Maternal acetaminophen use during pregnancy is associated with increased risk of ADHD in the child. This could reflect causal influence of acetaminophen on fetal neurodevelopment or could be due to confounding factors. The aim of the current study was to examine unmeasured familial confounding factors of this association.We used data from 26,613 children from 12,902 families participating in the prospective Norwegian Mother, Father, and Child Cohort Study (MoBa). The MoBa was linked to the Norwegian Medical Birth Register and the Norwegian Patient Registry. Siblings discordant for prenatal acetaminophen exposure were compared regarding risk of having an ADHD diagnosis.Children exposed to acetaminophen up to 28 days during pregnancy did not have increased risk of receiving an ADHD diagnosis compared to unexposed children. The adjusted Hazard ratio (aHR) was 0.87 (95% C.I. = 0.70‐1.08) for exposure 1 to 7 days, and 1.13 (95% C.I. = 0.82–1.49) for 8–28 days. Long‐term exposure (29 days or more) was associated with a two‐fold increase in risk of ADHD diagnosis . In the sibling control model, the association between long‐term acetaminophen use and ADHD in the child was aHR = 2.77 (95% C.I. = 1.48–5.05) at the between‐family level, and aHR = 1.06 (95% C.I. = 0.51–2.05) at the within‐family level.Both the exposed and the unexposed children of mothers with long‐term use of acetaminophen in one of the pregnancies had increased risk of receiving an ADHD diagnosis. This indicates that the observed association between long‐term acetaminophen use during pregnancy and ADHD in the child may at least partly be confounded by unobserved family factors. Maternal use of acetaminophen in pregnancy has been associated with increased risk of ADHD in childrenShort‐term acetaminophen use during pregnancy was not associated with ADHD diagnosis in the childLong‐term use was associated with a two‐fold increased risk of ADHD diagnosisThe association between long‐term use and ADHD in the child may be due to unmeasured familial confounding factorsFurther studies need to consider unmeasured confounding factors when examining the associations between medication use during pregnancy and child outcomesThe findings suggest that when pregnant women use acetaminophen long‐term during pregnancy, the family may have several risk factors for ADHDSeveral studies have shown an association between maternal use of acetaminophen during pregnancy and neurodevelopmental outcomes in children, including ADHD diagnosis and symptoms  . Approximately 30,000 of these children are siblings, and they constitute the sample of the current study. In accordance with previous studies on prenatal exposures and ADHD, children from multiple births were excluded . From 2008, all government‐funded clinics in Norway have reported diagnoses to the NPR. Use of privately funded mental health services for children is marginal. Children were classified as having ADHD in the current study if they were registered with Hyperkinetic disorder (F90) according to the 10th revision of the International Classification of Diseases  was reported for different time‐windows within each questionnaire, while number of days was reported as a total of all time‐windows and all medications for an indication in a questionnaire. The sum of number of days' acetaminophen exposure across all indications and all questionnaires was calculated for each child.Medications were classified according to the Anatomic Therapeutic Chemical (ATC) Classification System  of being exposed to acetaminophen for different numbers of days  was calculated with the Stata “predict” option, based on the following predictors: Type and numbers of indication groups for acetaminophen use, child's birth year, maternal age, alcohol use during pregnancy, smoking during pregnancy, symptoms of anxiety and depression, use of acetaminophen before and after pregnancy, number of co‐medications used during pregnancy, and child's sex. Maternal education and parity were not included as predictors of propensity scores, as these variables were not considered appropriate covariates in the sibling control model. Maternal education is highly correlated within mothers, and parity and maternal age are highly correlated.Cox proportional Hazard regression models were run with age at first registration of ADHD as outcome. Time at risk was defined to start with the establishment of NPR in 2008 or at age 36 months, whichever came last. The main exposure variable was number of days exposed to maternal acetaminophen use, divided into four categories , with “no use” as reference. Observations were censored if they had not received an ADHD diagnosis by December 2017, when the last data from the NPR were retrieved.First, a crude Cox regression analysis was run. Second, a Cox regression analysis was adjusted for propensity scores as well as maternal education and parity. Third, an analysis was adjusted for propensity scores and for the effects of unmeasured confounding factors shared by siblings by adding the mean of acetaminophen exposure for all siblings in a family , to avoid assumptions of normal sampling distributions.Sibling control analyses are prone to several sources of bias, such as lack of independence between exposure/outcome in the siblings , bias due to non‐shared confounding factors, and bias due to measurement error  was associated with a two‐fold increase in risk. A substantial family effect in the sibling control model suggested that unmeasured familial confounding factors may explain at least part of the observed association between maternal long‐term acetaminophen use and ADHD in the child.As discussed in the introduction, previous studies have shown an association between maternal use of acetaminophen during pregnancy and ADHD diagnosis and symptoms in children. The current results showed no evidence of increased risk of ADHD in the offspring after exposure for 28 days or less, in agreement with previous findings from the entire MoBa cohort  after controlling for the family effect discussed above. However, only discordant siblings contribute to detecting associations in sibling control models; thus, reduced power is reflected in wide confidence intervals. Our study is based on a large birth cohort and we are not aware of any other data that could be used to perform a more powered sibling control study of prenatal acetaminophen exposure and ADHD. Nevertheless, the finding of similar risk for ADHD in siblings discordant for long‐term maternal acetaminophen use must be interpreted with caution and needs to be replicated in other studies.Previous studies have addressed the problem of unmeasured confounding factors. In one study, the association between maternal regular use of acetaminophen during pregnancy and maternally reported ADHD diagnosis in the child was compared to associations with maternal regular acetaminophen use 4 years before and 4 years after pregnancy (Liew et al., A previous study using the MoBa cohort found an association between maternal acetaminophen use during pregnancy and mother‐reported symptoms of externalizing symptoms when the children were three years old (Brandlistuen et al., There are limitations that may reduce generalizability of findings. First, the response rate in MoBa was about 41% (Magnus et al., Maternal short‐term use of acetaminophen during pregnancy was not associated with an increased risk of child ADHD diagnosis. Long‐term use was associated with a two‐fold increase in risk. Results from the sibling control analysis suggest that this association may at least partly be due to familial confounding. The results also highlight the importance of using designs that allow accounting for unmeasured confounding factors when examining prenatal risk factors for neurodevelopmental disorders. As only discordant siblings contribute to information in sibling control models, even the current very large birth cohort provided limited statistical power. Hence, the results need to be replicated in other studies.Advances. The remaining authors have declared that they have no competing or potential conflicts of interest. Eivind Ystrom is Joint Editor for JCPP Gustavson contributed to conception and design of the study, she performed the analyses, interpreted results, and drafted the initial manuscript; Ystrom had a major role in conceptualizing and designing the study, he interpreted the results, and critically reviewed the manuscript; Ask, Ask Torvik, Hornig, Susser, Lipkin, Lupattelli, Stoltenberg, Magnus, Mjaaland, Askeland, Walle, Bresnahan, Nordeng and Reichborn‐Kjennerud contributed to conception and design of the study, interpreted the results, and critically reviewed the manuscript; and all authors approved the final manuscript as submitted.The MoBa cohort was initially licensed by the Norwegian Data protection agency and approved by The Regional Committees for Medical and Health Research Ethics, and is now regulated by the Norwegian Health Registry Act. Participants provided written consent. Supporting InformationClick here for additional data file.


Also, significantly lower blood lactate and glucose (BL & BG) concentrations were found after USRPT (p ≤ 0.001 and p = 0.037). Heart rate (HR) and rate of perceived exertion (RPE) were significantly lower after USRPT than HIIT (p < 0.001 and p = 0.015). According to the results, an USRPT swimming set consisting of 20 × 25 m at a 100 m pace seems to induce more specific responses in kinematic characteristics, biomarkers, HR and RPE compared to a 5 × 50 m HIIT set.The aim of this study was tο examine the acute responses to an Ultra-Short Race Pace Training (USRPT) and a High-Intensity Interval Training (HIIT), both oriented for the event of 100 m freestyle. Eighteen national-level swimmers  aged 13.5 ± 0.1 years, with 8.0 ± 0.5 years of experience participated in the study. All participants completed a USRPT and a HIIT protocol consisting of 2 × 10 × 25 m (USRPT1 & USRPT2) and 5 × 50 m. Significantly higher swimming velocity (SV) were achieved in USRPT compared to HIIT ( Swimming coaches use a variety of high-intensity interval training (HIIT) sets to increase and even evaluate swimmers’ performance. These kinds of set-tests are usually implemented in swimming training systematically. However, their frequent use may also be avoided by coaches to reduce the monotony in swimmers’ psychology  and the USRPT’s conceptualization mainly originated in the research of Astrand et al.  and BeidHIIT is used by coaches as an effective way for swimmers’ improvement ,8,9,10 i2max and work-to-rest ratio of 1:2 to 1:4. In swimming, standardized HIIT sets, in adult and puberty swimmers, is four to ten repetitions of 50 m with maximal intensity and work-to-rest ratio near to 1:4 [−1 after a 4 × 50 m maximal freestyle with a rest ratio of 1:4 [According to the American College of Sports Medicine  the durar to 1:4 ,8,9,16. o of 1:4  and rateo of 1:4 . Therefoo of 1:4 ,12,13,14o of 1:4 ,8,9,16. −1, RPE from 8.0 ± 1.6 to 18.0 ± 1.6 and HR up to 188 ± 9 beats per minute (bpm). Therefore, their conclusion was that USRPT is an anaerobic style of training and can be used by coaches for the improvement of a mostly anaerobic event, such as 100 m. Furthermore, in a case report where USRPT was used for the preparation of a middle-distance swimmer for 11 weeks, it appeared to be successful for performance improvement in the events of 200 and 400 m freestyle [In support of that notion, Cuenca-Fernández et al. , found tAccording to Rushall , the strAlthough USRPT has gained much attention, there is a lack of data about this training method, the potential responses to it, especially in young swimmers, and the claimed superiority compared to HIIT method. Thus, the aim of the present study was to examine the acute training responses of an USRPT set on kinematic characteristics, biomarkers, HR and RPE and compare them with those to a HIIT set, both oriented for the event of 100 m freestyle, in national-level adolescent swimmers. The purpose of comparing the two training methods was to explore new variations of high-intensity training. Based on the literature, our hypothesis was that USRPT would result in lower physiological demands compared to HIIT. Regarding the kinematic analysis, our expectations were that USRPT would be a more efficient training method when compared to HIIT.A total of 18 swimmers, 8 boys and 10 girls, aged 13.5 ± 0.1 years old (Mean ± SD) took part in the study. The swimmers had an average experience of 8.0 ± 0.5 years in the sport and 2 years in the competitive category, while they were trained for 12 h covering close to 30 km per week. Additionally, their best performances in the 100 m front crawl event in a long course pool were rather similar, with an average time of 66.4 ± 2.8 s. The anthropometric characteristics as well as the seasonal best performance in the short course pool at 25, 50 and 100 m front crawl were recorded prior to the study .Inclusion criteria were (a) healthy participants, (b) aged between 13–14 years old, (c) females in the middle period of menstruation (d) 100 m freestyle as one of their main events, (e) daily participation in swimming training, (f) participation in swimming meetings, (g) placed, in at least one swimming event, in the top sixteen of their age group’s national championship and (h) World Aquatics (WA) points > 500. Before the measurements, all the swimmers and their parents were informed about the study’s process and safety. Then, a written consent form was signed by the parents to ensure swimmers’ participation. The study was in accordance with the Declaration of Helsinki and the design was approved by the Research Ethics Committee of the School of Physical Education and Sport Science .The study included two tests, a HIIT and an USRPT one and was conducted in a randomized counterbalanced order on two separate days with 24-h of recovery before and between them. All participants were familiar with HIIT and USRPT sets from their usual workouts. The swimmers were asked to follow the same nutrition plan as well as daily schedule at these two days. Before the tests, the swimmers followed the same warm-up which included a five minute full-body dry land routine of dynamic and explosive exercises. This was followed by a 20 min warm-up with 900 m of swimming that they regularly did in training and included drills, kicking and a short high intensity set (2 × 25 m front crawl with 30 s of rest in between) for priming purposes. At the end of the warm-up procedure the swimmers had ten minutes of rest and continued with the swimming tests. The measurements were conducted in an indoor 25 m pool.The HIIT protocol consisted of 5 × 50 m front crawl ,7,8, at −1), stroke index (SI) (speed × DPS) (m2·s−1) and swimming velocity (SV) (distance/time) (m·s−1) [A digital video camera (SONY HDR-CX450 BLACK) was placed at a high point on one side and in the center of the pool , 20 m fr (m·s−1) . The kinBL and blood glucose (BG) concentrations were measured in capillary blood from a fingertip using portable analyzers . In the HIIT protocol, blood sampling for BL determination was taken before the set and 1 and 3 min after the 5 × 50 m repetitions, whereas BG measurements were measured before and 1 min after the set. In the USRPT protocol, blood sampling for BL determination was done before exercise, 1 min after USRPT1 and 1 and 3 min after USRTP2, while the BG measurement was done before exercise, 1 min after USRPT1 and 1 min after USRPT2 .The swimmers, during the measurements, were wearing a HR sensor  on their dominant arm. The sensor monitored their HR immediately before and after the 5 × 50 m sets in the HIIT protocol, as well as immediately before and after USRPT1 and USRPT2 in the USRPT protocol.RPE was measured via the revised category-ratio scale (0 to 10) before and after HIIT protocol and before USRPT protocol, after USRPT1 and after . The whoA priori sample size (n) calculation was completed with G*Power 3.1.9.7  on Windows . Determiη2) was estimated  [r analysis between the variables. The statistical analysis was performed with the software SPSS, Version 25.0 . The level of significance was set at α = 0.05.All values are shown as mean with standard deviation (±). Descriptive statistics and a test of normality (Shapiro–Wilk) for all the variables were used. Additionally, the measurements were checked for homogeneity and sphericity via Box’s M test of equality of covariance and Mauchly’s test, respectively. When sphericity was not met, Greenhouse Geisser was used to analyze the results. A three-way ANOVA (protocol × gender × measurement) with repeated measures, checking for possible within or between subjects’ effects, was utilized for data analyzation. Possible statistically significant differences were analyzed via Syntax, making pairwise comparisons between groups with Bonferroni’s post hoc test. The effect size (ES) with partial Eta square ( ≥ 0.14) . Also, cp > 0.05). Thus, parametric analyses were followed for all examined variables. Also, the data of the swimmers’ kinematic characteristics , biomarkers , HR, and RPE showed homogeneity (p > 0.05), according to Box’s test of equality of covariance test metrices.According to the Shapiro–Wilk test, the data were normally distributed (p < 0.05). Specifically, the swimmers had a lower DPS during USRPT1 and USRPT2 than during the HIIT set, with a large effect size (DPS(USRPT1), DPS(USRPT2) vs. DPS(HIIT): 1.41 ± 0.81, 1.46 ± 0.23 vs. 1.63 ± 0.37 m, p = 0.007 and p < 0.001 respectively, η2 = 0.20). On the other hand, no statistically significant difference was found between genders (p < 0.05).Statistically significant differences were found between USRPT and HIIT protocols . Specifically, the swimmers had a lower SI during USRPT1 and USRPT2 than during the HIIT set, with a large effect size (SI(USRPT1), SI(USRPT2) vs. SI(HIIT): 1.82 ± 0.70, 1.78 ± 0.71 vs. 2.26 ± 0.82 m2·s−1, p < 0.001 in both cases, η2 = 0.60). Moreover, a statistically significant difference between genders was found only in USRPT1, with a large effect size .Statistically significant differences were found between the USRPT and HIIT protocols and between genders (p < 0.05). Specifically, the swimmers had a faster SV during USRPT1 and USRPT2 than during the HIIT set, with a large effect size (SV(USRPT1), SV(USRPT2) vs. SV(HIIT): 1.61 ± 0.20, 1.60 ± 0.20 vs. 1.56 ± 0.20 m s−1, p < 0.001, η2 = 0.70). A statistically significant difference between genders was found only in the USRPT set, which had a large effect size   .p < 0.05). Specifically, the swimmers’ maximal BL concentration was higher at USRPT2 than USRPT1 (BL(USRPT1) vs. BL(USRPT2): 8.7 ± 0.8 vs. 10.0 ± 0.9 mmol L−1, p = 0.007). Also, in both USRPT sets, the swimmers had lower maximal BL concentration than in the HIIT set, with a large effect size (BL(USRPT1) & BL(USRPT2) vs. BL(HIIT): 8.7 ± 0.8 and 10.0 ± 0.9 vs. 12.9 ± 0.4 mmol L−1, p < 0.001 and p = 0.001, respectively, η2 = 0.90) (p < 0.05).Statistically significant differences were found between USRPT measurements and between USRPT and HIIT protocols ( = 0.90) . On the p < 0.05). Specifically, the swimmers’ BG concentration was higher in USRPT2 than in USRPT1 (BG(USRPT1) vs. BG(USRPT2): 6.0 ± 0.9 vs. 6.4 ± 1.4 mmol L−1, p = 0.038). Also, the swimmers had lower BG concentrations in USRPT1 than in the HIIT set, with a large effect size (G(USRPT1) vs. G(HIIT): 6.0 ± 0.9 vs. 6.4 ± 0.9 mmol L−1, p = 0.037, η2 = 0.40) (p < 0.05).Statistically significant differences were found between USRPT measurements and between USRPT and HIIT protocols ( = 0.40) . On the p < 0.05). Specifically, the swimmers had higher HR in USRPT2 than USRPT1 (HR(USRPT1) vs. HR(USRPT2): 173 ± 1 vs. 180 ± 0 bpm, p < 0.001). Also, the swimmers’ HR in USRPT1 and USRPT2 was lower than in HIIT, with a large effect size (HR(USRPT1), HR(USRPT2) vs. HR(HIIT): 173 ± 1, 180 ± 0 vs. 196 ± 1 bpm, p < 0.001, η2 = 0.90). Moreover, a statistically significant difference between genders was found only in USRPT2 set, with a small effect size : 181 ± 1 vs. 179 ± 1 bpm, p = 0.004, η2 = 0.02)  .p < 0.05). Specifically, the swimmers’ RPE was higher in USRPT2 than in USRPT1 (RPE(USRPT1) vs. RPE(USRPT2): 7 ± 0 vs. 8 ± 0, p < 0.001). Also, the swimmers’ RPE was lower in USRPT1 than in HIIT, with a large effect size (RPE(USRPT1) vs. RPE(HIIT): 7 ± 0 vs. 8 ± 0, p = 0.015, η2 = 0.30) (p > 0.05).Statistically significant differences were found between USRPT measurements and USRPT and HIIT protocols ( = 0.30) . On the r2 = 0.816, p < 0.001 and r2 = 0.829, p < 0.001). Also, BG in the HIIT protocol was correlated with BG in USRPT1 and USRPT2 .Statistically significant correlations were observed between USRPT and HIIT protocols in SR and BG. Specifically, SR in HIIT protocol showed a statistically significant correlation with SR in USRPT1 and USRPT2 . Having a lower DPS in USRPT protocol, one would expect SR to be higher than in HIIT. However, SR is a parameter which is mainly determined by neural activation [Regarding SR, there was no statistically significant difference between protocols while a high correlation was found (tivation . However−1) with our participants. Therefore, it could be hypothesized, that in swimming protocols which are oriented to a specific event distance, in this instance 100 m, swimmers show similar SR. In that sense, the absence of a difference in SR between USRPT and HIIT protocol was a rather relevant result.In addition, in the study from Wądrzyk et al. , it was SI is also an important determinant of front crawl swimming performance, especially in young and high-level swimmers ,30. AccoThe total volume of the sets (500 vs. 250 m) and of each repetition (25 vs. 50 m), most likely affected the SI. Notably, Sánchez and Arellano  suggesteAccording to anecdotal reports, some of the swimmers’ benefits who follow the USRPT method are relevant to the events’ swimming paces and the specific kinematic patterns . HoweverBoth USRPT and HIIT protocols induced increases in BL and BG concentration. These results are similar to the ones of Terzi et al. , William−1, implying an important contribution of anaerobic metabolism to energy demands while BG also increased, except for during the first half of the set (10 × 25 m), possibly indicating a metabolically stressful stimulus to the swimmers.According to Rushall , Cuenca-However, the maximal mean BL in USRPT was lower compared to the values found by Williamson et al. . It is bAdditionally, Cuenca-Fernández et al. , who comAnother reason that the HIIT protocol induced higher BL than USRPT is most likely that the more high-intensity work (mostly relied on the glycolytic system) before rest (where aerobic metabolism dominates) that had to be done in each repetition, as the average bout duration was 32.3 s for HIIT and 17.0 s for USRPT. This difference possibly indicates a greater glycolytic stimulus in HIIT than in USRPT, a result that Cuenca-Fernández et al.  found toBased on the present findings regarding biomarkers, the use of either USRPT or HIIT by coaches must be chosen according to the training period, the swimmers’ age and the distance of the event. Specifically, for maximal BL and stronger anaerobic stimulus in adolescent swimmers, who work for the event of 100 m, HIIT may be a better solution than USRPT. On the other hand, USRPT can be utilized when more moderate BL is required with higher SV.HR was lower in USRPT compared to HIIT. Moreover, HR was higher in USRPT2 than USRPT1, whereas RPE was also higher in USRPT2 than USRPT1. Therefore, the results, also considering the BL and BG results, enhance the notion that the USRPT protocol was most likely less physiologically demanding than HIIT . In addiWilliamson et al. , also moHigher HR was found in males compared to females, but only after USRPT2. The literature regards that, at rest and in submaximal exercise intensity, females, because of the lower cardiac output, show higher HR than males . While iRegarding RPE, the difference between USRPT1 and HIIT displays the higher internal load of HIIT compared to USRPT when total volume of the set is equal. On the contrary, RPE did not differ between USRPT2 and HIIT, showing that USRPT needed a double total volume of set  to reach the same RPE as HIIT. This pertains to Rushall’s  guidelinAccording to the results of the present study, an USRPT protocol, which consisted of 20 × 25 m on 100 m pace, can be identified as a novel approach to HIIT, inducing similar responses regarding only SR and different responses regarding DPS, SI, SV, BL, BG, HR and RPE compared to a more classic HIIT protocol which consisted of 5 × 50 m sets at maximal intensity. Coaches should be aware of the possible effects of the voluminous use of USRPT. This contrasts with Rushall’s guidelines; however, the aforementioned similar or different responses could suggest two viewpoints, one regarding the markers prioritized by coaches for the interpretation of the USRPT and HIIT effects and one regarding which markers are eventually more appropriate for the monitoring of the possible differences between these two protocols. For example, regarding the first viewpoint, coaches could choose a training protocol according to the responses of the kinematic parameters or the fluctuation of biomarkers. Regarding the second viewpoint, sport scientists could pick specific parameters for the differentiation of the responses of the two adjacent protocols.According to the present findings, the acute utilization of USRPT demonstrates differences in kinematics, such as higher SV, lower DPS and SI, in biomarkers, such as lower BL and BG concentration and lower HR and RPE. To conclude, USRPT can be used by swimming coaches as a training stimulus to improve 100 m performance. However, since this suggestion is based on acute responses, it is recommended for future studies to confirm whether or not the USRPT’s possible beneficial effects on swimming performance through the evaluation of its long-term implementation.


Attention‐Deficit Hyperactivity Disorder (ADHD) is associated with impaired school performance, but the impact of ADHD may vary across sex, family background, and school subjects. By using prospective population‐wide register data, we describe impairment in academic performance related to ADHD across different school subjects and investigate how this impairment differ across sex and parental education.We examined grades and Grade Point Averages (GPA) at age ∼16 among 344,152 Norwegian children born between 1997 and 2002. We linked grades with diagnoses from publicly funded general practitioners and with demographic information. Associations between ADHD diagnosed between age 10 and 16 and school performance were estimated with linear models, including sibling‐models which control for unobserved variables shared within families.Children with ADHD (4.0%) had −1.11 standard deviations lower GPAs compared to children without ADHD. This difference remained substantial after adjusting for demographic factors (−0.87), comorbid mental disorders (−0.82), early school performance (−0.54), and when comparing full siblings (−0.60). The relative ADHD deficit was 22% larger for girls than for boys and 39% larger for children with highly educated parents than for children of parents without completed high school, but the absolute deficit was smaller.The ADHD deficit in school performance was large and not easily attributable to other factors. Because the ADHD deficit was large in all school subjects, interventions should ideally address factors that affect school performance broadly, although targeting theoretical subjects specifically may be most effective given limited resources. Children with ADHD have substantially lower grades in all school subjects compared to children without ADHD. The deficit is larger for girls and for children of highly educated parents. This was found when investigating register data on school performance at age 16 linked with health data from primary care use. Children with ADHD have substantially poorer school performance than unaffected children. The ADHD deficit is not easily attributable to other factors, which suggest that interventions must target ADHD symptoms directly independent of sex, parental education, early school performance, and other psychiatric disordersThe relative ADHD deficit is larger for girls and for children of highly educated parents, but the absolute deficit is smaller The ADHD deficit is large in all school subjects, meaning interventions should target factors that is shared across different school subject, although the potential for improvement appears to be largest in theoretical subjects where the ADHD deficit is largest.Attention Deficit‐Hyperactivity Disorder (ADHD) is a heritable neurodevelopmental disorder characterized by dysfunctional inattention, impulsivity, and hyperactivity APA, . ADHD haAttention‐Deficit Hyperactivity Disorder is substantially more prevalent among boys than girls and among children of parents with less education or less income  accurately describe the ADHD deficit in school performance, (2) describe how the ADHD deficit in school performance varies across sex and parental education, and (3) compare the ADHD deficit in different school subjects. We do this using register data on all Norwegian children with appropriate statistical controls, including sibling‐comparisons, which should result in precise and representative analyses.N = 359,492). The Norwegian national population register includes personal identification numbers of all inhabitants, which allowed us to link data from separate sources. We linked data from publicly funded health services with data on school performance, parental education, and parentage from Statistics Norway. Norwegian school is compulsory up to 10th grade (age 16), meaning the resulting grades and GPAs are largely representative of the population. We identified 344,523 (95.7%) individuals who had GPA registered within 1 year of normed time (age 16) which we included in the main analyses . Henceforth, we treat ADHD and hyperkinetic disorder as synonymous. We defined individuals as diagnosed with ADHD if they, between the age of 10 and 16, had at least one contact with the primary care system registered with code P81.Due to the subsidized nature of the Norwegian healthcare system, general practitioners send reimbursement claims to the government each time a patient uses primary care facilities. These data are then indexed in the Norwegian Control and Payment of Health Refunds Database. These claims include the reason for encounter, which is documented with diagnostic codes or symptom codes according to the International Classification of Primary Care version 2 . The higher the grade, the better the performance. GPA was standardized to z‐scores  before analyses, meaning all coefficients can be interpreted as standard deviations. For individual school subjects, we limited our analyses to grades that most pupils share .At the end of 10th grade, children – normally 16 years old – are graded based on their whole‐year performance and take exams. Grades are integers on a scale from one to six and the grade point average (GPA) are the mean of all grades, including final exams . These were also standardized to z‐scores.n = 53,648), Bachelor's degree or equivalent , high school , or not completed high school , and a fifth category for children with missing information . Statistics Norway also provided information on sex, parentage , birth month, and parity .Statistics Norway provided information on parental education at the time of the child's graduation , which we coded into four categories reflecting the highest achieved education of either parent: Master's degree or equivalent  from the ICPC‐2, and entered the count as a categorical variable (truncated at three). In an alternative model, we used separate indicator variables for all individual disorders with a prevalence above 0.1% , and birth month. All of these were treated as categorical variables. The adjusted model only included covariates where reverse causation  is impossible or unlikely. Early school performance and comorbid mental disorders were therefore included in separate models. We used standardized test scores from fifth grade as a measure of early school performance. This variable had 28,765 missing observations, which were not included in the analyses using this variable. To investigate how the ADHD deficit varied across sex and parental education, we allowed ADHD to interact with sex and parental education in separate models. For comparison, we also estimated a regression model with covariates only .N = 145,051). Of the 69,765 sibships, 3952 (5.7%) included siblings discordant on ADHD. Covariates that vary within families  were included. As most full siblings will have equally educated parents, only the interaction between ADHD and sex was estimated with a within‐family model.The models were then re‐estimated in within‐family models (random‐intercept multilevel models with parents as grouping variable) where we compared full siblings with and without ADHD. Only children with full siblings in the sample were included in these models , 13,800 (4.01%) were diagnosed with ADHD  whereas unaffected children's average GPA was 4.16 (SD = 0.82), meaning children with ADHD had on average −1.11  standard deviations lower GPA than children without ADHD  standard deviations lower GPA at the end of 10th grade compared to those without ADHD. Among siblings who did equally well in fifth grade, those with ADHD had on average −0.33  standard deviations lower GPA.Of the 13,800 individuals with ADHD, 2293 (19.8%) had at least one other psychiatric diagnosis. When statistically controlling for other diagnoses, the ADHD deficit was attenuated down from −0.86 to −0.82  standard deviations in the adjusted model and from −0.60 to −0.58  in the sibling model. This is still larger than the deficit associated with having three or more other registered diagnoses. Entering each individual diagnosis as separate indicator variables yielded similar coefficients  standard deviations lower GPA than boys without ADHD, whereas girls with ADHD had on average −0.99  lower GPA than girls without ADHD. That is a 22% bigger deficit. The within‐family model had similar results  standard deviations larger for girls than for boys. As seen in Figure 0, −0.14 Similarly, the ADHD deficit was substantially greater among children of more educated parents, although it did not differ between the two highest education levels as illustrated by the overlapping confidence intervals in Figure We repeated the above analyses for each school subject, with similar results  in Science to −0.04  in Music. Regarding interaction effects between ADHD and parental education, we found few differences between the top three education levels, but the ADHD deficit was consistently larger than for children of parents who had not completed high school. The difference in ADHD deficit was particularly pronounced in Mathematics, with the ADHD deficit being −0.40  standard deviations larger for children of highly educated parents compared to children of parents who had not completed high school.without ADHD barely outperformed girls with ADHD, despite the ADHD deficit being larger for girls. Because grade differences by parental education are larger than sex differences, this pattern becomes more pronounced for parental education. Children with ADHD and highly educated parents perform better in most school subjects than children without ADHD but with parents who had not completed high school.Neither the ADHD deficit, general sex differences, nor parental educational differences are constant across school subjects, which must be considered when interpreting the relative deficits. Figure All analyses were repeated with standardized tests from eighth and ninth grade as outcome variables, which yielded similar results Tables . MissingUsing large and representative register data, we have found: (1) that the ADHD deficit in school performance is large and evident even when comparing siblings and when adjusting for comorbid disorders and early school performance, (2) that the relative ADHD deficit is somewhat larger for girls and children of highly educated parents but the absolute deficit is smaller, and (3) the ADHD deficit is largest in theoretical school subjects, but still substantial in all school subjects. In the sensitivity analyses, we also found that ADHD increased the likelihood of not being registered with a GPA, meaning the deficit on GPA is a conservative estimate of the association between ADHD and poor school performance.Even though children diagnosed with ADHD had substantially lower GPAs than other children, with an overall deficit of −1.11 standard deviations, this was partly due to family confounding. When comparing same‐sex siblings and therefore controlling for unobserved family characteristics and genetic similarity, the ADHD deficit was reduced to −0.60 standard deviations. The ADHD deficit remain large after adjusting for potential confounders, but it would nevertheless be premature to conclude that the relationship is causal. For example, siblings share only half of the genetic factors that vary in the population, implying that residual genetic variation may still influence both ADHD and school performance. However, despite both ADHD and school performance being highly heritable  or mediation (ADHD → poor early school performance), and adjusting for mediators will underestimate the effect.A third caveat is that ADHD often covaries with other mental disorders, such as depression and anxiety, which might confound the association between ADHD and school performance. We found that adjusting for other mental disorders had only a negligible impact on the ADHD deficit, meaning the ADHD deficit is generated independently of other mental disorders. This mirrors earlier research finding that ADHD impacts school performance independently of comorbid conduct disorders  or different symptom severities. Second, we only have data on primary health care visits, not medication use. Medication is common among Norwegian children with ADHD (Karlstad et al., We have found that the ADHD deficit in school performance is large, apparent in all school subjects, and not easily attributable to other factors. This strongly suggests that ADHD symptoms is an important risk factor for poor school performance which must be addressed directly independent of sex, parental education, early school performance, and other psychiatric disorders. Because it affects performance in all school subjects, ADHD must ideally be addressed by intervening on factors that affect school performance broadly, although interventions targeting theoretical subjects like Mathematics may be most effective given limited resources.The authors have declared that they have no competing or potential conflicts of interest.The study was approved by the Regional Committee for Medical and Health Research Ethics.Hans Fredrik Sunde: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Visualization; Writing – original draft; Writing – review & editing. Thomas H. Kleppestø: Conceptualization; Investigation; Methodology; Writing – review & editing. Kristin Gustavson: Conceptualization; Investigation; Methodology; Writing – review & editing. Magnus Nordmo: Conceptualization; Investigation; Methodology; Writing – review & editing. Bjørn‐Atle Reme: Conceptualization; Investigation; Methodology; Writing – review & editing. Fartein A. Torvik: Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Writing – review & editing.Supplementary Material S1Click here for additional data file.


Rye is a secondary crop that is characterized by a higher tolerance to climatically less favorable conditions than other cereal species. For this reason, rye was historically used as a fundamental raw material for bread production and as a supply of straw in northern parts of Europe as well as in mountain environments, such as Alpine valleys, where locally adapted landraces have continued to be cultivated over the years. In this study, rye landraces collected in different valleys in the Northwest Italian Alps have been selected as the most genetically isolated within their geographical contexts and cultivated in two different marginal Alpine environments. The traits concerning their agronomy, mycotoxin contamination, bioactive content, as well as their technological and baking quality were assessed to characterize and compare rye landraces with commercial wheat and rye cultivars. Rye cultivars showed the same grain yield level as wheat in both environments. Only the genotype selected from the Maira Valley was characterized by tall and thin culms and a proneness to lodging, thereby resulting in a lower yield capacity. Among the rye cultivars, the hybrid one presented the highest yield potential, but also the highest susceptibility to the occurrence of ergot sclerotia. However, the rye cultivars, especially the landraces, were characterized by higher concentrations of minerals, soluble fibers, and soluble phenolic acids, and thus both their flours and breads had superior antioxidant properties. A 40% substitution of refined wheat flour with whole-grain rye flour led to a higher dough water absorption and a lower stability, thereby resulting in lower loaf volumes and darker products. Agronomically and qualitatively speaking, the rye landraces diverged significantly from the conventional rye cultivars, thus reflecting their genetic distinctiveness. The landrace from the Maira Valley shared a high content in phenolic acids and good antioxidant properties with the one from the Susa Valley and, when combined with wheat flour, turned out to be the most suitable for bread making. Overall, the results have highlighted the suitability of reintroducing historic rye supply chains, based on the cultivation of local landraces in marginal environments and the production of value-added bakery goods. The position of the Susa Valley, that is, at the center of the Alps, determines less rainfall than other Northwest Italian valleys; it has mild winters and generally dry springs and summers, and a high frequency of windy days. The experiment was carried out on the south-facing side of the central sector of the hilly valley in a shallow alluvial soil of medium fertility. Since the territory is surrounded by high mountains, the climate in the Gesso Valley mountains is characterized by cold winters and hot summers, although it is not far from the Mediterranean Sea. The trial was set up in deep and shallow soil, originating from a glacial deposit. The locations where the field experiments were located are remarkably different in terms of ecological conditions: the climate in Bruzolo is sub-Mediterranean, while Entracque is characterized by a hypomesoxeric climate, according to Gaussen-Bagnouls classification method , with anFive rye genotypes were sown in each location, together with an ordinary bread-making wheat , which was used as a control. The three compared local rye landrace genotypes, called Susa, Maira and Tanaro, according to the respective Valleys of origin, were identified during a survey carried out in the alpine growing areas of Northwest Italy by 2 (6 x 2 m) in size. The previous crop in each growing season had been bread wheat or a meadow in the hilly and mountain locations, respectively, and the latter was often also used for grazing. The plots were seeded after an autumn ploughing (30 cm) and disk harrowing to prepare a suitable seedbed. Mechanical sowing was conducted in 12 cm wide rows  at a seeding rate of 350 seeds m-2, except for the hybrid rye for which a seeding rate of 200 seeds m-2 was applied. According to the low-input cropping system in force in the growing areas, no mineral or organic fertilizations, or chemical and mechanical treatments were applied to control weeds, diseases or insects during the cultivation.The cereal genotypes from each location were assigned to experimental units using a completely randomized block design, with three replicates. The plot was 12 m2.2st, while the flowering duration was counted considering the days that had elapsed between the first release of the anthers and complete anthesis (GS 60-69). The number of ears per unit of grown area (ear density) was counted manually before the harvest in two sampling areas (625 cm2) per plot. The number of kernels per ear was calculated in 10 randomly selected ears from each sampling area. The average plant height and the percentage of plot with severe lodging were recorded for each plot. The culm diameter was measured on the 1st internode length in 10 plants per plot using a digital gauge.The full flowering date, that is, when 50% of the ears had reached the complete extrusion of anthers from the spikelets , was monitored during spring and expressed as days from April 1® 2000 Grain Analyzer . The thousand-kernel weight (TKW) was determined on two 200-kernel sets for each sample using an electronic balance.The plots were harvested , by means of a Walter Wintersteiger cereal plot combine-harvester, and the straw was collected behind the combine-harvester and weighed immediately after harvesting. The grain yield (GY) and straw yield results were expressed on a dry weight (DW) basis, and the harvest index (HI) values were obtained by dividing the grain yield by the aboveground biomass (grain + straw) of each sample, expressed as a percentage. Aliquots of 2 kg of grain were taken from each plot, to determine the test weight (TW) and the grain moisture content using a GAC2.3® DON direct competitive immunoassays , according to the method reported by The number of ergot sclerotia were visually counted in 500 g grain samples randomly collected from each plot and expressed as g of sclerotia per kg of grain, according to the Commission Regulation (EU) 2021/1399 of 24 August 2021 . The deo2.42.4.1®, 99.8%), ethylacetate , (±)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid , hydrochloric acid , Iron (III) chloride hexahydrate , methanol , potassium sulfate , sodium hydroxide , 2,4,6-Tris(2-pyridyl)-s-triazine (TPTZ), trifluoroacetic acid (TFA), sodium carbonate (Na2CO3) and phenolic acid standards  were purchased from Sigma-Aldrich . Monosaccharide standards (L(+) Arabinose and D(+) Xylose) were purchased from Extrasynthese . Water (HPLC grade) was obtained from ELGA PURELAB Ultra system .2-2′-Azino-bis(3-ethylbeenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), ethanol  were ground to whole-meal using a laboratory centrifugal mill equipped with a 1-mm sieve . The grain protein content (GPC) and the ash content were determined according to AACC method 39-10.01  on whole2.4.2.12CO3 to pH 7, filtered using a syringe filter (pore diameter 0.20 µm) and then 10 µL of the sample was injected into an HPLC system, Agilent 1200 Series  coupled with an Agilent 1200 Series RI detector. Separations were carried out using SecurityGuard Cartridges, Carbo-Pb  and an SP08010 column (Shodex); the column temperature was set at 70 °C and the mobile phase was bidistillated water (flow rate of 0.6 mL min-1). Arabinose and xylose were identified using the retention times and the reflectance indexes of their respective standards, and the TAX content was calculated as the sum of the two sugars. Solutions of individual monosaccharide standards (L(+) Arabinose and D(+) Xylose) were prepared and diluted to different concentrations to obtain calibration curves for quantification purposes. All the samples were analyzed in triplicate, and the results are presented as DW%. The degree of arabinose substitution to the xylose units (A/X ratio) was calculated by dividing the arabinose content by the xylose content.The monosaccharide composition of the TAX was determined by means of high-performance liquid chromatography with reflectance index detection (HPLC/RID) after acid hydrolysis, according to the procedure proposed by 2.4.3Soluble  and cell wall-bound phenolic acids (CWBPAs) were extracted and quantified according to the procedure described in detail by ABTS) and ferric reducing antioxidant power (ACFRAP) assays, following the QUENCHER approach (direct measurement of AC on solid samples) previously described by n = 3), and the results are expressed as mg kg-1 (DW) for SPAs and CWBPAs, and as mmol Trolox equivalents (TE) kg-1 of sample (DW) for AC.The AC of the whole-grain flour and bread samples was determined by means of both ABTS  fitted with a 1-mm aperture sieve. The refined wheat flour was supplied by a milling company (0.76% ash content) and the main rheological properties are reported in 2.5.1® analyzer , according to the ICC Standard Method 173  at 45 °C; dough stability , or the elapsed time at which the produced torque is kept at the C1 torque value ( ± 11%); thermal weakening, i.e. decrease in dough consistency due to mechanical shear stress and a temperature increase from 45 to 60 °C , which provides information about the protein quality; starch gelatinization, i.e. an increase in viscosity due to the absorption of water by the starch granules and an increase in temperature from 60 to 90 °C ; cooking stability, i.e. the stability of the hot gel at a constant temperature of 90 °C ; and cooling setback, i.e. the retrogradation of the starch in the cooling phase from 90 to 50 °C .The mixing and pasting behaviors of the refined control and of the whole-grain wheat and rye flour blends were studied using a Mixolabthod 173 . This inThe solvent retention capacity (SRC) test was adopted to provide information on the water adsorption and on the content of pentosans, according to AACC method 56-11.02 . The fol2.5.2L*), redness (a*) and yellowness (b*) color values were determined directly by the instrument, in accordance with Commission Internationale de l’Éclairage  and the refined flour on its own were employed to prepare bread in a bread-making machine. The whole-grain flours of the wheat and rye genotypes were both collected from field experiments carried out in the 2019-20 growing season and milled as previously reported. Flour (1000 g) was added to water (670 g), as were 2.5 g of powder yeast and 2 g of salt. After 13 min of kneading, the dough was manually divided into three loaves of 550 g each and left to rest for 15 min at room temperature. Leaving was then carried out for 50 min at 30 °C and at 70% humidity. The loaves were baked for 40 min at 235 °C in a bakery oven. The specific volume, color, moisture content and antioxidant capacity of each loaf of bread were determined. The loaf volume was determined 1 h after baking, by means of rapeseed displacement, according to AACC method 10-05.01 . The chrclairage . The totABTS and ACFRAP). The AC results are expressed as mmol TE kg-1 (DW).Bread samples were freeze-dried using a Lyovapor L-200 Freeze Dryer  and the lyophilized samples were ground to a fine powder using a Cyclotec 1093 sample mill. The moisture content was obtained by oven-drying the samples at 105 °C for 24 h and the AC was determined by conducting the same assays that had been performed on the whole-grain samples (AC2.6p ≤ 0.05) based on the Ryan/Einot and Gabriel/Welsch (REGW-F) statistical test. Prior to the analysis, data were tested for normality and homoscedasticity. Pearson correlation analysis was performed to investigate the relationships between the agronomic, nutritional and phytochemical, qualitative and rheological traits. Statistical analyses were carried out by means of SPSS for Windows statistical package, version 28.0 .The data were compared separately for the two different Alpine environments, by means of an analysis of variance (ANOVA), to evaluate the effect of genotype (G), harvest year (Y) and their interaction (G × Y) on the agronomic and sanitary traits, the qualitative parameters, and the phytochemical content and profile of the whole-grain flours obtained from the wheat and rye varieties. The effect of bread formulation (BF) and Y and their interaction (BF × Y) on the rheological properties of the twelve blends and the refined control flour was also investigated separately for the two environments. One-way ANOVA was performed on samples from 2020 harvest to evaluate the effect of BF on the bread-making aptitude and the antioxidant properties of the composite breads. Means were identified as significantly different  sequencing approach. Libraries were produced according to the IGATech  custom protocol, with minor modifications with respect to  v 2.9.3  and visuAgronomic and qualitative parameters were used to cluster the rye cultivars into the main groups using a similarity approach. The most representative variables were selected by experts: culm diameter, plant height, HI, GY and TKW were selected to describe the variability of the agronomic parameters, while TW, GPC, β-glucans, TAX, SPAs, CWBPAs, DS, thermal weakening (C1-C2) and ergot sclerotia were selected to describe the variability of the quality parameters. A cluster analysis was performed, in the R environment, using the R package ‘factoextra’ v1.0.7 . A preli33.1-1) from April to June in 2019-20 than in 2020-21. As expected, the rainfall and temperatures were higher and lower, respectively, in the mountain environment than in the hilly one.The two growing seasons showed different meteorological trends throughout the cereal crop cycles Table S23.2-1) than in the mountain one (3.3 t ha-1), due to an overall higher number of kernels per ear in 2020, and ear density and TKW in 2021  in both environments, as a consequence of the lower TKW; moreover, it had the longest flowering duration, the lowest HI, the greatest plant height and the thinnest culm diameter. These morphological traits led to an extensive lodging phenomenon in both years, especially in the hilly environment, which was not observed for the other genotypes. Susa and Tanaro reported very similar agronomical traits to the commercial population cultivar.Overall, the GY was higher in 2021 than in 2020 in the hilly site, while an opposite trend was observed for the straw yield in both locations, although the G × Y interaction was never significant.3.3Claviceps purpurea (Fr.) Tul. were found in both sites and in both years among the collected samples of the rye genotypes, but they were never detected among those of the bread wheat , without any differences being observed among the rye genotypes in either location. Instead, there was no difference between rye and the wheat control as far as the calculated A/X ratio is concerned. The rye varieties had a higher β-glucan content than the wheat variety, that is, 1.2-fold greater at both sites. No significant differences among the rye varieties were found in the hilly site, whereas in the mountain site the highest value of β-glucans and the lowest were registered for Susa and for the commercial rye, respectively. The analysis of TDF was performed without any replicate, thus two-way ANOVA was not applied to this parameter. The rye varieties recorded higher values of TDF than the wheat control , with the highest values observed for the hybrid rye in the hilly environment (16.7%) and for Susa in the mountain environment (16.9%).p < 0.05) on both the A/X ratio and β-glucans in the mountain environment, with higher values observed in 2020 than in 2021 . The G × Y interaction was only significant for β-glucans in the mountain environment, with more marked differences among the rye genotypes being observed in 2020 (data not shown). In the first year, the commercial population cultivar presented a β-glucan content that was significantly lower than all the other rye genotypes (-20%), whereas this difference was not recorded in the second harvest.The year had a significant effect on some of the analyzed parameters, and differences were detected between the two environments. TW was significantly higher in 2020 in the hilly site (+3%), whereas no significant differences between the two years were observed for the mountain site. The ash content was influenced to a great extent by the year in both environments, with higher values observed in 2021 than in 2020 in the hilly site (+9%), while an opposite trend was observed in the mountain site (+4% in plots grown during 2020 compared to 2021). Two-way ANOVA showed a significant effect of the year . Gallic acid showed the lowest values, ranging from 0.9 to 3.5 mg kg-1 in the bound form, but it was only detected in traces in the soluble form. The genotype did not influence the total content of CWBPAs, although the effect was significant for most of the individual compounds. The wheat variety registered the highest ferulic acid value in the hilly site, although Maira and the commercial rye did not differ significantly from the control. As far as sinapic acid is concerned, the rye varieties showed higher values than the control, although, in some cases, the differences were not significant. As previously observed for the SPAs, the concentrations of bound vanillic and syringic acids were higher in the wheat variety than in the ryes, but they only accounted for a small share of the total content of the bound phenolic acids (0.2-0.7%). Additionally, the variation patterns in the phenolic acid compositions differed among the rye genotypes.CWBPAs constituted most of the phenolic acid concentration, and on average represented 85-91% of the total phenolic acids. Ferulic acid was the predominant phenolic acid detected in the bound form, accounting for 76-81% of total bound phenolics. The other abundant CWBPAs were: sinapic acid (12-17%) and Apart from the genotype, the year factor also affected the SPA and CWBPA concentrations. The highest content was observed in 2020 in both sites and for both parameters, but not for the SPAs in the mountain site, whose content did not differ significantly over the two years. The 2020 harvest was in fact characterized by higher SPA and CWBPA contents in the hilly environment , while the CWBPAs increased by about 22% in the mountain environment in 2020, compared to 2021. A similar trend was observed for the individual phenolic acids, although some of them were not influenced by the year.The G × Y effect was significant for both SPAs and CWBPAs in the hilly site, with marked differences among the rye genotypes being observed in 2020. Maira had a significantly higher content of both forms of phenolic acids in the 2020 harvest, while the differences were less distinct (SPAs) or were not detected (CWBPAs) among the genotypes in 2021 (data not shown). The interaction was only significant for SPAs in the mountain environment, with more marked differences among the rye genotypes being observed in 2021, with Maira presenting a higher content than all the other genotypes (data not shown).ABTS of the plots cultivated in the hilly environment (data not shown), where it resulted in higher levels in 2020 (+10%) than in 2021, in accordance with the higher phenolic acid concentration.The AC of the wheat and rye whole-grain flours was measured by means of two different assays, ABTS and FRAP. As shown in p-coumaric, were highly correlated to AC in the soluble form, with the exception of p-coumaric acid and ACFRAP, whose correlations was not significant (data not shown). Less marked, but still significant correlations were registered for sinapic and p-coumaric acids in the insoluble form and AC (data not shown).Significant relationships were found between the phytochemicals and AC of the analyzed whole-grain flours Table S43.6Twelve blends of refined flour were formulated for bread making, with a 40% replacement of the whole-grain flour obtained from the wheat and rye genotypes cultivated in the hilly and mountain environments, and characterized for their rheological properties; the refined commercial wheat flour (no replacement) was considered as the control.The refined flour control in the Mixolab test required a water supply of 55.8% (14% basis) to reach an adequate dough consistency (data not shown). The replacement with whole-grain wheat flour increased the amount of water (WA) required for the hydration process of the flour to 56.9% (average of the two sites), while the inclusion of whole-grain rye flour led to a further increase in the WA . The highest WA values were observed for the Tanaro blend in the hilly site and for the Maira blend in the mountain site (59.5%). The functionality of the whole-grain wheat and rye blends was estimated by determining the SRC profile and by comparing it with the SRC profile of the refined control (data not shown). SRC tests were carried out using two different solvents, namely water (W-SRC) and sucrose solutions (S-SRC), to provide information on some of the chemical and physical properties of the samples, and particularly on the ability of specific constituents to absorb and retain a given solvent. The water holding capacity (W-SRC) was similar for the refined control and the blend with whole-grain wheat flour substitution , while increasing values were observed for the rye mixes . Maira registered the highest W-SRC value in both the hilly and the mountain environments , while the lowest value was recorded for the commercial rye (90.8%). The rye blends were characterized by higher S-SRC values than the refined control .Increasing DDT values were observed, for the adapted hydration protocol, for the whole-grain wheat and rye blends (9 min), compared to the refined flour (3 min), while DS progressively decreased (data not shown), thus confirming the role of increasing levels of dietary fiber on the rheological behavior of the whole-grain blends. However, a similar behavior was recorded for all the rye blends when the standard protocol was adopted. On the other hand, significant differences were found among the rye genotypes using the FAST protocol at constant WA, as a result of the higher mechanical shear stress Table 5.3.7Fourteen breads  were produced with the previously described flours and were analyzed to establish some technological and antioxidant properties.One-way ANOVA showed a significant effect of the bread formulation on the bread volume, with differences emerging between the two growing locations Table 6.E parameter was assessed considering the refined bread as the control (L*) value and an increase in the redness (a*) value of the crust, while the blue-yellow component (b*) was similar to that of the refined control, with the exception of Maira and Tanaro in the hilly site, while the values in the mountain site were more heterogeneous. Rye inclusion also affected the color of the crumbs, with differences among the varieties and between the environments. The rye breads from the hilly site appeared redder and yellower than the wheat bread and the refined control, but the lightness component was higher than that of the wheat bread and lower than that of the refined control. A similar trend was observed for the mountain site, but no significant differences were detected among the rye and wheat breads for the lightness component, which presented lower values than the refined control.The color of the crust and crumbs of each bread was analyzed, and the Δ control Table 6.ABTS value for the hilly site did not differ significantly from that of the control. The AC of the breads made with rye flour was significantly higher than the refined control, but similar or higher than the bread with whole-grain wheat flour. Large variations were observed among the rye varieties, contrary to what was observed for the whole-grain flours. The maximum observed increase was recorded for Maira, when employing both the ABTS , and the FRAP (+91 and +116%) assays.The AC of the breads increased significantly when the refined flour was replaced with whole-grain flour Figure 34in vitro  with local landraces, which were selected according to their genetic diversity, and were cultivated side by side in the same marginal environments. Overall, only very small differences were reported for the agronomical and yield traits. The higher potential yield of the hybrid cultivar is the most evident trait, even in marginal environments, and it benefits from the heterosis effect, which resulted in a greater plant functionality and stability and in a higher HI. The superior yield capacity of hybrids than that of population cultivars has already been reported for intensive cropping systems . HoweverThe rye landraces were characterized by higher levels of SPAs and CWBPAS, in both environments, than the conventional rye cultivars, although the AC of the whole-grain flour, as measured by means of two assays, was similar among the rye genotypes, in agreement with that of The differences among the rye genotypes were more evident for distinctive agronomic and qualitative parameters, when specific landraces were considered. In particular, the genotype from the Maira Valley showed the most notable morphological differences, as it had the tallest and thinnest culm and suffered from lodging phenomena, which reduced its yield potential and HI. Maira also showed the main differences as far as the qualitative traits are concerned, compared to the other rye genotypes. The proximate composition analyses revealed the superiority of Maira over the rye landraces and commercial cultivars for bread-making purposes, as it was characterized by the highest protein and ash contents in both environments. On the other hand, the Susa and Tanaro landraces were characterized by low GPC values, like those of the hybrid rye, but higher TAX and β-glucan contents. Maira showed the highest SPA and CWBPA contents in the hilly site, while Susa registered the highest values in the mountain site. The dough formulation including the Maira flour showed the greatest ability to absorb and retain a highly concentrated sugar solution in both locations, and this was followed by Susa, which was in turn characterized by the highest level of soluble fibers. Differences in protein network weakening among the rye varieties were registered at constant hydration. In the hilly site, the blend including Maira was characterized by the highest thermal weakening (C1-C2), which can be explained by the high GPC of the source flour, which in turn resulted in bread characterized by the highest volume for that location. On the other hand, the blend containing the hybrid rye cultivated in the hilly site had a considerably low (C1-C2) value, mainly due to the low GPC and high TDF contents observed in the same site, which led to a final bread characterized by the lowest volume. Low bread volumes were registered for the blend with Susa in both environments, which was characterized by high β-glucan, high TDF and low GPC contents. Furthermore, this blend presented a low C2 value for the adapted hydration (data not shown), thus suggesting that the dough resisted deformation during kneading and heating, and this was confirmed by the DDT value, which was higher than those of all the other analyzed blends. The rye mixes presented a similar or lower starch gelatinization level (C3-C2) than the refined control, due to starch dilution of the DF compounds, except for the Maira blend, which registered much lower values and was also characterized by a low cooling setback (C5-C4). Furthermore, the Maira-based bread retained the highest AC, as measured by both assays, in both sites, thus suggesting that this landrace, in combination with wheat flour, was the most suitable for bread making, as it showed the best performances when the rheological and antioxidant properties were considered.Our results highlighted that genetically diverse genotypes have distinctive agronomic features which have been observed in different cultivation environments. Individuals from different cultivars resulted to be separated into coherent clades, thus revealing that the rye genotypes were well differentiated among populations, and the clades were well supported, with bootstrap values ≥ 75 . HoweverIn summary, to the best of the authors’ knowledge, this study is the first to have investigated a wide multiplicity of agronomic, nutritional, and qualitative parameters of locally selected rye landraces grown in marginal environments, along with wheat and commercial rye cultivars. The genotype selected from Tanaro Valley was found to be close to the commercial population cultivar, from the genetic, agronomic, and qualitative points of view. Maira, according to the genetic investigation, was found to be qualitatively divergent from all the other analyzed commercial and landrace rye genotypes, and to have less favorable morphologic and agronomic traits. Nevertheless, it was also characterized by the highest content of health-related substances and a better bread-making aptitude. A good bioactive compound content was also registered for Susa, together with a relevant number of soluble fibers, which, however, proved to be detrimental for its rheological properties. The present work has demonstrated the feasibility of cultivating local landraces in marginal Alpine environments, that is, in both hilly and mountain areas, to produce landrace-based foods with high nutritional value. The revival of historic rye supply chains could prove to be beneficial for the recovery process of marginal and mountain environments as well as for the preservation of the genetic heritage of rye.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.CS: Investigation, Formal analysis, Data curation, Writing—Original Draft; LC: Investigation, Methodology, Formal analysis, Writing—Review and Editing; MA: Investigation, Methodology, Formal analysis, Data curation, Writing—Original draft; MD: Formal analysis, Writing—Review and Editing; SRE: Investigation, Formal analysis, Writing—Review and Editing; FV: Methodology, Formal analysis, Writing—Review and Editing; ML: Conceptualization, Investigation, Writing—Review and Editing; MM: Conceptualization, Methodology, Formal analysis, Investigation, Writing—Review and Editing, Funding acquisition, Project Administration; MB: Conceptualization, Methodology, Formal analysis, Investigation, Writing—Original Draft, Funding acquisition, Supervision. All the authors have read and approved the final manuscript. All authors contributed to the article and approved the submitted version.


Functional abdominal pain disorders (FAPDs) are one of the most common gastrointestinal disorders in children. The aim of this study was to investigate the prevalence of FAPDs in children in southern Anhui Province, China and their association with academic stress.In this cross-sectional survey, we randomly selected children aged 6–17 years from 11 public schools in southern Anhui Province. FAPDs were diagnosed according to the Rome IV criteria, and a custom-designed questionnaire was used to investigate the association between academic stress and FAPDs in children.A total of 2,344 children aged 6–17 years were enrolled. The mean age was 12.4 ± 3.0 years. Of these children, 335 (14.3%) were diagnosed with FAPDs according to the Rome IV criteria. Among the children with FAPDs, 156 (46.6%) were boys, and 179 (53.4%) were girls. The prevalence was higher in girls than in boys. The most common disorder was irritable bowel syndrome (IBS) (n = 182 (7.8%)). Other types of FAPDs included functional abdominal pain–not otherwise specified (FAPNOS) (n = 70 (3.0%)), functional dyspepsia (FD) (n = 55 (2.3%)), and abdominal migraine (AM) (n = 28 (1.2%)). Academic stress, not meeting parental expectations, poor relationships with parents, and sleep disturbances were independent risk factors for FAPDs in children; academic performance was not associated with the development of FAPDs.There was a high prevalence of FAPDs among children in southern Anhui Province, China, and IBS was the most common subtype of functional abdominal pain. Academic stress, rather than academic performance, was associated with FAPDs in children. Functional abdominal pain disorders (FAPDs) are a group of disorders involving significant and recurrent symptoms of gastrointestinal discomfort without corresponding abnormalities on instrumental and laboratory tests. These symptoms are also difficult to explain in terms of structural or biochemical abnormalities of the digestive system . FAPDs aThe pathogenesis of FAPDs has not been elucidated. According to recent studies, it may be associated with abnormal gastrointestinal motility, decreased visceral nociceptive thresholds, abnormal brain-gut interactions, psychosocial disorders, and immune activation –9. The aThis cross-sectional study was conducted in 11 public primary and secondary schools in southern Anhui, China. A total of 2,344 students completed the interview between September 2022 and November 2022.Children aged 6 to 17 years were included; those unwilling to participate in the study, ≥ 18 years or < 6 years of age, or with incomplete data were excluded. We also excluded patients with the following alarm symptoms: persistent right upper and lower abdominal pain, dysphagia, persistent vomiting, gastrointestinal bleeding, nocturnal diarrhoea, arthralgia, perianal abscess or haemorrhoids, uncontrolled weight loss, growth retardation, unexplained fever, rash, or recurrent oral ulcers.Relevant questionnaires were completed according to the Rome IV criteria. After obtaining consent from the school and parents, all participating children were contacted, and all face-to-face interviews were conducted by trained investigators. Basic demographic data collected included their name, sex, age, height, weight, and only child status; presence of postprandial fullness, early satiation, epigastric pain or burning sensation; location and frequency of abdominal pain; duration of abdominal pain; stool condition ; relationship between abdominal pain and defecation; symptoms accompanying episodes of abdominal pain; presence of academic stress; academic performance; academic performance compared to parental expectations; sleep disorders; and parental relationship quality.The academic stress was measured based on a single indicator from the study ‘Health Behaviour in School-Aged Children (HBSC)’. All the children were asked to answer how stressed they felt due to the schoolwork they must do. The response scale ranged from 1 to 4 . Children who scored 3–4 are considered to have academic stress, while those who scored 1–2 are considered to have no academic stress , 12.The study was approved by the Ethics Committee of Yijishan Hospital, and all guardians of children included in the study signed an informed consent form indicating voluntary consent to participate in the study.According to the Rome IV criteria , FAPDs at test or the Kruskal–Wallis test as appropriate. All variables were explored by univariate analysis, and variables with P values < 0.05 in univariate analysis were entered into the multivariate logistic regression analysis. Data were expressed as ORs and 95% confidence intervals (CIs). Statistical significance was defined as a result for which P < 0.05. A nomogram was constructed based on the logistic regression results. Discrimination was evaluated using the area under the receiver-operating characteristic (ROC) curve, and calibration was evaluated using the calibration curve and the Hosmer–Lemeshow test.Statistical analyses were conducted using SPSS 26.0 software  and R software (version 4.2.2). Categorical variables are reported as counts and percentages and were evaluated using chi-square tests or Fisher’s exact tests as appropriate. Continuous variables are reported as the mean ± SD and were evaluated using a We randomly selected 2,890 students from 11 public primary and secondary schools in southern Anhui between September 2022 and November 2022; of these students, 546 were excluded because they failed to complete the questionnaire or were ≥ 18 or < 6 years old  were girls. The other 335 (14.3%) children were diagnosed with FAPDs; the FAPD group had a mean age of 12.2 ± 3.2 years and a mean BMI of 20.7 ± 4.6 kg/m2, and 179 (53.4%) were girls. Of children with FAPDs, 55 (2.3%) had FD, 182 (7.8%) had IBS, 28 (1.2%) had AM, and 70 (3.0%) had FAPNOS. Thus, IBS was the most common subtype of FAPD in children in southern Anhui, and AM was the least common subtype. The prevalence of FAPDs was higher in females than in males  of 20.9 ± 4.5 kg/mThe study subjects were divided into three age groups: 6–9 years, 10–13 years and 14–17 years. We found no significant difference in the prevalence of FAPDs among the age groups (p = 0.488). The difference in BMI between the FAPD group and the non-FAPD group was also not significant (p = 0.415). We also found that although the prevalence of FAPDs was higher in girls than in boys, female sex was not a risk factor for FAPDs . However, the prevalence of FAPDs was lower in only children than in children with siblings, and being an only child was a protective factor against FAPDs  . Thus, academic performance was not a risk factor for FAPDs. In contrast, analysis of academic stress exposure showed that academic stress , academic performance below parental expectations , and poor relationships with parents  were independent risk factors for FAPDs in children. Moreover, we classified children into three groups according to their sleep quality: normal sleep, difficulty falling asleep and early awakening. We found that sleep disorders, either difficulty falling asleep  or early awakening , were independent risk factors for FAPDs  in children in southern Anhui Province, China and the association between FAPDs and academic stress.This study also has some limitations. First, our study population was recruited from schools in southern Anhui, which may limit the generalizability of these findings due to potential regional differences between our study population and children from other provinces in China. Therefore, our findings may not reflect the reality of the child population in China.We plan to conduct a multiregional study in the future to learn the role of academic stress in children with FAPDs all over China. Our study is useful in educating parents not to underestimate their role in their children’s health, and we will conduct studies to develop guidelines on family education and assess the positive effects on symptoms after parents change their behaviours.The prevalence of FAPDs in children in southern Anhui was similar to that reported worldwide, with a higher prevalence in girls than in boys; IBS was the most common subtype of FAPDs. In addition, academic stress (but not academic performance) was a risk factor for FAPDs in children in southern Anhui. Specifically, independent risk factors for FAPDs included academic stress, academic performance lower than parental expectations, and poor relationships with parents. Treatment of FAPDs in children therefore requires examining not only the physical symptoms but also the family environment and mental health of the children. Only by addressing these concerns will children receive the best treatment.


This study examined longitudinal associations between attention-deficit/hyperactivity disorder (ADHD) symptoms and social isolation across childhood. The study tested the direction of this association across time, while accounting for preexisting characteristics, and assessed whether this association varied by ADHD presentation, informant, sex, and socioeconomic status.Participants included 2,232 children from the Environmental Risk (E-Risk) Longitudinal Twin Study. ADHD symptoms and social isolation were measured at ages 5, 7, 10, and 12. Random-intercept cross-lagged panel models were used to assess the directionality of the association across childhood.Children with increased ADHD symptoms were consistently at increased risk of becoming socially isolated later in childhood, over and above stable characteristics (β = .05-.08). These longitudinal associations were not bidirectional; isolated children were not at risk of worsening ADHD symptoms later on. Children with hyperactive ADHD presentation were more likely to become isolated, compared with inattentive presentation. This was evident in the school setting, as observed by teachers, but not by mothers at home.The study findings highlight the importance of enhancing peer social support and inclusion for children with ADHD, particularly in school settings. This study adds explanatory value beyond traditional longitudinal methods, as the results represent how individual children change over time, relative to their own preexisting characteristics.We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. First, isolation could manifest differently depending on ADHD presentation. Inattentive children withdraw or disengage from social situations, missing key observational learning,,Key social behaviors involved in building positive or negative interactions should be accounted for to ensure the independence of this association and to better understand the pathway by which children with ADHD symptoms become isolated. Negative outward behavior toward other children may account for the association between ADHD symptoms and social isolation. ADHD in childhood often co-occurs with antisocial, disruptive, or aggressive behaviors.In the current study, we investigated the associations between ADHD symptoms and social isolation across childhood in a nationally representative longitudinal cohort in the United Kingdom. First, we aimed to test the direction of the associations between ADHD and isolation while accounting for preexisting characteristics. We hypothesized that there would be bidirectional associations between experiences of social isolation and ADHD symptoms across childhood. Second, we aimed to ensure that the association between ADHD symptoms and social isolation cannot be explained by co-occurring antisocial or prosocial behaviors. We hypothesized that antisocial or prosocial behaviours would mediate the association between social isolation and ADHD symptoms. Third, we aimed to assess if the association differed for hyperactive/impulsive and inattentive presentations. We hypothesized that the association with social isolation would be stronger for children with a hyperactive presentation of ADHD symptoms. Fourth, we aimed to test for moderating effects of informant (parents and teachers), sex, and SES. We hypothesized that there would be differences in the strength of the association when stratified by informant, sex, and SES.Participants were members of the Environmental Risk (E-Risk) Longitudinal Twin Study, which tracks the development of 2,232 British children. The sample was drawn from a larger birth cohort of twins born in England and Wales in 1994-1995.et al.,DSM-IVAt ages 5, 7, 10, and 12, social isolation and ADHD symptoms were assessed using items from the Child Behavior Checklist (CBCL)rs at each age = 0.26-0.31; ADHD rs = 0.26-0.35). We averaged mothers’ and teachers’ reports to form a combined scale that integrates observations from different settings. Apart from analyses assessing informant differences, all models used the combined score (averaged reports from mothers and teachers). For ADHD, scores were summed separately for inattention and hyperactivity/impulsivity, then combined to create a total ADHD score. A total of 2,078 (93.10%) children had complete social isolation and ADHD data at all 4 time points. Missingness was handled using maximum likelihood estimation; thus all children had at least one rating of ADHD symptoms and social isolation and were included in analyses .Items were summed to create separate mother and teacher scales for social isolation and ADHD at each age . See Antisocial and prosocial behaviors were assessed at ages 5, 7, 10, and 12. Prosocial behavior included 10 items taken from the revised Rutter parent questionnaireWe used the random intercept cross-lagged panel model (RI-CLPM)RI-CLPM adds random intercepts to the CLPM for each variable, which accounts for stable, traitlike differences between individuals. This separates change that happens within one child from one time point to the next (within-person), while accounting for stable, time-invariant, individual differences (between-person). RI-CLPM is made up of autoregressive paths, which represent change or carryover effects in one construct over time , and cross-lag paths, which represent within-person bidirectional effects from one variable to the other over time . We refer to within-person associations as individual-level and the combination of within-person and between-person associations as group-level.p < .05. As a sensitivity analysis, we assessed the measurement invariance of social isolation and ADHD over time. Evidence of measurement invariance was found for both constructs, supporting the conclusion that the measures captured the same construct over time  using lavaan (v0.6-10).https://sites.duke.edu/moffittcaspiprojects/files/2022/02/ThompsonK_2022_bidirectional-associations_Erisk.pdf), and code is on GitHub .Model fit was evaluated by examining the comparative fit index , Tucker-Lewis index , root mean square error of approximation , and standardized root mean square residual . Maximum likelihood estimation with robust test statistics and robust standard errors was used throughout all analyses to account for nonnormality and nonindependence of twin pairs. The Satorra-Bentler scaled χSocial isolation and ADHD symptoms were relatively stable from one time point to the next and concurrently associated with one another throughout childhood according to the CLPM A. On aver = 0.54, p < .001)   . The mos < .001) B. When a < .001) B. However = 0.57, r = 0.46). At the individual level, cross-lag paths differed for hyperactivity/impulsivity and inattention: similar to the combined ADHD symptom model, we found significant cross-lag effects from hyperactivity to later social isolation (Separate models for symptoms of hyperactivity/impulsivity and inattention both showed good fit to the data using RI-CLPM . The betsolation A. Howevesolation B. Acrossp = .001), but not inattention . We found no overall sex differences for combined ADHD symptoms or for hyperactive/impulsive or inattentive presentations (p = .303-.612), and only longitudinal paths for low SES remained significant. This suggests that these apparent SES differences  and within-person  associations in psychiatric conditions across childhood is useful to inform individual prediction, understand psychiatric comorbidity, and discover developmental pathways underlying mental health disorders. Second, social isolation could be a mechanism by which children with ADHD may experience increased risk for comorbid mental health disorders. Previous research has shown that limited or harmful relationships can lead to anxiety and depression.Our findings also have implications for clinicians and educational professionals. Social difficulties associated with ADHD can be as detrimental as the core symptoms themselves.


Long-term medication use is a recommended treatment for attention-deficit/hyperactivity disorder (ADHD), however, discontinuation is common. Non-medical factors which might influence initiation and discontinuation are understudied. Therefore, we investigated how different sociodemographic factors and comorbidities were associated with the initiation and discontinuation of ADHD medication use among young adults.n = 59224). ADHD medication initiation was defined as the first prescription of ADHD medication in the period from 3 months before to 6 months after the cohort entry date. Those who initiated ADHD medication were followed up for medication use until discontinuation, death/emigration, or until 2019. Logistic and Cox regression models were used to investigate the associations between sociodemographics, health-related predictors and initiation, as well as discontinuation. Overall, 48.7% of the 41399 individuals initiated ADHD medication, most often methylphenidate (87%). Among the initiators, 15462 (77%) discontinued medication use during the follow-up (median time: 150 days). After mutually adjusting all other predictors, initiation was positively associated with older age, male sex, higher level of education, and negatively associated with living at home with parents, immigrant status, being unemployed during the year before inclusion, being on disability pension, having autism, substance use, schizophrenia-spectrum disorders, other mental disability/developmental disorders, cardiovascular diseases or previous accidents. Discontinuation was positively associated with being born abroad, living in big cities, being unemployed during the year before inclusion, having cancer, and negatively associated with a higher educational level, having depression, anxiety or stress-related disorder, autism spectrum disorder or diabetes.We conducted a population-based prospective cohort study using individually linked administrative register data, in which we included all individuals residing in Sweden, between the age of 19 and 29 who were first diagnosed with ADHD between January 2006 and December 2016 (Besides medical factors, sociodemographics, such as educational attainment and immigrant status might also play a role in the initiation and discontinuation of ADHD medication use among young adults newly diagnosed with ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric functional disorder, including symptoms such as attention deficiencies, problems with controlling the activity level, and impulsiveness that might affect social life, educational attainment, and workability negatively . The estThe usual and recommended treatment for ADHD is multimodal treatment with or without the use of ADHD-related medications to facilitate everyday functioning both in the family and at work or school , 10. In In general, stimulants seem to be more efficacious to alleviate symptoms of ADHD than non-stimulants, but the side effects of stimulants can hinder tolerability in some individuals , 18, 19.Among children, low socioeconomic status, social adversities, and mental comorbidities were associated with a higher probability of ADHD medication initiation . FurtherWe aimed to investigate how different sociodemographic, work-and health-related factors and comorbidities were associated with the initiation and discontinuation of ADHD medication use among young adults.N = 61507) were included  personal identification number . InpatieAll purchases of dispensed ADHD medications by the following ATC codes were included: centrally acting sympathomimetics (N06BA), clonidine (C02AC01), and guanfacine (C02AC02). These medications have been used as a treatment for ADHD internationally , and excInitiation of ADHD medication was defined as the first prescription in the period from 3 months before to 6 months after the cohort entry date, and individuals were categorized as initiators vs. non-initiators. Those who initiated ADHD medication were followed up for persistence of ADHD drug use until discontinuation of use (second outcome measure), by censoring to death or emigration, 2 years after initiation and end of data linkage on December 31, 2016. We defined discontinuation of ADHD medication use if the drug use period ended before the end of the follow-up. Polytherapy was defined as initiating more than one ADHD drug at the same time.Several sociodemographic, work-and health-related factors and comorbidities were considered as possible predictors of initiation and discontinuation of ADHD medication use. Sociodemographic factors were assessed at the end of the year preceding the ADHD diagnosis and included level of education , family situation , country of birth , living region . The following work and health-related factors were considered: being unemployed the year before the ADHD diagnosis , having sickness absence allowance over continuous 14 days periods  or being on disability pension at the time of the diagnosis. Psychiatric comorbidities were identified by ICD-10 codes from specialized outpatient and inpatient health within 2 years before the cohort entry date: depression/bipolar disorder (F30-34); anxiety and stress-related disorders (F40-48); autism-spectrum disorders (F84); substance use disorders (F10-19); behavioral and emotional disorders, excluding ADHD (F91-98); mental disability/developmental disorders (F70-89); schizophrenia-spectrum disorders (F20-29); other mental disorders (other F codes). Somatic comorbidities were categorized as musculoskeletal disorder (M00-M99); asthma (J45); diabetes (E10-E11); cancer (C00-D48); cardiovascular diseases (I00-I99); accidents (S00-S99); and other somatic disorders (other codes except O.80 and Z00-99).The distributions of study variables for the total population and by initiation and discontinuation are presented as a mean value and the standard deviation for continuous variables, and the number of individuals and percentages for categorical variables. Logistic regression was used to analyze the association between each predictor and the initiation of ADHD medication (the reference category was “non-initiation”). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the crude model and by adjusting to the other predictors simultaneously. Cox proportional hazard regression was used to estimate the hazard of discontinuation of medication use compared with continuous use during the follow-up. Crude and multi-adjusted hazard ratios (HR) and 95% CIs were calculated.Of the 59224 individuals with the first ADHD diagnosis, 41399 did not use medication during 4–9 months before diagnosis and were therefore included in this study . The disThe distribution of predictors by initiation is presented in N = 10358) had discontinued within 6 months and 76.4% (N = 13180) had discontinued within 1 year. The time to discontinuation is presented in n = 10325) re-initiated use later during the follow-up. The median time to reinitiation was 91 days (IQR: 43–258). For further analysis, long-acting and short-acting methylphenidate use were combined, as they followed similar discontinuation patterns. The distribution of study variables by discontinuation among those who initiated ADHD medication and the associations between the predictors and discontinuation are shown in Among those who initiated ADHD medication, 15462 (76.6%) discontinued medication use during the follow-up. Overall, 38 individuals died, and 13 individuals emigrated during the follow-up , 3B. TheN = 15462), 66.8% (N = 10325) re-initiated medication use later during the follow-up. The mean time to re-initiation was 245 days (SD 394), median time was 91 days (IQR 43–258).In the crude analysis, age, educational level, family situation, country of birth, sickness absence in the previous year, mental and somatic comorbidities, and type of medication were associated with discontinuation. In the multivariate analysis being born abroad, living in big cities, being unemployed during the previous year, having cancer, and initiating atomoxetine or lisdexamfetamine compared with methylphenidate was positively associated with medication discontinuation. A higher educational level, depression, anxiety or stress-related disorder, autism spectrum disorder or diabetes were negatively associated with ADHD medication discontinuation. Of those who discontinued ADHD medication use during the follow-up .The data analyzed in this study is subject to the following licenses/restrictions: The project utilized data from the REWHARD consortium, supported by the Swedish Research Council (VR grant number. 2017-00624). These data cannot be made publicly available due to privacy regulations. According to the General Data Protection Regulation, the Swedish law SFS 2018:218, the Swedish Data Protection Act, the Swedish Ethical Review Act, and the Public Access to Information and Secrecy Act, these types of sensitive data can only be made available for specific purposes, including research, that meet the criteria for access to these type of sensitive and confidential data as determined by a legal review. Requests to access these datasets should be directed to Kristina Alexanderson . We utilized data from the REWHARD consortium supported by the Swedish Research Council (grant number 2017-00624). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1152286/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.