Emergency medicine (EM) in the Netherlands has developed rapidly and initially without central guidance. This has led to heterogeneity in current EM practice. Our aim was to quantify this heterogeneity by answering the following questions: (1) What is the current position of emergency physicians (EPs) within hospital organizations? (2) Which roles and responsibilities do EPs have across emergency departments (EDs)?n = 56) in the Netherlands. Data was analyzed using descriptive statistics.During 2018, we conducted a survey among all EM consultant bodies , procedural sedation and analgesia (PSA), and emergency ultrasound (US) were performed by all EPs in the CB in a range between 5.9 and 78.4%. In 36.9% of EDs, EPs did not analyze patients with presumed cardiac pathology due to a separate We conclude that there is a high degree of heterogeneity between emergency CBs in regard to the position in the hospital and the role or responsibilities in the ED. Lack of uniformity might inhibit emancipation of the profession. In the Netherlands, emergency medicine (EM) as an independent profession started 20 years ago with the foundation of the Dutch Society of Emergency Physicians (DSEP). Before 1999, inexperienced junior doctors staffed most emergency departments (EDs) despite the growing complexity of delivered care. Different stakeholders realized that reorganization of these departments, including training of emergency physicians (EPs), could improve emergency care quality. Consequently, in 2000, the first EM residency programs in the Netherlands started . BesidesWhat is the current position of EPs within hospital organizations?Which roles and responsibilities do EPs have across Dutch EDs?Despite all these efforts, little research has been conducted regarding the current role and responsibilities of Dutch EPs, making it difficult to quantify their effect. One study described which organizational factors influence the position of EPs ; anotherResults can be used to develop future strategies to further develop EM in the Netherlands. In addition, our findings might be useful to EM leaders in countries in an earlier stage of EM development.In the Netherlands, one hospital can incorporate more than one ED and emergency consultants working in these hospitals typically work in all ED locations . Almost n = 74) of EDs were served by EPs through 56 consultant bodies (CBs). The EM residency program was taught in 39.2% (n = 29) of EP-staffed EDs. These programs were taught in both academic and non-academic hospitals. Academic hospitals are allied with Dutch universities  and deliver more tertiary care. The Netherlands count 8 academic hospitals of which 6 employ EPs. These 6 accounted for 8.1% of EP-staffed EDs and all offered EM residency programs. Non-academic hospitals accounted for 91.9% (n = 68) of EP-staffed EDs, and 33.8% (n = 23) of them offered EM residency programs [At the time of inclusion, 85.1%  in the first quarter of 2018 using SurveyMonkey. All EM CBs working in Dutch EDs were included, regardless of size. We did not have any exclusion criteria. For every CB, one EP was invited to answer on behalf of the CB. Respondents working in multiple locations could, for relevant questions, give separate answers for different locations.The survey was designed by the researchers because no applicable survey existed. It aimed to capture the areas where we expected the highest variation in job profile, responsibilities, and autonomy. The questions posed can be broadly divided into three categories: baseline data, questions regarding the position within the organization, and questions regarding the role of the EP in the ED  version 24. Questions were appropriately grouped per CB or ED.The response rate was 91.1% of CBs, which included 87.7% of all EP-staffed EDs. However, there was some missing data (range 0.0–55.4%) in most questions. The 51 participating CBs consisted of 443 EPs. Together, these EPs covered 379.0 full-time equivalents (fte) of 36 h/week (see Table n = 49) of EDs, while in 15.4% (n = 10), this was no EP. Missing data was 9.2% (n = 6). Most CBs were employed directly by the hospital , while 5.9% (n = 3) was employed through other medical specialists, and missing data was 7.8% (n = 4). Employment conditions were similar to those for other medical specialists on payroll for 37.3% (n = 19) of CBs, while 54.9% (n = 28) were hired under different conditions, and missing data was 7.8% (n = 4). A local document describing the responsibilities of EPs and other medical specialists regarding ED patients was present for 43.1% (n = 22) of CBs. This document was absent in 31.4% (n = 16), it was present but did not mention EPs in 3.9% (n = 2), and missing data was 21.6% (n = 11). EPs were the main consultant for all ED patients in 9.8% of CBs (n = 5), despite EM not having been recognized as a specialty on a national level. On the contrary, in 13.7% (n = 7) of CBs, EPs could not be the main consultant just because EM is not yet an official medical specialty. In several CBs , EPs could be the main consultants, but were limited to certain patient groups. These limits were related to referral status in 15.7% (n = 8) of CBs, to which resident  analyzes the patient in 3.9% (n = 2), to specialty in 2.0% (n = 1), or to disease in 2.0% (n = 1) and 11.8% (n = 6) remained unspecified. Missing data was 43.1% (n = 22).The medical director of the department was an EP in 75.4% (n = 45) of CBs were full members, 3.9% (n = 2) was not represented at all, and missing data was 7.8% (n = 4). There were several hospital-wide committees in which CBs were represented (see Table n = 15) of EDs; 4.6% of EDs (n = 3) had their previous 24/7 presence disrupted due to personnel problems. Coverage was highest during day shift on weekdays, when in 72.3% of EDs (n = 47), an EP was always present; in 3.1% of EDs (n = 2), an EP was sometimes present; and missing data was 24.6% (n = 16). Coverage was lowest during night shifts on weekdays, when in 23.1% of EDs (n = 15), an EP was always present, sometimes present in 6.2% (n = 4), never present in 46.2% of EDs (n = 30), and missing data was 24.6% (n = 16)  of CBs had the authority to instruct emergency medical services (EMS) to deviate to other hospitals. 5.9% of CBs (n = 3) did not have this authority, and 11.8% of CBs (n = 6) had the authority to suggest this measure, but it was executed by others. Missing data was 13.8% (n = 7), and rerouting of EMS did not occur in 9.8% of CBs (n = 5), for example, in remote areas.Of the in-hospital staff federation, which represents the interests of medical specialists on board level, 88.2% (n = 49), and missing data was 24.6% (n = 16). Referred patients were analyzed by EPs in 73.9% (n = 48) of EDs, EPs do not analyze referred patients in one ED (1.5%), and missing data was similar at 24.6% (n = 16). Within the referred patients subgroup, EPs analyzed patients for all specialties in 26.2% (n = 17) of EDs; however, specialty-bound limits for EPs to analyze these patients were present in 47.7% of EDs (n = 31). Missing data was 29.2% (n = 19) , time of day in 3.1% (n = 2), and which specific illness was suspected in 3.1% (n = 2) of EDs.Respondents were asked about the local division of workload based on referral status. Self-referred patients were analyzed by EPs in 75.4% of EDs , in which patients with presumed cardiac pathology are analyzed, was present in 49.2% of EDs (n = 32). Patients were treated solely by cardiology in 75.0% of these units (n = 24), while 25.0% (n = 8) were run as a cooperation between cardiologists and EPs. There was no EHH in 36.9% of EDs (n = 24), and missing data was 13.8% (n = 9).A separate Which procedures were performed by all consultants of the CB is detailed in Table n = 51), general practitioners (GPs) in training in 80.0% (n = 52), and junior doctors of other specialties in 41.5% (n = 27). Missing data was 21.5%, 20.0%, and 58.5%, respectively. CBs also mentioned supervising medical interns, military doctors in training, physician assistants, and nurse practitioners.EPs supervise EM junior doctors in 78.5% of EDs (n = 7) of EDs; this was 9.2% (n = 6) for the intensive care unit (ICU). In-hospital tasks remained unspecified for 7.7% of EDs (n = 5), there were no in-hospital tasks for 15.4% (n = 10), and missing data was 55.4% (n = 36). EPs are part of the medical emergency team (MET) in 21.5% (n = 14) of EDs.In-hospital tasks for EPs included care on the wards outside office hours for 10.7% . Heterogeneous training of EPs, variation in task allocation , and differences in standards of care  all contribute to this heterogeneity. A common foundation in the skillset of EPs and professional standardization are prerequisites to further professionalize emergency medicine in the Netherlands.EHH run solely by cardiologists is another cause of heterogeneity. It is of concern to see that in 36.9% of EDs, EPs have no role in analyzing and treating patients in the EHH, which hampers exposure to cardiac pathology. This creates disparities between EPs within the Netherlands as well as when comparing Dutch EPs to their international counterparts, for whom the management of acute cardiac disease is everyday business. No specific strategies have been employed to ensure adequate exposure to cardiac pathology for all EPs, but the issue is addressed to some extent by the DSEP postgraduate training programs which include cardiac care.The presence or absence of an The last cause of heterogeneity we would like to mention is supervision of junior doctors. Although supervision of EM junior doctors and GPs in training is a common task, this clearly contrasts with the infrequent supervision of junior doctors of other specialties. This has two potential negative effects. Firstly, it could lead to fragmented care in the ED, with patients receiving different care depending on which resident analyzes them. Secondly, differences in supervision make it more difficult to establish a uniform EP role model for future EPs and upcoming medical specialists.Previous research has shown that development of the EP role is influenced by institutional policies and the role EPs allocate themselves as well as legislation, training programs, support of medical managers, and hospital culture . Our stuStrengths of the study include the very high response rate and the novelty of this data, as there are no previous studies in this specific area. Limitations include the response rate per question, which was considerably lower than the overall response rate. This was possible because most questions were non-obligatory, which was a deliberate policy; we worked under the assumption that we would gain more generalizable data due to a higher overall response rate.A second limitation is that there was no validated questionnaire available and we have not validated our self-designed survey. Developing our own allowed us to inquest our specific interest, but might have left room for misinterpretation. It would have been of great interest to study perceived barriers in advancing EM using open questions, but that was beyond the scope of this study.We conclude that there is a high degree of heterogeneity between emergency consultant bodies across the Netherlands, both in regard to position in the hospital and responsibilities in the ED. Lack of uniformity might inhibit emancipation of the emergency medicine discipline. The way forward is to create more homogeneity by training both EPs and residents in a more uniform manner, developing standards of care, and recognition of EM as an independent specialty.Additional file 1. Complete survey (Dutch).Additional file 2. Baseline data frequency tables.Additional file 3. EP presence per shift.Additional file 4. Referred patients analyzed by EPs per specialty.


Metacognition, therefore, bears conceptual similarity with executive function: both are concerned with top-down monitoring and control of cognition in the service of ongoing goal-directed behaviour. Previous studies have shown a possible executive function advantage in multilingual speakers but also a possible disadvantage in metacognitive processing. To progress theory on metacognitive processing and the relationship with executive function and linguistic experience across the lifespan, we conducted a study testing 330 healthy individuals in four age groups from 7 to 80 years old. All participants performed a metacognition task and two measures of executive function, which included the Simon task and the Tower of London task. Half the participants were multilingual speakers since birth. We built developmental trajectories of metacognitive and executive function across the lifespan. The best metacognitive efficiency was observed in mid-adulthood, whereas the best executive function processing reached its peak in young adulthood. A steep cognitive decline was observed in older age, while metacognitive efficiency was preserved. Exploratory factor analysis indicated that metacognition and executive function are served by different factors across all ages. Contrary to previous findings in the bilingual literature, a multilinguistic experience conferred neither any significant advantage nor disadvantage in both executive function and metacognitive processing across the lifespan.The modern understanding of the term metacognition encompasses two levels of processing: a lower level  The modern understanding of metacognition as encompassing both a relatively passive (knowledge/awareness) function and an active (regulatory/control) function suggests conceptual overlap with mechanisms associated with executive function and cognitive control. In this study, we focus on the relationship between executive function and metacognitive abilities from childhood to older age.metamemory  broaden the focus to consider metacognition and executive function across the lifespan from childhood, through young, middle and older adulthood, (2) explore how the relationship between these abilities changes as a function of age, and (3) determine whether and how linguistic experience modulates the trajectory of these effects.In all, 330 typically developing individuals took part in this study. Their age ranged from 7 to 80 years. Half of them were English monolinguals and the other half were bilinguals/multilinguals of different linguistic backgrounds. They were split into four age groups : (1) chi1  learnt at school, but were not exposed to or used a foreign language in their daily life, nor had the ability to hold a basic conversation in a language other than English.no formal/primary, 2 = secondary, 3 = undergraduate, 4 = post-graduate, 5 = doctorate). They also received a score from 1 to 4 depending on occupation , and a score from 1 to 6 depending on total household income . Scores were averaged to create a composite SES score.All participants also provided socioeconomic status (SES) information indicating their highest level of education, employment, and household income. Each of the adult participants received a score depending on level of academic achievement , and was conducted in accordance with the tenets of the Declaration of Helsinki.® USB gamepad that was adapted with red and blue coloured stickers. All instructions were given in English.The experimental battery was conducted on an ASUS laptop with a mouse, standard keyboard, and a TechnoproAdult participants were tested in a quiet room made available at Anglia Ruskin University in Cambridge and at UCL–Institute of Education in London. Child participants were tested in three primary schools, two in London and one in the Cambridge area. All children gave their verbal consent before starting the session.Participants were all assessed on a range of background measures:The Raven’s Advanced Progressive Matrices Set I  was admiThe 30-digit sequences from the digit span forwards (DSF) and digit span backwards (DSB) subtest of the Wechsler Adult Intelligence Scale–Fourth Edition WAIS-IV;  were useThe British Picture Vocabulary Scale: Third edition  is described in the “Results” section.less to more confident using the left/right cursor keys to move the pointer and the down cursor key to submit their response. Then a new trial proceeded immediately. The perceptual decision task was response terminated but time limited, failure to respond within 1,500 ms resulted in a screen stating “Too slow” appearing for 750 ms and then a new trial was presented. Response time for the confidence judgement was unlimited.Following a training phase (described below), participants completed 10 practice experimental trials and four blocks of 25 experimental trials. For each experimental trial, participants were first presented with the perceptual decision making phase where they were required to make a quick choice as to whether the circle on the left or right contained more dots, pressing the corresponding left/right cursor keys on the keyboard. One circle always contained 50 randomly located dots and the other circle would contain either fewer or more dots. Two successive correct responses resulted in the next trial being more difficult (one less dot difference); one incorrect response resulted in the task getting easier . The training phrase calibrated a participant’s difficulty level in the experimental phase. In the first trial of the training phase, there was a 20-item dot difference; a correct decision resulted in the dot difference decreasing by four and in subsequent correct trials the difference gradually decreased to one dot difference; incorrect decisions increased the dot difference. Therefore, more difficult trials were those that had a smaller difference of dots contained in the two circles. The training phase ended after participants had switched between correct and incorrect answers eight times. All training trials were excluded from analyses.The task lasted approximately 12 min.The Simon task  was proghttp://pebl.sf.net), courtesy of The Tower of London task was administered . The tasThe trials consisted of four easy problems requiring 2–3 moves where the strategy of moving the coloured discs to match their target location worked and required minimal planning resources . Four trThis study had both a between-subject and a mixed-design in which first the developmental trajectories of metacognitive processing and executive function were built across age groups (Research Questions 1 and 2) and, subsequently, across both age and linguistic group (Research Question 3). Ability scores were obtained for the background task: BPVS III, Raven’s and Digit span and used as covariates in all comparisons. Accuracy and response time scores were calculated as the executive function tasks. Mratio was computed for metacognitive efficiency.T-tests, ANOVAs, and correlation analyses were performed using SPSS version 25 for Mac. Factor analysis was performed using the “FactorAnalyzer” package with Python .t-tests showed that the age difference between the language groups  was non-significant, t(124) = .12, p = .90. Statistically equivalent age in monolinguals and bilinguals was also confirmed within each age group .Independent t-tests conducted for each age group indicated that English monolinguals and multilinguals were largely comparable across the measures. However, in some cases, measures of English vocabulary knowledge (BPVS), working memory (digit span backward plus forward) and SES  differed significantly. We included these measures as covariates in our initial analyses. However, we conducted further tests to ascertain whether there was a correlation with the experimental measures and whether the covariates and groups were independent. We performed Pearson’s correlation analysis including all background and experimental variables, and linear regression analysis for all age groups separately. We observed overall weak correlations with all measures and the regression showed either no correlation or different directions among groups. We concluded that the independence and homogeneity assumptions were violated and therefore decided not to include the background variables as covariates here. The results of the analyses with covariates are reported in the online Supplementary Material II, Table G.Age-group scores and comparisons on background tests and SES scores between monolingual and multilingual individuals are reported in Note that the children’s SES index is lower than that recorded for the adults. This is due to the fact that two different questionnaires were developed for this study: one for the children (to be completed by their parents) and the other for the adults. The adult questionnaire contained two additional questions: (1) employment status, that is, unemployed, part-time, full-time and retired, and (2) highest level of education, that is, A-level, undergraduate, postgraduate, and doctorate. These questions were not applicable to children and, therefore, excluded.online Supplementary Material III.The results of first-order performance, that is, analysis of response times (measured in seconds), accuracy (measured by percentage of correct responses), and the difficulty of the trials (measured by dot difference) across all age groups and linguistic groups are reported in the https://github.com/smfleming/HMM). The Mratio scores for all age and language groups are reported in To estimate metacognitive efficiency we used the Mratio. An Mratio was fitted to each participant’s data using a hierarchical Bayesian estimation method  = 2.13, p = .096, F = .031, p = .86, F = .14, p = .94, ANOVA showed a trend main effect of age group, M = 1.12) than all the other groups, but the differences between the groups were not statistically significant (p > .10).Overall, better metacognitive performance was observed in mid-adulthood .In sum, metacognitive efficiency expressed by Mratio showed a consistent trend across all ages, with improvement through development, best performance in middle-age, and progressive decline in older age. Linguistic experience did not have any significant effect on metacognitive processing, that is, monolingual and multilingual speakers had comparable performance across all ages. Bayesian independent online Supplementary Material I, Table B and C, and illustrated in Response time and accuracy scores for congruent and incongruent trials in the Simon task are reported in the F = 464.7, p < .001, F = 9.0, p < .001, F = .58, p = .45, F = .22, p = .85, F = 78.47, p < .001, p = .89).For response time, a three-way ANOVA for age groups , language groups  and congruency  revealed a highly significant main effect of congruency overall, p < .001, p = .005 and p < .001, respectively). Performance in mid-adulthood was significantly better than in childhood and in older adulthood . The older adults’ performance was comparable with children’s . In sum, a developmental analysis of response time in the Simon task revealed a peak in best performance with both congruent and incongruent trials in young adults. As expected, performance was worse in childhood and declined in older age. The difference in linguistic experience between individuals in all age groups did not produce any statistically significant effect (p = .85).Bonferroni adjusted pair-wise comparisons  showed tF = 89.64, p < .001, F = 24.64, p < .001, F = .46, p = .50, F = 11.41, p < .001, p = .73, p = .65, p = .87, respectively).The same three-way ANOVA with accuracy scores again revealed a significant main effect of congruency, p < .001), but their performance did not differ from that of mid-adulthood and older participants . The middle-aged adults’ and older adults’ performance compared with childhood were also significantly different . A 2.8% difference in accuracy between mid-adulthood and older adulthood was not significant (p = .43).Bonferroni adjusted pair-wise comparisons  showed tt-tests comparing Simon accuracy and RT across linguistic groups on congruent and incongruent trials conducted separately for each age group indicated that the data were more than three times less likely to occur under the alternative hypothesis than the null hypothesis in all comparisons (BF10 < .34).As observed in the RT analysis above, the difference in linguistic experience between individuals in all age groups for accuracy in both trial conditions did not produce any statistically significant effect. Bayesian independent To summarise, a developmental analysis of accuracy in the Simon task revealed a peak in best performance with both congruent and incongruent trials in young adults. Children had worse performance compared with the other groups, and the difference in linguistic experience between individuals in all age groups did not produce any significant effect.F = 9.0, p < .001, F = .58, p = .45, F = .26, p = .86, t-tests comparing Simon cost across linguistic groups separately for each age group indicated that the data were more than five times less likely to occur under the alternative hypothesis than the null hypothesis in children (BF10 = .17) and more than two times less likely in all adult groups .The response time difference between congruent and incongruent trials (Simon cost) was computed for all participants across all age groups and analysed with an ANOVA. There was a highly significant main effect of age group, p = .001 and p < .001, respectively), but their performance was comparable with mid-adulthood . Performance in mid-adulthood was significantly better than in childhood and in older adulthood . In sum, a developmental analysis of the Simon cost again revealed a peak in best performance in young adults. There were no significant statistical differences among the other age groups . The difference in linguistic experience between individuals in all age groups did not produce any statistically significant effect .Bonferroni adjusted pair-wise comparisons showed that young adults had a smaller Simon cost than children, −27 ms and older adults, −41 ms (moderate (2 and 3 moves) and (2) challenging (4 and 5 moves). The rationale for this division is based on previous findings in bilingual research showing that multilingual speakers outperformed monolinguals only when the task presented an extra level of complexity  ty e.g., , 2015. MF = 271.29, p < .001, F = 2.75, p = .043, The three-way ANOVA for accuracy scores revealed an overall significant main effect of trial complexity, F = .46, p = .50, F = .27, p = .85, The two-way interactions between trial complexity and language group and the three-way interaction between complexity, age group, and language group were all non-significant  = 35.0, p < .001, p = .40 and p = .50, respectively).Tests between subjects showed a significant main effect of age group, p < .001). All other groups had comparable performance (p > .60).Bonferroni corrected pair-wise comparisons  showed tIn sum, a developmental analysis of accuracy in the Tower of London task revealed a comparable performance in all age groups, with the exception of children who performed significantly worse than adults overall.p > .40). Bayesian independent t-tests comparing overall accuracy performance across linguistic groups in each age group indicated that the data were more than five times less likely to occur under the alternative hypothesis than the null hypothesis in the childhood group (BF10 < .19), more than four times less likely in the mid-adulthood (BF10 < .25), more than three times less likely in the mid-adulthood group (BF10 < .32) and more than 1.6 times less likely among the older participants (BF10 < .74).There was no effect of linguistic experience: monolinguals and multilinguals in all age groups had similar performance  = 156.59, p < .001, F = 9.94, p < .001, F = 7.05, p = .008, F = 5.69, p = .001, p > .30).ANOVA for overall mean response time to complete the test showed a significant main effect of task complexity, p < .001) and young adults , but their performance was comparable with the middle-aged group (p = .40). Monolinguals were overall 3.1 s faster than multilinguals in completing the task (p = .008). This difference was particularly evident and statistically significant in young adults for both moderate and challenging trials  = −3.16, p = .002; mean difference = 6.3 s, t(63.1) = −2.70, p = .009, respectively). Bayes factors confirmed that, in young adults, the alternative hypothesis for the linguistic group effect was over 22 times more likely under the alternative hypothesis for overall RT (BF10 = 22.57), a figure far lower for children (BF10 = .26), middle adults (BF10 = .31), and older adults (BF10 = .41).Bonferroni corrected pair-wise comparisons  showed tmoderate and challenging trials. There was an overall significant effect of trial complexity, F = 49.55, p < .001, F = 13.01, p < .001, F = 7.38, p = .007, F = 7.67, p < .001, p > .20).The final ANOVA was carried out on the mean response time taken to plan the first move for both p = .010), middle-adults , and older adults . The other groups’ performance was comparable (p > .10).Bonferroni corrected pair-wise comparisons  showed tt(76) = −2.84, p = .006; mean difference = 6.3 s, t(61.5) = −2.75, p = .008, respectively). Bayesian analysis confirmed this considerable linguistic group effect in young adults, with the alternative hypothesis more than 20 times more likely than the null hypothesis (BF10 = 20.09), an effect absent in the other age groups .Monolinguals were, on average, 2.6 s faster than multilinguals in planning the first move. Consistent with overall RT, the difference was statistically significant in young adults for both moderate and challenging trials  and Kaiser–Meyer–Olkin (KMO = .781) measures verified the sampling adequacy for the analysis. The analysis yielded three factors with eigenvalues higher than 1, explaining a total of 52.65% of the variance for the entire set of variables. Nine variables were factor-analysed across all groups with varimax  rotation. The Bartlett sphericity  from 7 to 80 years old were tested on the same tasks measuring executive function , working memory, fluid intelligence, and metacognition. A second objective was to identify the relationship between metacognition and executive function and consider how this relationship changes across the lifespan. Finally, to address the viability of the bilingual cognitive advantage hypothesis, we determined whether the trajectory of these effects is modulated by participants’ linguistic experience.Our primary objective in this study was to chart the developmental trajectories of performance on measures of metacognitive processing and executive function across the life span. For this purpose, a large sample of healthy individuals  and subsequently rate their level of confidence in their choice. Metacognitive efficiency was computed and expressed by Mratio  and compParticipants’ linguistic experience did not produce any significant effect: both monolingual and multilingual speakers’ trajectories were comparable overall.This result is inconsistent with a study by The Simon task was used to measure executive function across the lifespan. Consistent with previous work  when the demand of the task was less challenging, that is, with trials requiring fewer moves to completion. However, the trajectory was different when the trials placed greater demands on strategic planning. Young adults had best performance and a progressive decline was observed with ageing, especially in the multilingual population, although the difference was not statistically significant. Developmental trajectories of response time revealed a different pattern, in which monolingual speakers in general, and especially in young adulthood, showed significantly faster overall performance in completing the task than multilingual peers in all age groups. This difference was particularly significant when the time to perform the first move was considered. English monolingual young adults demonstrated a faster response time with planning than multilingual peers both for less demanding and more challenging trials. These findings are consistent with a study of 45 young adults by Exploratory factor analysis is a statistical method designed to identify latent factors or constructs that contribute to performance across multiple variables entered into the model. The results presented here clearly indicate that metacognitive efficiency (as measured by Mratio) is independent of the mechanism(s) driving performance on our other tasks. We identified strong correlations between Raven’s matrices, digit span and Tower of London performance, and Factor 1, indicating that a working memory/executive attention construct underpins performance on these tests. Response times for both congruent and incongruent trials on the Simon test loaded strongly on a second factor. The key finding, however, was that our measure of metacognition showed a negligible correlation with Factors 1 and 2 and instead independently loaded on the third extracted factor in our full sample. Over 99% of the variance in our metacognition variable was unique, indicating that virtually zero variance was shared with the other variables in our model. This finding is consistent with studies of confidence judgements on fluid intelligence tasks e.g.,  metacognAcross the tests presented in the current study, comparable levels of performance were observed in monolingual and bilingual groups, and this finding applied in all age groups . The only significant effect favoured monolingual participants, who performed the Tower of London task faster than multilinguals (particularly the case in the younger age groups). However, the level of accuracy was comparable in both linguistic groups and across all ages. The evidence base for the bilingual cognitive advantage  has beenOur findings indicate that metacognitive efficiency and accuracy on measures of executive function show similar, non-linear trajectories across the lifespan, with children performing disproportionately worse than young and middle-aged adults, and older adults showing a marked decline. However, despite these trends, there was no statistical evidence for a relationship between metacognition and our sampled components of executive function  indicating that these broad cognitive abilities may be served by independent cognitive mechanisms. Our findings, based on carefully matched groups of participants, also indicate that bilingualism does not appear to confer advantages either in executive function or metacognition in children (over the age of 6) or adults of any age.Click here for additional data file.Supplemental material, QJE-STD-20-136.R2-Supplementary_Material for Developmental trajectories of metacognitive processing and executive function from childhood to older age by Roberto Filippi, Andrea Ceccolini, Eva Periche-Tomas and Peter Bright in Quarterly Journal of Experimental Psychology


To investigate predictors of postoperative acute intracranial hemorrhage (AIH) and recurrence of chronic subdural hematoma (CSDH) after burr hole drainage.A multicenter retrospective study of patients who underwent burr hole drainage for CSDH between January 2013 and March 2019.A total of 448 CSDH patients were enrolled in the study. CSDH recurrence occurred in 60 patients, with a recurrence rate of 13.4%. The mean time interval between initial burr hole drainage and recurrence was 40.8 ± 28.3 days. Postoperative AIH developed in 23 patients, with an incidence of 5.1%. The mean time interval between initial burr hole drainage and postoperative AIH was 4.7 ± 2.9 days. Bilateral hematoma, hyperdense hematoma and anticoagulant drug use were independent predictors of recurrence in the multiple logistic regression analyses. Preoperative headache was an independent risk factor of postoperative AIH in the multiple logistic regression analyses, however, intraoperative irrigation reduced the incidence of postoperative AIH.This study found that bilateral hematoma, hyperdense hematoma and anticoagulant drug use were independently associated with CSDH recurrence. Clinical presentation of headache was the strongest predictor of postoperative AIH, and intraoperative irrigation decreased the incidence of postoperative AIH. Chronic subdural hematoma (CSDH) is one of the most common types of intracranial hemorrhage; however, its pathogenic mechanism remains unclear. The incidence of CSDH is ~ 3.4–5/100000 per year in the general population and 60–80/100000 per year in those aged ≥65 . SeveralSurgical complications, such as irritability, wound infection and acute intracranial hemorrhage (AIH), occur at a rate of 0–38% –26. AIH,n = 315), and the Department of Neurosurgery of Shanghai Tenth People’s Hospital, Shanghai, China between January 2013 and May 2016 (n = 133). The patients were diagnosed by computed tomography (CT) or magnetic resonance imaging (MRI).We retrospectively analyzed the medical records of all patients diagnosed with CSDH at the Department of Neurosurgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China between September 2015 and March 2019 ; any other intracranial pathologies or intracranial surgery, such as ventriculoperitoneal shunt, epidural hematoma, parenchymal hemorrhage, intraventricular hemorrhage or ischemic insult; and recurrent CSDH.In this study, we defined CSDH as subdural hematoma that could be treated with BHD. We defined postoperative recurrence of CSDH as a subsequent radiographic discharge following the primary treatment, with re-bleeding and/or increased size of the subdural hematomas on the operated side, with or without any clinical presentation. AIH was identified as a hyperdense lesion in the ventricle, brain parenchyma, subarachnoid, subdural space or epidural space, visible on CT scan during hospitalization, and accompanied by neurological deterioration. Chronic intracranial hemorrhage (CIH) in this study refers to cerebral hemorrhage other than recurrent CSDH or AIH.The hematoma was classified as hypodense [< 30 Hounsfield units (HU)], isodense (30–60 HU), hyperdense (> 60 HU), or mixed density based on the density difference of the hematoma and the brain parenchyma. Patients with bilateral CSDH of different types were attributed according to which reflected the greater bleeding tendency.Unilateral or bilateral CSDH with maximum thickness > 10 mm and/or midline shift > 7 mm;CSDH of any thickness causing mass effect, midline shift, or neurological signs and symptoms, such as focal deficit, and mental status changes;Progressive increase in size of CSDH as observed through a series of CT or MRI scans.Surgical evacuation of CSDH was carried out when the following indications were observed:In bilateral CSDH, the decision to evacuate one or both sides was generally made based on hematoma size and neurological symptoms. (i) Unilateral evacuation of bilateral CSDH: when the maximum diameter of the CSDH on the operation side was > 10 mm, when the contralateral hematoma was < 10 mm thick, and when the laterality of neurological symptoms could only be attributed to the thicker hematoma. (ii) Bilateral evacuation of bilateral CSDH: both sides received the same treatment in a single operation.In all cases, a single burr hole was made under anesthesia. Local or general anesthetic was selected depending on the patient’s general status and ability to co-operate. A 4–5 cm vertical skin incision was made at the superior temporal line near the coronal suture or at the point of maximum thickness of the CSDH. A 1.5–2 cm craniotomy was performed. After opening the dura and outer membrane of the hematoma, a soft silicon tube was inserted into the subdural space through the burr hole overlying the large part of the subdural cavity, and tunneled for a minimum of 5 cm away from the scalp incision. Irrigation was not carried out in all surgeries. If carried out, irrigation was with 0.9% normal saline via the tube, until the output was clear. The drain was connected to a soft collection bag and the drainage tube was removed when there was no more drainage fluid. The patient stayed in bed until the drain was removed. If CT scan showed that subdural collections remained in the hematoma cavity after the operation, the patient was treated with urokinase, according to the surgeon’s preference. CT scanning indicated if the affected brain region showed sufficient re-expansion or when the amount decreased to < 50 ml per day.All patients had their anticoagulant or antiplatelet status optimized prior to surgery, ensuring a preoperative international normalized ratio (INR) between 0.8 and 1.2. It was managed in various ways depending on the type of anticoagulant treatment. Agents used to reverse anticoagulant or antiplatelet medications were vitamin K1, thrombocytes, blood plasma, tranexamic acid, prothrombin complex concentrate, and desmopressin analogs. Antiplatelet or anticoagulant agents were usually re-started 1 month from the day of surgery.Following CSDH diagnosis, some patients were given atorvastatin (20 mg per night) prior to the operation. The decision to give the patient preoperative atorvastatin was made by the neurosurgeon. In general, atorvastatin was discontinued for at least 1 month after surgery or based on follow-up imaging. All patients were followed-up for at least 12 months.Demographic, clinical and radiographic data were collected using a standardized case report form and the information was added to a database. The following data were included: gender, age, history of anticoagulant or antiplatelet, head trauma event, GCS score on admission, medical history , preoperative main clinical symptoms , operation side , hematoma density characteristics on CT , hematoma maximal thickness , midline shift, anesthesia method, intraoperative irrigation (non-irrigation versus irrigation), duration of drainage (days), urokinase injection after operation, complications , time interval between initial operation and recurrence (days), time interval between initial operation and bleeding (days), and hospitalization time (days). All CT interpretations and measurements were made by a neurosurgeon and recorded after corroborating with the neuroradiologist’s report.SPSS software (version 16.0) was used for the statistical analysis.P < 0.1 in the univariate analysis were included in the multivariate model. Statistical significance was defined as P-value < 0.05.Continuous data are expressed as the mean ± standard deviation (SD) and categorical data are expressed as the median value (IQR). Univariable (Student t-test and the Mann–Whitney U-test), bivariable (Chi-square) and multivariable (multiple logistic regression) analyses were performed to determine which, if any, of the studied variables were associated risk factors of CSDH recurrence and AIH. The variables with A total of 448 patients  were included in the analysis. The mean age was 68.1 ± 12.4 years (range: 14–98 years). CSDH recurrence occurred in 60 (13.4%) patients, including 26 with unilateral BDH evacuation, 11 with unilateral evacuation of bilateral CSDH, and 23 with bilateral evacuation of bilateral CSDH. Complications occurred in 122 patients (27.2%), including 23 (5.1%) with AIH . One patient died . The mean duration of hospitalization time was 14.0 ± 5.5 days (range: 3–42 days). Patient information is provided in Table Sixty patients  experienced CSDH recurrence following the initial BHD. The mean age was 69.6 ± 10.8 years (range: 31–88 years). The mean time interval between initial BHD and recurrence was 40.8 ± 28.3 days (range: 12–180 days).P = 0.038), density of hematoma (P = 0.009), operation side (P < 0.001), and atorvastatin administration (P = 0.021) were significantly related to CSDH recurrence. Unilateral or bilateral evacuation of bilateral CSDH were not significantly correlated with CSDH recurrence following BHD . Although there was no significant correlation between gender and recurrence (P < 0.1), it was included in the multivariate analysis according to our multivariate inclusion analysis criteria. Other variables that were not significantly correlated with CSDH recurrence are shown in Table Univariate analysis Table  showed tn P = 0.01 were siP = 0.001], mixed density  and anticoagulant drugs  were significantly associated with CSDH recurrence. Other variables not significantly associated with CSDH recurrence are detailed in Table In the multivariate logistic regression model, bilateral hematoma [Odds ratio (OR), 2.563; 95% confidence interval (CI), 1.439–4.563; Twenty-three patients  experienced postoperative AIH. The mean age was 68.5 ± 11.5 years (range: 42–87 years). The mean time interval between initial BHD and postoperative AIH was 4.7 ± 2.9 days (range: 1–10 days).P = 0.046), preoperative hematoma thickness (P = 0.043) and intraoperative irrigation (P = 0.020) were significantly related to postoperative AIH (Table P = 0.683) was not significantly related to postoperative AIH, and there was no significant difference in the incidence of postoperative AIH between unilateral or bilateral evacuation of bilateral CSDH . Other variables with P > 0.1 in the univariate analysis are shown in Table Univariate analysis indicated that preoperative headache P = 0.06, preopeP = 0.021) and intraoperative irrigation  were significantly associated with postoperative AIH. Other variables not significantly associated with postoperative AIH or CSDH recurrence are shown in Table Multivariate analysis showed that preoperative headache . The relationship between hematoma density and postoperative AIH has not been reported in the literature. In our study, hematoma density was not significantly associated with postoperative AIH. We suspect that when hyperdense hematoma are compared with the other three types of hematoma density, repeated microhemorrhages from the immature capillary network in the outer membrane take place and accumulate over time, causing CSDH recurrence [Many studies suggest that preoperative hematoma density is associated with CSDH recurrence, and hyperdense hematoma is an independent risk factor for CSDH recurrence , 38. In Preoperative hematoma thickness has been reported as an independent risk factor for CSDH recurrence . It is tOur results showed that anticoagulant drug use is an independent risk factor for CSDH recurrence. Antiplatelet drugs did not increase the CSDH recurrence rate following BHD. Similarly, a recent systematic study showed that anticoagulant drugs increased re-bleeding on the operation side of CSDH, but antiplatelet therapy did not . HoweverAtorvastatin is another management option, which may be used alone or in conjunction with surgery. Several studies have shown that CSDH is caused by impaired angiogenesis in the neomembrane and localized inflammation, and that atorvastatin improves angiogenesis and reduces the inflammatory response , 43. A rIn our study, intraoperative saline irrigation was based on the surgeon’s preference. Some studies have shown that intraoperative saline irrigation of the hematoma cavity does not improve the incidence of postoperative AIH and CSDH recurrence , 46. Accp < 0.1. However, it may lead to too few variables and too many confounding factors, which will have a greater impact on the results.Our study had some limitations. First, our study is a retrospective design, which usually produces a risk of bias. Based on our data and personal communication with neurosurgeons in each participating department, neurosurgeons not only choose the surgical method based on symptoms and hematoma size, but also according to their preferences. For example, the use of a single burr hole, the 1.5-2 cm craniotomy and whether to irrigate is based on neurosurgeon preference. However, according to literature reports and our results, the selection of these surgical methods did not result in significant differences postoperative complications in total and recurrence rates . Second,In this study, we evaluated predictors of CSDH recurrence and postoperative AIH following BHD in a multi-center retrospective study of patients with CSDH. We identified bilateral hematoma, hyperdense hematoma and anticoagulant drugs as independent risk factors for recurrence of CSDH. Preoperative headache is an independent risk factor for postoperative AIH, and intraoperative irrigation reduces the incidence of postoperative AIH. Further prospective multi-center studies will be required to evaluate these findings.


Since the inception of newborn screening programs in China in the 1990s, pregnancy among patients with inherited, metabolic disorders has become more common. This study explores the management and outcomes of planned, full-term pregnancies in patients with phenylketonuria (PKU).Married patients with PKU from 2012 to 2017 were enrolled to receive prenatal counseling and regular health assessments. Study-related assessments included the timing of Phe-restricted diets, maternal weight gain, gestational age, pregnancy complications, and blood Phe concentrations (both pre-conception and during pregnancy), obstetrical data, and offspring outcomes.r = 0.886, p = 0.016).A total of six offspring were successfully delivered. The mean ± SD (range) age of the mother at delivery was 26.3 ± 4.7 (range: 21.1–32.5) years. The mean duration of Phe control before pregnancy was 5.5 ± 1.3(range: 3.1–6.5) months. During pregnancy, the proportion of blood Phe concentrations within the clinically-recommended target range (120–360 μmol/L) ranged from 63.2–83.5%. Low birth weight (< 2500 g) offspring occurred in two women who experienced suboptimal metabolic control. In addition, offspring DQ was related to the proportion of blood Phe levels per trimester that were within the recommended range (4) may be an option to improve the management of blood Phe levels.This is the first report of women in China with PKU who successfully gave birth to clinically healthy babies. Infant outcomes were related to maternal blood Phe management prior to and during pregnancy. In maternal PKU patients with poor compliance to dietary treatment, sapropterin dihydrochloride (6R-BH Phenylalanine hydroxylase (PAH) deficiency [phenylketonuria (PKU)] is a rare, inherited, metabolic disease that can result in high blood phenylalanine (Phe) concentrations that are toxic to the brain. Chronic hyperphenylalaninemia (HPA) can lead to mental disabilities and neuropsychological abnormalities . Early dThe offspring of pregnant patients with PKU are at risk for post-natal complications because elevated maternal blood Phe is associated with teratogenicity , 8. In tThere is little research in the literature to describe pregnancy outcomes to help guide physicians and obstetricians with the management of pregnant women with rare diseases in China. One case study has been published of a Chinese woman with methylmalonic aciduria (MMA) and homocystinuria, cblC type, who reportedly delivered a healthy child . The purAll patients with PKU married between 2012 and 2017 were recalled to healthcare centers within China to receive prenatal counseling and education and to receive regular clinical evaluations. Marriage partners were screened for heterozygous PAH genes. As an autosomal recessive disorder, all offspring of women with PKU will carry at least one abnormal gene for PKU, which is inherited from their homozygous-affected mother. Therefore, genetic counseling was provided to all women with PKU in this study prior to conception. Written consent was obtained from each affected woman during the genetic counseling. After genetic counseling, all of the affected patients were advised to maintain blood phenylalanine (Phe) levels to less than 360 μmol/L for at least 3 months prior to conception and to maintain blood Phe between 120 and 360 μmol/L during pregnancy. In order to obtain optimal pregnancy outcomes, patient education included the calculation of Phe intake in order to for patients to maintain blood Phe within the clinically-acceptable blood Phe target range (120–360 μmol/L) while sustaining adequate nutrition for the developing fetus.Study-related assessments included the timing of Phe-restricted diets, maternal weight gain, gestational age, pregnancy complications, and blood Phe concentrations (both pre-conception and during pregnancy). During the pregnancy, all the affected women received at least five ultrasound examinations: two in the first trimester, two in the second, and one in the third for structural abnormality screening, especially focusing on the growth rate of head circumference and physical growth. During 24–26 weeks of gestational age, fetal echocardiography was conducted for screening of severe congenital heart malformations. In addition, all the affected women were advised to visit their local antenatal care service at least once a month during the first and the second trimester: two visits every month during the third trimester, and one visit every week after the 37th gestational week. Local obstetricians measured and recorded weight gain, body mass index, uterine height, and abdominal circumference measurements to assess the physical growth of the fetus.Mothers were interviewed in person (if patients were located within Beijing area), by telephone, WeChat , or referred to local centers (if patients were located outside of the Beijing area). Interviewers discussed current diets and other medical concerns. Usual care consisted of bi-weekly to monthly communication with a metabolic nutritionist to review diet, weight and weight gain, dietary Phe intake calculations, and calorie counts. Dietary changes were advised based on the degree of metabolic control, derived from fasting plasma Phe concentrations, and maternal weight gain.At the patient’s local hospital, fasting blood Phe concentrations were measured weekly prior to conception and twice a week during pregnancy with all data recorded in pregnancy diaries. Blood Phe was measured by high-pressure liquid chromatography (HPLC) using tandem mass spectrometry. An overall review of blood Phe results was used for the assessment of maternal adherence to a Phe-restricted diet during pregnancy.Throughout their planned conception and pregnancy, patients were asked to keep a daily record of all food and beverages consumed so that quantities of low-Phe and Phe-free synthetic protein, dietary Phe, calories, and fluid intake volume could be derived. Laboratory examinations included plasma amino acids, hemoglobin and hematocrit, prealbumin, and iron. A nutritionist reviewed the dietary records and provided advice to patients every 2 weeks.After birth, offspring anthropomorphic assessments consisted of gender, weight, length, and occipitofrontal circumference (OFC). Neuropsychometric assessments for offspring consisted of development quotient (DQ) measurements using the Gesell Child Developmental Age Scale .p-value < 0.05 was considered to be statistically significant  for Windows, version 15.0 . Descriptive analysis of demographic characteristics was conducted with calculation of means and standard deviations for continuous variables, and proportions for categorical variables. Data were expressed as mean ± SD unless indicated otherwise. Spearman correlations were conducted between DQ and the mean proportion of blood Phe levels per trimester that were within the recommended range. A As one of the national healthcare centers in China, our unit has diagnosed and treated more than 2930 patients with HPA since 1984. By the end of 2017, a total of 172 female patients reached 20 years of age and 10 were married. Four of 10 were diagnosed by NBS, five were diagnosed symptomatically within their first year of life, and one was diagnosed at 26 years of age after delivering a baby with a congenital anomaly. The patients originated from Shanxi, Tianjin, Hebei, Shandong provinces or from the Beijing municipality and were all of Han nationality. None of their partners carried PAH heterozygous genes. In terms of educational attainment, two of the mothers graduated from middle school, three graduated from high school, and one attended college. Demographics for this cohort are listed in Table By the end of 2017, six of the 10 women had become pregnant: four of them had a single pregnancy, one had two pregnancies, and one had three pregnancies. The mean age at pregnancy was 26.3 ± 4.7 years and all patients had initiated a Phe-restricted diet during pre-conception. The condition during pregnancy was generally normal without anemia, gestational hypertension, or other severe complications Table .Table 2Six maternal patients with PKU successfully delivered 6 babies, 5 males and 1 female. The mean gestation period was 38.2 ± 0.6(range: 37.4–39.1) wks. Table p = 0.016).For this cohort, both offspring birth weights and DQ assessments were found to be related to maternal Phe control during pregnancy. Low birth weight (< 2500 g) offspring occurred in two women (Patients No. 2 and No.3) who experienced suboptimal metabolic control during pregnancy. Two low birth weight neonates (range: 2350-2480 g) were offspring of Patients No. 2 and No.3 who had < 70% of blood Phe measurements within range during pregnancy. These same two women gave birth to offspring with lower DQ assessments (DQ range: 80.6 to 85.7). Overall, the DQ of infants correlated with the proportion of blood Phe levels per trimester that were within the recommended range  c.1238G > C(p.R413P)/ c.1238G > C(p.R413P). This patient initiated a Phe-restricted diet 3.1 months prior to becoming pregnant. She learned how to count dietary protein and Phe intake from each meal during the 3 months and filled three diaries during pregnancy. Baseline blood Phe was 489.7 μmol/L. She lived in Tianjin city and came to the clinic every 2 weeks. Blood Phe levels were mostly stable during all three trimesters of her pregnancy. The mean proportion of blood Phe levels per trimester that were within the recommended range were 55.6, 73.9 and 95.5% during the 1st trimester, 2nd trimester and 3rd trimester, respectively. After a full-term pregnancy, she gave birth to a healthy, male baby weighing 3050 g and measuring 52 cm in length. The infant developed normally, the DQ assessment was 88.2.+ 1 W with a low birth weight: 2350 g, birth length: 46.6 cm, and a remarkably smaller OFC-B 31.5 cm. Gesell assessment revealed that the infant had mild language and fine motor development delays and a DQ assessment of 80.6 at nearly 3 years of age.Patient No.2 originated from Shanxi province and genetic analysis showed a PAH gene mutation  c.728G > A(p.R243Q)/c.838G > A(p.E280K). This patient initiated dietary treatment 5.0 months prior to becoming pregnant. Baseline blood Phe was 523.9 μmol/L. Even though dietary management education was provided, she and her family didn’t fully comply with a Phe-restricted diet during the first period of pregnancy. Because of a financial burden, she didn’t have frequent blood examinations at hospital visits. This patient had high blood Phe concentrations during her first trimester (605.4–908.1 μmol/L for 6 weeks) which resulted in a dramatic change in blood Phe when the first trimester is compared to the third trimester. The proportion of blood Phe levels per trimester that were within the recommended range were 36.2, 66.3 and 92.7%, respectively. Patient No. 2 delivered a male baby with a gestational age of 38+ 4 and a low birth weight (2480 g). The baby exhibited feeding difficulties during the first 6 months and had a weight of 6950 g at 1 year of age. After feeding patterns were corrected, the infant reached 9000 g at 19 months and a DQ assessment of 85.7.Patients No.3 was late diagnosed at 28 years old, when she delivered a baby with cardiac anomalies of Tetralogy of Fallot. Initial maternal blood Phe was 1278.0 μmol/L and genetic analysis showed a PAH gene mutation  c.728G > A(p.R243Q)/c.728G > A(p.R243Q). Patient No. 3 lived in rural area of Hebei Province and had exhibited yellow hair color from childhood. She had 8 years of education, but failed to graduate from middle school. She could communicate on simple daily issues, but the Wechsler Adult Intelligence Scale (WAIS) indicated moderate mental retardation. She married at 26 years of age. Her second pregnancy was electively aborted due to lack of blood Phe control. She came to our hospital for genetic counseling and started dietary treatment 6 months before her third pregnancy. Baseline blood Phe was 622.1 μmol/L. In order to decrease her blood Phe level rapidly, this patient kept a very strict diet and limited dietary protein intake. The fetus demonstrated intrauterine growth restriction likely due to the poor maternal nutritional status in the first trimester. After improving blood Phe control during the second and trimester, Patient No. 3 delivered a male baby with a gestational age of 38Patient No.4 was a native of Beijing and maternal baseline blood Phe was 460.3 μmol/L and genetic analysis showed a PAH gene mutation  c.1222C > T(R408W)/ c.975C > G(Y325X). She was the only one of this pregnancy cohort who attended college. Patient No.4 married at 29 years of age and implemented recommended dietary treatment immediately after marriage. The patient balanced maternal nutrition with blood Phe control and had frequent inquiries and visits with a specialist in obstetrics and metabolic diseases. Blood Phe concentrations were within the recommended range 87.5% of the time during pregnancy. A healthy female baby was delivered with a gestational age of 39 + 1 weeks by Cesarean section. The infant was presented for follow-up checkups every month during the first 6 months and every 3 months thereafter, demonstrated normal growth and development milestones, and the DQ assessment was 98.8.+ 3 Wks. The infant was feeding well and growth data was around 60% percentile from birth to 1 year old. The DQ assessment was 92.5.The first pregnancy of Patient no. 5 was spontaneously aborted at 9 weeks due to arrested fetal development. Patient No. 5 originated from Shandong Province and genetic analysis showed a PAH genetic mutation  c.1238G > C(p.R413P)/c.782G > A(p.R261Q).. Patient No. 5 lived in Jinan city where there is a local metabolic center and had a second pregnancy after dietary treatment for 5.9 months. She visited a local specialist every 1–2 weeks and visited our clinic every 1–2 months. The entire pregnancy went smoothly and the patient maintained 80.2% of blood Phe levels within the recommended range. Patient No. 5 gave birth to a male baby with a gestational age of 37Patient No. 6 had maternal PKU, originated from Shandong province, and genetic analysis showed a PAH gene mutation  c.1068C > A(p.Y356X)/c.1045 T > G(p.S349A). She was one of patients from our clinic who was among the last to marry. She was on Phe-restricted diets 6.5 months prior to becoming pregnant and her baseline blood Phe was 348.6 μmol/L. She received consultations from a local center and our clinic. Blood Phe levels were well-controlled and were maintained within the recommended range 89.5% of the time, and was one of the most stable patients in our clinic cohort. Patient No. 6 gave birth to a healthy male baby with a gestational age of 37 + 6Wks. The infant developed normally with a weight of 8.9 kg and length of 69.7 cm at 7.3 months of age. The DQ assessment was 96.2.Even though several reports on the maternal management of inherited diseases in western countries have been published , 15, 16,Maternal PKU syndrome refers to the teratogenic effects of elevated maternal blood phenylalanine during pregnancy . ElevateIn this study, six maternal patients started a Phe-restricted diet from 3.1 months to 6.5 months prior to conception and successfully delivered six healthy babies - demonstrating that metabolic control during pregnancy is beneficial. Previous studies have shown the effect of the degree of blood Phe variability on maternal offspring outcomes. The investigators found strong negative correlations with IQ scores and blood Phe variation at 4, 8 and 14 years suggesting that ideal blood Phe should be both consistent and within the recommended range . Our stuAlthough patients with HPA were strongly encouraged to seek frequent counseling from a metabolic nutritionist to achieve optimum metabolic control, there are still women who live in rural areas who failed to come to clinic or were unable to follow-up in a timely manner, such as Patients No.2 and No.3. The MPKUCS study recommended twice-weekly blood Phe measurements prior to conception and thrice-weekly measurements afterwards , 9. Howe4), has been shown to improve the management of blood Phe levels in responsive patients [Upon investigation, we found several reasons for inadequate prenatal care and suboptimal metabolic control. First, not all local hospitals have a multi-disciplinary team comprised of a biochemical geneticist and a nutritionist. Therefore, some patients were unable to receive immediate, knowledgeable PKU management advice. Second, some patients’ adherence to a Phe-restricted diet led to insufficient prenatal nutrition. For example, in order to keep the Phe concentration within the normal range, Patient No.3 was too strict with her diet, which resulted in a weight loss of 5 kg during the first trimester and subsequent heavy hyperemesis gravidarum and intrauterine growth restriction within the first trimester. This same patient failed to increase her weight until the third trimester. Third, proper medical care of maternal PKU is associated with a cost-prohibitive financial burden. As we published previously , many papatients –24.This is the first study on reproductive outcome in patients with PKU after 20 years of follow-up in China. Maternal and offspring data was recorded from the prenatal period to offspring for up to 3 years of postnatal age. One of the limitations of this study was that six cases of pregnancy is a relatively small cohort and more cases are suggested for future studies. Another limitation was the relatively short follow-up period for infants, whose median postnatal age was 17 months. A longitudinal follow-up study would provide more information related to the duration of any detrimental neurological impacts.These results indicate that a greater effort is warranted to assist women with PKU to remain on a Phe-restricted diet during their reproductive years. Despite clinical management approaches, PKU can exert a high burden on patients, caregivers, and society. This burden of PKU includes social , economic , and other burdens associated with a lifelong chronic disease. A national association like MCPKUS and a national guideline to optimize maternal PKU care are urgently needed in order to share experiences and best practices between hospitals and practitioners. The goal of this information sharing would be to increase the awareness of metabolic conditions and factors on offspring outcomes. The ideal clinical team would include a perinatologist, a neonatologist, and other genetic and metabolic specialists who would work together to manage patients with high-risk pregnancies. Rural PKU patients may be able to receive counseling from experienced geneticists and nutritionists remotely using the internet. Additional therapeutic options for blood Phe control (e.g.:6R-BH4) should be considered, and made available in the clinic, especially for the patients with poor compliance to dietary treatment , 23.4) may be an option to improve the management of blood Phe levels.This is the first report of women in China with PKU who successfully gave birth to clinically healthy babies. Infant outcomes were related to maternal blood Phe management prior to and during pregnancy. In maternal PKU patients with poor compliance to dietary treatment, sapropterin dihydrochloride (6R-BHAdditional file 1.


People revisit spatial locations of visually encoded information when they are asked to retrieve that information, even when the visual image is no longer present. Such “looking at nothing” during retrieval is likely modulated by memory load  and the strength of mental representations. We investigated whether words that are more difficult to remember also lead to more looks to relevant, blank locations. Participants were presented four nouns on a two by two grid. A number of lexico-semantic variables were controlled to form high-difficulty and low-difficulty noun sets. Results reveal more frequent looks to blank locations during retrieval of high-difficulty nouns compared to low-difficulty ones. Mixed-effects modelling demonstrates that imagery-related semantic factors (imageability and concreteness) predict looking at nothing during retrieval. Results provide the first direct evidence that looking at nothing is modulated by word difficulty and in particular, word imageability. Overall, the research provides substantial support to the integrated memory account for linguistic stimuli and looking at nothing as a form of mental imagery. Under this integrated model, mental representations  and environmental sources internalised via eye movements  work cooperatively. According to the integrated model, representations are integrated and composed of spatial and linguistic input. If one part of the representation  is reactivated through probing, other parts  will be retrieved from memory as well. Task conditions such as repetition can make the linguistic component stronger, which stabilises the mental representations as a whole. In turn, people do not “need” to refer to spatial information for accurate retrieval. Thus, they look less at nothing. In other words, stronger internal memory and stronger mental representations require less environmental support through eye movements. In line with this view, Johansson, Holsanova, and Holmqvist  and so-called “external memory”  in a flexible way. There is evidence for the effect of task difficulty on memory-guided eye movements as discussed above. However, we lack direct evidence that looking at nothing is modulated by word difficulty.Different word properties such as frequency have varying effects on how easily words are remembered. If words that are more difficult to remember lead to more reliance on environmental support via eye movements, the following question arises: which lexico-semantic variables contribute to looking at nothing? Word properties could affect memory-driven eye movements via two possible channels: memory load or mental imagery.Individual properties of a word that make it difficult to remember  increase memory load . Specifically, people simulate perception during imagery by re-enacting the eye movements that are executed during viewing  rather than conceptual elements activated by word meanings . 75% of them were psychology students. All participants were monolingual native speakers of British English as determined with the Language History Questionnaire version 2.0  or course credit (n = 21) for participation. All participants were fully informed about the details of the experimental procedure and gave written consent. Post-experiment debriefing revealed that all participants were naïve to the purpose of the experiment.The experiment was carried out with 48 students at the University of Birmingham  as high-difficulty and low-difficulty word groups based on the mean imageability of the whole set (4.99). It is not viable to manipulate one dimension by holding others constant due to intercorrelations between the variables. Thus, high-difficulty words were less imageable, more abstract, less available, less pronounceable, learnt later in life, longer (both in number of letters and syllables) and had less phonologic and orthographic similarity with other words in the language . Probe words in the yes trials were among the four study words in the encoding phase, whereas a different, not seen, word was probed in the “no trials”. There were no significant differences in any of the variables between yes and no groups within high- and low-difficulty word groups .Both high- and low-difficulty groups were further divided into yes and no trials  and five words . Words within sets were matched on all variables  both in the yes and no trials. Words were further controlled such that no word started with the same letter or had any semantic relationship with any other word in the set. Monosyllabic, disyllabic and trisyllabic words were evenly distributed .t tests revealed no significant differences between the probe and distractor words in any of the variables or in any of the four sub groups  . Thus, any word among the four or five words in each trial set was as likely to be remembered as any other word in the same set.The word in each trial set with median imageability was selected as the probe leaving the others as distractors. Welch’s Finally, we formed 180 unique mathematical equations  to present as memory interference between encoding and retrieval phases . Participants viewed the visual material with both eyes but only the left eye was tracked. Auditory material was produced by a native female speaker of British English in a sound attenuated room and recorded using Audacity . Participants responded (yes/no they had seen the word) by pressing one of two keys on a standard keyboard. Eye movement data were extracted using the SR EyeLink Data Viewer . No drift or blink correction procedure was applied.Stimuli were presented on a TFT LCD 22-in. widescreen monitor operating at 60 Hz with a resolution of 1680 × 1050 pixels (501.7 mm × 337.4 mm). The monitor was placed 640 mm in front of the participant. A chin and forehead rest was used to reduce head movements. Participants’ eye movements were monitored using SR EyeLink 1000  saw the same probe word with a congruent cue, an incongruent cue or without any cue. (4) Interference: participants were presented a mathematical equation  and asked to identify whether the equation was correct or not within 20,000 ms (or they timed-out). (5) Retrieval: the probe word was auditorily presented as participants looked at the blank grid with empty boxes. There was a 500-ms gap between the presentation of the blank retrieval screen and the presentation of the probe word. Participants were asked to make an unspeeded yes/no judgement to determine whether they had seen the probe word among the four words shown in the encoding phase within 20,000 ms (or they timed-out).(1) Fixation: a fixation cross appeared at the centre of the screen for 500 ms. (2) Encoding: participants were presented four words in capital letters on a 2 × 2 grid for 1800 ms. Words  were centrally placed in rectangular boxes . Word difficulty was a within-subject variable and all participants saw the high- and low-difficulty words. (3) Cueing: a flashing black dot appeared in cue trials for 1000 ms either in the same (congruent cue) or in the diagonal quadrant (incongruent cue) as the original location of the probe word in the encoding phase. There was also a third condition where no cue was presented between encoding and interference. Cue condition was a within-subject variable and three cue conditions were randomly presented in a session. That said, an equal number of random participants  with varying trial durations due to differences in word length between high- and low-difficulty words. Second, we assumed that fixations rather than the time spent on particular region  are important for the link between memory and eye movements. Fixation-based measures are reliable indicators of memory load and attention in a given location . They framed the rectangular boxes that words were presented in . Binomial models were fit for categorical target variables (hit rate and correct rejection rate) and with We started fitting models by building the random effects structure and followed a maximal approach. That is, random effects were included as both random intercepts and correlated random slopes (random variations) as long as they converged and were justified by the data  and Bayesian information criterion (BIC), where lower is better in both cases  and κ (96.34). To address collinearity, we performed exploratory factor analysis and clustered the variables in components. Results of Bartlett’s test of sphericity, χ2(45) = 17011.77, p < 0.0001 and Kaiser–Meyer–Olkin measure of sampling adequacy (0.78) supported the existence of factors within the data. Hence, we proceeded to conduct the factor analysis using a principal component analysis extraction method with an orthogonal (varimax) rotation method. Both Kaiser’s criterion and the scree test criterion indicated the presence of three factors in our data. This conclusion was also supported by the percentage of variance criterion   = 1.16, p = 0.28. In other words, participants retrieved the probe words in incongruent cue condition (mean hit rate = 79%) as accurately as congruent cue condition (mean hit rate = 77%). Cue location did not improve the model fit either when no cue condition (mean hit rate = 78%) was included; χ2(2) = 1.18, p = 0.55.First, we analysed whether there was a difference in hit rate across congruent and incongruent cue conditions. The fixed effect was cue location with two levels (congruent and incongruent cue). Imagery and length and similarity factors were added as random slopes into participants. Imagery, lexical and length and similarity factors were added as random slopes into items. Cue location did not improve the model fit when compared against a null model; χ2(1) = 13.20, p = 0.0003. Length and similarity factor contributed to the model with even higher magnitude; χ2(1) = 24.49, p < 0.0001. Whereas, lexical factor was not predictive of hit rate; χ2(1) = 0.02, p = 0.90. The best-fit model converged with length and similarity and imagery factors; χ2(1) = 13.19, p = 0.0003. This model was supported by a large AIC difference of 11.2 and a BIC difference of 4.8 compared to the next best model converged with length and similarity factor only. Participants were more accurate when retrieving high imageable and concrete; β = 0.18, z = 3.96, p < 0.0001 and shorter and less similar words; β = 0.24, z = 4.86, p < 0.0001.Second, we examined lexico-semantic variables modulating hit rate. As reported above, we did not find any differences in hit rate across cue conditions. Thus, mixed-effects models including all cue conditions were fit. All factors  were added as random slopes both into participants and items. Imagery factor improved the model fit significantly; χ2(1) = 23.89, p < 0.0001 but not orthographic similarity; χ2(1) = 0.12, p = 0.73. Models with syllable length and phonological similarity did not change the results.Length and similarity included four different variables  which might have contradicting effects on the memory performance. We, therefore, fitted simpler models to identify the individual effects of the variables on hit rate within length and similarity factor. To avoid collinearity, we selected length in letters from the word length set and orthographic similarity from the similarity set as fixed effects (VIF < 2). Models including word length and orthographic similarity as random slopes within items and word length within participants indicated that hit rate was predicted by word length; χ2(1) = 2.16, p = 0.14. Results did not change when no cue condition (mean hit latency = 2027.86 ms) was included; χ2(2) = 2.04, p = 0.36.Linear mixed-effects models were fit to identify any difference in hit latency between cue conditions. Imagery and length and similarity factors were added as random slopes into participants. Imagery, lexical and length and similarity factors were added as random slopes into items. As in hit rate, likelihood tests indicated that there was no difference in hit latency between congruent (mean hit latency = 1978.22 ms) or incongruent (mean hit latency = 2057.67 ms) cue conditions; χ2(1) = 4.62, p = 0.03, imagery factor; χ2(1) = 6.14, p = 0.01 and with a considerably higher magnitude, length and similarity factor; χ2(1) = 34.29, p < 0.0001 predicted hit latency. Thus, the best-fit model converged with all three factors as the fixed effects; χ2(1) = 4.34, p = 0.04. Participants were faster to retrieve high imageable and concrete; β = − 48.66, t = 2.38, p = 0.02 and shorter and less similar words; β = − 83.24, t = 4.73, p < 0.0001. They were slower to retrieve more frequent, more available, more pronounceable words which were learned earlier in life; β = 41.49, t = 2.13, p = 0.04.Next, we investigated the effect of lexico-semantic factors on hit latency. Imagery, lexical and length and similarity factors were added as random slopes into participants. Imagery and length and similarity factors were added as random slopes into items. All three factors, that is, lexical factor; χ2(1) = 8.57 p = 0.003 but not orthographic similarity; χ2(1) = 0.49, p = 0.49. Models with syllable length and phonological similarity did not change the results. Correlation between variables within lexical factor  did not allow us to investigate their individual effects on hit latency due to high collinearity (VIF > 2).As in hit rate, simpler models with word length and orthographic similarity demonstrated that hit latency was predicted by word length; Correct rejection rate was the proportion of “no trials” to which the participants correctly responded no. Visual cues in yes trials were located according to the location of the probe words at encoding; whereas, a different, not seen, word was probed in no trials. Thus, “no trials” were not presented with different cue conditions and there is necessarily no effect of cue for these trials. As a result, only the effect of lexico-semantic variables on correct rejections was investigated.χ2(1) = 3.23, p = 0.07, imagery factor; χ2(1) = 0.13, p = 0.72, lexical factor; χ2(1) = 0.23, p = 0.63]. Word length and orthographic similarity as raw values rather than regression scores of the length and similarity factor did not predict correct rejection rate either.Imagery, lexical and length and similarity factors were added as random slopes into items. Participants were added as a random intercept as the random-slope model did not converge. None of the lexico-semantic variables predicted correct rejection rate: [length and similarity factor; We first analysed whether participants looked at nothing during memory retrieval. In other words, we investigated whether there were more looks to relevant, blank locations where probe words were shown at the encoding stage compared to irrelevant, blank locations.The target variable was fixation percentage in correctly answered yes trials. The fixed effect was quadrant with two levels (relevant and irrelevant quadrant). Imagery, lexical and length and similarity factors were added as random slopes into participants and items.χ2(1) = 8.60, p = 0.003. Models with a single cue condition indicated that quadrant improved the model fit in congruent; χ2(1) = 5.70, p = 0.02 and in no cue conditions; χ2(1) = 5.39, p = 0.02 but not in incongruent cue condition; χ2(1) = 0.13, p = 0.72. That is, participants looked more at the relevant location in congruent; β = 0.02, t = 2.39, p = 0.02 and no cue conditions; β = 0.02, t = 2.32, p = 0.02. However, they did not look at nothing when they were shown a visual cue that was incongruent with the original location of the probe word during encoding. Hence, we analysed the effect of word difficulty and lexico-semantic predictors on looking at nothing in congruent and no cue conditions.Quadrant improved the model fit when all cue conditions were factored in; A further sub-analysis was performed on the two conditions with overall evidence of looking at nothing behaviour (congruent and no cue conditions), to determine the role of word difficulty. Linear mixed-effects models with high- and low-difficulty word sets were fit separately. The target variable was fixation percentage in correctly answered yes trials. Fixed effect was quadrant with two levels (relevant and irrelevant quadrant). All lexico-semantic factors were included into participants and items as random slopes.Congruent cue condition Quadrant improved the model fit for high difficulty; χ2(1) = 7.00, p = 0.008 but not low difficulty word set; χ2(1) = 0.59, p = 0.44. Participants looked more at the relevant quadrant than the irrelevant quadrant only when retrieving more difficult words; β = 0.04, t = 2.65, p = 0.008  = 9.59, p = 0.002. Quadrant did not improve the model fit in low-difficulty word set; χ2(1) = 0.08, p = 0.77. Participants looked more at the relevant quadrant than the irrelevant quadrant when retrieving more difficult words; β = 0.04, t = 3.10, p = 0.002  = 3.21, p = 0.07, length and similarity factor; χ2(1) = 1.27, p = 0.26 or lexical factor; χ2(1) = 0.24, p = 0.62 did not significantly predict fixation percentage in the relevant quadrant. Along with that, the best-fit model explaining the data was fit with imagery factor; β = − 0.02, t = 1.76, p = 0.08 based on AIC (0.74) and BIC differences (5.75) as to the next best model converged with imagery and length and similarity factors.No cue condition Imagery factor predicted fixation percentage in the relevant quadrant; χ2(1) = 4.31, p = 0.04. Length and similarity; χ2(1) = 1.37, p = 0.24 or lexical factor; χ2(1) = 0.69, p = 0.41 were not significant predictors of looking at nothing. As a result, the best-fit model explains the data were the one with imagery as the fixed effect; χ2(1) = 4.06, p = 0.04. Higher imageability and concreteness predicted less fixations in the relevant quadrant; β = − 0.02, t = 2.03, p = 0.04.β = 0.30, z = 1.24, p = 0.22, no cue; β = 0.02, z = 0.09, p = 0.93) or hit latency . Models fit with high-difficulty or low-difficulty words only did not change the results.The current experiment was not designed to test the functionality of looking behaviour in memory. Nevertheless, we examined whether memory performance was predicted by the proportion of fixations in the relevant, blank locations. Imagery factor was added as random slopes into participants. Imagery and length and similarity factors were added as random slopes into items. Looks to relevant, blank locations did not predict hit rate  whether looking at nothing increases as participants are asked to study and retrieve more difficult words in a yes/no recognition memory paradigm and if so, (2) which lexico-semantic variable(s) predict the change in memory-guided eye movements to relevant, blank location. We further tested how a visual cue presented between encoding and retrieval stages modulates the effects of word difficulty and word properties on memory performance and looking at nothing.As shown previously  to verify the experimental manipulations and to compare against looking behaviour results. Unlike their effect on fixations, cue locations did not affect memory performance. Participants performed equally well under all retrieval conditions as demonstrated by both hit rate and hit latency. On the other hand, memory performance was superior in the retrieval of low-difficulty words in comparison with high-difficulty words as expected. Taken together, it is probable that visual cues were salient enough to modulate eye movements but not memory performance as memory performance was based more on the nonvisual, verbal parameters.In line with our hypothesis, participants looked more at the blank, relevant quadrant compared to irrelevant quadrants when retrieving high-difficulty words but not low-difficulty words in congruent and no cue conditions. That is, participants relied on additional external sources when memory load was high, and they returned back to internal memory sources only when memory load decreased. We conceptualised memory load as the mental effort to maintain and reconstruct information as a function of difficulty. In this respect, such retrieval behaviour is in line with previous studies showing a proportional relation between memory load (via difficulty) and looking at nothing  accurately. However, integrated memory engaged spatial indices when retrieving difficult words. Thereby, the verbal component of the memory representations corresponding to high-difficulty words was reinforced with stronger spatial information through eye movements and, as a consequence, memory load was alleviated.High-difficulty words in the current study were in fact more distinctive than low-difficulty words in orthographic and phonological similarity, age of acquisition, availability and pronounceability. That is, high-difficulty words were less similar with others in the lexicon, learnt at later ages, less available  and less pronounceable. If high-difficulty words were more distinctive in these variables, then why did participants still retrieve low-difficulty words more accurately than high-difficulty words? The variables which made high-difficulty words more distinctive  did not play a role in hit rate in the current study. Major predictors of hit rate, and by extension we assume, memory load, were word length, imageability and concreteness. Low-difficulty words were more imageable, more concrete and shorter (in letters and syllables). As a result, low-difficulty words imposed less load on memory and were retrieved more accurately.). Rather, findings support the position that the external world has a supportive role in memory and environmental indices complement mental representations . Eye movements are of particular importance in this pattern as they bind the internal representations to external information.The results have important implications for theories postulating that cognitive work can be offloaded onto the environment . Use of word properties as independent and continuous variables instead of within difficulty categories in mixed-effects models eliminated the possibility of any confounding influence of stimuli design on the results. Imagery, that is, imageability and concreteness, was predictive of looking at blank locations during retrieval. Participants looked more at nothing when retrieving less imageable and more abstract words in no cue, that is, a “pure” looking at nothing condition. The effect of imageability and concreteness on fixations in the relevant quadrant under congruent cue condition was at a Why did participants look more frequently to blank regions when retrieving less imageable words? As discussed in the introduction, imageability might have modulated eye movements in two different ways: due to its contribution to (1) word difficulty and thus, memory load or (2) mental imagery of words.There is robust evidence that imageability is among the strongest predictors of performance in verbal recognition memory Paivio, . AccordiAs this was not the case, it appears more probable that imageability predicted looking at nothing mainly due to its contribution to the mental imagery of the words. We assume that participants relied more on mental imagery by looking at blank locations when the internal images activated by words fell short. This interpretation is also supported by the difference between congruent cue and no cue conditions in the effect of imageability on looking at nothing. The effect of imageability was revealed in the no cue condition but not in the congruent cue condition. As we discussed in the introduction, visual information emphasising the location of the probe word could have interfered with the mental imagery process and minimised the effect of imageability on looking at nothing.In a nutshell, weaker mental images corresponding to less imageable words were compensated for by looking more at nothing during retrieval. The effect of imageability on eye movements also disproves the prediction that participants treated the words as orthographic units when remembering them on a blank screen. It is safe to assume that participants formed and relied on conceptual mental images rather than images reflecting the physical properties of words. The role of mental imagery in the current study is noteworthy considering that the participants were not instructed to generate mental images to retrieve the words (cf., Laeng & Teodorescu, From a wider perspective, reducing internal demands is a crucial and consistent function of behaviours in which cognitive work is externalised Gilbert, . Here, w