The study aim was to examine the secular trends and regional variations in pharmacotherapy of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Germany.n = 262,766 in 2016). The examined drugs were methylphenidate, amphetamines, atomoxetine and guanfacine.We used nationwide drug prescription data of outpatient care (2009 to 2016). The study population comprised patients aged between 5 and 14 years with the diagnoses “hyperkinetic disorders” (ICD-10 code F90) . The proportion of methylphenidate prescription was higher in Western than Eastern federal states. However, atomoxetine was more often prescribed in Eastern than Western federal states. The proportion of methylphenidate prescriptions issued by pediatric psychiatrists increased from 28% (2009) to 41% (2016).A decreasing trend in use of pharmacotherapy may be explained by prescription restrictions issued by the Federal Joint Committee in recent years. Attention-deficit/hyperactivity disorders (ADHD) is one of the frequent neurodevelopmental disorders among children and adolescents. A recent population-based study in Germany showed a stagnating trend in the period between 2009 and 2016 .There has been controversy regarding ADHD over decades . In partThe aim of the study was to examine the secular trends and regional variations in pharmacotherapy of children and adolescents with ADHD. In particular, we were interested in the effect of restrictions issued by the G-BA on prescription prevalence and prescribing patterns.We used nationwide SHI-physician outpatient prescription data from the years 2009 to 2016. The data contain all prescriptions and diagnoses of statutory health insured individuals (SHI), who visited a SHI-authorized physician at least once per year. SHI-insurees account for about 87% of the total German population. In brief, prescriptions are issued by SHI-authorized physicians and redeemed by the patients in a pharmacy. Amongst other things, the data contain the date of prescription and dispensation, the anatomical therapeutic chemical (ATC) code, and the drugs’ generic and trade names. In the current analysis we considered the ATC codes from the group N06B exclusively used for ADHD therapy . In Germany, the ATC classification is published annually by the German Institute of Medical Documentation and Information (DIMDI). The examined drugs were methylphenidate (ATC: N06BA04), atomoxetine (N06BA09), dexamfetamine (N06BA02), lisdexamfetamine (N06BA12) and guanfacine (N06BA14). Finally, data contain information on physicians  and patients . The latter consists of 17 regional Associations of Statutory Health Insurance Physicians (ASHIPs). Of them, 15 ASHIPs correspond to 15 German federal states whereas the federal state of North-Rhine-Westphalia has two ASHIPs. The data were used in accordance with Section 300 (2) of the Social Code V .n = 274,202 in 2009; n = 262,766 in 2016). Diagnoses are coded according to the German modification of the 10th edition of the International Classification of Diseases and Related Health Problems (ICD-10-GM) [The study population comprised children and adolescents aged between 5 and 14 years diagnosed with ADHD  and separately for each medication for the period of 2009 to 2016. The curves of prevalence over time were fitted using a cubic spline function. The joinpoint regression analysis was then used to assess time trends in prescription prevalence. This was performed for prevalence of at least one prescription and separately for each medication (dependent variables) and year (independent variable) with the Joinpoint Trend Analysis Software (version 4.9.0.0) available from the National Cancer Institute .https://www.r-project.org).In addition, we performed univariate cross-sectional analysis by sex, age and region (2016). Analyses were performed with the R Foundation for Statistical Computing, version 3.4.4 (The size of the study populations (i.e. children and adolescents between 5 and 14 years diagnosed with ADHD) ranged across years between 262,000 and 287,000  received at least one prescription of (any) stimulant or non-stimulant. The most frequently prescribed medication was methylphenidate; 38% of all children and adolescents with ADHD received this prescription, followed by lisdexamfetamine (6.5%), atomoxetine (2.9%) and guanfacine (1.1%). The prevalence of dexamfetamine prescriptions was negligible (0.69%). The prescription prevalence of all medications was higher among boys than girls in all age groups . Figure p = 0.047). The prevalence of atomoxetine prescriptions also showed a downward trend with one joinpoint . Overall, in 2009 and 2016 its prevalence was 5.0 and 2.9%, respectively, corresponding to a relative decrease of 42%. The prevalence of lisdexamfetamine prescriptions increased from 1.7% in 2013 (i.e. the year of license) to 6.5% in 2016 . The prescription prevalence of dexamfetamine (which was licensed in 2012 in Germany) displayed a rising trend , but was very low in all years .The trends in prescription prevalence over the period of 2009 to 2016 are presented in Fig. Regional variations in prescription prevalence of stimulants and non-stimulants in 2016 are presented in Fig. In its second directive in 2010 the G-BA issued explicitly the physician specialties to prescribe stimulants. The stimulants were only allowed to be prescribed by specialist physicians including pediatric psychiatrists, specialists for behavioral disorders in children and adolescents etc. Only in exceptional cases stimulants could be prescribed by pediatricians and general practitioners (GPs). We examined physician groups who prescribed the most frequent stimulant – methylphenidate – in 2009 and how it changed over the observation period Fig. A. In 200Using the nationwide prescription data we examined the trends and regional variations in pharmacotherapy of ADHD among children and adolescents in Germany. Overall, we observed a decreasing trend in prescription prevalence of stimulants and non-stimulants over the period 2009 to 2016. In addition, there were regional variations in prescription.n = 33,192). All five substances were included in the study, however, only overall trends for ADHD medication were reported without differentiation of specific substances.Previous research in Germany observed rising trends in use of stimulants . The G-BWe observed the only increase in prescription prevalence of amphetamines. In 2013 licenced lisdexamfetamine showed a nearly 4-fold increase within the first 3 years . In the year of license lisdexamfetamine was the third most frequently prescribed medication. In 2014 it was already the second most frequently prescribed medication. Dexamfetamine prescriptions increased by a factor 2.6 from 2012 (0.26%) to 2016 (0.69%). However, overall, the proportion of children receiving amphetamine prescriptions was low. Of note, the introduction of new medications and an increase of amphetamine prescriptions did not result in an overall increase of children prescribed medications.One possible explanation for declining prescription trends would be the decrease in prevalence of ADHD. However, in the same period of time we did not observe a decrease in prevalence of ADHD . The prep = 0.86). Unfortunately, a regional analysis on a district level is not possible as this information is not available in the dataset due to the current data protection regulations. One possible explanation for regional variations in prescription prevalence is the availability of various physician groups. For instance, the density of pediatric psychiatrists and psychotherapists is higher in Western than Eastern federal states [Regionally we observed distinct patterns, which have not been described previously. Methylphenidate was more commonly prescribed in Western than in Eastern federal states. A similar finding was seen for lisdexamfetamine although the regional pattern was not so clear. On the contrary, atomoxetine prescriptions were more common in Eastern federal states. The reasons for these variations are not known and need to be explored. Grobe et al. examined regional differences in methylphenidate use on a district level and observed a high correlation between ADHD prevalence and medication use (r = 0.84) . We did l states . This isWe observed a shift towards increasing proportion of physician groups specialized in psychiatry and psychotherapy prescribing stimulants. Whereas in 2009 the most frequent physician group prescribing methylphenidate were pediatricians, this pattern changed gradually over years. In the last year of observation (2016), the most frequent physician group prescribing methylphenidate were pediatric psychiatrists and psychotherapists. The proportion of pediatricians showed a slow decrease over years. However, in 2016 every third patient with ADHD still received a prescription from a pediatrician. The proportion of GPs prescribing methylphenidate showed a more rapid decline; e.g. in 2016 only every 15th patient with ADHD received a prescription from this physician group. Overall, we observed changes in prescribing patterns which can be attributed to the second directive of the G-BA issued in 2010. The G-BA restricted prescriptions to certain physician groups. The prescription of stimulants by pediatricians and GPs was only allowed in exceptional cases.We used the nationwide outpatient drug prescription data of all statutory health insured individuals covering 87% of the total German population. The dataset does not contain information on individuals insured privately. The latter have a higher socio-economic status, which was associated with a lower risk of ADHD . We cannThe prescription prevalence of stimulants and non-stimulants showed a decreasing trend over the period of 2009 and 2016 among children and adolescents. In addition, the proportion of pediatric psychiatrists prescribing stimulants increased whereas the proportion of prescriptions issued by pediatricians and GPs decreased. This might be the effect of strict directives of the G-BA issued in recent years. These directives may contribute to increasing awareness among physicians regarding the need of a pharmacological therapy of ADHD.


Although evidence has shown that both RD and ADHD-I children suffer from working memory problems, inconsistencies in impaired modalities have been reported. This study aimed to (1) compare the three WM domains  among pure ADHD-I, pure RD, comorbid ADHD-I+RD, and typical control groups and (2) examine the impact of comorbidity on the three WM domains. A Chinese sample of participants from Hong Kong included 29 children in the ADHD-I group, 78 children in the RD group, 31 children in the comorbid group (ADHD-I+RD), and 64 children in the TD control group. All participants completed the assessments individually. The findings showed that the children with ADHD-I and/or RD exhibited diverse cognitive profiles. In particular, RD was associated with verbal and visual-spatial working memory deficits, while ADHD-I was associated with behavioral working memory deficits. Interestingly, the comorbid condition demonstrated additive deficits of the two disorders but with greater deficits in behavioral working memory. These findings support the cognitive subtype hypothesis and provide a clearer picture of the distinctive working memory profiles of different groups, allowing for the development of intervention programs in the future. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children worldwide, with 8.4% of school-aged children having ADHD . AccordiIn fact, children who exhibit purely inattentive behavior are likely to underachieve in reading  and haveExtensive evidence has shown that both RD and ADHD-I children suffer from working memory (WM) problems . WM is aThe limited capacity of WM varies widely among individuals. The cognitive and behavioral profiles are the two major directions for understanding individual differences in WM. The cognitive profile is mostly based on the multicomponent model , which cOther studies have adopted behavioral measures, such as the Working Memory Rating Scale WMRS;  and the Although evidence has shown that both RD and ADHD-I children suffer from WM problems, inconsistencies in the impaired modalities have been reported. Previous epidemiological studies have suggested that ADHD-I is likely to be associated with poorer verbal  and visuVerbal WM deficits, on the other hand, have been associated with children with RD . For insWhen examining the impact of comorbidity, many studies have confirmed that cognitive deficits seem to be more severe in the comorbid group . MartinuTo understand the impact of comorbidity, three mutually exclusive hypotheses reign. Early studies proposed the “phenocopy hypothesis,” according to which one disorder might produce symptoms of the other. For example, The purposes of this study were as: (1) to compare the three WM domains  among the pure ADHD-I, pure RD, comorbid ADHD-I+RD, and typical control groups and (2) to examine the impact of comorbidity on the cognitive and behavioral WM domains. Based on previous research, it was hypothesized that children with ADHD-I would be associated with deficits in behavioral WM, while children with RD would be associated with deficits in verbal WM. It was also hypothesized that the comorbid group of ADHD-I and RD would exhibit severe forms of WM deficit shared by the pure groups, which supported the cognitive subtype hypothesis.Mage=9.3; SD=1.1) were recruited from four primary schools in Hong Kong. This sample size was estimated using G*Power  in the ADHD-I group, 78 participants  in the RD group, 31 participants  in the comorbid group, and 64 participants  in the TD group. All of them had normal intelligence (≥80) and no suspected brain damage or neurological, sensory, or psychiatric problems.Two hundred and two primary school students ]}  as well During the assessment phase, the third edition of the backward digit span subtest from the Wechsler Intelligence Scale for Children  was collected using self-report. A comprehensive assessment battery of WM tasks was also administered to the participants, and data on reading performance and behavioral outcomes were collected from multiple informants  using questionnaires.Raven’s Standard Progressive Matrices  were usenever) to 3 (often). The internal consistency was 0.80–0.98, and the test-retest reliability was 0.82, indicating good reliability of the BRIEF  to rate the behavioral measure of WM in children with ADHD. It is a well-researched instrument that provides researchers with a comprehensive assessment tool that results in reliable and valid data . The WM he BRIEF .α=0.80  to measure visual-spatial WM. It has established a large normative data set and has been widely used in research studies, with over 2,400 peer-reviewed papers supporting its use . The tesSeveral statistical methods were employed using the Statistical Package for Social Sciences =3.87, p<0.05] and IQ . In terms of age, post-hoc comparisons using the Tukey HSD test indicated that the mean score for the TD group was significantly different from that of the comorbid group (p<0.05). As for IQ, post-hoc comparisons using the Tukey HSD test indicated that the mean score for the TD group  was significant different from the RD  and comorbid  groups. The difference between the ADHD-I  and RD  groups was also significant (p<0.05). No significant difference was found in education level  , and education level, in the four groups. There were significant differences in age [.58] see .χ2 =8.67, p<0.05]. In the ADHD-I group, there were 69% males and 31% females. In the RD group, there were 53% males and 47% females. In the comorbid group, there were 81% males and 19% females. In the TD group, there were 56% males and 44% females =18.86, Pillai’s Trace=0.25, p<0.001, F=3.26, Pillai’s Trace=0.05, p<0.05, F=9.26, Pillai’s Trace=0.14, p<0.001, F=53.98, p<0.001] and RD on verbal WM . The main effect of RD on visual-spatial WM was marginally significant . Furthermore, there were significant interaction effects between ADHD-I and RD in all three domains of WM: behavioral WM , verbal WM , and visual-spatial WM [F=5.27, p<0.05; see The scores on the three types of WM were entered into a MANCOVA. After controlling for age and IQ, the multivariate main effects of ADHD-I [p<0.001; RD: p<0.05; comorbid: p<0.001) was significantly worse than that of the TD group in behavioral WM. Significant differences were also found between the RD and comorbid groups (p<0.001), between the ADHD-I and RD groups (p<0.001), and between the ADHD-I and comorbid groups (p<0.05) in behavioral WM. The bar chart shows that individuals with ADHD-I status, having RD, had an impact on behavioral WM, while individuals without ADHD-I, having RD, showed no difference in behavioral WM , RD (p<0.01), and ADHD-I+RD (p<0.01) groups. No significant differences were found between the other three disorder groups . The bar chart illustrates that individuals without ADHD-I status had an impact on their verbal WM performance. In contrast, for individuals with ADHD-I, RD made no difference . The differences between the TD and ADHD-I groups (p=0.076) and the TD and comorbid groups (p=0.086) were marginally significant. No significant differences were found between the other three disorder groups . The bar chart reveals that individuals without ADHD-I status, having RD, had an impact on their visual-spatial WM performance. Conversely, for individuals with ADHD-I, RD made no difference . The ADHD-I group still exhibited comparatively poor cognitive and behavioral WM compared to the control group in our study. Such findings align with earlier studies that correlated ADHD-I with behavioral WM deficits ,b, 2015.In the current study, ADHD-I was not associated with any significant weaknesses in the two cognitive WM measures. These findings are consistent with prior research that found slightly reduced or intact visual-spatial WM and verbal WM in the ADHD sample . This isWith respect to the comorbid group, our study yielded interesting results. On the one hand, children with comorbidity of ADHD-I and RD had similar scores in verbal and visual-spatial WM compared to the pure groups. On the other hand, the score for behavioral WM was significantly higher in the comorbid group than in the other pure groups. It may be possible to conclude that children with pure RD or ADHD-I manifested distinct cognitive deficits, while both forms of deficit occurred together in the comorbid condition and produced an augmented clinical manifestation of behavioral WM deficits. These findings are consistent with a previous study conducted by Some limitations of the present study should be noted. First, the dosage of ADHD medication taken by children with ADHD-I was not reported by the parents. Previous research reported that low doses of ADHD medication improve WM, whereas high doses impair WM in a group of children . TherefoDespite these limitations, our findings have potential implications. The present study was a response to earlier calls for targeted interventions for ADHD-I, RD, and comorbid groups of children. These include computerized training targeting WM, which has been associated with a reduction in ADHD symptoms and an improvement in the visual domains e.g., . For exaIn conclusion, this study indicated that children with ADHD-I and/or RD exhibited diverse cognitive profiles, particularly in the Chinese population in Hong Kong. Children with comorbid symptoms demonstrated poorer performance in behavioral WM than those in the pure groups. Furthermore, children in the RD group demonstrated weaker ability in verbal WM and visual-spatial WM than did the pure groups. These findings provide a clear picture of the distinctive WM profiles across different groups, allowing for the development of intervention programs in the future.The original contributions presented in the study are included in the article/supplementary material, and further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Human Research Ethics Committee, The Education University of Hong Kong. Written informed consent to participate in this study was provided by the participants’ parents.KP was responsible for the conception of the research questions, study design, data interpretation, and writing. MH was responsible for data analysis and writing. L-CW was responsible for providing input on this paper. All authors have agreed the final version of the manuscript.This work was partially funded by the Block Grant Faculty Fund from the Faculty of Education and Human Development at The Education University of Hong Kong. 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.


BackgroundSymptoms experienced by adult patients with attention-deficit/hyperactivity disorder (ADHD) frequently result in functional impairment across academic/occupational functioning, daily life, and social functioning. A substantial proportion of undiagnosed and untreated ADHD has been suggested in Japan. This study aims to better understand the potential undiagnosed ADHD population in Japan by quantifying the burden associated with ADHD symptoms through a comparison of the prevalence of comorbidities, health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and healthcare resource utilization (HRU) between undiagnosed potential ADHD respondents who were screened positive and negative using Adult ADHD Self-Report Scale (ASRS)-v1.1.MethodologyRespondents from Japan National Health and Wellness Survey 2016 who answered ASRS-v1.1 without an ADHD diagnosis were included. Respondents checking ≥4 items from ASRS-A and ≥9 from ASRS-A+B were classified as ASRS A+ (n = 309) and ASRS AB+ (n = 227), respectively. ASRS negative  were respondents who were neither ASRS A+ nor ASRS AB+. Data on the presence of comorbidities, HRQoL, WPAI, and HRU were compared.ResultsASRS A+ and ASRS AB+ respondents reported higher coexistence of mental comorbidities , sleep problems , and physical comorbidities . They also reported greater WPAI and HRU and lower HRQoL than matched ASRS-negative respondents.ConclusionsA significantly higher burden was identified among undiagnosed adults with potential ADHD symptoms. Appropriate diagnosis may help those at risk or those who present with symptoms overlapping with ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder that is characterized by inattention and/or excessive activity and impulsivity symptoms . SymptomADHD prevalence was reported to be 6-10% in US children and adolescents between 1997 and 2016 . In adulSeveral studies have reported that diagnosed adult ADHD patients have high rates of comorbidities associated with psychiatric diseases, including depression and generalized anxiety disorder, and somatic diseases, including allergic diseases, obesity, and metabolic disorders, and are suffering from the disease burden of ADHD -13. HoweADHD in adults is diagnosed according to the guidelines of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) . The AduAlthough the ASRS-v1.1 instrument has been commonly used as an initial self-assessment tool and changes in the DSM-5 criteria increase the likelihood of identifying ADHD in adults, it remains unknown how the disease burden and baseline characteristics differ between respondents who had not been diagnosed with ADHD but were screened positive and negative. Knowing the potential disease burden and baseline characteristics of at-risk ADHD adults would help better inform and navigate them for proper diagnosis and treatment.This study aims to address this by quantifying the burden associated with potential ADHD symptoms through a comparison of the prevalence of comorbidities, health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and healthcare resource utilization (HRU) between respondents screened ASRS-v1.1 positive and negative but not clinically diagnosed with ADHD in Japan.Data sourceThe study utilized existing data from the Japan National Health and Wellness Survey (NHWS) conducted in 2016. The NHWS is a cross-sectional, internet-based, self-administered survey of a nationwide sample of respondents aged 18 or above. Respondents for the NHWS were recruited from the existing members of web-based opt-in consumer panels, and only those who provided informed consent were included in the study. Panel members were recruited through opt-in e-mails, e-newsletters, banner placements, and co-registration with panel partners. A stratified random sampling procedure, stratified by age and gender, was implemented to ensure that the demographic composition of the NHWS respondents was representative of the general adult population in Japan.The NHWS survey was approved with exemption status upon review by Pearl Institutional Review Board . All NHWS respondents provided informed consent prior to participating.Study populationA random subset among all 2016 Japan NHWS respondents was selected and asked to complete the ASRS-v1.1 Symptom Checklist. Only respondents who responded to the ASRS-v1.1 Symptom Checklist were included in the study. Those who self-reported a diagnosis of ADHD by a physician were excluded. Respondents would indicate in the boxes of the copyrighted two-part ASRS-v1.1 Symptom Checklist that most closely represent the frequency of the occurrence for each symptom ,16. RespMeasures, survey instruments, and outcome assessmentDemographic and general health characteristics measured in this study included gender, age, marital status, education, household income, employment status, Charlson Comorbidity Index (CCI) -20, bodyExperience of comorbidities , obesity, hypertension, alcoholism, and non-alcoholic steatohepatitis) was self-reported in the NHWS.HRQoL was assessed using the Medical Outcomes Study Short-Form 36-Item Health Survey Version 2 (SF-36v2), an instrument used to measure an individual’s general health status . The insThe six-item WPAI validated questionnaire  was usedHRU was measured by the reported number of visits in the past six months to the emergency room (ER), healthcare providers , and for hospitalizations because of the patient’s medical condition.AnalysisTo understand any underlying differences between respondents screened positive using ASRS-v1.1 Part A and controls, as well as between respondents screened positive using ASRS-v1.1 Part A+B and controls, a descriptive summary and comparison of their baseline demographic and health characteristics were made. Crude odds ratio (OR) of experiencing selected comorbidities among respondents screened positive using Part A and Part A+B compared to respondents screened negative were described.A greedy matching algorithm was used to form the matched control groups for ASRS-A+ and ASRS-AB+ groups, respectively. Age, gender, marital status, education, employment status, household income, health insurance, CCI, BMI, alcohol consumption, and whether a respondent was a smoker were used in 1:4 propensity score matching. These factors were used in matching as previous studies have identified an association between the factors and health outcomes -29. BivaStatistical significance was evaluated at the 0.05 significance level during data analysis using SPSS Statistics Version 25   and R VeParticipantsA total of 9,643 respondents without a diagnosis of ADHD who responded to the ASRS-v1.1 Symptom Checklist were included in the study. Of those, 9,280  were screened negative using Part A and Part A+B (control), 309  were screened positive for Part A (ASRS-A+), and 227 (2.4%) were screened positive for Part A+B (ASRS-AB+). A total of 173 (1.8%) respondents were screened positive for both Part A and Part A+B  and had a higher CCI (0.26 [0.80] and 0.23 [0.85] vs. 0.19 [0.56]) , generalized anxiety disorder , bipolar disorder , insomnia , allergies , and asthma  than ASRS-negative controls , compared to matched ASRS-A- respondents. In addition, significantly more ASRS-A+ respondents also reported experiencing some physical illnesses, including allergies, asthma, alcoholism, and non-alcoholic steatohepatitis, compared to matched ASRS-A- respondents Table . SimilarHealth outcomes assessment among ASRS-positive and negative respondentsAfter propensity score matching, ASRS-A+ respondents reported significantly lower HRQoL relative to matched ASRS-A- respondents in PCS , MCS , and EQ-5D-5L index  , MCS , and EQ-5D-5L index   and 2.4% (n = 227) were found to have been screened ASRS-A+ and ASRS-AB+, respectively. Only 1.8% (n = 173) were screened positive for both ASRS-A and ASRS-AB. In Japan, the prevalence of diagnosed ADHD was previously reported to be 1.65% [In our study, those who were undiagnosed for ADHD but were screened ASRS-positive (irrespective of ASRS-A or ASRS-AB) tended to be younger, had lower income levels, and were significantly less likely to be married or living with a partner or have completed a university education compared to non-ADHD controls Table . The socIn terms of health characteristics, previous studies have reported a higher risk of substance use and dependence, for example, consumption of alcohol and smoking, in patients with ADHD ,33. In aOur study showed that ASRS-positive respondents with potential ADHD symptoms experienced significantly more mental and neurological comorbidities  and physical comorbidities , even after propensity score matching. This is in line with previous studies reporting that ADHD patients have higher rates of other comorbid mental disorders with symptoms overlapping ADHD ,35. CompWhile Kooij et al. only focused on central nervous system (CNS)-related conditions, other studies have investigated the association between ADHD and physical disorders such as inflammation, allergic diseases ,36, obesIt is well established that ADHD with or without the presence of comorbidities contributes to poorer HRQoL ,12. Our While our study could not evaluate the severity of ADHD symptoms, the ASRS+ group had more health problems, as shown by their significantly greater healthcare resource use compared to controls. The ASRS+ group reported approximately 1.7-2.0 times more physician visits, 4.6-12.0 times more emergency room visits, and 2.6-4.0 times more hospitalizations than their respective matched controls Table . BecauseSimilar to what has been reported for patients with ADHD , poorer While most studies highlighted the burden of ADHD among diagnosed adults compared to adults without ADHD, there remains a paucity of information regarding the potential burden associated with missed ADHD symptoms among the undiagnosed population. A cross-sectional, retrospective analysis of 247 patients revealed that the presence of any psychiatric symptom, in the presence or absence of a formal diagnosis, had a negative impact on the patient’s quality of life . Here, tLimitationsDue to the cross-sectional nature of the NHWS data, no causal inference can be made. As the data were provided by self-administered questionnaires, it is subject to recall bias, and no verification was done for patient-reported outcomes. While the NHWS sample was made to be predominantly representative of the adult population in Japan, the representativeness of ASRS+ respondents to the larger population is uncertain. As the NWHS was an online self-administered questionnaire, respondents with Internet access and those better-versed in technology might be relatively well-educated or have high socioeconomic status compared to those without access to this survey. Therefore, generalizability might be considered. Our study did not evaluate the severity of ADHD symptoms nor did it explore the potential presentation type of ADHD symptoms ; therefore, no comparison can be made with patients diagnosed with ADHD nor any association of the observed burden among ASRS+ respondents with the ADHD presentation type. Although ASRS is a screener of ADHD, it is possible that symptoms of comorbidities can increase the likelihood of screening ASRS positive. Thus, it is worth noting that ASRS-positive individuals may not necessarily be clinically diagnosed with ADHD. Our study did not exclude the possibility of the involvement of comorbidities in ADHD symptoms.Undiagnosed adults who demonstrate potential ADHD symptoms in Japan experience a significant personal and professional burden. They reported a substantial prevalence of comorbidities and suffer decreased QoL, impaired work productivity, and greater HRU, similar to patients diagnosed with ADHD, compared to the ASRS-negative population. These preliminary results raise considerations to take note of to ensure the appropriate diagnosis of those at risk for ADHD or for those who present with symptoms overlapping with ADHD. Future studies that assess comorbidities, HRQOL, WPAI, and HRU focusing specifically on clinically diagnosed ADHD patients could provide further insights into the disease burden of ADHD in Japan.


Background: Children are especially sensitive to a broad range of influences and show a remarkable capacity for learning. One prominent example is declarative memory, which may be influenced by a variety of factors and is impaired in attention deficit hyperactivity disorder (ADHD). Exercise and sleep, or both combined, might foster declarative memory. Methods: Here, 12 typically developing children (TDC) and 12 age-matched children with ADHD participated in an exercise and rest condition before a night in the sleep laboratory. Declarative memory was encoded before exercise or rest and retrieved before and after a night of sleep. Results: Exercise in TDC but rest in ADHD lead to a transient destabilization of declarative memory, while there were no more differences after a night of sleep. Rapid eye movement (REM) sleep latency was prolonged after exercise in both groups. Conclusions: Exercise leads to opposing effects on immediate declarative memory formation. The factors or contexts that promote or hinder declarative memory formation in children ADHD and TDC differ, and further work is needed to determine the recommendations for declarative learning in children with ADHD. The formation and long-term storage of declarative memories comprises various processes and may be influenced by multiple antagonistically or synergistically interrelated factors . While tThere is compelling evidence that sleep benefits declarative memory consolidation more than wakefulness , particuThe developing brain shows a remarkable capacity for plastic changes and is especially sensitive to a wide range of experiences . ChildreAttention deficit hyperactivity disorder (ADHD) is characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity . Among oWe are only beginning to understand the exact impact of physical activity on sleep and memory . Based ot(22) = 2.77, p = 0.110). However, parental ratings on the Children Sleep Habit Questionnaire ((CSHQ) [t(20) = 5.8, p = 0.025). Seven of the 12 patients were on methylphenidate; this medication was discontinued 48 h  prior to each test session. All participants had to pass a medical examination that consisted of history taking, physical examination, and exercise electrocardiogram (ECG). While there was a trend towards a lower resting heart rate in the control group (69.4+/−2.6 beats per minute (bpm) for controls and 76.2+/−2.7 bpm for ADHD; F(22) = 3.247; p = 0.086); systolic blood pressure (F(22) = 0.328; p = 0.572) and diastolic blood pressure were equal between the ADHD and the control group (F(22) = 1.253; p = 0.275). Although the calculated maximal heart rate (Hfmax [p = 0.032), the mean difference of 0.6 bpm can be considered technically irrelevant as the range of our exercise condition was quite broad . All of the participants reached their calculated Hfmax with no symptoms or irregularities in the ECG. Participants’ characteristics are given in Here, 12 male children diagnosed with ADHD according to DSM-IV-TR  (6 with  ((CSHQ) ; criticae (Hfmax ) was staThe study was approved by the ethics committee of the Medical Faculty of the University of Kiel and followed the Declaration of Helsinki. We used a 2 × 2 × 3 factor design with the between-factor GROUP (ADHD vs. controls) and the within factors of CONDITION (exercise vs. rest) and TIME . All participants underwent two experimental sessions consisting of a declarative memory encoding session (E), followed by an interval of intense exercise in the first experimental night and rest in the second experimental night or vice versa, a retrieval session in the evening (R1), followed by a night of sleep and a second retrieval session (R2) in the morning. The first experimental session was preceded by an adaptation night in order to familiarize participants with the sleep laboratory. The experimental sessions were at least one week apart. Declarative memory was assessed with a computerized 2D object location task based on the game “Concentration” (see below). Intense physical exercise consisted of four 10-min blocks of intense exercise with 85–90% of the calculated Hfmax  on an auThe 2D object-location task has previously been used in adults  and in cAll EEG data were collected in the sleep laboratory of the Center for Integrative Psychiatry in Kiel using a 33-channel somnography device . Electrodes were placed according to the international 10–20 system at the locations F3, F4, C3, Cz, C4, Pz, O1, and O2 referenced to the bridge of the nose with a ground placed at Fpz. EOG was recorded from the lower right and upper left canthi in a diagonal fashion. EEG and EOG were sampled at 256 Hz (band-pass filter: 0.2–35 Hz). EMG was recorded from the chin and from the left and right lower legs at 128 Hz (0.2–150 Hz). During the adaptation night, nasal air flow, nasal air pressure, and chest motion were monitored with a thermistor and a piezoelectric band, respectively. The raw data were visually scored  by a trat-tests.Statistical analysis was performed with IBM SPSS Statistics, version 25, for Windows. With respect to declarative memory performance, correct card pairs were analyzed by an analysis of variance (ANOVA) for repeated measurements with the between factor GROUP (ADHD vs. controls) and the within factors EXERCISE (exercise vs. rest) and TIME (E vs. R1 vs. R2). In addition, working memory was analyzed as a cognitive control parameter using ANOVA for repeated measurements with the between factor GROUP (ADHD vs. controls) and the within factors EXERCISE (exercise vs. rest) and SESSION (E vs. R1 vs. R2). Differences in single means were tested by paired p > 0.05). The polysomnographic results are depicted in p < 0.001) with no effect of GROUP (F(1.21) = 0.05, p = 0.943) or GROUP × CONDITION interaction (F(1.21) = 0.3, p = 0.56). Paired t-tests revealed that REM latency—corresponding to the duration of the first sleep cycle—was profoundly prolonged in the exercise condition both in ADHD individuals  and in the controls . Sleep data are summarized in ANOVA for repeated measurements with the within-factor CONDITION (exercise vs. rest) and the between-factor GROUP (ADHD vs. controls) revealed no main effect of CONDITION, no main effect of GROUP, and no GROUP × CONDITION interaction for the duration of sleep stages , total sleep time, or sleep efficiency (p = 0.81), but a main effect of SESSION (F(2.34) = 26.02, p < 0.001). Moreover, there was trend to a GROUP effect (F(1.21) = 3.69, p = 0.068).In the 2 × 3 × 2 ANOVA with the within factors CONDITION (exercise vs. rest) and SESSION  and the between factor GROUP (ADHD vs. controls), there was no main effect of CONDITION (F(1.21) = 0.01, p = 0.824), SESSION × GROUP (F(1.21) = 0.02, p = 0.982), or CONDITION × GROUP interaction (F(1.21) = 0.18, p = 0.675). However, there was a GROUP × CONDITION × SESSION interaction (F(1.21) = 7.18, p = 0.002). The interaction was decomposed with t-tests. This indicated that, with respect to the REST condition and starting from a comparable number of word pairs in both groups  = 1.07; p = 0.298), there was a decline in card pairs recalled in R1 in the ADHD group , which was not true for the controls . After a night of sleep, the number of accurately located card pairs in R2 was again equal between the groups  = 0.09; p = 0.982), with a rise in the ADHD group overnight (p < 0.001) that was not there in the controls (p = 0.175). In the EXERCISE condition, this pattern was exactly reversed: starting from equal numbers of card pairs  = 1.35; p = 0.19), there was a decline from E to R1 in the control group , which was not present in the ADHD group . There was an overnight gain in the control group , while there was a trend to an overnight gain in ADHD individuals . The results of the declarative memory task are given in There was no CONDITION × SESSION (F(1.21) = 0.19, p = 0.002) and a main effect of GROUP (F(2.34) = 5.00, p = 0.037), but no main effect of CONDITION (F(2.34) = 2.52, p = 0.128). There was no GROUP × SESSION (F(2.34) = 0.69, p = 0.509), no GROUP × CONDITION (F(2.34) = 0.43, p = 0.521), and no GROUP × CONDITION × SESSION (F(2.34) = 1.87, p = 0.167) interactions.With respect to our working memory control task, there was a main effect of SESSION (F(2.34) = 18.19, We investigated the effect of acute physical exercise with immediate retrieval after an interval filled with daytime wakefulness and delayed retrieval after a night of sleep. In typically developing children, we found reduced accuracy in a 2D object-location task after exercise compared to passive listening to an audio drama after immediate wake time consolidation, whereas there was no more difference during delayed retrieval after a night of sleep. In a group of age-matched children diagnosed with ADHD, we found the inverse pattern, with reduced accuracy of memory retrieval after audio drama listening while there was no difference after exercise. Again, after a night of sleep, there was no difference between the exercise and the rest condition. Substantially prolonged REM-latency, which we reported for typically developing children , was truIn contrast to our hypothesis that we were expecting physical exercise to induce plasticity and declarative memory consolidation during wake and sleep, we observed that it did not generally support declarative memory consolidation in typically developing children or children with ADHD. For typically developing children, this inferior immediate retrieval after physical exercise does not necessarily mean that they performed worse than after rest. One might interpret this decline as being an induction of plasticity, as indicated by transient destabilization  while reThe most prominent finding in our experiment is the inverse pattern in children with ADHD compared to typically developing children. While exercise might lead to transient destabilization of declarative memory in healthy children, this was true for children with ADHD in our rest condition, while exercise produced no such effect. We assume that acute exercise might foster plasticity in typically developing children, leading to the attenuation of declarative memory, while a contrasting activity, such as listening to an audio drama, shows a similar transient destabilization in children with ADHD. The transient destabilization might indicate that exercise has a more stimulating effect on the brain than rest, while for untreated children with ADHD, passive auditory input might represent a stressful stimulus and exercise is perceived as more usual or “normal”. In light of hyperkinetic symptoms and an accumulation of physical activity from earlier in the day before encoding and physical exercise, a “saturation” or passing of a maximum of an inversed u-shape of plasticity as a function of activity following the Yerkes−Dodson law  might seUnlike word lists ,41, retrp < 0.001) and no gain or loss in the exercise condition (p = 0.59). This is in sharp contrast to our previous findings in children with ADHD [p = 0.001). With the results of our experiment, we cannot claim that the overnight gain with audio drama before immediate recall and reconsolidation and equal performance in R1 (evening) and R2 (morning) was amenable to the respective activities. However, considering better overnight consolidation in both conditions in children with ADHD, reconsolidation by repetition of declarative memory content proved beneficial for sleep-dependent consolidation in ADHD. Moreover, the direct comparison of the ADHD groups from the present (10.7 +/− 0.2 years) and the previous study (12.1 +/− 1.4 years) should be regarded with caution because of the age differences.Of note, we observed a substantial overnight gain of declarative memory from R1 to R2 in ADHD children in the rest condition (ith ADHD , where, In conclusion, we found opposing acute effects of physical exercise and audio drama listening on the immediate declarative memory retrieval in typically developing children and children with ADHD, with differences being no longer present after a night of sleep. Based on our results, we cannot conclusively argue for one or the other activity as being supportive of sleep-dependent declarative memory formation in children with or without ADHD. However, confirming previous findings that the developing brain is highly sensitive to different environmental conditions and stimuli , we can


Information about optimal use of heparin in flush fluids during endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) is lacking. Variables that determine total heparin dose entering the patient by flush fluids are mostly unknown. We aim to provide insight in these unknown but highly relevant variables.n = 79) collecting data on used concentration of heparin in infusion bags, number of infusion bags connected, timing of connecting the flush line and the dripping rate (ml/sec). We calculated potential heparin dose entering the patient per hour through flush fluids (IU/h). Twenty-eight interventionists (35%) representing 17 Dutch stroke centers completed the survey. Eight interventionists responded not to add any heparin to flush fluids (18%). The highest amount of heparin entering the patients was 13,500 IU/h, reported by 2 interventionists from the same center (4%).We performed a survey including all Dutch interventionists performing EVT (We provide insight in the use of heparinized flush during EVT in the Netherlands. Total amounts of heparin administered via flush fluids may go up to 13,500 IU/h. With this paper we intend to set a starting for future research and development of guidelines on the use of heparinized flush fluids during EVT for AIS.The online version contains supplementary material available at 10.1186/s42155-021-00264-0. During endovascular treatment (EVT) for acute ischemic stroke (AIS), catheters are continuously flushed, using saline infusion fluids, to avoid thrombus formation during the procedure and thus to reduce the risk for distal embolization. These flush fluids are often heparinized. In an earlier study, we showed wide variance in used heparin concentrations in flush fluids and investigated its potential impact on functional and technical outcome  in the Netherlands by creating a Google Form questionnaire  completed the survey.Thirteen interventionists had 1–5-years experience in neuro-intervention. Eleven had 5–10-years experience and 4 had more than 10 years experience in the field of neuro-intervention.Twenty-one participants responded to which concentration of heparin they used in the flush fluids. For the non-responders, we used heparin concentrations derived from colleague responders from the same center (if available) or from known heparin concentration from an earlier conducted center-based survey  guiding catheter and / or one on the aspiration catheter and / or one on the microcatheter), 5 interventionists use 2 bags  guiding catheter, aspiration catheter or microcatheter) and 7 use only 1 bag  guiding catheter).Twenty-six interventionists connected the infusion bag immediately at the start of the procedure. Two interventionists connected the infusion bag after catheterization of the common carotid artery. We did not include the time-delay from groin puncture to carotid artery catheterization (time of using catheter without flush) in our final calculations of total dose, because of the small number and potentially short time delay.n = 18), followed by 0,5 drip per second  (n = 10); 2 drips per second  (n = 2) and 1 drip per 5 s  (n = 1).All the participating interventionists set up their dripping speed manually. The most often set drip rate was 1 drip per second   national consensus and guidelines on the use of heparin in flush fluid bags during EVT for AIS, which translates into a large variety on center level . Furthermore, most of the respondents set up their drip rate manually, meaning that they adjusted the drip rate visually, with inherent inaccuracy.We provide an insight in the use of heparin in flush fluids in Dutch EVT centers. Total amounts of heparin administered via flush fluids may go up to 13,500 IU per hour while in other cases no heparin is administered. With this paper we intend to set a starting for future research and development of guidelines regarding the use of heparin in flush fluids during EVT for AIS.Additional file 1: Table S1. Different heparin doses (IU) per hour are depicted for the different heparin concentrations (IU/L) given a drip rate of 1 drip / sec.


To review literature regarding existing and recommended roles for nurses in the management of children with ADHD.MEDLINE and CINAHL were searched from 2010 to the end of 2019 with the following keywords: ADHD, nurse, child, and inclusion criteria published in an English journal.Forty-three records were found. However, only five articles scientifically evaluated the nurse role. The nurse role in ADHD management seemed to vary across countries with nurses working independently or as part of a team with delegated responsibility.The literature review gave information to suggest that nurses can have a significant role in providing a range of medical and non-medical management. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, and for many of the children, this will last until adulthood and is often referred to as a chronic condition –3. SymptIn 2019, AAP introduced a revised edition of Clinical Practice Guidelines for the diagnosis, evaluation, and treatment of ADHD in children and adolescents , 8. The Some studies have identified that the shortage of psychiatrists in CAMHS often becomes a bottleneck both for diagnostics and for treatment of ADHD children , 9, 10. Given the above challenges and the fact that ADHD is a major aspect of the work within CAMHS, it is pertinent to explore which of the tasks suggested in the American Psychological Association (AAP) guidelines need to be profession-specific. The aim of this study was to review literature regarding existing and recommended roles for nurses in the assessment and treatment of children with ADHD.We performed a systematic review of the literature based on the keywords ADHD, nurse, and child. The search strategy was developed in collaboration with a university librarian experienced in systematic literature searches. The searches were conducted in MEDLINE (1946 to February 2020) and CINAHL (1981 to current).After the first search in MEDLINE and CINAHL, we retrieved 652 articles. Then we removed duplicates and narrowed the search from 2010 to the end of 2019, to 205 articles.n = 63). Full-text articles were excluded because of other conditions than ADHD, nurse role but not ADHD-specific related, language, or age limitations were 20 years, leaving 43 articles for evaluation.We screened 205 articles, including main and running titles, for nurse role, and ADHD. Of these, 128 records were excluded because of non-relevant topics. For the 77 abstracts, 58 were available and assessed. Reference list for these 58 articles was reviewed, and five more articles were found and included . From these reports, it was concluded that long-term follow-up of children and adolescents with ADHD appeared useful, in particular from a user perspective. Regular reviews are identified as crucial, given that ADHD symptoms change during the course of development and during times of change, for instance, during transfer to infant and secondary school. Furthermore, continuity of care has been highlighted as important and recommended to be delivered by nurses. The follow-up of children and adolescents with ADHD is different from other chronic conditions, for example, diabetes mellitus, which can be maintained through simple medical consultations. Impairment associated with ADHD often includes more than core symptoms such as emotional and social impairments in addition to comorbid conditions. Qualitative studies , 13 focuIn this review, we found descriptions of nurses involved with ADHD management in 28 articles. Nurses already carry out many key tasks relating to children and adolescents with ADHD, although the extent of this practice seems to vary between areas and countries. In fact, nurses were recommended to be involved in almost every aspect of ADHD management including assessment and diagnostics, psychosocial support, medical, and non-medical treatment, and in the lead of entire ADHD services. The contribution of nurses was suggested by some authors to involve a caring and supportive quality. Providing support and care may be of particular importance for lifelong chronic conditions , 52, 53.The reports evaluating a nurse-led care pathway gave favorable reviews of implementation and adherence to clinical guidelines.Although there is a need for further evaluation and development of the nurse role, there seem to be good indications that nurses are already successfully integrated in teams for children and adolescents with ADHD and that they can provide a life course and family perspective  and suppThis literature review gives information to suggest that nurses can play a major role in providing continuity of care for children and adolescents with ADHD.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.LK has participated in preparing the literature search, in reviewing papers, and writing of the manuscript. LV has conducted the literature search. IE has participated in preparing the literature search, reviewing papers, writing of the manuscript, and for the method and result section. All authors contributed to the article and approved the submitted version.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.


Structured ratings of ADHD symptoms, impairment, side effects, and symptoms of oppositional defiant disorder (ODD) were collected every 2–12 weeks for the duration of the study. Medication use was measured by pill count and parent report. The IRR group comprised 28% of all participants. The IRR group had significantly higher levels of ADHD and ODD symptoms, impairment, and side effects ratings at baseline. In the IRR group, ODD symptoms, emotional lability, and impairment significantly decreased for participants with higher medication use. Total side effects increased for non-IRR participants with higher medication use. Emotional side effects decreased for IRR participants with higher medication use. Central nervous system stimulants were a tolerable and efficacious treatment in treatment naïve youth with ADHD with irritability.This study compares the efficacy and tolerability of central nervous system (CNS) stimulants in children with attention deficit hyperactivity disorder (ADHD) with and without prominent irritability (IRR) over the course of 30 months. This is a secondary analysis of a study examining growth patterns in medication naïve children with ADHD subsequently treated with CNS stimulants  for 30 months. Participants had to meet full diagnostic criteria for ADHD and been treated with CNS stimulants for under 30 days. Children were classified as IRR if they were rated as Clinical Trials Registration: NCT01109849 Persistent non-episodic irritability is one of the most common presentations in child mental health  and presIn the randomized 14-month treatment phase of the Multimodal Treatment Study of children with ADHD (MTA) study, Central Nervous System (CNS) stimulants were associated with large reductions in symptoms of ADHD and moderate reduction in levels of parent-rated irritability in participants with elevated irritability at baseline. Moreover, irritability did not appear to influence the treatment response for ADHD symptoms . HoweverOutside of the MTA, most studies assessing the impact of CNS stimulants on irritability only briefly examined treatment effects before adjunctive medications were added. They enrolled participants meeting criteria for disruptive mood dysregulation disorder (DMDD)/severe mood dysregulation or recurrent physical aggression , 17–22. The related concept of emotional lability refers to a more general dysregulation of mood. It is a commonly reported side effect of CNS stimulants that can lead to treatment discontinuation . The tolAs part of a NIH-funded longitudinal study examining the impact of ER CNS stimulants on physical growth in medication naïve children with ADHD , we systth percentile or above the 85th percentile, use of other psychotropic medications, autism spectrum disorder, or medical contraindications to CNS stimulants. Of the 230 participants in the original sample, 226 were included in this study; the four children not included were missing irritability data at baseline. The participants were ages 5–12 years and met criteria for DSM-IV ADHD (any subtype) with a lifetime use of stimulant medication that was under 30 days. Only five participants (2.1%) had previously used any CNS stimulants.Participants were drawn from a study that examined effects of stimulant medication on the physical growth of children with ADHD . ExclusiAttention deficit hyperactivity disorder was diagnosed using the Disruptive Behavior Disorders Structured Interview , combinepretty much) or 3 (very much) by parents on either of the “often angry” or “easily annoyed” items plus “lose temper,” which was also supplemented by Teacher-DBDRS. Others have used a similar symptom threshold to identify youth with behavioral problems as having elevated irritability or not  to 3 (Very Much). The first IOWA was completed at baseline for all participants and were completed an average of 13 times over the course of the study . At each time point, relevant items were averaged to compute the following scores: Inattentive-Overactive-Impulsive , Oppositional-Defiant , and Emotional Lability . Emotional Lability score was computed as the average of the following items: “temper outburst” “demands must be met immediately” “cries often and easily” and “mood changes quickly and drastically” . As in past studies, each item on the IRS was examined as an outcome  measures impairment in peer relationships, getting along with parents, academic performance, classroom behavior, self-esteem, functioning in the family, and overall outcome , 46. The outcome , 47, 48.None) to 3 (Severe). Parents completed the PSERS an average of 12 times over the course of the study  with the first always at baseline. At each time point items were averaged to compute a total side effect score  and items assessing mood-related side effects  were averaged to complete an Emotional Side Effects score The Pittsburgh Side Effects Rating Scale (PSERS) measures side effects that are often associated with medication treatment of ADHD . Items wR2-values and variance explained by fixed and random effects was estimated by computing conditional R2-values (Groups (IRR vs. Non-IRR) were compared on baseline data using one-way ANOVAs or chi-square tests. Time and treatment effects were examined using mixed models computed in Proc Mixed in SAS 9.4. Medication (Med), Time, IRR, and the interactions between them were predictors, along with Behavior Therapy as a covariate. IRR was a categorical variable . Medication (percent of study days medicated), Time , and Behavior Therapy (number of sessions) were continuous measures. A random intercept term was included to accommodate non-dependence due to repeated measures. Variance explained by fixed effects was estimated by computing marginal 2-values . Signifi2-values . Mixed m2-values . ConsistThere were significant main effects of Time, Medication, and IRR. The main effect of IRR showed that higher Inattentive-Overactive-Impulsive (IO) scores were associated with being in the IRR group .*IRR interaction, but these were qualified by a significant Time*Medication*IRR interaction. Simple slopes tests of the three-way interaction : conceptualization, methodology, and writing—review and editing. WP (4th author): conceptualization, methodology, data collection, writing—review and editing, supervision, project administration, and funding acquisition. JW: conceptualization, methodology, investigation, resources, data collection, writing—original draft, review, editing, supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.JW has received research funding from the National Institutes of Health, Supernus, and Pfizer in the past 3 years. WP (4th author) has received funding from NIMH, NIAAA, NIDA, and the Institute of Education Sciences. The remaining 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.


Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and serious neurodevelopmental disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Chronic and childhood stress is involved in ADHD development, and ADHD is highly comorbid with anxiety. Similarly, inflammatory diseases and a pro-inflammatory state have been associated with ADHD. However, while several works have studied the relationship between peripheral inflammation and stress in affective disorders such as depression or bipolar disorder, fewer have explored this association in ADHD. In this narrative review we synthetize evidence showing an interplay between stress, anxiety, and immune dysregulation in ADHD, and we discuss the implications of a potential disrupted neuroendocrine stress response in ADHD. Moreover, we highlight confounding factors and limitations of existing studies on this topic and critically debate multidirectional hypotheses that either suggest inflammation, stress, or anxiety as a cause in ADHD pathophysiology or inflammation as a consequence of this disease. Untangling these relationships will have diagnostic, therapeutic and prognostic implications for ADHD patients. ADHD is the most common childhood neurodevelopmental disorder and a public health concern, as about three-quarters of childhood cases persist into adulthood . FurtherIf stress is associated with ADHD, additional emerging evidence also indicates alterations in inflammatory profiles and neuroendocrine stress reactivity in ADHD patients, possibly leading to immune dysregulation ,28,29. WTherefore, since there is substantial evidence that (i) inflammatory pathways are dysregulated in some psychiatric illnesses, (ii), anxiety and stress are associated with inflammation and immune dysregulation, and (iii) anxiety and stress play a pivotal role in ADHD as in other emotion dysregulation disorders, we will review the existing literature on the relationship between stress, anxiety and immune dysregulation in ADHD, and how anxiety, stress, and acute stress, in particular, may induce a dysregulated inflammatory response in ADHD patients. Understanding stress and immune dysregulation from a pathophysiological viewpoint in ADHD may offer therapeutic interventions for treating the disorder and may help validate biomarkers to stratify ADHD severity. The definition of stress is intriguing and can be approached from different points of view, for example, by focusing on the response resulting from a certain negative stimulus in an individual. This approach may describe stress as a disruption of the normal psychological and/or physical homeostasis following external events that lead to a state of tension and pressure in the individual, or “an emergency state of an organism in response to a challenge to its homeostasis” . Such exInterestingly, although they are distinct entities, a bidirectional interplay exists between stress and anxiety, which may be defined as “a temporally diffused emotional state caused by a potentially harmful situation, with the probability of occurrence of harm being low or uncertain” or “the anticipation of a future threat” . Stress Additionally, anxiety and stress have been increasingly linked with inflammation . In healFinally, through imaging studies, inflammation has been shown to have an impact on connectivity in multiple brain structures and on some regions involved in anxiety  in particular . SimilarInflammation is increasingly recognized as a pivotal factor in a number of somatic pathologies and the interest in inflammatory biomarkers is growing , a human experimental gold standard ,66. UsuaImportantly, most of the markers that we mentioned may also be measured in post-mortem brain tissues and in CSF, reflecting central inflammation. Definitive evidence is lacking concerning the link between central and peripheral inflammatory markers, their pathophysiological relevance, and the potential directional causality. Despite this, peripheral inflammatory markers are easily obtained and have been shown to correlate in some cases with central markers. For instance, in major depressive disorder, CSF CRP strongly correlates with plasma CRP . In psycChildhood trauma is associated with ADHD onset, severity, and persistence into adulthood ,25,26. BIn turn, ADHD, being a neurodevelopmental disorder, exposes patients to stress early in childhood. In fact, ADHD symptoms potentially expose patients to conflict, neglect, or physical and emotional abuse in social, schooling, and family settings ,23. It sMoreover, as mentioned, anxiety disorders are a common comorbidity in ADHD and increase the severity of the condition. Further research is needed on treatment implications in ADHD with anxiety comorbidity, as contrasting results have been found on the efficacy of methylphenidate in this population .The diversity of the studies that can be found on inflammation and ADHD indicates how much researchers and clinicians are looking into the origins of the disorder, but, at the same time, it highlights how far we are from pinpointing specific causes to the development of ADHD . DiscussMore to the focus of this review, we found four ,106,107 Regarding measures of inflammation in relation to cortisol, definitive results have yet to be reached. In 44 ADHD patients of the inattentive subtype, there was a negative correlation between the level of pro-inflammatory markers  and cortisol awakening response . As mentFurthermore, in ADHD adults, cortisol circadian levels present a significant delay of phase compared to controls . It oughIn summary, the studies reviewed here support a multidirectional relationship between stress, anxiety, and inflammation with ADHD, but how these variables connect to each other has yet to be clarified . The majDue to the multifaceted nature of the research topic and for the sake of clarity, we performed a narrative review and not a systematic one, and we chose to focus on ADHD only, without including, for instance, papers discussing autism spectrum disorders or depression, although they might also be influenced by stress and inflammation ,121,122.A fascinating, albeit intricate, network of connections between ADHD, inflammation, anxiety, and stress emerges from this review. Although some experimental evidence and several hypotheses exist on this topic, the implications and the directions of such connections are still undetermined, and future research is warranted to pinpoint their precise interplay.primum movens that predisposes subjects to ADHD through the mediation of inflammation. In fact, inflammation can negatively impact brain structures, leading to neurodevelopmental disorders such as ADHD, possibly as a consequence of a dysregulated stress response.Hypothetically, ADHD and its symptoms (such as emotion dysregulation ) may expHowever, an unknown confounding variable might exist, which may expose individuals to a higher ADHD risk, but also to inflammation, stress, and/or emotion dysregulation. Thus, the pro-inflammatory status observed in ADHD might be a cause, an effect, or just an epiphenomenon of this disorder. For example, some alimentary components and exposure to environmental toxic substances may be risk factors for both ADHD and a pro-inflammatory state/stress vulnerability, independently. Alternatively, the effect of these factors on ADHD risk may be mediated by inflammation. Indeed, it has been suggested that gluten-free or casein-free diet, food additives exclusion diet, and oligoantigenic diet are effective in reducing ADHD children’s symptoms, although study designs including food challenges and/or a reintroduction phase are needed ,125. If As mentioned, exposure to environmental toxic substances may also increase the risk of ADHD and related symptoms through inflammatory mechanisms. Children are likely more susceptible to exposure risks than adults due to their increased respiratory rate, smaller body size, and ongoing development . In factAn important point to be considered is the fact that anxiety is a common ADHD symptom, possibly mediating the aforementioned associations. As discussed, anxiety has been linked with inflammatory dysregulation, and we can hypothesize that increased levels of anxiety imply higher stress sensitivity, but the opposite may also be true . In factThe identification of these relationships has important implications, whatever their mechanistic explanations or the direction of each association. Future studies should take into account the aforementioned environmental and clinical possible confounding variables, as well as potential sex, age, and subtype differences in stress reactivity in ADHD patients. Peripheral markers of HPA axis dysregulation and/or inflammation are easily measured, especially in relation to experimental anxiety and stress. On a hypothetical note, once better defined, these markers may become part of screening tests for subjects at high-risk for ADHD, or aid in diagnosis, for instance, possibly differentiating between ADHD subtypes. Should biomarkers of response to therapies be identified, they could assist in tailoring treatment and, speculatively, direct therapeutical interventions aimed at reducing inflammation and/or environmental exposure, as discussed above. Furthermore, the aforementioned relationships highlight the importance of identifying and treating comorbidities of ADHD. Thus, studies focusing on the association between inflammation, anxiety, and acute and chronic stress in ADHD are highly pertinent and might have quickly translatable clinical implications for assessing treatment response in patients, as well as diagnosis, prognosis, or risk evaluation in vulnerable individuals.


The properties of the starch-amylolytic complex of commercial low-extract rye flour were determined based on the traditional method, such as falling number and amylograph test as well as differential scanning calorimetry (DSC). The starch, pentosans and protein had a significant effect on the thermal properties of the tested rye flours. Based on the falling number, it was revealed that rye flours were characterized by medium and low alpha-amylase activity. The falling number and amylograph test are not sufficient methods to determine the suitability of currently produced rye flours for bread making. The gelatinization process of the rye flour starch could be evaluated by the DSC test, which, together with the falling number and amylograph test, may allow a better way to evaluate the usefulness of rye flours for bread making. Many significant correlations between parameters determined by DSC endotherm and quality parameters of rye bread, such as volume and crumb hardness, were reported. Breads made from flour with higher enthalpy in DSC were characterized by higher volume and softer crumb. Secale cereale L.) is a widely grown cereal in Central, Northern and Eastern Europe. Rye grain is a good source of saccharides, proteins, fat, minerals and vitamins, mainly from group B . The increase of crumb hardness during storage of bread (IH) was calculated from the formula: IH = H72 − H24. Crumb moisture content (CM) was analyzed using the oven drying method. In this case, 10 g of bread crumb was dried in an oven at 130 °C for 60 min. The moisture content was expressed in % as the difference of the weight.Rye breads were obtained during the laboratory baking trial. The bread variants were prepared with a one-stage process. Dough samples with a yield of 178% were prepared for each sample of rye flour. The dough was prepared with the following ingredients: 1000 g of rye flour (adjusted to the standard moisture content of 14%), 15 g of salt, 30 g of yeast, 8 cmt method ; crumb hp < 0.01 and p < 0.05. In order to determine the extent to which the tested rye flours were diversified in terms of starch-amylolytic properties and determine which of the analyzed parameters had the greatest impact on this, principal component analysis (PCA) was performed. The principal component analysis (PCA) was performed on average values of each flour, which corresponded well with the analysis performed for all replicates. Data were analyzed using Statistica 13 software .All tests were carried out at least in three replicates for all quality parameters. One-way analysis of variance (ANOVA) was performed, and the homogenous groups were determined by Tukey’s test. The tests were performed with the significance level of α = 0.05. The Pearson’s correlation coefficients between selected flour and bread parameters were calculated with a significance level of p < 0.05, p < 0.01, respectively; The data concerning the basic components of the tested rye flour samples are presented in The value of FN, which is a measure of alpha-amylase activity, was in the range of 183 s RF7) to 288 s  . Accordi to 288 sThe amylograph peak viscosity (APV) was measured in the range of 275 AU (RF7) to 1045 AU (RF4) . In our o) and peak temperature (Tp) . The sample RF8 was characterized by the highest value of To , while the sample RF9 was characterized by the highest value of Tp . According to Fredriksson et al. [o is related to the amylose content in the starch granules. The study conducted by the above-mentioned authors showed significant negative correlations between To and the amylose content. In our study, the To obtained from the DSC endotherm was on average 4.8 °C higher than the IT determined during amylograph tests. One of the reasons for this situation may be the differences in the flour-water (F:W) ratio of studied samples by both the amylograph and DSC test . The sample RF5 was characterized by the lowest value of conclusion temperature (Tc) (72.2 °C), while the highest Tc was observed for the sample RF7 (77.4 °C). According to Cornejo-Ramirez et al. [c obtained from the DSC endotherm is higher for small starch granule fractions, influenced by differences in the chain length distribution of amylopectin. The study conducted by Sasaki [c. The above studies showed that there is a negative correlation between Tc and amylose content. This may suggest that the differences in Tc between the studied rye flours are related to the different proportions of amylose in the starch granules. The tested rye flour samples varied significantly in respect to the enthalpy of starch gelatinization. According to Tester and Morrison [−1); reversely of sample RF4 (6.5 J g−1). Differences in the starch gelatinization enthalpy values between the rye flour samples may result, among others, from the ratio of amylose and amylopectin [The rye flour samples were significantly different in terms of all parameters recorded from differential scanning calorimetry (DSC) endotherm . The samn et al. , the To z et al. , the Tc y Sasaki  showed tMorrison , the entlopectin  and diffvalue 59. °C, whillopectin  reportedlopectin  stated a2 because their stretching time is longer; this supports bread volume and the bread crumb softness [Our study revealed that the mainly chemical components of rye flour such as protein, starch and pentosans have a significant impact on all parameters recorded from the DSC endotherm . Flour isoftness .3 100 g−1 for flour items RF9 and RF3, respectively (3 100 g−1.ectively . In the 3 100 g−1). Bread from sample FR7 had considerably lower volume (178 cm3 100 g−1). The reason for this probably results from the differences in APV and protein content (Pro). Sample RF1 was characterized by APV in the optimal range , their FN values indicate their possible use in the production of good-quality rye bread. Only bread obtained from sample RF1 was characterized by high BV  and three (H72) days after baking , while for RF7 and RF9, the highest values of crumb hardness were observed . In the study conducted by Ostasiewicz et al. [24 and H72. The correlation coefficients between H24 and Pro, PC and S were: 0.766 (p < 0.01), 0.731 (p < 0.05) and −0.782 (p < 0.01), respectively, while the correlation coefficients between H72 and these parameters were: 0.789 (p < 0.01), 0.729 (p < 0.05) and −0.815 (p < 0.01)   , respectctively) . Signifip < 0.05; The tested rye breads were significantly different in terms of increases in crumb hardness (IH) during the storage of bread . This qup < 0.05; The crumb moisture content (CM) ranged from 45.4% (bread from RF1) to 47.7% (bread from RF10) . The flo24) and three (H72) days after baking. The S, APV, BV and gelatinization enthalpy are located on the right side of the loading plot. Meanwhile, the rest of the parameters are located on the left side of the loading plot. The PC2 explained 16.36% of the variation and was strongly positively related to falling number (FN) and amylograph pasting temperature (IT), as well as negatively related only to increased bread crumb hardness (IH). The analytical: Pro, PC; DSC: Tp and To; and bread quality parameters: H24, H72 are closely located on the same side of the loading plot indicating that crumb of bread from rye flours, which are characterized by higher PC and Pro, have higher hardness. Whereas gelatinization enthalpy, S and BV are present closely on the opposite side of the loading plot. This indicates that flour, which is characterized by higher starch content, is also characterized by higher enthalpy.Based on correlations among variables tested and linear combinations of them, the PCA method builds so-called latent variables , which extract as much data variability as possible. The multi-axes space of the original variables is usually altered by 3D-space with rectangular coordinates PC1-PC3, which are independent of each other. A condition of successful data transformation is explaining at least 70% of the original data by these triple of PCs. Further, principal components PC4 and PC5 are commonly omitted owing to their small contribution to the data scatter explanation. Within the present study, the closeness of quality among flour items RF1–RF10, as well as the potential alternation among quality features observed, were explored. The results of PCA showed that the first two principal components  explained 74.55% of the variation of original quality parameters A. The PCo and Tc compared to rye flour samples located on the left side. The breads obtained from flour on the right side of the graph compared to breads from flour marked on the left side are characterized by relatively higher BV and lower H24 and H72.The score plot B clearly−1, are characterized by relatively higher quality, e.g., higher volume and lower crumb hardness. From all study parameters used for the study, the starch-amylolytic complex of rye flour, a good indicator for the prediction of rye bread volume is gelatinization enthalpy. In respect of rye crumb bread hardness, the best indicators for prediction are DSC parameters such as conclusion temperature and gelatinization enthalpy. Therefore, the DSC test may find application in the determination of the starch-amylolytic complex of the current production of rye flours. Used together with traditional methods such as the falling number and amylograph test, they can better determine the suitability of rye flour for baking purposes.The tested ten rye flours were characterized by medium and low alpha-amylase activity. The study revealed that falling number and amylograph test are not sufficient to determine the baking quality of currently produced rye flours. Using flour with an optimal value of falling number for bread making does not guarantee high-quality bread. There were no significant relationships between traditional methods for assessing the properties of the starch-amylolytic complex of rye flour and the DSC test. The initial temperature of starch gelatinization determined during the amylograph test was, on average, about 4.8 °C higher than the onset temperature recorded from the DSC endotherm. The content of nutrients present in the flour, such as starch, protein and pentosans, have a significant impact on the thermal properties of tested rye flour. Generally, the rye flour samples with higher contents of protein and pentosans and lower starch content were characterized by higher onset and peak temperatures as well as lower gelatinization enthalpy. Our study revealed that breads from rye flour, which are characterized by gelatinization enthalpy above 4.0 J g


PERCEIVE is a service evaluation counting whether nurse demographics correlate with reported subjection to violence and verbal aggression. The setting was a large mental health, learning disability and neuropsychiatry NHS trust in England. This continues our work to understand correlations reported in the literature between temporary staff and violence.We consulted the Caldicott, legal, equality & diversity, teams and gained service evaluation permission SER-19-031 from CNTW R&D department. We briefly consulted with staff regarding themes relevant to temporary nurse workers. They expressed concern that staff perceived to be “other” would be at more risk.Employees’ age, ethnicity, employment status, nationality, length of service and seniority are routinely collected for the running of the trust. Therefore, these were anonymously collated then cross-referenced with violence and aggression incident reports (VA IR1s). Chi-squared was used to identify statistical significance. Ethno-national status was taken from self-report. We could not control for hours worked nor could we get agency staff demographic data.We compared “exposure to at least one violent incident” in June, July and August 2019 against the following demographic categories:Substantive vs bank staffBand 5 and above vs band 4 and belowStaff with < 1 year of service vs staff with ≥ 1 year of service“White British” staff vs Non-“White British” staff“British” staff on self-report vs “Non-British” staffAge ≤30 years vs ≥ 31yearsA minimum of 1682 nursing staff were analysed for each category in each month.Substantive staff, “White British”, “British”, younger, and staff of shorter employment length had greater frequencies of at least one VA IR1s compared to the complementary groups. Length of service was significant only in two months but judged significant overall. There was no statistically significant correlation with seniority. Substantive staff have three times the risk vs bank staff, perhaps mediated by hours worked. Other risk ratios were in the region x1.2 to x1.8.Being British, White British, younger, less experienced or substantive staff correlate with subjection to reported aggression. This did not fit with staff speculation during consultation. Survival effects may be relevant. We are working to get more detailed information. Induction may help reduce aggression against newer staff.