These associations were not present after multivariate adjustment or stratification by first and second trimester of pregnancy. The Hb levels were not related to any of the CPRS-R:S subscales in unadjusted or multivariate-adjusted models. We observed no association between maternal SF or Hb levels and the risk of ADHD symptomatology . Our results suggest that neither maternal SF nor Hb levels during pregnancy are related to ADHD symptoms in 7-year-old children.Evidence suggests that iron status may be linked to symptoms of childhood attention deficit/hyperactivity disorder (ADHD), but there is little data available on the relationship between iron status in pregnancy and the risk of developing ADHD. And the data that does exist is inconsistent. Our aim here is to assess the effect of maternal serum ferritin (SF) and haemoglobin (Hb) levels during pregnancy on manifestations of ADHD in children at 7 years of age. This prospective study analysed data from 1204 mother–child pairs from three Spanish cohorts participating in the INMA project. Maternal SF and Hb levels during pregnancy and other mother and child characteristics were collected. The children’s ADHD behaviours were reported by their parents using Conners’ Parent Rating Scale-Revised Short Form (CPRS-R:S). In the unadjusted regression analysis, maternal SF was positively associated with children’s T-scores on the subscales Cognitive problems/Inattention (β: 0.63, 95%CI 0.06–1.19;  It is characterised by a constellation of symptoms that include inattention, impulsivity, hyperactivity, and altered executive functions. The disorder has also been linked to other psychological alterations, such as disruptive behaviours, processing speed problems, reading and writing difficulties, and emotional problems, resulting in impaired learning and adaptative ability in children3. The precise aetiology of ADHD remains unclear, but evidence indicates that it is a multifactorial disorder with a strong genetic component (with heritability averaging 76%)4 and in which early environmental factors can also play an aetiological role or trigger expressions of different behaviours in genetically predisposed children5. Thus, identifying early modifiable determinants of childhood ADHD could help to identify specific actions to maximise the impact on public health.Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder, with a worldwide prevalence of 5–7.7% among school-aged children6 during pregnancy—a critical period for brain development—such as maternal intake of iron7, folic acid8, omega-39, vitamins D10 and B1211, and caffeine12 may be linked to symptoms of ADHD in childhood. A good prenatal iron status is essential for correct neurodevelopment in children13 since it plays a key role in regulating dopaminergic activity, myelination, and other processes related to brain growth and function15. Low maternal iron levels during pregnancy, assessed by serum ferritin (SF) concentration, can cause iron deficiency in the brain in offspring, leading to neurocognitive disturbances related to neurodevelopmental disorder16. Unfortunately, neurocognitive alterations caused by iron deficiency during the critical prenatal period of brain development are difficult to remedy and persist later in life16. In this regard, low SF levels in the umbilical cord have been associated with poorer auditory recognition memory in newborns17 and impaired cognitive and psychomotor development in early infancy20. However, to our knowledge, only two prospective studies have evaluated prenatal iron status and ADHD in children of different ages, with mixed results21. In a large cohort of Swedish women and their offspring aged 6–29 years, Wiegersma et al.21 found that iron deficiency anaemia during early pregnancy (at ≤ 30 weeks of gestation) was associated with a greater risk of ADHD, co-occurring with autism spectrum disorder and/or intellectual disability disorder. However, associations did not reach statistical significance with anaemia diagnosed later in pregnancy (at > 30 week of gestation) or when only ADHD was considered as the outcome. Along similar lines, in our Spanish INMA (Environment and Childhood) birth cohort7 an inverse association between maternal SF in early pregnancy and inattention and total ADHD symptoms in boys at pre-school age (4 years) has been previously reported. However, SF levels were not predictive of hyperactivity/impulsivity symptoms7.Some epidemiological studies suggest that nutritional factors13. However, little is known about the trimester in which the foetus is most susceptible to prenatal iron status or indeed how this might affect child ADHD symptomatology. Although we previously7 reported an inverse association between maternal SF levels and child ADHD symptom scores, it is not known if the scores indicated a clinical diagnosis of ADHD. This relationship may also be confounded by other maternal ADHD-related factors, regardless of genetics, such as sociodemographic and/or lifestyle factors, inflammation, and others. Previous studies have rarely considered a large range of risk factors simultaneously, which increases the possibility of residual confounding.The little evidence and the inconsistent findings in this field of research point to a need for further research. Furthermore, it remains to be determined whether the association between prenatal SF and ADHD symptoms persists into school age, when environmental factors that affect children’s development and learning could act as modulators. Likewise, there is evidence to suggest that maternal iron status during pregnancy affects child neurodevelopment differently depending on the trimester of pregnancyConsidering the body of literature described above, we hypothesised that higher maternal SF and Hb levels during pregnancy act as protective factors for the development of ADHD symptoms at school age. As an additional follow-up analysis in the same INMA birth cohort, this study (1) investigates the relationship between maternal SF and Hb levels during pregnancy and manifestations of ADHD symptoms in school-aged children at 7 years old and (2) assesses the relationship between these maternal iron parameters and gestation period.http://www.proyectoinma.org). INMA is an ongoing multicentre mother–child cohort study evaluating the long-term impact of environmental exposures and diet during pregnancy on child growth and development. The study design and protocol are described in detail elsewhere23. The population-based INMA birth cohort used a common protocol22 to recruit 2,150 pregnant women at approximately 12 weeks of gestation (first trimester of pregnancy) from the general population in three Spanish regions between 2003 and 2008. Women were eligible if they met the following inclusion criteria: age ≥ 16 years, ability to communicate in Spanish, intention to deliver at the reference hospital, singleton pregnancy, and no assisted conception. This study was approved by the Clinical Research Ethical Committees of Donostia (Gipuzkoa), La Fe  Hospitals, and the Medical Assistance Municipal Institute (Barcelona) and written informed consent was obtained for all participants from parents or legal guardians. The study complies with the tenets of the Declaration of Helsinki.This longitudinal population-based study analyses data from healthy pregnant women and their children from three sub-cohorts of the INMA project: Valencia , Sabadell  and Gipuzkoa (Basque Country)  at approximately 7 years old. The final study population consisted of 1204 mother–child pairs.The main exposure of interest for this study was maternal iron status during pregnancy, which was assessed in terms of SF concentrations, an established biomarker of body iron. Maternal ferritin (µg/L) levels were measured at a single point in the first trimester  2.5) or second trimester  of pregnancy in serum samples collected and stored at − 80 °C until assessment. SF measurements in the first and second trimester as a whole (combined) were defined as the first period of pregnancy and analysed as total SF levels. For the Gipuzkoa and Sabadell cohorts, SF concentrations were quantified by time-resolved fluorescence immunoassay (DELFIA Ferritin kit A069–101) at the Gipuzkoa Public Health Laboratory, and for the Valencia cohort they were quantified by immunoturbidimetry  at La Fe hospital. The secondary exposure of interest was Hb. Data on maternal Hb levels (g/dL) were also obtained during the first trimester  2.7) and third trimester  of pregnancy from medical records. Iron deficiency was defined as SF levels < 12.0 µg/L and anaemia as Hb levels < 11.0 g/dL.24, which consists of 27 items distributed in four subscales: Oppositional (6 items), Cognitive problems/Inattention (6 items), Hyperactivity (6 items), and an ADHD index (12 items). Each item was rated on a 4-point Likert scale . For each subscale, raw total scores were summed to provide continuous measures and converted into T-scores based on age-and-sex appropriate reference groups, with higher scores indicating greater severity of ADHD. In the INMA sample, the CPRS-R:S showed good internal consistency for each of the four subscales . To apply a more clinical approach, we also generated dichotomous variables of ADHD risk using a T-score ≥ 65 (elevated score) as the cut-off point on any of the CPRS-R:S scales. This score is indicative of a ‘significant problem’24.At a median age of 7.5  years old, child ADHD behaviours were reported by parents using the CPRS-R:SIt is important to note that all the psychometric assessment tests were reviewed/checked to ensure that they had been correctly completed, by cohort-based psychologists with extensive experience in the INMA Project fieldwork.2), educational level , social class , medium status (III comprising skilled workers), low status (IV–V comprising semiskilled/unskilled workers), ethnic group , smoking during pregnancy , alcohol consumption during pregnancy (g/d), mode of delivery , parity , and breastfeeding duration (weeks of breastfeeding).Information on mother and child characteristics was obtained through face-to-face interviews conducted by trained interviewers at different times in the first and third trimester of pregnancy, at birth, and when the children reached 7–8 years of age. Maternal variables included cohort , age (years), maternal pre-pregnancy body mass index (BMI) (kg/m25 collected at 28–32 weeks of gestation (to estimate dietary intakes during second and third trimesters). Reference values from the U.S. Department of Agriculture (USDA) and Spanish food composition tables27 were used to calculate iron intake (mg/d), which was adjusted for energy intake using the residual method28. Data on iron supplement use and dose was collected using a structured questionnaire at the same time (28–32 weeks) as the FFQ. Total daily iron intake was obtained by adding daily iron intake (in mg) from diet and from supplements, and classified as ≤ 27 or > 27 g/d according to the recommended dietary allowances (RDA) for pregnant women.Dietary intake of iron during pregnancy was assessed with a validated 101-item semi-quantitative food frequency questionnaire (FFQ)C-reactive protein (CRP) levels were also measured in serum samples collected during the first trimester in only two cohorts using an immunoturbidimetric method at Consulting Quimico Sanitario Laboratory (Gipuzkoa cohort) and Echevarne Sabadell Laboratory (Sabadell cohort). The CRP level was used to assess the presence of infection or inflammatory conditions and to complement the SF information. In our population of healthy pregnant women, CRP levels ranged from 0.2 to 5.4 mg/L. Values at or above 0.65 mg/L (corresponding to the 75th percentile) were considered to be high.Information about the children’s sex , as well as anthropometric measures at birth such as standard weight (grams) and head circumference (cm) at gestational week 40, and gestational age  were obtained from clinical records. The weight and height of each child were measured at 7 years of age, and BMI was used to estimate age- and sex-specific z-scores. The children’s exact age (years) was also obtained at the time of the assessment of ADHD symptoms.Descriptive data is presented as a number (percentage) for categorical variables and as a mean (± SD) for continuous variables unless otherwise indicated. SF and Hb were assessed for normality using both the Shapiro–Wilk test and visual inspection (quantile–quantile plot). Because of skewed distributions, SF was log transformed before analyses. Comparisons of general characteristics between cohorts and categories of CPRS-R:S scores were assessed by ANOVA, chi-square or Student’s t tests, as appropriate.7, we selected a priori maternal and child covariates as potential confounders. These are summarized in Table For the analyses, maternal SF (log transformed) and Hb concentrations were treated both as continuous variables and categorical variables using tertiles, with the lowest tertile as reference. Associations between each maternal iron parameter  and the children’s T-scores on the four CPRS-R:S subscales (as continuous variables) at 7 years old were evaluated using separate univariate and multivariate linear regression analyses. The results are shown as β coefficient and 95% confidence intervals (CIs). Based on previously reported/known associations/risk factors for ADHD symptomsLastly, we also performed separate multivariate logistic regression analyses to assess the risk  of elevated T-scores (≥ 65) (as a dichotomous variable indicating the presence or absence of ADHD symptoms) for each CPRS-R:S subscale in 7-year-old children associated with maternal total log-SF levels (per SD increment) in the first period of pregnancy (first and second trimester combined) and trimester-specific Hb levels (first and third trimester).p < 0.05 was considered significant. The data was analysed using the application STATA, version 15.0 .In all analyses, a two-sided All procedures performed in the study were in accordance with the ethical standards of Donostia (Gipuzkoa), La Fe  Hospitals, and the Medical Assistance Municipal Institute (Barcelona) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.2 (SD 4.1 kg/m2). Most of the women (98.6%) were Caucasians, 38.2% had secondary/university studies, 24.2% were of high social class, and 21% smoked during pregnancy. Median maternal SF during the first period of pregnancy (first and second trimester combined) was 28.9 µg/L (inter quartile range (IQR) 17.5–45.5 μg/L). Average Hb during the first and third trimester was 12.8 (SD 0.8 g/L) and 11.6 g/L (SD 0.9 g/L), respectively. Of the 1,204 women, only 2% were anaemic  in the first trimester and 12% (n = 149) had iron deficiency (SF < 12 μg/L) in the first period of pregnancy. As expected, the proportion of women with anaemia increased  in the third trimester of pregnancy.The study sample consisted of 1204 mother–child (49% girls) pairs with complete data on the main variables of interest, maternal SF and child CPRS-R:S. The mean age of the mothers was 30.8 years (SD 3.9 years) and mean pre-pregnancy BMI was 23.5 kg/mThe proportion of children with elevated T-scores (≥ 65) for each of the CPRS-R:S subscales was 7.6% for Oppositional, 12.2% for Cognitive problems/Inattention, 14% for Hyperactivity, and 9.6% for the ADHD index . The general characteristics for women in each cohort are shown in Supplementary Table The women of the cohort included in this analysis were older, had a higher level of education and social class, and tended to be smokers more than non-participating women  and ADHD index . These associations were not present after adjusting for cohort region, mother’s age, pre-pregnancy self-reported BMI, social class, smoking during pregnancy, total iron intake above the RDA (27 mg/d), mode of delivery, parity, breastfeeding duration, children’s sex, age at delivery, birth weight, birth head circumference, children’s age at the time of the test, and BMI-for-age z-score at 7 years of age. We also added Hb levels during the first trimester of pregnancy to the model in order to evaluate the independent impact of SF levels on outcomes and vice versa. Similarly, no association was observed in the analyses stratified by first and second trimester of pregnancy . We observed no effects of the children’s sex on interactions .Figure The present study investigated the associations between maternal SF and Hb levels during pregnancy and ADHD symptoms in 7-year-old children from the Spanish cohorts of the INMA project. We observed no relationship between these indicators of iron status (SF and Hb) and ADHD symptoms.31. However, the body of evidence regarding maternal SF and Hb levels and their effect on childhood ADHD is much more limited, consisting of only two previous studies21 and the present data, which means that the true extent of any such effects remains unresolved. Our findings here regarding SF levels were relatively inconsistent with our previous findings from the same INMA cohort at age 4 years7. At 4 years old, we reported a significant inverse association between maternal SF levels during pregnancy and Inattentive-type and total ADHD symptom scores in boys, but positive associations in girls. However, no associations were found with Hyperactivity-type symptom scores. This apparent disagreement between the two assessment periods, at 4 and 7 years of age, may be partly explained by the age differences of the children since ADHD symptoms alter over time as children grow33. Also, positive environmental influences  on the brain development of children may have impaired or nullified any effect of maternal ferritin on ADHD symptoms in children at school age. Likewise, other child factors such as SF levels or pharmacological and/or psychological interventions at 4 and 7 years old will also probably influence their neurocognitive abilities. This information is not available now, but it is worth examining in future research. Finally, methodological differences between the two INMA studies should be considered. That is, the instrument that we used to measure the ADHD symptoms (the CPRS-R:S at 7 years old) in the present analysis was different from the previous INMA study  which was completed by the children’s classroom teacher and not by parents. This could decrease the comparability of results between both age periods because agreement between parents and teachers regarding ADHD symptoms is usually relatively poor34. It also limits our ability to disentangle age from both instrument and informant influence on the ADHD symptoms score. Likewise, in the present study, standardized T-scores enabled us to identify the presence and/or absence of ADHD symptoms from the cut-off-scores  so the approach was more clinical.In terms of iron parameters, a large body of evidence suggests that ADHD is related to lower SF levels in children2. We also found sex-related differences in specific symptom profiles, which may be largely due to biological factors related to brain sex differences (e.g. hormones and genes)36; specifically, boys had higher Oppositional and Hyperactivity Symptom scores than girls. However, in contrast with data from the INMA study at 4 years old, we found no evidence for sex differences in the associations between maternal SF levels during pregnancy and children’s T-scores in any of the CPRS-R:S subscales or ADHD symptomatology at 7 years of age .As far as the children’s sex is concerned, in our study, the overall prevalence rate of ADHD symptoms (T-score ≥ 65) was 9.3%, and was slightly higher in boys (10.9%) than in girls (8.2%), which is in line with previous studies21 recently found that maternal anaemia diagnosed before but not after 30 weeks of gestation in a large cohort of 299,768 Swedish women and their 532,232 offspring aged 6–29 was associated with increased offspring risk of ADHD, which co-occurred with autism and/or intellectual disability disorder. Nonetheless, although this association is partly consistent with our findings, it was not statistically significant when only ADHD was considered as the diagnosis. In this regard, to check critical periods of susceptibility, we examined whether the associations between levels of maternal Hb (in the first and third trimester) and SF (in the first and second trimester) and child CPRS-R:S scores might differ depending on the trimester of pregnancy. However, unlike previous studies on child neurodevelopment13, our work consistently yielded null results for ADHD symptoms. It should be noted that our study provided information about SF and Hb levels at different points in pregnancy, so our findings might reflect representative exposure throughout pregnancy. Furthermore, no previous studies have evaluated both indicators of iron status throughout pregnancy.In addition to assessing the iron deposited by ferritin, the present study also examined the relation between maternal Hb concentrations during pregnancy, a marker of iron metabolism used to detect the presence of anaemia with or without iron deficiency, and ADHD in offspring. There was no significant association between maternal Hb levels and anaemia (based on Hb levels < 11.0 g/dL) and any child ADHD symptoms. In this context, Wiegersma et al.37, giving birth at younger ages38, high pre-pregnancy BMI37, smoking40, and breastfeeding duration41. Importantly, in our analyses we controlled for all these factors in addition to other potential confounders or mediators linked to ADHD in the literature, and we found that the associations between maternal SF or Hb levels during pregnancy and the development of ADHD symptoms in children remained unchanged. Taken together, the paucity of available evidence and the inconsistency of findings in this field of research make it difficult to draw any firm conclusions about the causal relationship between maternal SF and Hb levels during pregnancy and ADHD symptoms at school age. Further research is required to confirm/refute this tentative hypothesis.The present study also supported other socio-environmental factors during pregnancy that have been consistently linked to ADHD in offspring, such as lower maternal education and social class44, we obtained information from only one source —the family and not the school. It may be important that ADHD symptoms be perceived by different observers  because these symptoms are required to be present in multiple settings. Moreover, other factors in children such as ferritin levels, intellectual quotient, psychological or pharmacological treatments and familial risk of ADHD, which has been linked to child ADHD symptoms, were not collected. Finally, sample sizes for trimester-specific associations regarding FS were limited , so we cannot discard the possibility that they are underpowered. Thus, this issue merits further research.The present study has several strengths. First of all, the sample size is relatively large, which increases the reliability of any conclusions that are drawn from it. Furthermore, we examined all ADHD symptoms both as a continuous outcome (score) and as a dichotomous outcome (symptom diagnostic criteria) to ensure a more clinical approach. Our analyses were also controlled for a wide variety of modifiable prenatal and postnatal factors related to the risk of ADHD symptoms. Nevertheless, we also acknowledge some limitations. Firstly, the study assessed ADHD symptomatology but not diagnosis with standardized criteria. Thus, the CPRS-R:S collects symptoms from the last month but does not assess duration and severity, the age of onset, or interference in child functioning. In addition, although the Conners’ Parent Rating Scale has shown good psychometric properties in Spanish school populations and is reliable and valid for detecting ADHDIn summary, this study provides no evidence to support any relationship between maternal iron status during pregnancy and symptom severity or risk of ADHD symptoms in 7-year-old children. Nevertheless, these findings should be replicated with the use of fully standardized ADHD diagnostic instruments during different assessment periods and for longer follow-up times if we are to understand the trajectory patterns of this complex outcome. Randomized trials are also required to determine how different doses of iron supplementation during pregnancy adapted to initial levels of SF and Hb can affect ADHD diagnosis in offspring.Supplementary Information.


Previous research highlighted that adolescents with attention-deficit/hyperactivity disorder (ADHD) are four times as vulnerable to suicidal behavior as the healthy population. Maladaptive perfectionism is also viewed as an important risk factor for suicide. Yet, there are no studies which focused on the relationship between perfectionism and suicide among adolescents with ADHD.The objective of the present study was to explore if perfectionism may be a risk factor for suicidal behavior in adolescents with ADHD.The clinical group was recruited from outpatient clinics, while the non-clinical group was recruited from high schools around Hungary. The clinical group’s inclusion criterion was ADHD diagnoses, while the non-clinical group required the absence of any current or past psychiatric treatment or diagnoses.In the ADHD group 88 adolescents participated, and 96 adolescents participated in the non-clinical group. There was no difference regarding the level of perfectionism in the groups, except one dimension of perfectionism, which is ‘Organization’. The ADHD group had significantly higher level of suicidal behavior than the control group ((χ2 (1) = 11.222, p < .001, V = 0.25). Among the ADHD group adaptive perfectionism was significantly negatively correlated with suicidal behaviour.Adolescents with ADHD did not have a different level of perfectionism than the healthy control group only in ‘Organization’ trait. This result could add to the therapeutic work with adolescents diagnosed with ADHD with underlining the importance to focus on organizational skills. The result highlights that adaptive perfectionism appears to be a protective factor against suicidality.No significant relationships.


Sleep disturbances may be a significant source of distress for children with neurodevelopmental disorders, and consequently also for their families. Crucially, sleep disturbances might be influenced by comorbidity. Attention deficit hyperactivity disorder (ADHD) and specific learning disorder (SLD) often co-occur, and consequently, investigating sleep disturbances in children with comorbidity of ADHD and SLD is essential. Our study aimed at detecting sleep difficulties in a group of 74 children with ADHD, 78 children with SLD, and 76 children with ADHD and SLD by using the Sleep Disturbances Scale for Children. The results showed that sleep difficulties emerge more clearly in children with comorbid ADHD and SLD compared to children with only ADHD or SLD. These sleep difficulties were not due to differences in ages and behavioral/emotional problems. In conclusion, evaluating sleep disturbances is important when assessing and managing children with ADHD, SLD, and particularly with the two comorbid conditions, to better understand their difficulties and develop tailored interventions. Sleep disturbances are common in children with neurodevelopmental disorders and might become a significant source of distress, compromising the quality of life of both children and families . InsuffiSleep disturbances have been unevenly studied in neurodevelopmental disorders. In children with attention deficit hyperactivity disorder (ADHD), 55% to 74% of sleep difficulties have been documented , such asHowever, findings documenting atypical sleep and reduced sleep quality in children with ADHD are controversial ,14,15. AWhen sleep measures were collected via actigraphy , childreUnlike ADHD, sleep difficulties in children with specific learning disorders (SLD) have been overlooked. In the pioneering study by Mercier et al. , the sleBruni et al.  measuredSleep disorders may be exacerbated in the case of comorbidity ,25,26,27Sleep disorders have never been investigated for comorbidity between ADHD and SLD, despite the two disorders having a very high co-occurrence ,29 with The present study aimed to investigate sleep disturbances in ADHD and SLD and to clarify how sleep disturbances are affected by ADHD and SLD comorbidity. To this end, we compared a group of children with ADHD and SLD comorbidity (ADHD+SLD), a group with ADHD, and a group with SLD on the scores of the Sleep Disturbances Scale for Children .Children and adolescents with ADHD+SLD, ADHD, and SLD were retrospectively selected on the basis of age and IQ from a large database. This database consisted of several hundred outpatients with behavioral problems and/or learning difficulties referred to the Child and Adolescent Neuropsychiatry Unit of the Bambino Gesù Children’s Hospital in Rome for in-depth diagnostic investigation. All participants were evaluated between 2017 and 2020 by expert neuropsychiatrists and developmental neuropsychologists.The criteria for inclusion in the study consisted of having a diagnosis of ADHD and/or SLD (reading disorder and/or math disorder and/or writing disorder) according to DSM-5  criteriaThe diagnosis of ADHD was made according to DSM-5 criteria  based onThe diagnosis of SLD, reading disorder, and/or math disorder and/or writing disorder was diagnosed when the performance (level of accuracy or speed) was at least 2 SDs below the mean for school-age on norm-referenced measures ,42,43,44The final sample consisted of: 74 participants with ADHD , 78 participants with SLD , and 76 participants with ADHD+SLD . The IQ scores were obtained using the Wechsler Intelligence Scale for Children-IV  or the c2,225 = 1.01, p = 0.36, ηp2 = 0.01) and for IQ .In accordance with matching criteria, children with ADHD+SLD, ADHD, and SLD did not differ for chronological age  is an eThe SDSC provides a standardized measure of sleep disturbance in childhood and adolescence through a sleep index score. The development of the SDSC was based on a database of a large population in order to define normal values and identify children with disturbed sleep . TherefoThe Child Behavior Checklist for Ages 6–18  is a widA Chi-square test for association with the odd ratios (ORs) and 95% confidence intervals (95% CI) was conducted to compare the number of participants with clinical scores of each group  in each SDSC subscale . To take into account multiple comparisons , the Benjamini–Hochberg procedure was adopted .A repeated-measure analysis of variance (RMANOVA) with the Group  as between-subject factors and SDSC Subscales  as within-subject factors was run to test whether scores of SDSC subscales differed among groups.Another RMANOVA with the Group  as the between-subject factor and CBCL broadband scales  as the within-subject factor was run to verify whether the scores of CBCL broadband scales differed between groups.2) were reported as measures of the effect size.For both RMANOVAs, post hoc analyses were conducted by means of Tukey’s HSD tests. Partial eta squares (ηpp = 0.05/12 = 0.004). Additionally, Pearson’s correlation was used to measure the relation between scores of SDSC subscales  and scores of CBCL broadband scales . To take into account multiple comparisons , Bonferroni correction was applied  was run, with the Group  as between-subject factors, the SDSC subscale  as within-subject factors, and the CBCL broadband scale as the covariate.As shown in 2,225 = 11.43, p = 0.001, ηp2 = 0.09) was found. Post hoc analyses (Tukey’s HSD tests) showed that children with ADHD+SLD had significantly higher scores than children with ADHD (p = 0.011) and children with SLD (p = 0.001). Coversely, children with ADHD and children with SLD did not differ (p = 0.157)  .5,1125 = 22.66, p = 0.001, ηp2 = 0.09). As shown in 10,1125 = 1.31, p = 0.224, ηp2 = 0.01). A significant main effect of the SDSC subscale was also found , with lower scores (Tukey’s HSD tests) in children with SLD than in children with ADHD (p= 0.001) and children with ADHD+SLD (p = 0.001), while children with ADHD and children with ADHD+SLD did not differ (p = 0.214). A significant main effect of the CBCL broadband scale was also found  with scores (Tukey’s HSD tests) of the internalizing problems subscale significantly higher than scores of the externalizing problems subscale (p = 0.001). In addition, the Group × CBCL broadband scale interaction was significant . Post hoc analyses (Tukey’s HSD tests) showed that scores of internalizing problems were significantly lower in children with SLD than in children with ADHD+SLD (p = 0.019), whereas scores of externalizing problems were significantly lower in children with SLD than in children with ADHD (p = 0.001) and with ADHD+SLD (p = 0.001). Children with SLD and children with ADHD did not differ on internalizing problems scores (p = 0.989), and children with ADHD and with ADHD+SLD did not differ in externalizing problems scores (p = 0.998).Regarding differences among groups on the CBCL broadband scales scores, a significant main effect of the Group was found , with higher scores in children with ADHD+SLD than in children with ADHD (p = 0.003) and with SLD (p = 0.001). In addition, the main effect of SDSC Subscale was still significant . The Group × SDSC subscale interaction was not significant , as in the previous analysis without covariates.In order to take into account the possible influences of emotional and behavioral symptoms in comparing the three groups on sleep disturbances, group differences in SDSC subscales were tested controlling for CBCL broadband scale scores. A significant main effect of the Group was confirmed  or differences in behavioral and emotional problems .The critical role of sleep on cognitive functioning has emerged in numerous studies. In children and adolescents who had undergone sleep education programs, improvements in sleep quality were associated with improvements in cognition and academic performance ,49. IndeTo assess sleep disturbance in children with ADHD and SLD, we opted for the SDSC questionnaire . This inIn children with SLD, studies using the SDSC are very sporadic and have yielded mixed results: Some studies have documented problems with initiating and maintaining sleep, sleep breathing, and arousal , while oAccording to our findings, comorbidity between ADHD and SLD exacerbates sleep disorders. Specifically, the number of children with ADHD and SLD comorbidities who had clinical levels of disorders in initiating and maintaining sleep, disorders of arousal, sleep–wake transition disorder, and disorders of excessive somnolence was higher than that of children with SLD. In addition, the number of children with ADHD and SLD comorbidity and clinical levels of sleep–wake transition disorder and nocturnal hyperhidrosis exceeded that of children with ADHD. Since comorbidity between ADHD and SLD can be as high as 76% , the incOur findings indicate that sleep disturbances should not be overlooked, especially when there is comorbidity between ADHD and SLD. It is important to take this into account because of the role that sleep disturbances have on memory, learning, attention, or executive functioning. In children with ADHD, sleep difficulties have been found to be associated with lower attention skills, specifically the ability to remain alert and vigilant to numerous incoming stimuli ,68,69, aIn addition, it is critical to understand how sleep disturbances interfere with the effectiveness of treatments for ADHD and SLD . To dateHowever, brief behavioral sleep therapy can result in wide-ranging benefits, such as reduced sleep difficulties, alongside improvement in ADHD symptoms, classroom behavior, and working memory tasks ,77. SimiContrary to previous reports ,26,27, sOur study has some limitations. The main one is the lack of a control group. Comparison with a control group could help clarify whether and how much sleep disturbance is exacerbated by the presence of a neurodevelopmental disorder.Another limitation is the lack of objective measures to assess sleep such as polysomnography and actigraphy. Although evidence supports the validity and reliability of sleep questionnaires, particularly the SDSC , future Another aspect that was not assessed in our study was cognitive measures, such as memory and executive functioning. This would allow us to study how any difficulties in memory, learning, and attention are associated with sleep problems in the neurodevelopmental disorders we examined.Future studies are needed to assess the effects on sleep disturbances of other potentially crucial factors, such as drug treatment and socioeconomic status.Finally, future longitudinal investigations would also be needed to explore how sleep disturbances may have long-term consequences for neurodevelopmental disorders.Our results showed that ADHD and SLD are associated with sleep disturbances and that when the two disorders coexist, sleep disturbances are greater. In conclusion, this result confirms and highlights how complex the relationship between neurodevelopmental disorders and sleep disorders is. Furthermore, this relationship might be bidirectional ,12,13. NUnderstanding this relationship is important when assessing and managing patients with ADHD, SLD, and the two comorbid conditions to better understand their difficulties and develop tailored interventions while also paying attention to sleep difficulties.


Novel P2Y12 ADP receptor blockers (ADPRB) should be preferred in dual-antiplatelet therapy in patients with acute coronary syndrome. Nevertheless, there are still patients who do not respond optimally to novel ADP receptor blocker therapy, and this nonoptimal response  could be connected with increased risk of adverse ischemic events, such as myocardial re-infarction, target lesion failure and stent thrombosis. In addition, several risk factors have been proposed as factors associated with the phenomenon of inadequate response on novel ADPRB. These include obesity, multivessel coronary artery disease, high pre-treatment platelet reactivity and impaired metabolic status for prasugrel, as well as elderly, concomitant therapy with beta-blockers, morphine and platelet count for ticagrelor. There is no literature report describing nonoptimal therapeutic response on cangrelor, and cangrelor therapy seems to be a possible approach for overcoming HTPR on prasugrel and ticagrelor. However, the optimal therapeutic management of “resistance” on novel ADPRB is not clear and this issue requires further research. This narrative review article discusses the phenomenon of high on-treatment platelet reactivity on novel ADPRB, its importance in clinical practice and approaches for its therapeutic overcoming. Novel P2Y12 ADP receptor blockers (ADPRB), namely prasugrel, ticagrelor and cangrelor, have emerged as a potent therapeutic approach for ADP signaling pathway inhibition in patients with acute coronary syndromes (ACSs), with  or withoThe aim of this article is to provide a brief traditional (narrative) review, which summarizes current data regarding the prevalence and clinical significance of HTPR on novel-generation ADPRB, namely prasugrel, ticagrelor and cangrelor, in patients with acute coronary syndrome. To achieve this aim, the most relevant medical scientific literature databases—Web of Science, PubMed and Scopus—were searched, using selected keywords: “high on treatment platelet reactivity” or “resistance” or “insufficient response” and “prasugrel” or “ticagrelor” or “cangrelor” and “acute coronary syndrome” or “myocardial infarction” or “STEMI” or “NSTEMI” or “unstable angina”. If needed, additional keywords, such as “major adverse cardiac event” or “stent thrombosis” or “stent failure” or “target lesion failure” were added, and the literature was researched. The authors non-systematically identified relevant articles matching their aim. Subsequently, a review of findings from these articles was provided, together with a discussion of the clinical implications of published observations.ADPRB treatment failure is a major risk factor for stent thrombosis and early PCI failure . PatientDespite the abovementioned evidence, there is still an ongoing discussion about the association between antiplatelet drugs HTPR and major adverse cardiovascular events (MACE), and the clinical implication of antiplatelet therapy HTPR is not fully determined. Several factors could be responsible for this ambiguity. First, the results of so-far published studies are controversial , and there are studies that did not confirm the relation between HTPR and the risk of future ischemic adverse events ,21,22,23®, VerifyNow®, PFA-100® and platelet mapping thromboelastography® (TEG®), have been designed. Multiplate®  is a point-of-care assay, which tests citrated whole blood samples using the electrical impedance aggregometry principle. The assay uses platelet stimulation with specific inducers (ADP) to activate platelet aggregation. Once the aggregated platelets attach the sensor wires in the Multiplate® device, electrical resistance (impedance) is detected and displayed as aggregation units (AUs) against time (area under the curve = AUC) [®  assay is performed as a point-of-care test using a citrated whole blood sample. In this turbidimetry-based assay, ADP induction is used to initiate platelet aggregation on fibrinogen-coated beads. Platelet aggregation is determined by the percentage of the light transmission and expressed in P2Y12 reaction units (PRUs). Low PRU indicates the high P2Y12 receptor inhibition and better response to P2Y12 ADPRB. VerifyNow® assay is a rapid test, which can be performed even at the bedside within 5 min, which is an advantage when compared with LTA and VASP-P assays. Moreover, the examination itself (due to a simple technique) and the interpretation of results can be carried out easily . Both assays have been used for PFT in post-marketing studies, including randomized ones [®  is another point-of-care assay, which can be used to monitor the effect of P2Y12 ADPRB. The assay uses citrated whole blood sample and measures the platelet aggregation and effect of antiplatelet agents under higher shear stress. This test can be performed rapidly (in less time) and, similarly to VerifyNow® assay, has a simple test technique, which is an added advantage when compared with conventional PFT. PFA-100® has collagen-coated, epinephrine-coated and ADP-coated cartridges. If ADPRB is present in a sample, the blood will flow under higher shear rate through the capillary and through a small aperture of the PFA-100® analyzer. Subsequently, platelets will aggregate and form the ADP-induced platelet plug by blocking the aperture. The time taken for complete occlusion of the aperture is recorded as closure time (CT). Prolonged CT indicates a better response to ADPRB [® assay has been used in clinical studies mostly for the detection of aspirin resistance [® assay, cut-off values of >280 PRU, >272 PRU, >235 PRU and >230 PRU have been used to define HTPR in previously published studies [®, at least two cut-off values  have been reported. All these unclosed issues could explain the ongoing discussion regarding the clinical implication of HTPR.Fourth, there is an issue in laboratory testing for HTPR detection. In fact, various platelet function tests (PFTs) with different test principles have been tested  for the detection of HTPR . Some ofe = AUC) . VerifyNzed ones ,30,32. Psistance ,34; howesistance . On the sistance ,37. Addi studies ,30; for Nonetheless, considering the fact that, with clopidogrel, ADP-induced platelet aggregation remains significantly high in ACS patients, even after 48 h from standard loading , it is urd-generation thienopyridine P2Y12 ADPRB, which is indicated for combined (with aspirin) antiplatelet therapy in PCI-treated patients with ACS [Prasugrel is an irreversible, 3with ACS . Prasugrwith ACS  provideswith ACS ,19.rd-generation non-thienopyridine P2Y12 ADPRB, approved for combined antiplatelet therapy in patients with ACS (with or without PCI) and for long-term combined antiplatelet therapy in coronary artery disease (CAD) patients with high ischemic and low bleeding risk [Ticagrelor is a reversible, 3ing risk . Ticagreing risk ,39,40. Aing risk ,41,42 anCangrelor is a reversible, parenteral, 3rd-generation non-thienopyridine P2Y12 ADPRB, which is indicated for combined antiplatelet therapy in patients undergoing PCI (both for ACS and stable CAD) who are not pre-treated with oral ADPRB . Cangrel®) in 103 consecutive, high-risk ACS patients 12 to 24 h after administration of loading dose (60 mg) of prasugrel. The authors of this study reported significant inter-patient variability in platelet reactivity after all doses of prasugrel, and the prevalence of HTPR was significantly higher during the maintenance dose administration. On the other side, another study enrolling PCI-treated ACS patients receiving prasugrel reported HTPR (defined as VASP-P index > 50%) 2 to 4 weeks after hospital discharge only in 6.8% of patients [In one of the first studies examining the prevalence of insufficient response on prasugrel, Bonello et al.  reportedpatients . Similarpatients . A previpatients  reportedpatients . Howeverpatients ,54, in tBased on these data , one couA question regarding the mechanism of prasugrel HTPR could be posed. In fact, right now, no satisfactory answer to this question exists, as there is no study examining this problem. Theoretically, several factors could be responsible for this insufficient drug response . PrasugrAlthough first observations reported no risk of HTPR on ticagrelor ,61, LainLooking at the mechanism of ticagrelor HTPR, it is obvious that impaired (pro)drug conversion (metabolism) does not play a role, as ticagrelor is an active metabolite, which does not require metabolic transformation to achieve its drug activity. In theory, all the other possible mechanisms discussed in connection with prasugrel HTPR  could beLooking at the currently available data, there is no study examining the prevalence of cangrelor HTPR in patients with acute coronary syndrome, no study describing this phenomenon or clinical case report describing a case of ischemic adverse post-PCI event related to failure of cangrelor therapy. Moreover, cangrelor seems to be a promising agent for treatment (overcoming) prasugrel HTPR ,80 or to2) [The next question should be what are the risk factors for HTPR on novel-generation ADPRB? Searching the literature, several factors have been proposed as factors associated with this phenomenon. For prasugrel, obesity (BMI > 30 kg/m2) ,82,83,842) , carryin2) ,86, high2)  and impa2)  have bee2) , type 2 2) , elderly2) , were st2) . Verdoia2)  reported2) . Other c2) ,90,91.In theory, novel-generation ADPRB HTPR can be managed by modification of drug dosing (either with re-loading or increasing the maintenance dosage) , by addiBased on the limited evidence discussed in this review article, we can conclude that the phenomenon of HTPR or resistance on novel-generation ADPRB therapy might exist. The prevalence of novel-generation ADPRB HTPR is lower compared to clopidogrel HTPR. Additionally, several studies suggested that this phenomenon could be connected with a high risk of adverse ischemic events; however, the evidence for this association is still limited. Therefore, there is a need for future research dedicated to clinical impact and optimal management of this phenomenon.


Attention-deficit/hyperactivity disorder (ADHD) is one of the common neurodevelopment disorders. Children with ADHD typically have difficulties with emotional regulation. Previous studies have investigated the assessment for underlying emotional biases using the visual probe task. However, one of the significant limitations of the visual probe task is that it is demanding and repetitive over time. Previous studies have examined the use of gamification methods in addressing the limitations of the emotional bias visual probe task. There has also been increased recognition of the potential of participatory action research methods and how it could help to make the conceptualized interventions more relevant.The primary aim of this study was to collate health care professionals’ perspectives on the limitations of the existing visual probe task and to determine if gamification elements were viable to be incorporated into an emotional bias modification task.A co-design workshop was conducted. Health care professionals from the Department of Development Psychiatry, Institute of Mental Health, Singapore, were invited to participate. Considering the COVID-19 pandemic and the restrictions, a web-based workshop was conducted. There were 3 main phases in the workshops. First, participants were asked to identify limitations and suggest potential methods to overcome some of the identified limitations. Second, participants were shown examples of existing gaming interventions in published literature and commercial stores. They were also asked to comment on the advantages and limitations of these interventions. Finally, participants were asked if gamification techniques would be appropriate.Overall, 4 health care professionals consented and participated. Several limitations were identified regarding the conventional emotional bias intervention. These included the nature of the task parameters, included stimulus set, and factors that could have an impact on the accuracy of responding to the task. After examining the existing ADHD games, participants raised concerns about the evidence base of some of the apps. They articulated that any developed ADHD game ought to identify the specific skill set that was targeted clearly. Regarding gamification strategies, participants preferred economic and performance-based gamification approaches.This study has managed to elucidate health care professionals’ perspectives toward refining a conventional emotional bias intervention for children with ADHD. In view of the repetitiveness of the conventional task, the suggested gamification techniques might help in influencing task adherence and reduce the attrition rates. Attention-deficit/hyperactivity disorder (ADHD) is one of the common neurodevelopment disorders. Children with ADHD typically display symptoms such as hyperactivity, impulsivity, and inattention . These iAlthough the visual probe task appears to be a relatively simple task to administer for the measurement of underlying emotional biases, and potentially for modifying biases, it is not without its inherent limitations. The numerous repeats that an individual needs to complete make such an intervention laborious. In recent years, serious games and gamification technologies have been considered for conventional psychological interventions ,7. It isMore recently, regarding ADHD, there have been further studies examining the evidence base of existing games for individuals with ADHD and the potential of gamification for serious games targeting individuals with ADHD. Jiang et al  conducteThere has also been increased recognition of the potential of participatory action research methods and how it could help to make the conceptualized interventions more relevant . TherefoPrinciples of participatory action research were used for this study. A co-design workshop was conducted, and relevant key stakeholders  were invited. Only health care professionals were invited, as they had knowledge of the psychiatric conditions and were best able to advise how the task could be modified, while adhering to the evidence base.Health care professionals from the Department of Development Psychiatry, Institute of Mental Health, Singapore, were invited to participate. A diverse group of health care professionals was invited, and it included both psychiatrists and psychologists. We had originally planned to recruit occupational therapists also, but none of them expressed an interest in participating in the study.On the basis of our previous protocol , we planOwing to the current COVID-19 pandemic and local governmental restrictions, we applied for the conduct of the workshop via the web. Therefore, all participants  who have had expressed interest were contacted separately to sign the informed consent form. The participants also had to complete a baseline demographic questionnaire individually. This questionnaire collated information regarding age, sex, and years of experience in treating children and adolescents with psychiatric disorders. Upon completion of the questionnaire, the principal investigators liaised with each of the participants separately to identify a common time for conducting the web-based workshop.The workshop was subsequently conducted on May 19, 2021, via the web. Both principal investigators facilitated the workshop and recorded the field notes. All participants  were informed of the study’s rationale and the session’s specific objectives. Participants were also informed that their responses and comments were confidential and that the session would be audio-recorded. All participants  were given participant numbers to identify themselves, to provide further anonymity. First, participants were shown an example of the visual probe task paradigm that has been traditionally used for cognitive bias modification. The example that participants viewed was based on the previous study by Zhang et al “The design of the task, flashing multiple images in quick succession, can be distressing and could cause fatigue.” [Participant 1]“I think the number of trials is ok. I think the speed I am not comfortable with.” [Participant 3]“I am wondering about the practice trial. There are 8 trials. Do they go at the same speed as the actual 32? I don’t know whether existing emotional bias trials. When it is applied to children and adolescent. Could the speed be moderated? Or you could do half half. 8 which is lower speed to aid understanding the next 8 is at actual speed.” [Participant 2]“I think just now my mind was a blank at the speed. Wow. What was there. Even I know what the instructions were and what I am supposed to do, I was not able to process when I saw the program.” [Participant 4]Theme 2Limitations—Stimulus setVerbatim comments“The other thing I wonder whether erm. In terms of the pictures, would it make a difference if you are used Asian versus Caucasian pictures. Would it make a difference?” [Participant 4]“I am just wondering about the size of the photos. Some of the photos were quite big. Because the speed was quite fast, all I saw was a blur of colours. For this current picture, there was white space. For the previous example, all I saw was a blur of colours.” [Participant 4]“I just want to echo the other respondent. If you could frame the picture like in the slide now, it homes the picture better. Rather than big white background. Black border, framing into a small visual field, might be more user-friendly.” [Participant 1]Theme 3Limitation—Other confounders that may affect the accuracy of the taskVerbatim comments“Whether the speed would trigger impulsivity and so. Perhaps there is a confounder. Impulsivity or desire to put in an answer. Might confound with reaction time in measuring attentional biases. This is my gut feel. I do not know the research behind it.” [Participant 2]“Children with ADHD do have comorbidities. Some of them have processing speed abnormalities. Could confound. Going back to your inclusion criteria you might want to think about.” [Participant 3]“I am concerned about impulsivity. Because it is going so far, I suspect that it is still going to be quite novel for kids with ADHD. But novelty aside, I think if they don’t know what they are doing, they just guess. You probably get a big bias which is not what you are looking for.” [Participant 2]Theme 4Recommendations pertaining to presentation of the stimulus setVerbatim comments“For this current picture, there was white space. For the previous example, all I saw was a blur of colours.” [Participant 4]“I just want to echo the other respondent. If you could frame the picture like in the slide now, it homes the picture better. Rather than big white background. Black border, framing into a small visual field, might be more user-friendly.” [Participant 1]In this phase, participants were asked to provide their perspectives about the existing ADHD games. Several themes arose from the discussion. Participants highlighted that the games needed to be age-appropriate and clearly explain the specific skill sets that were targeted. Participants also raised concerns regarding the scientific evidence base for some of the presented games. Participants also highlighted issues with existing games regarding their novelty and stated that the consideration of novelty was important when implementing games for individuals with ADHD.Theme 1Being age-appropriateVerbatim comment“Erm. I think these games appear to cater to different age groups. The animations. Some of them appear more sophisticated than other. For example, the first game appeared more sophisticated and complex. The third one seems to cater to younger population. So I think we need to be aware of how appealing it is to each age group of the child is in.” [Participant 1]Theme 2Skill sets targetedVerbatim comments“The second one, Jumpy car seems to be psychoeducational. Comprehensive package of game and psychoeducation. For psychoeducation, the second games seemed to be having more of that. For the other two, it seems to focus on skills and skills building. That is my first and most immediate observations of these games.” [Participant 1]“The other thing I noted for the second one. Between the games they give you psycho education.” [Participant 4]“I do quite like Jumpy car ADHD. I don’t have ADHD but I thought it is a good tool to engage them and helping them to understand what ADHD is. Of course, I have checked out the language and whether it is child friendly. Not sure about this memory card game. not sure what it was targeting about.” [Participant 2]“This is number 3. I also like the jumpy car and I do have ADHD. I can’t download it. Just had a thought. Just now you mentioned about combining. Jumpy car just seemed to get through all the distractors and getting to the point destination. Wondering if you could combine that frustration with not being able to cross the hurdles. So, the distractions. When they cannot cross the distractions, they are somehow emotional. So, one way may be is to add on to that. Does that make sense? Instead of getting from A to B, that it. Just to get rid of the distractor or to recognise the distractions. Teach them to recognise their emotions. A cognitive component to it.” [Participant 3]“Just wondering about the objective of doing emotional bias modification game for children with ADHD. So, what are we hoping the kids with kids with ADHD would become after the end of the game?” [Participant 2]“Mine is along the same line. What is the game setup to do. Is it going to be specific for emotional biases, capturing emotional biases. So the game, how it is designed, needs to tackle that. It needs to be valid and also be specific. Intending to assess and moderate. Teach skills on how to minimise the emotional biases. Some of the games shared seemed to focus on different skill sets. Jumpy car was to ignore distractions. So there was actually no emotion. Not much emotional component to that. And then the third one. About ADHD memory game. More like on working memory. They may be. My sense is that they are targeting different deficiencies seen in ADHD. I think the game design would have to include situations in which they could trigger emotional reactions. Frustrations or disappointments. We do understand from past research. The brains of the child is different from adult. Different parts of the child brain is being activated when given a similar task, compared to adult brain. And there is also less. They also have more problem, for teenagers especially, in recognising neutral emotions, they tend to over interpret neutral faces as anger. If you want to have a game that addresses emotional biases, then we have to also take on this consideration as well. The game must be specific to you know. To target emotional situations for example.” [Participant 1]“I think I may have misunderstood what you have asking. I think it is viable to convert to game. But like what participant 1 said, it has to be a situation that evokes the emotions. It is rather challenging now to kind of. Scope it in games, especially for our gen Z population right now. Just having situations taking example, game I, this is not going to really elicit that. Back to the previous point where you presented with ADHD games. Different ADHD games train different functions. Memory game would be working memory. Jumpy car would be impulsive control, or distraction. If you could add that emotional component to existing game. Would it be adding another layer? That is what I am trying to say? They run into situations and they do react. If there is a psycho edu component, what you can do about it and what you could do about it. Do I make sense now?” [Participant 3]“I am also wondering how the kids can play this and how this can be translated to real life. Because a lot of times they play the game, the skills stay in the game. When I am out in the real world, everything in the game, the skills I learnt does not apply in the real world. Some way for the kids to know that the skills they applied can be applied to the real world. Maybe like a short film clip or someone demonstrating that skills can be used. Kids should know that this is something that can be used in the real world.” [Participant 4]Theme 3Scientific evaluationsVerbatim comment“I suppose I am wondering that in terms of games that have been subjected to research evaluations, in terms of the follow-up period, whether the improvement have been sustained. I know that endevour RX has some trials back. Data sustained attention. What sort of ratings are being used during the trial. We have a few of attention improvement games. We also try to include blinded and objective rating for example measuring brain waves to measure whether there are actual changes. I wonder about the follow-up period, sustainability in terms of improvement and whether there are any objective measures for these kinds of game. Ditto for those who does not have any research behind.” [Participant 2]Theme 4Novelty and motivation to useVerbatim comments“The other thing I noted for the second one. Between the games they give you psycho edu. If there is a skip function, I suspect that a lot of kids would skip and go to the game. They might not listen to it at all. If it is too repetitive and increasing in difficulty, kids would just give up especially when the novelty wears out. They try out the first few stages, but it is getting tougher, I just skip to something else.” [Participant 4]“I am going to start that I don’t know enough about EB games. I wonder about. If we have a monkey going down the supermarket, ignoring negative emotional faces. number 1. I am thinking about novelty. After a while ADHD kids would lose interest. Number 2 is it going to have an impact on emotional dysregulation. Games are seemingly more friendly platform to engage kids with ADHD versus paper and pencil. There is definitive value in gamifying it. Effectiveness whether it does modify EB. How do we make it more interesting? Stage base. Can’t be monkey going down the aisle. They are going to get bored soon.” [Participant 3]In this phase, the facilitator explained to the participants more about the common gamification strategies that have been used. Then, participants were asked to select the most appropriate gamification strategies that could be applied to the conventional emotional bias modification task. Strategies such as economic and performance-based gamification were deemed to be more appropriate.Theme 1Economic approachesVerbatim comments“Like in my work with children and parents with ADHD. Often talk about how children with ADHD are motivated by 3 different factors. First novelty, second interest and third competition. I am looking at the gaming approaches. Things like having economic gamification approach, having digital rewards or real-world rewards might be one.” [Participant 2]“I think digital rewards will be helpful. A lot of kids have problems with delayed gratification. Some form of immediate reward would be helpful.” [Participant 1]“I agree with what has been said as well. And also, I think the kids are motivated when they can buy some. They like to browse the store and see what they can buy.” [Participant 4]“I have been taking about novelty.Real world prizesmight be more relevant. After a while, digital rewards might not be too attractive for them.” [Participant 2]Theme 2Performance-based approachesVerbatim comments“The other thing that I am looking at is performance orientated gaming approach. Where there is some sort of competition. Mindful that it is not too hard for the child. That the child is being ranked very far below. Competition, having that interest, economic gamification. Those two are ones to go with.” [Participant 2]“A lot of local kids have a competitive edge as well. Having a game, allowing them to level up. A lot of reinforcement, feedback that reinforces the child behaviour would fare better.” [Participant 1]“I agree with 1 and 2. The performance one, like what 2 said. Ranking low might result in them losing motivation.” [Participant 3]Theme 3Inappropriate strategiesVerbatim comment“I have been taking about novelty. Real world prizes might be more relevant. After a while, digital rewards might not be too attractive for them. You asked about which techniques are not suitable. I do wonder about the team part. Where they play with other people or interact with other community. Some of the children I work with have bad experiences gaming in teams, where they have social conflicts. We do see some form of social conflicts in children with ADHD. That a question mark for me. There are ones who go onto form close knitted communities?” [Participant 2]Theme 4Risk of gamificationVerbatim comments“I generally do not have any concerns about gamification as treatment modality. My concern is how accessible it is and its affordability as well. I think gamification has the benefit of allowing participant to play the game at his own time, under the supervision of caregiver or parent. Therapy could take place outside of the clinics. Probably more about accessibility and affordability. Probably more research studies to show that It works over the long term.” [Participant 1]“I would always caveat it. It must be supervised and moderated by adults. ADHD population has problem moderating screen time.” [Participant 2]Introduction section, which demonstrated the presence of emotional biases among children and adolescents with ADHD. In our study involving health care professionals, several limitations were identified regarding the conventional emotional bias intervention. These included the nature of the task parameters, included stimulus set, and factors that could have an impact on the accuracy of responding to the task. After examining the existing ADHD games, participants raised concerns about the evidence base of some of the apps. They articulated that any developed ADHD game ought to clearly identify the specific skill set that was targeted. When health care professionals were eventually asked to select gamification strategies that could improve the conventional intervention, they preferred economic and performance-based gamification approaches.This is the first study that has explored the use of participatory action research as a research design to refine the conventional emotional bias modification task. This study complements the ongoing research that has been highlighted in the Some of the identified limitations of the existing conventional visual probe paradigm used for the assessment of emotional biases are congruent with the findings of previous studies. In our study, health care professionals identified limitations pertaining to the task parameters, particularly that which pertains to the speed of presentation of the stimulus set. This is congruent with the previous co-design workshop, by Zhang et al , involviOne of the concerns raised by health care professionals about existing ADHD games was whether these games were based on validated frameworks and adhered to the evidence base. In our workshop, we presented participants with examples of ADHD games that are commercially available, some of which have been previously evaluated. In a recent review by Penuelas-Calvo et al , they exOur participants also reported various gamification strategies that may benefit our emotional bias assessment task. Previous study has justified the importance of considering gamification strategies, given that they help with the improvement of engagement rates and reduction of dropouts . The perThe main strength of this study was the use of co-design methods in the refinement of an existing evidence-based paradigm for the assessment of emotional biases. This helped to ensure that the eventual design is based on evidence but meets the potential needs of end users. This study also presented examples of existing ADHD apps to participants. In doing so, we were able to allow the participants to have a better in-depth understanding of existing apps and identify issues and limitations with existing apps. Despite these strengths, our study had several limitations. Although we initially planned to recruit a total of 8 participants, we managed to eventually recruit only 4 (50%) participants. The COVID-19 pandemic affected our ability to recruit participants, as they may have to attend to other clinical needs. In addition, although we had previously planned for a physical workshop, the COVID-19 pandemic prevented the execution of such a workshop owing to infection risks. Thus, we were limited to conducting a web-based workshop, which may have resulted in challenges among participants in responding. It would be ideal to also obtain insights from patient participants or their caregivers.This study has managed to elucidate health care professionals’ perspectives on the refinement of a conventional emotional bias intervention for individuals with ADHD. Taken together, gamification strategies could be applied to conventional emotional bias interventions. The findings from this study have implications on the subsequent studies seeking the personalization and gamification of such apps. Although we have sampled the perspectives of health care providers, it remains necessary to discuss these perspectives with the intended sample group as the next step, to ensure that the future conceptualized app will be consistent with their needs.


Several studies have observed an inverse relationship between attention deficit hyperactivity disorder (ADHD)-related behavior of children, as reported by parents or teachers, and the amount of green space in their residential environment. Research using other, more objective measures to determine ADHD prevalence is scarce and could strengthen the evidence base considerably. In this study, it is investigated whether a similar beneficial association will be observed if the use of ADHD-related medication is selected as an outcome measure. More specifically, registry data from a health insurance company on the reimbursement of ADHD-related medication in 2011 were available for 248,270 children between 5 and 12 years of age. Amounts of green space within 250 and 500 m of the home address were calculated. Multilevel logistic regression analyses for the prevalence of use were conducted, including the following covariates: sex, age, urbanity of the neighborhood, neighborhood socioeconomic status (SES), and percentage of people with a non-Western migration background in the neighborhood population. Results showed that the amount of green space was inversely related to the prevalence of use of ADHD medication. Moreover, the relationship was strongest among children living in the least wealthy neighborhoods and absent among those living in the wealthiest neighborhoods. Results also show that in less wealthy neighborhoods, there is, on average, less green space available nearby: children who are likely to benefit most from nearby green space tend to have the least of it. Due to increasing urbanization, daily contact with nature is becoming less common, also for children . A systeThis latter result is consistent with a much larger body of experimental evidence, mainly based on research on adults, showing that contact with nature has attention-restoring and stress-reducing effects . TheoretThe cross-sectional studies mentioned previously make use of ADHD-related behavior, as reported by parents or teachers  is almost exclusively prescribed for AD(H)D-related symptoms. To the best of our knowledge, this type of information has not been used before in studies looking at the relationship between residential green space and ADHD among children. Although Medication data were provided by Achmea, the main Dutch health insurance company in the central part of the Netherlands at the time of the research. According to Residential greenness was assessed using two methods. The first method was to look at all green types of land use, based on a national land-use database . In thisThe second method involved the use of normalized difference vegetation index (NDVI) scores, based on satellite imagery. NDVI scores indicate the amount of green biomass present. In the present study, the average NDVI scores for 25 May and 25 July 2012 was used, two cloudless days. Originally, NDVI scores range from –1 to + 1, with scores above 0 indicating the presence of green biomass. Scores below 0 may indicate water surfaces. To avoid water and vegetation averaging each other out, the original NDVI scores were recoded: scores above 0 were multiplied by 250, and scores of 0 and below were recoded to 1. Average-recoded NDVI scores were calculated for the same two distances: 250 and 500 m. NDVI scores have also been used before in studies on green space and ADHD, although not in the Netherlands . HoweverIn addition to the two greenness indicators, each for two buffers, several characteristics of the neighborhood in which the six-digit postcode was located were added to the environmental database. The 2012 values for these characteristics were available at Statistics Netherlands (CBS) and included the level of urbanity , the percentage of children between 0 and 14 years of age within the population (twenty 5%-classes), the percentage of inhabitants with a non-Western migration background (twenty 5%-classes), and the average residential property value  . The latSeveral children are likely to live in the same neighborhood and/or be registered with the same family doctor. Thus, the dataset has a nested structure, which calls for multilevel analyses. The first level consists of children. Neighborhood and family doctor are cross-classified: children living in the same neighborhood may be listed as patients registered with a different family doctor, and vice versa. Given the large number of possible combinations of neighborhood and family doctor, both these higher levels cannot be taken into account simultaneously. To start with, separate analyses have been performed, with either neighborhood or family doctor as the second level. Based on the first results, to be reported later on, additional analyses were only performed with neighborhood as the second level. The dependent variable was whether or not the children used ADHD medication in 2011. Therefore, logistic regression analyses were performed. Regression models were built up in several steps. In the first model, only the available covariates, at either the individual or the neighborhood level, were included in the model: age, sex , urbanity , average real estate property value , percentage of non-Western immigrants, percentage of children younger than 15 years. In the second model, one of the greenness indicators was added: the percentage of green area within either 250 or 500 m or the mean NDVI score for the built-up area within one of those distances. In the third model, both the percentage of green area and the average NDVI score for the same distance were included in the model. In a fourth step, different moderators were tested one by one, by introducing interaction terms. This was carried out for average residential property value, sex, and age. For the average residential property value, interaction terms were created by first reducing the number of categories to three, by combing the lowest two, the middle three, and the upper two categories, respectively. For age, this was performed by means of a multiplicative interaction term (with both variables centered beforehand). The multilevel analyses were performed by MLwiN, versions 2.32 and 3.05, and the more descriptive analyses by SPSS, version 22.r = 0.66 for the 250-m buffer and r = 0.67 for the 500-m buffer. This indicates residential environments with much green area also tend to have quite many smaller natural elements within the built-up part of the environment. However, the correlations are not that high that using both in the same regression analysis will cause multicollinearity problems. On the other hand, percentages for the 250- and 500-m buffers correlate with r = 0.90, and the average NDVI scores for those two distances r = 0.91. Thus, neither the two percentages nor the two NDVI scores can be used in the same analysis.Before regression analyses were performed, correlations between the different greenness indicators were calculated. The percentage of green area and the average NDVI score correlate The basic model, with only covariates, is presented in p < 0.01).The logistic regression analyses in which the greenness indicators for the 250-m buffer are added to the basic model (one by one) show that the percentage of green space is significantly associated with the prevalence of ADHD medication use, with the prevalence being lower when the percentage of green area is higher , model 2p < 0.01). The parameter for the average NDVI score of the built-up area within 500 m added to model 1 is not significant , and neither it is significant when added to the model that already includes the percentage of green area , whereas also the parameter for the percentage of green area stays virtually the same: OR = 0.984 (95% CI: 0.975–0.994); p < 0.01).The regression results for the greenness indicators for 500-m buffer are quite similar to those for the 250-m buffer (not in table). Also, the parameter for the percentage of green area is significant, and the association is negative: OR = 0.985 .The analyses were repeated with family doctor as the second level, rather than neighborhood. The results were quite similar, with the same green space parameters being significant (not in table). The between variance for family doctor was somewhat smaller than that for neighborhood. For example, for the basic model (model 1), it was 0.140  in the amount of green area present. The relationship is predominantly linear in nature: the percentage of green area within 250 m increases with the property value , a difference of 20% points of green space (25 vs. 45%) is associated with an over 10% lower probability of the child using ADHD medication. The observed beneficial association is in line with the outcomes of previous as well as more recent studies on green space and ADHD-related symptoms among children as reported by their parents/guardians and/or teachers, as well as with those of a study using a formal ADHD diagnosis as outcome measure . It is aAssuming causality for a moment, we briefly discuss the wider implications of a lower prevalence of ADHD. Given the cross-sectional nature of the study, the causality of this association is open to discussion. However, we did try to rule out likely alternative explanations by including several covariates in our statistical analyses, such as level of urbanity and average property values. The percentage of non-Western immigrants proved to be an important factor in this respect because it is negatively associated with both the average residential property value and the prevalence of use of ADHD medication, whereas the residential property value itself is also negatively associated with the prevalence of use. The relationship between ethnicity and the use of ADHD medication seems to be at least partly due to a cultural difference in the perception of the same type of ADHD-related behavior . It may As for which type of green space is most likely to be beneficial, green elements within the residential environment outside green areas did not show a similar relationship with the prevalence of use of ADHD medication, neither when it was the only greenness indicator in the regression model nor when added after the percentage of green area was already included. Therefore, the presence of green areas seems to be more important than that of smaller elements such as street trees and domestic gardens. This might be taken as an indication that it is especially by outdoor play that the relationship occurs see , with a. AccordiThe pattern of the amount of nearby green space being stronger beneficially associated with the mental wellbeing of children living in less wealthy neighborhoods is consistent with the findings of A strength of the study is that it makes use of administrative data. This precludes a self-selection bias with regard to participating in the study. Another strength is that the data were available at the individual child, rather than only at a spatially aggregated level. Furthermore, the large number of children in the database made it possible to test more complex models, for example, with urbanity as a categorical covariate and an interaction between average residential property values and the percentage of green area. An additional advantage is that the study employs medication use as an indicator and thereby complements previous studies which have been largely based on (possibly quite subjective) ratings of the children’s behavior by their parents. This does not mean that the present study has no limitations. To begin with, as already mentioned, the children in the Achmea Health Database cannot be considered representative of all Dutch children. A more specific limitation in this regard is that only children who (a) are brought to the attention of the family doctor , (b) are diagnosed with ADHD, and (c) are subsequently prescribed ADHD-related medication have been identified as suffering from ADHD. This was already acknowledged in the Introduction see . StartinFurthermore, as already mentioned, the study is cross-sectional in nature, limiting the ability to arrive at firm conclusions regarding the causality of the observed relationships. In addition to this, we also only looked at green space in the residential environment and did so in a static way . During Despite these limitations, we feel that this study adds to the evidence base that contact with nature is important for the health and wellbeing of children, especially those living in deprived neighborhoods.The datasets presented in this article are not readily available because data can only be made available upon request and under certain conditions after approval by relevant Zilveren Kruis (formerly Achmea) Health Database governance bodies. Requests to access the datasets should be directed to corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the participants or their legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.Both authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.