Cue-approach training has been shown to effectively shift choices for snack food items by associating a cued button-press motor response to particular food items. Furthermore, attention was biased toward previously cued items, even when the cued item is not chosen for real consumption during a choice phase. However, the exact mechanism by which preferences shift during cue-approach training is not entirely clear. In three experiments, we shed light on the possible underlying mechanisms at play during this novel paradigm: (1) Uncued, wholly predictable motor responses paired with particular food items were not sufficient to elicit a preference shift; (2) Cueing motor responses early – concurrently with food item onset – and thus eliminating the need for heightened top–down attention to the food stimulus in preparation for a motor response also eliminated the shift in food preferences. This finding reinforces our hypothesis that heightened attention at behaviorally relevant points in time is key to changing choice behavior in the cue-approach task; (3) Crucially, indicating choice using eye movements rather than manual button presses preserves the effect, thus demonstrating that the shift in preferences is not governed by a learned motor response but more likely via modulation of subjective value in higher associative regions, consistent with previous neuroimaging results. Cue-approach training drives attention at behaviorally relevant points in time to modulate the subjective value of individual items, providing a mechanism for behavior change that does not rely on external reinforcement and that holds great promise for developing real world behavioral interventions. Monetary and food reinforcements have traditionally been employed to influence behavior , but tarDevelopment of the cue-approach task was largely inspired by the attentional boost effect , which rexcept when they heard a tone cue in the cue-avoidance task. In our original published cue-avoidance studies and two additional unpublished studies, we did not see significant avoidance of stop-cue-associated food items during a choice phase identical to that used in the cue-approach studies. However, several other researchers have demonstrated a shift in preferences away from stop- or nogo-associated stimuli  on only 75% of all trials. Because the task in Experiment 2 is easier (since they have a full second rather than ∼250 ms to press a button), participants should have higher success rates. If the cue-approach effect relies on internal reinforcement for the subjective feeling of correctly pressing a button, we would expect a more dramatic shift in preferences following training in Experiment 2 than in the standard delayed cue design due to the higher success rate for pressing the button in time. However, our main hypothesis is that cue-approach training relies on heightened attention at behaviorally relevant points in time rather than internal reinforcement. We hypothesize that participants learn to expect a cue when a Go food item appears on the screen. We expect that heightened attention to detect the cue to perform an action modulates preferences. In Experiment 2, the tone sounds at the same time as the food image appears, thus no expectancies can be formed. Thus, we expect that eliminating the need for heightened attention to detect the cue in Experiment 2 yields no shift in preferences.Whereas Experiments 1 and 2 address the relevance of behaviorally important cues and their timing to the cue-approach effect, neither address what type of values  are being modulated during training. Decision-making in the cue-approach task involves choices between two food stimuli, each involving a different physical action . Although we hypothesized that cue-approach training perturbs the value of stimuli directly, it remains possible that cue-approach training instead modulates values of the possible actions to indicate choice. If the latter is true, then the choice effect would be motor effector specific and we would see a shift in preferences when choices are executed using the trained motor effector , but not if the choice is executed using a different motor effector . The first indication that cue-approach training may not modulate action values lies in the fact that we found no bias for choosing the food item on the left of the screen using the index finger (the finger used to press the button when cued during training) in any of studies 1 though 4 in The set of experiments presented here test three main hypotheses and narrow the field of possible mechanisms responsible for the cue-approach effect. These findings help to better understand which automatic cognitive processes are targeted during the cue-approach task to achieve lasting behavioral change. The mechanism underlying the shift in preferences following cue-approach training is not yet fully understood. In the three experiments reported here, we address three questions: (1) Is a non-cued motor response sufficient to induce a shift in preferences? (2) Is the delay in cue appearance after the food stimulus onset required for a shift in preference? and (3) Is the shift in preferences motor effector specific?Figure 1A), a training phase , and a probe phase . For details of the procedures used, please refer to In the experiments reported here, we modified the standard cue-approach task to better understand the mechanisms responsible for a shift in preferences for appetitive junk food items. The standard cue-approach task implemented in studies 1 through 4 in Color photographs of 60 appetitive junk food items were used in this experiment. The same stimuli were used in previous experiments ,a. StimuFigure 1A). The auction followed the procedure outlined by Upon arrival at the laboratory, participants were endowed with $3 and told that they would take part in an auction  to least preferred . Items were split into high-value (rank order numbers 1–30) and low-value items (rank order numbers 31–60). Items were then placed into one of two training conditions; Go items required a button press during training and NoGo items required no response from the participant. Eight items were designated as Go items to later be paired with NoGo items matched for WTP in comparisons of interest during probe (see below): 4 high-value Go items  each to be paired with 4 high-value NoGo items  to yield sixteen unique high-value pairs, 4 low-value Go items  each to be paired with 4 low-value NoGo items  to yield sixteen low-value pairs of interest. This pairing procedure ensured that pairs of items presented during probe would be matched for WTP but differed on Go status, such that participants should a priori be indifferent in a choice between a Go and a NoGo item. To maintain ∼25% cue frequency as is common in stop-signal tasks , we seleFigure 1B). Sixteen stimuli consistently required the participant make a button press on the keyboard , while the rest (44 items) required no motor response (NoGo items). The order of Go and NoGo trials was randomized per block of 60 trials. Participants were told to press a button on the keyboard as quickly as possible only when they heard a tone. The auditory Go cue sounded a variable time averaging 750 ms after food stimulus onset and was adjusted using a 1-up/3-down staircase procedure that ensured that participants would successfully press the button in time on only 75% of Go trials. If the participant successfully pressed the button in time, go-signal-delay (GSD) was increased by 17 ms, making it harder to press the button in time on the next Go trial. If the participant failed to press the button in time after the tone, GSD was reduced by 50 ms, making it easier to press the button in time on the next Go trial.Participants viewed one food item at a time appear on the screen for 1 s followed by an inter trial interval (ITI) that lasted between 1 and 12 s and generated from an exponential distribution with mean 3 s . On each trial, two food items appeared immediately to the right and left of a central fixation cross, and the participant was told to choose one item. They were told that a single trial would be selected at random at the end of the experiment and their choice on that trial would be honored for real, meaning they would receive the item they chose on that trial to eat at the end of the experiment. Each pair of interest was made up of two items with similar WTP; one was a Go and the other a NoGo item such that participants’ a priori preference for either item should be equal given their stated pre-experimental preferences measured by the auction. Full details of the pairing procedure are described in Supplementary Figure 1 of After filling out a computer adapted version of the Barratt Impulsiveness Scale questionnaire BIS-11,  and on aFigure 1B, Experiment 1). At the beginning of each block participants were told to either press a button on the keyboard every time an item appears on the screen, but before it disappears in Go blocks or are told to passively view the items on the screen without pressing any buttons in NoGo blocks. Go items only appeared in Go blocks and NoGo items always appeared only in NoGo blocks. Stimuli appeared in random order per block. The order in which blocks appeared was counterbalanced across participants. Each of the 30 training items was repeated 15 times in different blocks for a total of 450 training trials. The probe task in Experiment 1 was identical to that described above; participants used the index and middle finger of their right hand to make choices .The auction was identical to the procedure described above. Training, however, was different. Participants viewed food items on the screen one at a time in blocks of Go or NoGo trials . This contrasts with the cue-approach task in the original studies, in which the Go cue sounded after a variable delay (mean GSD = 750 ms) following the food stimulus onset. Each of the 60 items was presented 16 times for a total of 960 training trials. The probe task in Experiment 2 was identical to that described in The auction was identical to the standard procedure described above. The training phase was very similar to the standard training procedure, but differed in the timing of the tone cue. Participants were instructed to view food stimuli appearing on the screen one at a time. They were instructed to press a button on the keyboard as quickly as possible and before the food stimulus disappeared from the screen only when they heard an auditory tone. In Experiment 2, the auditory cue always sounded immediately and concurrently with Go food stimuli presentation onsets .The auction was identical to the standard procedure. Participants also underwent standard cue-approach training identical to that described above. Each of the 60 items was presented 16 times for a total of 960 training trials. The probe phase was different from the standard procedure, however. It differed in the actions required to make a choice. Participants were required to make eye movements rather than manual button presses to indicate choice. Participants were asked to fixate on one of the two items on the screen for 750 ms continuously in order to confirm their choice for that item on each trial rather than press one of two buttons on the keyboard to indicate choice , Experiment 2 included 25 participants  and Experiment 3 included 25 participants . Exclusion criteria are described below. Participants in the three experiments did not differ in age or BMI (p’s > 0.4). Sample sizes are similar to previously published studies , GSD was increased by 17 ms on the next Go trial, making it more difficult to press the button on time. But if the participant failed to press the button in time, GSD was decreased by 50 ms on the next Go trial, making it easier to press the button on time. This 3:1 ratio ensured that participants would be accurate on about 75% of Go trials. Most participants’ GSD ladders converged around 750 ms. One participant in Experiment 3 was excluded from analysis because their ladders did not converge , indicating that they were not following instructions and were behaving erratically during training.During training and probe in Experiments 1 and 3, we recorded participants’ eye movements using an Eyelink-1000 by SR Research . We obtained coordinates for eye position on the computer screen at a rate of 250 Hz. Additionally, we used eye position data in real time in Experiment 3 by providing feedback to facilitate participants’ choices during the probe phase. Participants in Experiment 3 were required to fixate on one of the two items on the screen for 750 ms in order to confirm their choice of that item on each trial.To test whether different forms of cue-approach training induced a preference change or whether using a different modality during choice reveals a preference shift, we performed repeated-measures logistic regression to compare the odds of choosing Go to NoGo items against equal odds for high-value and low-value pairs separately. To test any differences in reaction time (RT) or stimulus viewing time, we performed repeated-measures linear regression to compare these measures when participants chose Go vs. when they chose NoGo items.We conducted this experiment to test the hypothesis that approach behavior alone modulates action values. To test this hypothesis, we eliminated the auditory cue and presented approach (Go) and no-approach (NoGo) item trials in blocks of trials. Each block was preceded by instructions indicating which block the participant was about to start.Figure 2 summarizes the probe behavioral results in Experiment 1. Participants chose Go over NoGo items on 48% of high-value pair trials , p = 0.5 for odds of choosing high-value Go to NoGo items, Bayes Factor in favor of the null (BFn) = 5.06] and 50% of low-value trials . The high-value pair choice effect in Experiment 1 are significantly different than the effect in the four original studies that employed the standard cue-approach design in p = 0.001 for choices of high-value Go items in Experiment 1 compared to the four original studies). The low-value pair effect in Experiment 1 did not differ from the effect in the four original studies .Eliminating the auditory cue to press a button during cue-approach training, and thus rendering button presses completely predictable, eliminated the shift in preferences toward Go items. Figure 3, mean proportion for chosen item = 0.41, mean proportion for unchosen item = 0.32, β = 0.09, 95% CI = [0.08 0.10], p < 0.0001). However, unlike previous findings using the standard cue-approach task, there was no main effect of Go status on the proportion of time participants viewed the item . There was no interaction between item chosen/unchosen and Go/NoGo status on proportion of time spent viewing the item. These results suggest that training with no auditory cue did not bias attention toward Go items. Previous findings showed that participants tended to look at the Go item longer, even when that Go item was not chosen . There was no interaction between pair type  and choice of Go or NoGo on RT . RT also did not differ for choices of Go or NoGo .Participants were on average slower at choosing between low-value items than they were choosing between high-value pair items  – i.e., the delay to sound the auditory cue to press a button after food stimulus onset – during cue-approach training.Figure 2 summarizes the probe behavioral results in Experiment 2. Participants chose Go over NoGo items on 55% of high-value pair trials  and 52% of low-value trials . The choice effect for the high-value pairs was marginally lower than in the four previous studies in p = 0.08, for choices of high-value Go items in Experiment 2 compared to the four original studies). The choice effect in the low-value pairs did not differ from the effect in the previous samples . These choice effects do not differ between Experiments 1 and 2 .Eliminating the delay between food stimulus onset and auditory cue onset during cue-approach training eliminated the shift in preferences toward Go items. p’s > 0.2, β’s < 12.5, and BFn’s > 7).Reaction times did not differ between low-value and high-value pair choices. RTs were also the same for choices of Go and NoGo items  and 59% of low-value trials . The choice effects in Experiment 3 did not differ from those in the previous four studies in p’s > 0.4, BFn’s > 2.93). Choices of high-value Go items were significantly higher in Experiment 3 when compared to choices in Experiment 1 , but not significantly different than in Experiment 2 . Choices of low-value Go items were not different between any of the experiments .Using a different motor effector (eye rather than hand) during the probe phase revealed a choice preference for Go items following standard cue-approach training. Cue-approach training likely affects item valuation/processing rather than simpler action values. Figure 3). However, we ran a mixed effects linear regression model examining the effect of Go status (two levels: Go and NoGo) on proportion of choice time viewing a particular food with participant as a grouping factor. We found a main effect of Go status on viewing time . This finding replicates previous results using eyetracking during the standard cue-approach task when participants chose between the two items using button presses (i.e. using the same motor effector that was trained). Moreover, using the same mixed-effects model above on data for times participants were fixated on unchosen items only, we found a simple effect of Go status on viewing time within unchosen items . Participants viewed Go items longer than they viewed NoGo items even when the item was not ultimately chosen.Participants were instructed to fixate on the item they would like to choose for 750 ms in order to execute their choice. Thus, the main effect of choice on the proportion of choice time the eyes are fixated on a particular item is artificial . This finding, in combination with our previous finding that an auditory cue in the absence of a motor response is also not sufficient to induce a change in choice preferences, reinforces our claim that attentional as well as motor mechanisms are likely at play during cue-approach training. It should be noted that the design of this version is also different from the original task as the presses are entirely predictable and do not involve heightened anticipation. Due to this fact we also incurred a very high percentage of excluded participants as they were not watching the items that were not associated with a button press. However, in a post hoc analysis of the probe phase data including all participants did not change the pattern of results. Excluding participants that did not view the Go and NoGo items equally ensured that mere exposure was not a factor in this experiment and that participants were indeed maintaining visual attention on the foods equally in both task conditions. An alternative task design was considered where participants are instructed to press the button when they wanted to without a cue as was implemented in Cueing a motor response during training appears to be important for the shift in choice preference. In the standard cue-approach training task, the food stimulus is presented first, followed by the cue to perform a motor response. Performing an uncued motor response during blocks of training trials at the beginning of which the participant receives instructions to follow for the whole block of trials (press a button or passively view items), does not lead to a shift in choice behavior . Choices for Go over NoGo items were not significant, but were only marginally lower than in previous studies. This suggests that sustained attention toward particular Go items enhances the modulation of preferences during the cue-approach task. After participants learn to anticipate the tone once a Go item appears on the screen in the standard cue-approach design, they focus more intently on that item in anticipation of the cued motor response. However, the tone onset time in the standard version of the task is not perfectly predictable since it sounds at a variable time after the food stimulus onset to ensure 75% Go success. The timing of the cue during the cue-approach task seems to play a more central role than in the attentional boost task, where overlap in time between the to-be-remembered image and the target is crucial, but the timing of the overlap has been shown to matter little  rather than item-specific intrinsic value was being modulated. If action value was being modulated and played a role in the cue-approach effect, we would expect there to be a bias toward choices executed using the index finger (which is the trained effector). However, we found no bias toward choices made with the index finger in our previous studies employing standard cue-approach training . FurtherFurther evidence is consistent with our hypothesis that the cue-approach task works at the level of modulating individual items’ intrinsic value by driving attention toward those items at behaviorally relevant points in time. Thus far, we have only shown that the value of initially already high-value stimuli (appetitive snack foods) can be boosted following cue-approach training. For compelling relevance of the cue-approach task for real-world applications, future work should investigate the effectiveness of this training in shifting preferences toward initially lower-valued stimuli such as less palatable but healthier foods, for example. However, this research has already modestly improved our understanding of how value can be modulated and holds great promise in the development of novel real-world behavioral change interventions.AB, RP, and TS designed the studies. AB, AH, and NG programmed the tasks. CL, AH, and NG collected the data. AB, CL, and TS analyzed the data. AB, RP, and TS wrote the paper.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.


Chronic pain following lower-limb amputation is now a well-known neuropathic, chronic-pain syndrome that usually presents as a combination of phantom and stump pain. Controlling these types of neuropathic pain is always complicated and challenging. If pharmacotherapy does not control the patient’s pain, interventional procedures have to be taken.The aim of this study was to evaluate the efficacy of using pulsed radiofrequency (PRF) on the dorsal root ganglia at the L4 and L5 nerve roots to improve phantom pain.Two patients with phantom pain were selected for the study. After a positive response to segmental nerve blockade at the L4 and L5 nerve roots, PRF was performed on the L4 and L5 dorsal root ganglia.Global clinical improvement was good in one patient, with a 40% decrease in pain on the visual analogue scale (VAS) in 6 months, and moderate in the second patient, with a 30% decrease in pain scores in 4 months. PRF of the dorsal root ganglia at the L4 and L5 nerve roots may be an effective therapeutic option for patients with refractory phantom pain. Phantom limb pain is a perception of a painful sensation that feels as if it originated from the missing limb after amputation. Phantom limb pain can appear in three possible ways: Phantom pain: painful sensation in the amputated limbPhantom sensation: any sensation, other than pain, in the amputated limbStump pain: localized pain in the amputated region .The location and characteristics of the sensation are important in controlling the pain. Stump pain usually coincides with the development of phantom limb pain . PhantomConservative therapy consists of drug treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. When conservative treatment fails, lumbar sympathetic blockade, pulsed radiofrequency (PRF) ablation of the stump neuronal or the spinal ganglion, or spinal cord stimulation could be considered . OperatiThe phenomenon of phantom limb pain remains poorly understood. As of this writing, no successful treatment exists and these patients continue to suffer from significant pain and disabilities. Careful and systematic application of available treatment methods will help to diminish pain without causing significant morbidity related to poor treatments. Ongoing laboratory and clinical research will continue to improve our understanding of this complex type of pain and improve treatment in the future.The aim of this study was to evaluate the efficacy of using pulsed radiofrequency on the dorsal root ganglia at the L4 and L5 nerve roots to improve phantom pain.In our case study we identified two patients with phantom pain. Both patients had phantom pain for more than 3 months and were not responding to conservative treatments. They had no history of drug abuse. Magnetic resonance imaging (MRI) of the lumbosacral was normal and they had no lumbar radiculopathy or facetogenic pain. Both patients had a VAS of more than 5 and reported that their pain began from the stump and radiated to the lumbar and then the leg. Neither of the patients used prosthesis. Their physical examinations were normal except for hyperalgesia in the stump location in one of the patients and allodynia in the other. In both cases the major nerve responsible for the phantom pain was the sciatic nerve. At first a diagnostic selective nerve root (L4 and L5) blockade was performed in aseptic condition. For mild sedation, 1 mg of midazolam and 50 µg fentanyl were administered intravenously. At first in the anterior- posterior (AP) view, the position of fluoroscope was changed to the cephalo-caudal direction to flatten the vertebrae end plate. Then, the C-arm was moved to an oblique position at a 20-degree angle. The target point in oblique view was below the pedicle at 6 o’clock. Local anesthesia was made by lidocaine . Then, an introducer (Gauge 16) was inserted in tunnel view, its stylet was removed, and a blunt, curved-tip needle (Gauge 22 and 150 mm in length) was placed through the introducer. After confirming the tip of the needle was inserted in the oblique, AP, and lateral views , non-ionic water soluble contrast media (omnipaque 320) was administered. After confirming that the needle was not into the vascular bed, ropivacaine  and triamcinolone (40 mg) were injected under live fluoroscopy. Two weeks after the first diagnostic blockade which was administered to decrease the patients’ pain, a PRF was performed on the patients in the same way as the diagnostic blockade technique, except that a blunt, curved-tip radiofrequency needle  was inserted. After confirming the position of the tip of the needle , a radiofrequency probe was placed instead of the stylet needle. Sensory stimulation was made , which resulted in paresthesia in the stump or the amputated leg (sensation in the leg and fingers). Because the PRF did not have any significant side effects for the motor nerves, and it was impossible to achieve motor response for the amputated extremity, the functional test was not performed. A PRF was conducted on the dorsal root ganglia (DRG) in two cycles, 42 °C, 120 seconds in both L4 and L5. Then ropivacaine  and triamcinolone (40 mg) were injected. This technique was performed for L4 and L5 in one patient but only for L4 in the other patient due to disturbed vertebral anatomy caused by hemipelvectomy . A 35-year-old woman had an amputation right above the knee 3 months ago because of osteosarcoma. The chief complaint was intermittent and sharp right-side stump pain with radiation to the lumbar and then the right leg. She had phantom pain and phantom sensations. In the physical examination her stump had only a little hyperalgesia at one point. Also, the pain sometimes radiated to the left posterior thigh. Her lumbosacral MRI was normal. After diagnostic blockade, her stump pain completely disappeared, but the phantom sensation did not show any changes, and the patient reported that, after the blockade, she felt sensation again in what would have been the toe area of her right amputated leg. At first, she was very satisfied with the blockade, and a PRF of the right dorsal root ganglion was performed on this patient at L4 and L5. She reported a 40% decrease in pain on the VAS within 6 months.A 25-year-old woman presented with a history of left hemipelvectomy due to an accident from her childhood. Her chief complaint was left-side stump pain and right-side phantom pain. She had intermittent electrical-shock-like sensations shooting from her left stump up to her lumbar and then to her right leg. The pain sensations had gradually increased from once a year to every day. Her pain score (VAS) was about a 5 or 6 out of 10. Her physical examination was normal except for allodynia in the stump (at one point). Her lumbosacral MRI was normal. After diagnostic selective nerve root (L4) blockade, she underwent a PRF of the left L4 dorsal root ganglion (L5 was not possible due to anatomic distortion). She was satisfied and reported a 30% decrease in her VAS in 4 months.The PRF on the L4 and L5 dorsal root ganglia was somehow effective in controlling phantom pain in the patients.Dorsal root ganglia transfer sensory signals to the central nervous system, and they play a very important role in the pathogenesis of chronic pain syndrome. The application of PRF by creating an electromagnetic field has found a very special place in controlling chronic pain. This method can be used on lumbar dorsal root ganglia in controlling lumbosacral and stump pain -11. DorsElectric field by PRF causes different effects on the tissues. This electric field penetrates into the axon’s membrane and dorsal root ganglia and raptures important subcellular structures that will change or disable cell activities. This field changes the activity and behavior of the Schawnn cells and causes neural excitation. Also, by effecting the ions’ oscillations and polarization of the cells’ membranes, the field modifies cell structure and decreases pain messages by long-term depression of the dorsal root synaptic connections, which results in analgesia . A PRF oA PRF on dorsal root ganglia is effective in controlling pain after thoracic surgery and stump pain of amputated limbs , 18. For


A possible increase in thyroid cancer in the young represents the most critical health problem to be considered after the nuclear accident in Fukushima, Japan (March 2011), which is an important lesson from the Chernobyl disaster (April 1986). Although it was reported that childhood thyroid cancer had started to increase 3–5 yr after the Chernobyl accident, we speculate that the actual period of latency might have been shorter than reported, considering the delay in initiating thyroid surveillance in the then Soviet Union and also the lower quality of ultrasonographic testing in the 1980s. Our primary objectives in the present study were to identify any possible thyroid abnormality in young Fukushima citizens at a relatively early timepoint (20–30 months) after the accident, and also to strive to find a possible relationship among thyroid ultrasonographic findings, thyroid-relevant biochemical markers, and iodine-131 ground deposition in the locations of residence where they stayed during very early days after the accident.This is a cross-sectional study. We targeted the Fukushima residents who were 18 yr old or younger (including fetuses) at the time of the accident. Our examinations comprised a questionnaire, thyroid ultrasonography, thyroid-related blood tests, and urinary iodine measurement. We analyzed a possible relationship among thyroid ultrasonographic findings , serum hormonal data (731 subjects), urinary iodine concentrations (770 subjects), and iodine-131 ground deposition . We did not find any significant relationship among these indicators, and no participant was diagnosed to contract thyroid cancer.At the timepoint of 20–30 months after the accident, we did not confirm any discernible deleterious effects of the emitted radioactivity on the thyroid of young Fukushima residents. This is the first report in English detailing the thyroid status of young Fukushima residents after the nuclear disaster. A subsequent tsunami severely damaged the cooling systems of the Fukushima Daiichi nuclear power plant (FNPP1), and a resultant hydrogen explosion caused the release of a large amount of radioactive material into the environment over March 2011. It was reported that iodine-131 (131I), cesium-134, and cesium-137 constituted a major proportion of the radioactivity discharged from the FNPP1 th a highly radioactive plume mainly arrived in such residential quarters that are located to the west and northwest of the crippled FNPP1 th to the early morning of March 16th a continual rainfall occurred especially in the northern area of Fukushima Prefecture. It is considered that this rainfall lasting for about half a day deposited the atmospheric radionuclides including 131I on the ground of Fukushima Prefecture, and this constituted the majority of radiocontamination in the prefecture A great earthquake of 9.0-Richter magnitude (Great East Japan Earthquake) struck the Pacific coast of Japan on March 11th 1986 131I or the differential distribution of ground 131I contamination across Fukushima Prefecture.This accident in Fukushima created a genuine concern about the human health risks that might be caused by radiation exposure. The most crucial health problem to be considered on the occasion of nuclear accidents is a possible increase in thyroid cancer in the young as a consequence of radioiodine taken up by the thyroid, because childhood thyroid cancer is the only malady that was accepted as the indubitable consequence of the Chernobyl nuclear disaster that occurred on April 26Targeting the same age bracket of Fukushima residents as examined by Fukushima Prefecture, we also commenced thyroid examinations from November 2012 independently of the prefecture. Our thyroid examinations comprised a questionnaire (including an inquiry whether prophylactic stable iodine was taken), ultrasonography, and UIC measurement for all participants, and thyroid-relevant blood tests for those aged 6 yr or older at the time of the examinations, which as a whole constituted a more detailed study protocol than that by Fukushima Prefecture.It was reported that childhood thyroid cancer had started to increase 3–5 yr after the Chernobyl accident 131I ground deposition in the locations of residence where individual participants stayed during a very early period after the FNPP1 accident.Therefore, in this study we aimed to conduct the following in more than 1,000 children and adolescents in Fukushima Prefecture: (1) to identify any possible abnormality in the thyroid by ultrasonography at a relatively early timepoint (20–30 months) after the accident, and (2) to strive to find any possible relationship among thyroid ultrasonographic findings, the data of thyroid-related blood tests and UIC, and also http://www.fukkousien-zaidan.net), and all participants  signed an informed consent form. A separate written informed consent was obtained for fine-needle aspiration biopsy of the thyroid (see “ultrasound examination” below). This study was conducted according to the principles of the Helsinki Declaration.This study was reviewed and approved by the ethical committee of the Radiation Countermeasures Research Institute for Earthquake Disaster Recovery Support (th 2012 and September 30th 2013 (20–30 months after the accident) from all across Fukushima Prefecture. Our examinations comprised a questionnaire , thyroid ultrasonography , thyroid-related blood tests (for the subjects aged 6 yr or older at the examinations unless they declined), and UIC measurement . All these examinations were done on the same day.A total of 1,222 subjects , who all were 18 yr old or younger (including fetuses) at the time of the FNPP1 accident, participated in this study between November 10th 2011 th 2011 (the date when the majority of the radiocontamination occurred in Fukushima). This final inquiry was not applicable to the subjects who evacuated outside Fukushima. As to KI, Fukushima Prefecture recommended that KI be taken upon instructions from the prefecture at different doses in different age groups in accordance with the WHO's Guidelines for Iodine Prophylaxis Following Nuclear Accidents All participants or their legal guardians were invited to fill out a questionnaire that addressed personal and family histories of any disease (including thyroid disorders), whether and when they took potassium iodide (KI) distributed by Fukushima Prefecture immediately after the hydrogen explosion at the FNPP1 Unit 1 on March 12All subjects underwent thyroid ultrasonography using a 9.0-MHz linear transducer  by certified ultrasonographers. Presence of nodules, echostructure, and pattern of echogenicity were recorded as per the guidelines for the diagnosis and treatment of thyroid tumors publicized by the Japan Society of Clinical Oncology 3), free thyroxine (fT4), thyroglobulin (Tg), anti-thyroglobulin antibody (TgAb), and anti-thyroid peroxidase antibody (TPOAb). TSH, fT3, and fT4 were measured by immunochemiluminescence assay utilizing the kits produced by Siemens Healthcare Diagnostics Inc. . Tg, TgAb, and TPOAb were measured by electro-chemiluminescence immunoassay utilizing the kits produced by Roche Diagnostics International Ltd. . All assays were done in duplicate. The analytical sensitivities and normal ranges (in parentheses) of the assays for TSH, fT3, fT4, Tg, TgAb, and TPOAb were 0.008 mIU/L (0.4–4.0), 0.31 pmol/L (3.4–6.3), 1.3 pmol/L (10.3–24.5), 0.1 µg/L (<32.7), 10 kIU/L (<28.0), and 5 kIU/L (<16.0), respectively. In all the six assays, both the inter- and intraassay coefficients of variation were less than 10%.Blood samples were drawn for the measurement of thyroid-stimulating hormone (TSH), free triiodothyronine . All urine samples were assayed in duplicate. The sensitivity of the assay was 25 µg/L, and both the inter- and intraassay coefficients of variation were less than 10%.131I ground deposition in Fukushima Prefecture at early days after the FNPP1 accident, until Torii et al.131I described in this previous study did not encompass all areas of Fukushima Prefecture. Thus, we constructed a map of estimated ground deposition of 131I all across Fukushima Prefecture based on the data reported elsewhere 131I is decay-corrected as of March 15th 2011, at which time the majority of radioiodine was considered to have been deposited in Fukushima Prefecture 131I in Only limited information had been available as to t-test, analysis of variance (ANOVA), Kruskal-Wallis test, or non-parametric multiple comparison test was used as appropriate. Correlation among variables was tested using regression analysis. Intergroup differences and correlation were considered significant if P was smaller than 0.05.Results were expressed as percentage, the mean ± S.D., or the median (IQR). To compare data among different groups, Chi-square test, pairwise th 2011 for the residents living within a radius of 20 km from the crippled FNPP1 131I ground deposition that was integral for our analyses (th to 31st 2011 (for 17 days). This 17-day period was such a length of time by the end of which the radioactivity of 131I, a gamma and beta emitter with a physical half-life of 8 days, must have decayed down to about 23% of that released on March 15th 2011. In subsequent analyses involving 131I ground deposition, each participant's domicile during these 17 days was employed to apply area-specific levels of deposited 131I to each individual. In a small proportion of the participants who changed their domiciles during these 17 days, the areas where such individuals stayed for the longest period of time were employed to allocate to them individual levels of 131I ground deposition.Thirty-five (2.9%) of the 1,222 subjects did not agree that their personal data would be used for analyses, so that the results from these participants were not subjected to subsequent analyses . The queanalyses . From thOf these 1,154 subjects, 17 did not contribute to statistical analyses because of their ultrasonographic and/or hormonal data . Fifteenth and 10:00 p.m. March 15th 2011. This timing of KI intake seemed appropriate considering a previous report that KI is effective to reduce thyroid uptake of radioiodine only when it was taken between 48 h before and 8 h after exposure to radioiodine th 2011, and 0.4%  of the subjects both took KI and increased seaweed ingestion. We also learned from the questionnaire that every participant had kept up their dietary habits on and after March 12th 2011 until they underwent examinations in this study. th–31st 2011.Collectively, in the present study the questionnaire and ultrasonographic data from 1,137 subjects , blood test results from 731 subjects , and UIC data from 770 participants  contributed to the analyzed results given below . The que131I (KI intake and increased seaweed consumption after the accident). As shown in In the first place, we compared the two groups with and without the prophylactic deeds against thyroid exposure to 131I ground deposition in the locations of residence where individual participants stayed during the early days after the nuclear accident. As shown in 131I levels were slightly (1.2-fold) but significantly (P = 0.007) higher in the “three-nodule” group than in the “zero-nodule” group. Similarly, the “three-cyst” group had a slightly (1.2-fold) but significantly (P = 0.004) higher level of deposited 131I than the “zero-cyst” group. The number of solid nodules was not significantly related to the deposited levels of 131I. We also analyzed whether the largest diameter of solid nodules (detected in 47 subjects) and cysts (detected in 811 subjects) had any significant correlation with 131I ground deposition, and found that neither of these thyroid indicators was significantly correlated with the extent of 131I contamination on the ground  and the number of solid nodules or cysts had any significant relationship with the e ground  and 5.We analyzed whether the thyroid nodularity and thyroid-relevant hormonal data altered as a function of the UIC. As per the WHO criteria for the UIC 3, fT4, and Tg, and found no significant relationship among these parameters (data not shown). Finally, in 46 subjects who were in utero at the time of the nuclear accident, we analyzed the relationship between thyroid nodularity and 131I ground deposition in the locations of residence where their mothers stayed between March 15th and 31st 2011. The result was that neither the number nor the largest diameter of their solid nodules and cysts was significantly related to the deposited levels of 131I (data not shown). Results of the questionnaire revealed that none of the mothers of these 46 children took KI or increased seaweed consumption after the accident.We examined a possible relationship between the number and the largest diameter of solid nodules and cysts and the serum levels of TSH, fT131I ground deposition elevated.In this study we examined the thyroid status of 1,137 children and adolescents in Fukushima Prefecture at the timepoint of 20–30 months after the FNPP1 accident. The results were that we did not detect any confirmed case of thyroid cancer in our sample population, and that we did not find any significant relationship among thyroid ultrasonographic findings, thyroid-relevant hormonal data and UIC. However, as discussed below, the total number of thyroid nodules and the number of cysts tended to be larger as the th 2011, Fukushima Prefecture distributed KI to the residents aged 40 yr or younger who lived within a radius of 50 km from the damaged FNPP1 so that they could take KI when instructed The questionnaire in the current study revealed that after the nuclear accident in Fukushima 4.0% of the participants took KI, and 23.1% of the subjects increased seaweed consumption of their own will. Immediately after the hydrogen explosion on March 12131I ground deposition was slightly but significantly higher in the “three-nodule” group than in the “zero-nodule” group, and also in the “three-cyst” group compared to the “zero-cyst” group. Because the number of solid nodules was not significantly related to the 131I ground deposition, it is very likely that the significantly higher 131I levels in the “three-nodule” group reflected the similar predominance of deposited 131I levels in the “three-cyst” group over the “zero-cyst” group. However, because there was no dose-dependent relationship between the 131I ground deposition and the number of nodules or cysts, we do not interpret our present data as suggesting a cause-and-effect relationship between radioiodine exposure and thyroid cyst formation. Even so, further investigations along these lines would be interesting and also warranted.In the present study we found that the 129I and 131I discharged had been observed in organic gaseous form 131I ground deposition as a surrogate marker for the individual exposure to 131I. However, this is one of the limitations to the present study because the transfer of the deposited 131I to the thyroid represents a major dosimetric uncertainty. Notwithstanding these limitations, we believe that our present study is the first to have analyzed in the young Fukushima residents the relationship between the thyroid ultrasonographic findings and the differential levels of 131I ground deposition across Fukushima Prefecture. As of today, Fukushima Prefecture or any other institution has yet to report the results of studies conducted from the same standpoint. All the latest information publicized by Fukushima Prefecture as regards the exposed radiation dose in young Fukushima citizens is that the external exposure of radiation was able to be estimated in only 57 (0.019%) of 295,689 people aged 18 yr or younger at the time of the accident, and the dose was universally below 2.5 mSv 131I In the atmosphere, iodine exists in both gaseous and particulate forms 3, FT4, and Tg. However, it has been reported that Tg is a suitable indirect marker for iodine status in both adults and children, with higher Tg levels being observed under both deficiency and excess of iodine th 2011 (the date when the hydrogen explosion broke out at the FNPP1 Unit 1) until they underwent examinations in the present study, it is very likely that the UIC data reported herein well reflected the iodine status of our participants back in the early days after the nuclear accident.A previous report that iodine deficiency is a significant potentiator of radiogenic thyroid cancer risk in the young in utero radiation exposure on thyroid cancer risks in postnatal life. Results from several previous studies on this issue are inconclusive in utero, and found no significant relationship between the thyroid nodularity of the children and the 131I ground deposition in the locations of residence where their mothers stayed during the very early days after the FNPP1 accident. Fukushima Prefecture commenced thyroid ultrasonography only from April 2014 on such residents who were in utero at the time of the accident Information is very limited regarding the effects of According to the latest data publicized by Fukushima Prefecture in August 2014 (3 yr and 5 months after the FNPP1 accident), the prefecture detected 104 cases of confirmed or suspected thyroid cancer among 295,689 Fukushima citizens who were 18 yr old or younger at the time of accident 131I ground deposition densities measured in Fukushima after the accident Chernobyl and Fukushima are similar in that they both are a nuclear reactor accident, but there are notable differences between the two in terms of the risk for thyroid cancer development as in the following: (1) The total amount of radioiodine emitted from the FNPP1 was as small as about one-tenth of that released after the Chernobyl accident 131I ground deposition elevated, the results obtained were not solid enough to suggest a cause-and-effect relationship between radioiodine exposure and thyroid cyst formation. We admit that the present study suffers two major methodological limitations, i.e., (1) We employed the differential levels of 131I ground deposition as a surrogate marker for individual thyroid exposure estimates, and (2) The UIC data in the current study do not necessarily reflect the participants' iodine status at the time of the nuclear accident. However, both of these limitations were insurmountable. Whether all the negative results in the current study suggest an insignificant health impact of the FNPP1 accident or reflect the relatively early implementation of thyroid examinations in the wake of the accident, must await forthcoming studies. Further continuing studies are warranted in terms of the long-term health surveillance and protection of the radiation-exposed children and adolescents in Fukushima. Although the sample size in our investigation was small, this is the first report in English detailing the thyroid status of young Fukushima residents after the nuclear disaster.In summary, this study examined the thyroid status of 1,137 children and adolescents in Fukushima Prefecture at the timepoint of 20–30 months after the FNPP1 accident. The results obtained revealed no discernible deleterious influences of the emitted radioactivity on the young thyroid. In addition, we did not find any significant relationship between the thyroid ultrasonographic findings and thyroid-relevant biochemical markers. Although the number of thyroid cysts tended to be larger as the


In March 2013, NHS England extended its national Bowel Cancer Screening Programme to include ‘one-off' Flexible Sigmoidoscopy screening  for men and women aged 55. With less than one in two people currently taking up the screening test offer, there is a strong public health mandate to develop system-friendly interventions to increase uptake while the programme is rolling out. This study aimed to assess the feasibility of sending a reminder to previous BSS non-responders, 12 months after the initial invitation, with consideration for its potential impact on uptake.This study was conducted in the ethnically diverse London Boroughs of Brent and Harrow, where uptake is below the national average. Between September and November 2014, 160 previous non-responders were randomly selected to receive a reminder of the opportunity to self-refer 12 months after their initial invitation. The reminder included instructions on how to book an appointment, and provided options for the time and day of the appointment and the gender of the endoscopist performing the test. To address barriers to screening, the reminder was sent with a brief locally tailored information leaflet designed specifically for this study. Participants not responding within 4 weeks were sent a follow-up reminder, after which there was no further intervention. Self-referral rates were measured 8 weeks after the delivery of the follow-up reminder and accepted as final.n=5), 30 (19.4%) self-referred for an appointment, of which 24 (15.5%) attended and were successfully screened. Attendance rates differed by gender, with significantly more women attending an appointment than men , but not by area (Brent vs Harrow) or area-level deprivation. Of the 30 people who self-referred for an appointment, 27 (90%) indicated a preference for a same-sex practitioner, whereas three (10%) gave no preference. Preference for a same-sex practitioner was higher among women than men , with only 67% of men (six of nine) requesting a same-sex practitioner, compared with 100% of women (n=21).Of the 155 participants who received the 12 months' reminder (returned to sender, Sending previous non-responders a 12 months' reminder letter with a brief information leaflet is a feasible and efficacious intervention, which merits further investigation in a randomised controlled trial. Colorectal cancer (CRC) is the fourth most common cancer in the United Kingdom and the second leading cause of cancer deaths , 2015b. A recent appraisal of the options for CRC screening in England highlighted that a combination of ‘once-only' flexible sigmoidoscopy (FS) at the age of 55, delivered in conjunction with the current biennial faecal occult blood-testing strategy offered to 60–74-year olds, would be highly cost-effective, and would provide significant reductions the incidence, mortality and treatment costs associated with the disease .As with all screening programmes, the extent to which the cost and public health benefits of including BSS are realised will depend largely on uptake ; worry about pain, discomfort, or injury associated with the examination; and not wanting to know about any health issues e.g., . For womSimilar to other screening programmes, the BSS programme structure incorporates specific strategies to maximise uptake  . A review of the methods and invitation process employed was included in order to help refine the strategy in any subsequent RCT.We performed a single-centre feasibility study at St. Mark's Hospital in London. St. Mark's Hospital serves an ethnically diverse population with a high level of socioeconomic deprivation; the majority (56%) of people invited to take part in screening at St. Mark's during the first 14 months were living within either the most deprived areas in England , or the most ethnically diverse areas  and, in total, only 40.5% of invitees attended an appointment, which was significantly less than the national average (43.5%)  gave us acceptable levels for power (β>0.8) and significance (α<0.05) to test for a minimum level of efficacy, with the unacceptable response rate based on the self-referral rate of non-responders of the previous year , and the desired response rate based on a 5% improvement .To explore the feasibility of including a 12 months' reminder in the routine operations of the centre, we set out to run the study for a minimum of 10 weeks, with 16 previous non-responders sent a reminder per week, giving a total sample size of 160 participants. The sample size also allowed us to test for a minimum level of efficacy within the intervention arm, to check whether investigation in a RCT was merited (minimum number of self-referred appointments needed=3), as well as obtain estimates to inform the statistical parameters required to design such a study (which would be powered to confirm the efficacy of the intervention via a direct comparison with a control arm). The A'Hern single-stage design, which is commonly used in smaller studies with such aims , confirmn=844) were identified on the National Bowel Cancer Screening System (BCSS): an electronic system which provides an up-to-date record of individual-uptake data for patients enrolled in the national screening programme. For a period of 10 weeks (September 2014 to November 2014), 16 people per week were randomly selected for inclusion in the study from a variable weekly total of non-responders using simple computerised pseudo-random selection methods  see . ParticiFor those participants who made an appointment, a confirmation letter and BSS consent form was sent to their home address. The BSS consent form and confirmation letter used in this study were the same as those used for routine appointments in the national screening programme. Participants were asked to read the BSS consent form, which contained information regarding the risks and benefits of the procedure, before attending their appointment, and to call the screening centre if they had any questions. Participants were asked to bring the BSS consent form to their appointment, where a specialist screening practitioner/endoscopy nurse would discuss the risks of the procedure with the individual to ensure an informed decision to be screened was made.The study was approved by the South Central Oxford B Research Ethics Service (Ref: 14/SC/1246).n=5; three female, two male). The semi-structured telephone interviews were conducted with previously screened adults to learn more about the key factors which influenced the decision to be screened. Statements from the interviews were then selected for use in the leaflet, with permission from interviewees. Initial designs of the reminder letter and leaflet were developed by Resonant and then tested in a co-design workshop, facilitated by the company, in which screening eligible adults from the London Boroughs of Brent and Harrow  gave feedback to inform future iterations. A revised version was then presented to individuals who were either the eligible age or approaching the eligible age for screening  and feedback obtained through interviews conducted by a member of the UCL Research Team. The final leaflet  invited participants to make a screening appointment by returning an ‘appointment–request slip' or by calling the Freephone telephone number for St. Mark's Bowel Cancer Screening Centre; (2) reminded participants that they had previously been invited for an appointment 1 year earlier and were eligible to make an appointment up until their 60th birthday; (3) gave participants the opportunity to select a preference for the day and time of the appointment and the gender of the practitioner performing the test and; (4) highlighted three key messages: i) that the risk of developing bowel cancer is highest in the patients' age group (55+ years), ii) screening is for people who do not have any signs or symptoms of bowel cancer and iii) screening can help prevent bowel cancer by removing small asymptomatic growths , which have the potential to become malignant over time see .The development of the leaflet was guided by two psychological models of health behaviour that have previously been used to explain individual level factors associated with screening   and SociA follow-up reminder letter was sent to individuals not responding to the 12 months' reminder within 4 weeks. This follow-up reminder repeated the information included in the 12 months' reminder, but also highlighted individuals had recently received a reminder letter see .Routinely available data stored on the BCSS were used to verify self-referral and attendance 4 weeks following the distribution of the 12 months' reminder, and 8 weeks following the distribution of the follow-up reminder. The BCSS was also consulted to obtain the gender, area (Harrow or Brent) and an area-based socioeconomic deprivation score for each participant. Ethnicity is not routinely collected or available on the BCSS, and so this information could not be extracted.Socioeconomic deprivation was obtained by converting each individual's postcode to a score on the 2010 Index of Multiple Deprivation (IMD) . The IMDX2-test of independence  were randomly selected to receive a 12 months' self-referral reminder; however, five (3.1%) reminders were found to be undeliverable and were ‘returned to sender'. Subsequently, 155 people  were monitored as part of this study . VariatiA total of 30 (19.4%) adults self-referred for BSS. Of these, 24 (80%) attended their appointment and were screened, 3 (10%) did not attend, 2 cancelled and 1 did attend but was not screened owing to high blood pressure . The oven=21 (20.7%) vs n=9 (8.8%), respectively; OR=2.73, 95% CI=1.02–7.35, P=0.05). There were no statistically significant differences between localities (Brent vs Harrow) or tertiles of area-level deprivation .Of the 30 people who self-referred for a BSS appointment, 28 (93.3%) did so by returning the ‘appointment–request slip' the remaining two (6.7%) did so by calling the provided Freephone telephone number.A total of 21 people (13.5%) responded to the self-referral reminder within 4 weeks. Subsequently, 134 follow-up reminders were sent with a further nine (6.7%) responses received within the remaining 8-week response period. No responses were received beyond the 12-week cut-off period.Of the 30 people who self-referred for a BSS appointment, 24 (80%) expressed a preference for a specific day and/or time. It was not possible to accommodate preferences for 12 people (50%); only one went on to cancel.vs 67% χ2=7.78, P<0.05).Of the 30 people who self-referred for a BSS appointment, 27 (90%) indicated a preference for a same-sex practitioner; none (0%) indicated a preference for a practitioner of the opposite sex; and three (10%) gave no preference. It was not possible to accommodate the preference of eight (30%) people; however, no-one asked to be rescheduled. Preferences for the sex of the practitioner were examined by gender: women were significantly more likely to request a same-sex practitioner than men, with all of the women who self-referred for an appointment requesting a same-sex practitioner, compared with two-thirds of men . The self-referral rate for individuals not sent a 12 months' reminder during the study period was higher than anticipated (1.2% vs 0.35%); however, our results would have exceeded the minimum level of efficacy even assuming this higher rate  by the proportion of adults attending screening in response to the 12 months' reminder (0.15)). This would increase overall uptake at St. Mark's to almost 50%. If similar rates are observed in a multicentre study, the implementation of a 12 months' reminder in the national programme could have considerable public health benefits  and may not be representative of the proportions of men and women who would request a same-sex practitioner in the general population. For instance, the current study was set in an ethnically diverse area and so the impact of the gender preference option may have been all the more apparent here, as previous research has found the gender of the endoscopist to be a pertinent barrier for black and ethnic minority women , and so without the appropriate control groups the contribution of each factor to the success of the reminder could not be teased apart. The next step would be to perform a RCT testing each of these components with appropriate controls.One potential concern regarding the leaflet used in this study is that information within was not balanced. It was specifically designed to promote uptake by addressing the barriers and highlighting the benefits associated with the test. However, as the leaflet supplemented the existing information , the requirements of consent when making a screening decision were still met in accordance with the General Medical Council guidelines . NonetheAt last, it is important to note that in the UK, one in six people have a reading level below that expected of an 11-year old (This study found that a locally tailored information leaflet and mailed reminder letter, with options for the day and time of the appointment and the gender of the practitioner performing the test, was feasible, efficacious and exceeded a minimum level of efficacy needed to merit further investigation in a RCT.


For the selection of relevant information out of a continuous stream of information, which is a common definition of attention, two core mechanisms are assumed: a competition-based comparison of the neuronal activity in sensory areas and the top-down modulation of this competition by frontal executive control functions. Those control functions are thought to bias the processing of information toward the intended goals. Acute stress is thought to impair these frontal functions through the release of cortisol. In the present study, subjects had to detect a luminance change of a stimulus and ignore more salient but task irrelevant orientation changes. Before the execution of this task, subjects underwent a socially evaluated cold pressor test (SECPT) or a non-stressful control situation. The SECPT revealed reliable stress response with a significant increase of cortisol and alpha-amylase. Stressed subjects showed higher error rates than controls, particularly in conditions which require top-down control processing to bias the less salient target feature against the more salient and spatially separated distracter. By means of the EEG, subjects who got stressed showed a reduced allocation to the relevant luminance change apparent in a modulation of the N1pc. The following N2pc, which reflects a re-allocation of attentional resources, supports the error pattern. There was only an N2pc in conditions, which required to bias the less salient luminance change. Moreover, this N2pc was decreased as a consequence of the induced stress. These results allow the conclusion that acute stress impairs the intention-based attentional allocation and enhances the stimulus-driven selection, leading to a strong distractibility during attentional information selection. Every day we get besieged with information of our environment and we are not able to process and respond to all information at once. Attention is one of the most important cognitive functions to deal with this problem. By selecting the most conspicuous or relevant information it helps us to achieve our current behavioral goals.According to the biased competition account of attentional selection  or magneto encephalography  is thought to be a key structure for regulating attention, thought and action  and an increase in response errors when distracting stimuli are present. The attentional conflict should also go along with an increased N1pc toward distracting stimuli and the absence of the following N2pc as an index of post-selective target processing.SD = 4.43 years). They were all in good physical health, medication-free, normally weighted , non-smokers, right-handed and with normal or corrected-to-normal vision. Only men were included to avoid possible gender and ovarian cycle effects on adrenocortical reactivity  were exposed to the Socially Evaluated Cold Pressor Test  submerged their right or left forearm, excluding the hand, for 3 min in warm water (35–37°C); they were neither video-taped nor monitored by the experimenter.In the warm water control condition, participants . Immediately after the SECPT subjective stress ratings were collected using a visual analog scale (VAS) to validate the efficacy of the SECPT. Therefore, participants rated on an 11-point scale ranging from 0  to 10 (“very much”) how painful the previous situation had been.Both groups were comparable in the time they kept their hands in the water (Control: 2), and could be oriented horizontally or vertically, were presented left and right from a fixation cross .During the task, all participants were seated in a comfortable armchair inside a dimly lit, sound attenuated and electrically shielded room in front of a 20″ computer monitor (Mitsubishi—DiamondPro 2070SB), that subtended 14.03 × 18.65° at the viewing distance of 120 cm.To avoid any influence of the circadian profiles of adrenocortical reactivity and cognitive ability, all measurements were conducted in the afternoon (starting between 14:00 and 15:00 p.m.). After a participant's arrival, pre-experimental saliva  measurements were taken. Then, participants were exposed either to the SECPT or to the warm water control condition. Immediately thereafter, subjective assessments of the previous situation were measured again. Twenty min after the SECPT/control treatment  and after the experimental session, saliva  measurements were taken again. All subjects performed these SECPT/control procedure three times . Salivary free cortisol and sAA levels were obtained using a chemiluminescence immunoassay  as described in detail by Dressendorfer et al. . SamplesResponse times (RTs) were measured from the onset of the second frame until the button press. Pressing the button too quickly (< 80 ms) was defined as a premature response error. Further substantial response errors could be wrong button presses, false alarms in the no-go condition, and misses (no response within 1500 ms). All error trials were excluded from response time and EEG analyses. Global accuracy was tested in an ANOVA with the repeated-measurement factor Type of change , and the between-subject factor Group (stress vs. control). RT analysis was restricted to correct responses in those conditions in which subjects had to respond. Thus, this analysis consisted of only three types of change  for the two groups (stress and control).The electroencephalogram (EEG) was recorded with a QuickAmp  DC-amplifier set at 200 Hz low pass filtering from 45 scalp positions according to the extended 10/20 System  were defined for further processing. Baseline was set to 200 ms preceding the first frame. These selected segments were checked offline for artifacts . Trials with horizontal eye movements (saccades) preceding the latency of the components of interest (up to 400 ms after the change) were excluded by manual inspection. The influences of remaining eye movements  on electrocortical activity were corrected by the algorithm proposed by Gratton and co-workers  and the between-subject factor Group .Further analysis included only trials with correct responses. Due to the fast sequence of the two frames, ERP responses of the two stimuli, in particular sensory components did largely overlap. Thus, to address visuo-spatial processing, posterior (PO7/PO8) event-related asymmetries of the EEG were calculated  like a lateralized readiness potential is computed  but were restricted to the fronto-central site FCz. There, an enhanced negative going ERP appeared that was maximal if participants got stressed. Since there were no distinct peaks, N2 and P3a were measured as the mean amplitude between 170 and 220 ms (N2), 250 and 300 ms (P3a).p-values, (uncorrected) degrees of freedom, and the Greenhouse–Geisser estimate  are reported. Planned comparisons were computed as follow-up tests to break down the omnibus ANOVA effects. Any additional post-hoc analyses are described in the text below.In case of a violation of the assumption of sphericity for analyses with more than one degree of freedom data were Greenhouse-Geisser corrected , electrophysiological activity of the PFC  or posterior attention-related components (N1pc and N2pc) correlations were calculated for each Type of change  using delta increases for the neuroendocrine measures (post treatment minus baseline). For the cortisol- and sAA-level delta increases were defined as the mean concentration on the +3 min , +20 min  and +35 min  measurement minus baseline. Because one participant of the stress group showed high absolute as well as high relative cortisol levels, we only report and graphically present those correlations, which were still significant when excluding him. Due to the small sample size and the different scales of the measures that were entered into the analysis, Spearman's Rho (ρ) with one-tailed significance level is reported. For the sake of perspicuity, only significant effects are reported.F = 61.94, p < 0.001].Participants' subjective ratings and cortisol changes indicated that stress was successfully induced by the SECPT. By means of the VAS participants of the SECPT group rated the forearm immersion as significantly more painful (5.67) than participants in the warm water control group , the interaction Time by Group  indicates that only stressed participants show an increase in cortisol levels for every experimental session .While both groups did not differ in the baseline cortisol measurement  = 4.538, p = 0.016; see Figure Although alpha-amylase data revealed a large variance, particularly for the stress group, the stress induction went along with a fast increase in alpha-amylase, which is quantified by the interaction of the factors Group by Time  and the conflict condition LOB , but not for orientation changes  and for trials with unilateral changes of both features .Additionally, stress led to increased error rates (24.25 %) compared to the warm water control condition  a significant trend in form of a cubic contrast indicates that the stress effect was most pronounced for the conflict condition (LOB) in which stressed participants committed 17.84% more errors than the warm water control group .Although there was no significant interaction between the Type of change and Group .It is also worth mentioning that response errors made by the stress group include a very large portion of misses (19.55 %) compared to the control group , further pairwise comparisons showed that all unilateral conditions revealed a reduced N1pc for the stressed group  except orientation changes . In contrast to that, in conflict trials stressed participant show an enhanced N1pc toward the irrelevant orientation change .Additionally this early asymmetry, which is thought to reflect a first orientation of attention, was modulated by the stress manipulation, t(11) > 2.89, all p's < 0.015], the other conditions LOU and ORI showed no reliable N2pc at all . Furthermore, a significant group effect can only be shown for those conditions in which an N2pc was evident (LUM and LOB). This is supported by the interaction of Group by Type of change . Post-hoc pairwise comparisons show that the stress group show a reduced N2pc response for unilateral luminance changes  and for the conflict condition  but not for the remaining two conditions LOU and ORI .Around 300 ms a phasic N2 was visible contralateral to the position of the attended luminance change. While for the conditions with a spatially separated change in luminance (LUM and LOB) this N2pc differed reliably from zero  compared to the control group. Post-hoc pairwise comparisons show, that this group difference was evident for all conditions .In the early time window of the N2 (170–220 ms) stressed participants show an enhanced negativity .While for stressed participants further EEG progression reveal no distinct ERP components that differ reliably from zero, 250–300 ms after the second stimulus display control subjects show a large P3a-like positivity [N = 23, all p's < 0.041, see Figure Across all subjects, correlations with the fronto-central brain activity underline the negative effects of stress on cognitive control functioning. At all measurement time points  increases in salivary cortisol went along with an increased fronto-central N2 for all Types of change . As obvious from Figure N = 12, all p's > 0.10). For all Types of change an additional correlation between stress-induced salivary cortisol levels and the P3 amplitude at all measurement time points was evident . The higher the cortisol levels, the smaller the P3 amplitude. When calculating correlations for the two experimental groups separately, a significant interrelation was only evident for stressed participants .Restricting the analysis to stressed participants, this correlation got even stronger . The following N2pc, which can be seen as an index for the expression of top-down control, was significantly correlated to salivary cortisol levels in trials with orientation changes. This interrelation was evident +3, +20, and +35 min after the stress induction  but not in the warm water control group .Twenty min after the stressor a relation between cortisol levels and the initial allocation of attention, by means of the N1pc, was evident for the conflict condition only .Although levels of salivary alpha-amylase were not related to the behavioral performance or fronto-central brain activity, immediately after the stress induction (+3 min) it correlated with the N2pc amplitude in trials where a unilateral luminance or orientation change had to be detected  seems to be unlikely. On the contrary, the findings rather point toward a specific effect of acute stress on task performance. Stressed individuals seemed to display a mis-weighting of the relevant feature that had to be detected. The fact that increased error rates for the stress group included a very large portion of response misses even emphasize a lack of top-down controlled selection bias toward the less salient target feature (the luminance of a bar).This result fits with the fundamental principles of competitive interactions that the enhancement of one stimulus occurs at the expense of other stimuli in the display  the N1pc was even enhanced but contralateral to irrelevant orientation change. Thus, the data pattern suggests that the initial attentional orientation toward the relevant feature, the luminance, was weakened by the stressor. Moreover, the data suppose that in case of a spatial attentional conflict the stress group even amplified and concentrated on the irrelevant feature, the orientation changes.The results of Shackman et al.  show an Regarding the fact that attention had not been initially allocated to the relevant change, based on activation in the N1 time window, a subsequent top-down bias in favor of the target should be required for successful target change detection  seem to be rather complex, stress can be directly linked to frontal lobe functioning. By that increased cortisol levels went along with an overall enhanced fronto-central N2 as well as a reduction/lack of a P3a.Animal studies show dissociations between psychosocial  and physiological  effects of stress (Gesing et al., In conclusion, indicated by the N1pc, situations of acute stress led to a mis-weighting of the relevant stimulus feature so that irrelevant but very salient orientation changes dominated the initial processing stage. A subsequent top-down bias toward the luminance target in the form of an N2pc was required for successful change detection. However, this top-down controlled re-allocation of attentional resources was decreased or even absent in conditions of stress. The present study additionally shows a direct interrelation between stress-related cortisol levels and PFC functioning. Although enhanced early fronto-central brain activity suggests that stressed participants show an increased effort to solve the task, this did not have any impact on the task performance and further progression of the ERP did not reveal any differentiated task processing. Thus, stressed participants were not able to maintain the intentional control to bias the competition toward the less salient but relevant target feature, which resulted in increased response errors, particularly when the spatial attentional conflict was high.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.


SM to evaluate the proportion of rotavirus vaccinated infants who completed the 3 dose series of RV5. We evaluated potential error introduced by restricting analyses to infants with complete follow-up by estimating completion rates among infants with complete follow-up, and using Kaplan-Meier analyses to estimate completion rates including infants with incomplete follow-up.RotaTeq® pentavalent human rotavirus vaccine (RV5) is effective against rotavirus illness and rotavirus-related hospitalizations and death. Effectiveness depends on adherence to the dosing schedule, which includes 3 doses at ages 2, 4 and 6 months. Two studies have used automated claims databases to estimate the proportion of vaccinated infants who complete the dosing schedule, but excluded from analysis vaccinated infants who were not enrolled in the database for a sufficient period to observe all 3 doses. Restricting study populations based on duration of follow-up can introduce bias if a large number of subjects are excluded due to insufficient follow-up, and if their outcomes differ from subjects who are included. To address the possibility that exclusions may have been extensive and led to biased estimates of completion rates, we conducted a claims database analysis in the HealthCore Integrated Research DatabaseThe inclusion criterion requiring continuous enrollment for the first year of life resulted in only 108,533 (40%) of 233,143 vaccinated infants from 2006–2012 being included in the analysis. After relaxing inclusion criteria, we were able to include 86% of vaccinated infants. The estimated completion rate among infants with continuous enrollment from birth through the first year of life was 78.1% , and among the expanded population the estimated completion rate was 77.4% .These results indicate that most infants were not followed in the database through the first year of life, but the impact of excluding infants with incomplete follow-up was negligible when assessing RV5 completion rates for this commercially insured population. Nonetheless, to increase the size of study populations and reduce the potential for bias, it is preferable to include subjects with incomplete follow-up in automated database analyses, and adopt more robust approaches to defining and analyzing study populations that account for missing data. Rotavirus is a common cause of severe gastroenteritis among infants. There are two live rotavirus oral vaccines marketed in the US, RV5  approved in 2006, and RV1  approved in 2008 [Two automated database studies used commercial insurance claims and estimated the proportion of rotavirus vaccinated infants completing all 3 doses of RV5 as 79% and 83% ,3. BecauRestricting study populations based on duration of follow-up can introduce bias if a large number of subjects are excluded due to insufficient follow-up, and if their outcomes differ from subjects who are included ,5. NeithSM (HIRD). The HIRD is an automated database comprising medical and pharmacy insurance claims data from approximately 38 million health plan members across the United States. Member enrollment, medical care , outpatient prescription drug use, outpatient laboratory test result data, and health care utilization are tracked longitudinally for health plan members in the database since January 2006.We conducted a retrospective study using the HealthCore Integrated Research DatabaseWe identified all infants who received at least 1 dose of RV5 during the first year of life between February 1, 2006 and November 30, 2012. For the initial cohort extraction, we did not require any continuous period of enrollment or that first enrollment occur by any specific age; instead, we included any infant who had at least 1 dose of RV5 between birth date and first birthday to identify as completely as possible all vaccinated infants. Exposure to RV5 was identified using medical claims with Current Procedural Terminology (CPT) code 90680. For all infants identified, information was collected on dates of all RV5 vaccinations, geographic region of residence, and insurance coverage information.To evaluate completion, we first identified infants with complete follow-up . Among the cohort of infants having received at least 1 dose of RV5 in the first year of life, we identified infants who were continuously enrolled in the health plan from birth through their first birthday.To include infants with incomplete follow-up, we sought to identify infants for whom the first dose of RV5 recorded in the database was in fact the first dose of RV5. We examined RV5 doses administered by infant age to examine age ranges during which different doses occurred. To exclude as few infants as possible, we determined the latest age for which we could be confident that no vaccination would have been given earlier, so that the next vaccination received would be the first dose. We then followed these infants for RV5 vaccination as long as they remained in the database.Among infants with complete follow-up through the first year of life, we computed completion rates as the proportion of vaccinated infants receiving all 3 doses (Cohort A). Among infants who terminated health plan enrollment during the first year of life, and for whom we could determine the first dose, we computed completion rates using Kaplan-Meier analyses with right censoring upon the earliest of receipt of the third dose, termination of database enrollment, or end of the follow-up period (Cohort B). To evaluate change over time in completion rates, we stratified results according to calendar periods 2006–08 and 2009–12. The calendar period stratum was assigned according to the date the of the first RV5 dose. Confidence limits (CLs) were computed using the Wald method for binomial data [We identified 272,142 infants in the database having at least 1 dose of RV5 in the first year of life. Among these infants, we identified 108,533 (39.9%) infants who were enrolled continuously from birth through the first year of life , the possible range of completion rates compatible with the data was 31.1% to 91.2%  by estimating the proportion of infants receiving at least 1 dose who went on to receive the complete schedule of 3 doses, and estimated completion rates of 79% and 83% ,3. These by estimWhile restricting analyses to subjects with complete data is discouraged in clinical trials, complete case analysis is a common practice in automated database research. Further, the number of subjects excluded due to missing data often goes unreported, precluding any possibility of assessing the potential bias. The potential for bias would be a concern if a large number of subjects were excluded from analysis. If the proportion of subjects excluded is large, and their outcome rates differ from the outcome rates among those included, then study results would be biased. For instance, if a large proportion of infants were excluded and they were less likely to complete their vaccine schedule, the observed completion rates would be biased upward.In light of these concerns, we used a claims database to address the potential impact of missing data due to incomplete follow-up on estimated completion rates of RV5 vaccination. After identifying the total number of vaccinated infants in the database, we determined that only 40% of infants receiving at least 1 dose of RV5 during the first year of life were continuously enrolled from birth through their first birthday. After including infants who received the first dose but who were not continuously enrolled during the first year of life, we were able to increase the proportion of vaccinated infants included in the analyses from 40% to 86%. Although the size of the population analyzed increased dramatically, the observed RV5 completion rates declined only slightly, from 78.1% to 77.4%. Completion rates varied little over time, suggesting temporal trends are not a major source of variation in completion rates during the study period. These results indicate that the impact of excluding infants with incomplete follow-up in the database was negligible when assessing RV5 completion rates in the insured population. Duration of follow-up in the claims database, therefore, appears to not be strongly related to the likelihood of receiving RV5 vaccination. If study populations across different claims databases used in previous studies were similar, excluding infants with incomplete follow-up in previous studies of RV5 would have had little effect on observed RV5 completion rates. By including in the analysis infants with incomplete follow-up, the range of possible completion rates was reduced by about 50%; nonetheless, the data are compatible with completion rates from 54.5-85.3%, indicating considerable uncertainty about completion rates among these infants after they disenroll from the database. This source of uncertainty due to missing data is not reflected in the conventional confidence limits, which capture only uncertainty due to random variation, and is an order of magnitude larger than random variation. Additional data on vaccination rates among uninsured infants are thus needed to understand the relation between insurance status and vaccination rates.In conclusion, restricting database analyses to infants with complete follow-up appears to give valid estimates of RV5 completion rates for this commercially insured population. Caution is warranted in generalizing beyond the insured population. Nonetheless, it is preferable to include in analyses subjects with incomplete follow-up . In gene