and to have a family history of diabetes (Table p for trend = 0.01) . These included 16 prospective cohort studies, four nested case–control studies, one case–cohort study and one pooled analysis of prospective cohort studies, which were included in the meta‐analysis (Supporting Information Data). Of those 22 prospective studies, 16 used self‐reported physician‐diagnosed diabetes (i.e. previously diagnosed), five combined both previously diagnosed and screen‐detected diabetes through specific tests , and one reported previously diagnosed and screen‐detected diabetes separately (Supporting Information Data). We further identified 11 record linkage studies (Supporting Information Data) but they were not included in the meta‐analysis due to large heterogeneity in study characteristics . Four studies had information on duration of diabetes (Supporting Information Data). The detailed characteristics of the included studies are provided in Supporting Information Table 6.n = 18) increased risk of PC, with moderate heterogeneity between studies  and European studies  than in North American studies . There was no significant heterogeneity between studies conducted in East Asia and Europe, but a large between‐study heterogeneity in North America , but not in Europe or East Asia .Among 18 studies including CKB, involving 4.1 million individuals with 13,072 cases of PC, previously diagnosed diabetes was associated with a 52%  or of screen‐detected (n = 1) diabetes with PC. When meta‐analysed together with CKB, there was little heterogeneity in risk estimates according to how diabetes was ascertained, although the ability to detect a difference was limited due to the small number of studies involved . For previously diagnosed diabetes, studies with adjustment for BMI appeared to have lower RRs . Likewise, studies with exclusion of more years of follow‐up also tended to show somewhat lower RRs . But, apart from CKB, few other studies had compared directly the RRs with exclusion of different years of follow‐up within the same study. In meta‐analysis, there was no significant trend for studies reporting longer duration of diabetes at study enrolment to have greater risk of PC .Six other studies also assessed the associations of both previously diagnosed and screen‐detected diabetes (p = 0.52).In a meta‐analysis of CKB and five published studies, among participants without diabetes, each 1 mmol/L increase in blood glucose was associated with a 15%  increased risk of PC for RPG, a 13% (1.13 [1.08–1.19]) for FPG and a 11% (1.11 [1.02–1.20]) for post‐load glucose , suggesting that adiposity played little role in mediating or confounding the association between diabetes and PC in Chinese populations. This finding appeared to be consistent with the limited evidence from other East Asian studiesIn contrast with CKB findings, three previous meta‐analyses of prospective cohort studiesBoth animal and epidemiological studies have suggested that new‐onset diabetes might be a manifestation of, rather than an aetiological factor for, PC.A recent meta‐analysis of nine prospective studies reported a 14% increase risk of PC per 0.56 mmol/L increase in blood glucose across the range of pre‐diabetes and diabetes. However, most studies used FBG and only one study used RBG.Hyperglycaemia and insulin resistance have been hypothesized as the underlying mechanisms linking diabetes and PC.The strengths of CKB include a prospective design, a large and diverse study population , and careful adjustment for risk factors for PC. In addition, we examined separately screen‐detected diabetes, which represented undiagnosed diabetes not affected by treatment or lifestyle changes. One major limitation of CKB was that screen‐detected diabetes was defined using RPG, and thus may be subject to greater misclassification.In summary, among Chinese adults, diabetes was associated with almost twofold increased risk of PC. Moreover, among participants without prior diagnosis of diabetes, RPG was associated positively with risk of PC. Our results suggest that diabetes might be an aetiological factor of PC in Chinese, largely consistent with evidence from previous studies in Western populations. Further research is needed to determine whether diabetes or high plasma glucose is a causal factor for PC. Given that the majority of diabetes cases are undiagnosed in China,Supporting InformationClick here for additional data file.


Despite the fact that deficits in social communication and interaction are at the core of Autism Spectrum Conditions (ASC), no study has yet tested individuals on a continuum from neurotypical development to autism in an on-line, cooperative, joint action task. In our study, we aimed to assess whether the degree of autistic traits affects participants' ability to modulate their motor behavior while interacting in a Joint Grasping task and according to their given role.Sixteen pairs of adult participants played a cooperative social interactive game in which they had to synchronize their reach-to-grasp movements. Pairs were comprised of one ASC and one neurotypical with no cognitive disability. In alternate experimental blocks, one participant knew what action to perform (instructed role) while the other had to infer it from his/her partner’s action (adaptive role). When in the adaptive condition, participants were told to respond with an action that was either opposite or similar to their partner. Participants also played a non-social control game in which they had to synchronize with a non-biological stimulus.In the social interactive task, higher degree of autistic traits predicted less ability to modulate joint action according to one’s interactive role. In the non-social task, autistic traits did not predict differences in movement preparation and planning, thus ruling out the possibility that social interactive task results were due to basic motor or executive function difficulties. Furthermore, when participants played the non-social game, the higher their autistic traits, the more they were interfered by the non-biological stimulus.Our study shows for the first time that high autistic traits predict a stereotypical interaction style when individuals are required to modulate their movements in order to coordinate with their partner according to their role in a joint action task. Specifically, the infrequent emergence of role-based motor behavior modulation during on-line motor cooperation in participants with high autistic traits sheds light on the numerous difficulties ASC have in nonverbal social interactions.The online version of this article (doi:10.1186/s13229-017-0141-0) contains supplementary material, which is available to authorized users. Autism Spectrum Conditions (ASC) are characterized by such deficits in social communication and interaction as the difficulty in understanding another person’s perspective, reduced use of verbal and nonverbal signals to regulate interaction, reduced use and understanding of gestures, abnormalities in body language, and difficulties in reciprocal, cooperative social play .ASC cooperative behavior has usually been investigated in one of two ways: (1) via high-order cognitive tasks requiring participants to make a decision after having inferred something about their partner’s choices, as in computer-based social hunting games  or the pVery few studies have tested ASC participants in on-line cooperative motor tasks in which they have to coordinate their actions with those of a partner to achieve a common goal. Distinctive features of realistic interpersonal coordination include the need to predict, imitate, or complement what a partner will do , 9, as wCoordination strategies to achieve successful interactions are likely based on a variety of motor, social, and cognitive skills. In particular, it has been proposed that on-line prediction of and adaptation to another person’s action may rely on a sensory-motor simulation of the observed action –24 that Some studies investigating on-line motor coordination in ASC showed that ASC children are less able than children with developmental delay to coordinate their actions when completing simple motor interactive tasks that require two persons in cooperation to make an object/toy function , 31. OthImportantly, no study has tested whether autistic traits impact sensory-motor simulation used to predict a partner’s behavior and adapt to it, or the ability to modulate one’s own motor behavior depending on the role played in the interaction. Our study investigates the motor cooperative behavior of ASC and neurotypical individuals during an on-line joint action task in order to address these questions for the first time.We applied our cooperative joint action task  by askiWe tested 19 pairs of same sex, adult participants . IQ scores were not available for one NT and two ASC participants. As these participants had all received a master’s degree, we considered them to be within the normal range. ASC participants received an Asperger syndrome diagnosis according to DSM IV criteria .∆RT = adaptive RT − instructed RT).Difference in reaction times (ms) (∆RT): trial-by-trial time interval between the release of the start button by the participant in the adaptive role and that of the participant in the instructed role  (RT): interval between auditory instruction delivery time and start button release time.Movement duration (ms) (MD): interval between start button release time and grasp time.For each trial, we considered the following behavioral measures of individual performance:∆RT, as it would not have allowed us to investigate trial-by-trial time course of pair interaction.For each dependent variable, participant, and condition, we excluded values that fell 2.5 standard deviations (s.d.) above or below the mean as outliers. Z-transformation within participant/couple and across conditions was performed on all dependent variables but Movement’s spatial kinematics  was also recorded with a SMART-D motion capture system (Bioengineering Technology & Systems (B|T|S)). See Additional file In our social interactive task, we wanted to investigate behavioral changes outside the classic and often limiting case-control framework. When possible, we thus analyzed the data from all participants collapsed via an ANOVA with the number of autistic traits (AQ) as continuous predictor.We report parametric repeated measures ANOVA when variables are all normally distributed (Shapiro-Wilk’s test) or when their skewness and kurtosis can be considered normal . This isFor reaction time, we report in the main text parametric ANOVA with AQ as a continuous predictor because (i) deviation from normality is minor, (ii) parametric analyses suggest a role for the AQ in mediating the effects, (iii) nonparametric results generally confirm nonparametric ones, and (iv) there is not a simple non-parametric counterpart of mixed model ANOVA nor of ANOVA with a continuous predictor . We include nonparametric analyses in the Additional file Lastly, we report nonparametric analysis when the majority of variables are not normally distributed (Shapiro-Wilk’s test) and their skewness and kurtosis are not normal .ACC entered nonparametric, repeated measure, Friedman ANOVA, and, if significant, we ran nonparametric Wilcoxon matched pair tests.GraspAsynch and ∆RT entered separate repeated measures analyses of variance (ANOVAs) with 2 role (instructed/adaptive) × 2 congruency (opposite/same) as within-subjects factors. In pair performance analyses only, (i) position (down/up) was collapsed because 50% of trials  involve one participant going down while the other going up; and (ii) role was coded according to the role of the ASC participant, i.e., the trial was coded as adaptive when the ASC participant of the pair had the adaptive role.RT and MD entered separate repeated measures ANOVAs with 2 role (instructed/adaptive) × 2 congruency (opposite/same) × 2 position (down/up) as within-subjects factors and the autism quotient  scores aAs a control analysis, we also divided participants depending on their diagnosis and entered the same dependent variables in a mixed model ANOVA with 2 role (instructed/adaptive) × 2 congruency (opposite/same) × 2 position (down/up) as within-subjects factors and group (ASC/NT) as between subjects factor  were removed as outliers.ACC did not show significant main effects of role and congruency, nor a significant role × congruency significant interaction  = 3.22, p = 0.36), indicating that pairs reached an equal level of accuracy in all experimental conditions.Friedman ANOVA on F = 6.84, p = 0.02, η2 = 0.31), with greater asynchrony when participants performed opposite vs. same movements. All other ps > 0.17.Analysis on GraspAsynch showed a significant main effect of congruency  = 75.07, p < 0.00, η2 = 0.83), indicating longer ∆RT for opposite trials and a significant role × congruency interaction  = 5.27, p = 0.04, η2 = 0.26)  started to move after his/her partner, while negative values indicate that he/she started to move before his/her partner. Post hoc tests showed that ∆RT values are longer in opposite vs. same trials (ps < 0.001) and that only in same trials there is a difference in ∆RT, depending on which pair member takes the adaptive role (p = 0.02). This difference is not significant in opposite trials (p = 0.60).Analysis on t tests against zero ASC adaptive t(16) = 4.75; NT adaptive t(16) = 5.16, ps < 0.001), meaning that the adaptive player always started to move after his/her partner, regardless of being ASC or NT. This was not the case for same trials, when ∆RT was positive only when NT had the adaptive role (one sample t tests against zero ASC t(16) = 0.92, p = 0.37; NT t(16) = 2.09, p = 0.05). That is, in same trials, ASC participants in the adaptive role started their movement at the same time as their partner, rather than waiting to see which grip their partner would make.Mean ∆RT was always positive in opposite trials  = 17.88, p < 0.001, η2 = 0.37), indicating that participants in the adaptive role exhibited longer reaction times than those in the instructed role. This effect was modulated by participants’ autistic traits  = 4.635, p = 0.039, η2 = 0.13). To interpret this interaction, we subtracted individuals’ RTs in the instructed condition from their RTs in the adaptive condition  and correlated this index with their AQ score. We found a negative correlation , indicating that the lower the AQ, the longer the RT in the adaptive as compared to the instructed condition   Fig. .Fig. 3CoN = 30, r = −0.38, p = 0.04), indicating that the higher the autistic traits, the shorter the time taken to initiate the movement  , indicating that the higher the autistic traits, the longer the time taken to initiate the movement  Fig. . We alsoent Fig. .F = 42.78, p < 0.001, η2 = 0.58) and congruency  = 90.84, p < 0.001, η2 = 0.75). The former indicates that RTs were longer for up than they were for down grasps; the latter indicates that opposite movements caused longer RTs than same ones. This latter effect was modulated by the autistic traits of participants  = 5.8, p = 0.02, η2 = 0.16). To interpret this interaction, we subtracted individuals’ RTs in the same condition from their RTs in the opposite condition  and correlated this index with their AQ score. We found a positive correlation , which indicates that the higher the AQ, the slower the RT in the opposite compared to the same condition    Fig.  and shor03) Fig. .Fig. 4CoF = 23.3, p < 0.001, η2 = 0.43), congruency × position  = 31.7, p < 0.001, η2 = 0.51), and role × congruency × position  = 22.0, p < 0.001, η2 = 0.42). The latter indicates longer RT in opposite-up trials for participants in the adaptive condition (p = 0.001). All other ps > 0.16.Significant interactions include role × congruency  = 5.15, p = 0.03, η2 = 0.14) and position  = 5.7, p = 0.02, η2 = 0.16). The former indicates longer MD in opposite vs. same trials; the latter indicates longer MD in up vs. down trials , as well as a significant role × AQ interaction  = 6.15, p = 0.02, η2 = 0.17). To interpret the latter interaction, we subtracted individual MD in the instructed from individual MD in the adaptive condition  and correlated this index with the AQ. We found a positive correlation . This indicates that the lower the AQ, the longer the MD in the instructed vs. the adaptive condition  and positively in the adaptive condition . This suggests that the lower the autistic traits in the instructed role, the longer the MD  = 36.3, p < 0.001, η2 = 0.54) and a trend to significance of the role × congruency × AQ interaction  = 3.9, p = 0.06, η2 = 0.11). All other ps > 0.12. To interpret the latter interaction, we subtracted individual MD in the instructed condition from individual MD in the adaptive condition. We did this separately for opposite and same trials, correlating this index with the AQ. We found a positive correlation for both opposite and same trials , indicating that the higher the AQ, the longer the MD in the adaptive vs. instructed condition of both trials. These results indicate that participants with high autistic traits performed slower movements in the adaptive condition, regardless of their congruency with their partner’s movement.Analysis on MD also showed a significant role × congruency interaction  that moved on a screen toward two possible targets placed next to either the upper or lower part of the bottle . Participants received auditory instructions as in exp. 1.As described in exp. 1, participants performed the task while following one of two different roles  and were asked to perform opposite or same movements with respect to the dot’s trajectory and target location.Trial-time line and Task structure is same as exp. 1.Only correct trials were entered in the analysis. Trials in which participants started their movement before hearing the auditory instructions were discarded, as were those in which the wrong part of the bottle was grasped  .Accuracy (ACC): percentage of trials in which participant grasped the object in the correct location.Grasping asynchrony (ms) (GraspAsynch): trial-by-trial absolute time interval between participant’s grasp time and dot’s stop time [abs(participant_grasp time − dot_stop time)].Reaction time (ms) (RT): interval between delivery time of auditory instructions and start button release time.Movement duration (ms) (MD): interval between start button release time and grasp time.For each trial, we considered the following behavioral measures:The data analysis of experiment 2 is as Exp. 1.ACC was significant  = 16.55, p = 0.02). We then ran a Wilcoxon matched pair test in order to investigate differences in ACC between roles and between congruency. None of the contrasts survived Bonferroni’s correction for multiple comparisons , indicating that participants reached an equal level of accuracy in all experimental conditions.Friedman ANOVA on F = 55.19, p < 0.001, η2 = 0.64) and position  = 16.14, p < 0.001, η2 = 0.34). The former indicates that participants in the instructed role were more synchronous with the dot than in the adaptive role; the latter indicates that participants were more synchronous with the dot when grasping the lower part of the bottle. Results also included significant congruency × AQ  = 4.24, p = 0.048, η2 = 0.12) and role × congruency  = 6.45, p = 0.016, η2 = 0.17) interactions, explained by the significant third level Role x Congruency x AQ interaction  = 4.95, p = 0.03, η2 = 0.14).Analysis on GraspAsynch showed significant main effects of role  for each role and correlated it with the AQ moderator .N = 31, r = 0.49, p = 0.005) where the higher the autistic traits, the worse the performance  in the opposite vs. the same condition   index  Fig. . All othF = 260.00, p < 0.001, η2 = 0.90), and congruency  = 55.74, p < 0.001, η2 = 0.65) that are explained by the significant second-order role × congruency interaction  = 36.61, p < 0.001, η2 = 0.55). This indicates that participants showed longer RTs in opposite vs. same trials when taking the adaptive (p < 0.001) but not the instructed (p = 0.33) role. Results also show a significant role × position interaction  = 14.70, p < 0.001, η2 = 0.32), indicating that RTs are longer for up trials when taking the instructed (p = 0.001) but not the adaptive (p = 0.07) role. The absence of significant interactions with the AQ moderator  indicates that autistic traits did not modulate participants’ RTs in the individual coordination task. All other ps > 0.21.Analysis on RT showed significant main effects of role  = 94.41, p < 0.001, η2 = 0.75) and position  = 94.41, p < 0.001, η2 = 0.75), as well as a significant congruency × position interaction  = 4.25, p = 0.048, η2 = 0.12) that was explained by the significant higher order role × congruency × position × AQ interaction  = 6.07, p = 0.01, η2 = 0.17). To interpret this last interaction, we calculated the difference between individuals’ mean MD in opposite minus same trials for each role and position, and correlated it with the AQ moderator. Correlational analysis revealed a positive linear correlation between AQ and the adaptive (opposite-same) down index . This indicates that in the adaptive role, movement duration in the opposite down trials is longer the higher the autistic traits. This suggests that when performing a down movement in the adaptive role, participants with higher autistic traits were less able to ignore the dot’s upward spatially incongruent trajectory and target location. All other ps > 0.12.Analysis on MD showed significant main effects of congruency  when they had to perform opposite movements, regardless of which pair member took the adaptive or instructed role. Previous results on pairs of NT participants , 44 instModulation of action planning and execution during joint action depends on the role individuals take to achieve the shared goal , 47. In A number of studies have found that ASC participants have longer reaction times and movement durations than controls in simple goal-directed reach-to-grasp movements. These results have been interpreted either as atypical movement planning –52 or atOur findings seem unlikely to be related to either movement planning or execution deficits per se, as the differences in motor behavior are selectively modulated by the role taken in the interaction. We interpret them in the light of previous studies on sensorimotor communication strategies during joint action, which found that neurotypical participants engage in systematic modulations of their movements to foster coordination and synchrony , 19, 26.When taking the instructed role, our participants with low autistic traits may have therefore slowed their movement in an attempt to reach better pair synchronization by making adaptation easier for their partner. In the adaptive condition, on the other hand, participants with low autistic traits showed shorter movement duration, possibly because they had to keep up with their high autistic traits partner who did not slow his/her movement to foster coordination. ASC reduced use of communicative and adaptive strategies to facilitate coordination during joint action suggests a difficulty in on-line updating individual actions according to the constraints of the interactive task, which might relate to the ASC tendency to not benefit from an interactive context, e.g., when they have to detect an interacting agent presented via point light display . On the The results of our non-social reach-to-grasp task are informative about individuals’ motor performance in a way that goes beyond the social nature of the interactive task and support the idea that the social task’s results do not depend on AQ-related differences in motor planning or execution. Coordination performance in the adaptive-opposite condition was predicted by participants’ autistic traits, i.e., the higher the autistic traits, the worse participants were able to synchronize with the dot when they had to move toward an opposite location. Worse performance in opposite vs. same trials can be considered as evidence of interference effect exerted by the incongruent trajectory of the observed dot over participants’ movement execution. Previous studies found no difference in the interference effect when NT and ASC participants observe real human motion or a dot moving with a biological velocity profile , 57. FurMotor difficulties, often present in ASC individuals , 52, couIn this study, we investigated for the first time the influence of autistic traits on the ability to engage in a cooperative joint action task requiring predictive and adaptive abilities. We tested pairs of ASC and neurotypical participants in a joint-grasping task in which they had to synchronously grasp objects in front of them. By assigning participants to the instructed or adaptive role, we were able to investigate their ability to modify their behavior consistently with their role in order to ease coordination. We also tested participants in a non-social coordination task that allowed us to control for differences in motor execution per se. Results showed that higher autistic traits lessened participants’ ability to modulate their joint action according to their interactive role in the social task. In particular, participants with high autistic traits did not wait for their partner and showed longer movement duration when performing both same and opposite actions during trials in which they needed to adapt to their partner’s movement. No such effect was found in the conditions that did not require adaptation to the partner’s movements nor was it found in the non-social task. Indeed, autistic traits did not predict differences in movement preparation and planning in the non-social task, thus ruling out the possibility that the results of the social interactive task were due to basic motor or executive function difficulties. Overall, reduced use of communicative and adaptive strategies to facilitate coordination during joint action seems to suggest that participants with high autistic traits might find difficult to on-line update their action plans according to the constraints of the interactive task. Such reduced interpersonal coordination strategies during on-line motor cooperation may shed light on various ASC difficulties in social interaction.N = 16) that may not represent ASC heterogeneity.We should be cautious to generalize our results to the whole ASC population, as we only tested ASC individuals with no cognitive disability and, even if our sample size is consistent with that of similar published studies , 26, it Having one ASC and one NT participant cooperating in the joint action task allowed us to investigate, for the first time, interactive dynamics when participants with different levels of social and communicative skills interact, as is often the case in real life. The present study did not also test the same NT participants playing with another NT. This condition would allow for the investigation of an additional experimental question, that is, whether NT participants change their motor behavior when they interact with ASC compared to a NT partner. We might expect NT participants to be more interfered by NT than ASC motor behavior, as it is more similar to their own and they might consider it more interpretable, informative, and reliable as a result . Future