Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric condition in which children suffer from inattentiveness, hyperactivity, and or impulsivity. ADHD patients frequently present comorbid psychiatric disorders: in adults, the most common are depression, substance-related disorders, anxiety, and eating disorders. Children and adolescents present conduct disorders, learning disorders, anxiety and depression. Since ADHD and its psychiatric comorbidities share similarities, a partial overlap of their pathophysiological mechanisms has been suggested. ADHD, can be treated with lisdexamfetamine (LDX), a prodrug indicated by the FDA as treatment for binge eating disorder (BED) and ADHD.in silico method, the efficacy of LDX as first-line ADHD treatment to improve ADHD psychiatric comorbidities. Furthermore, we explored the molecular mechanisms behind LDX’s action.To evaluate, through a systems biology-based We used the systems biology- and artificial intelligence-based Therapeutic Performance Mapping System (TPMS) technology to characterise and model ADHD comorbidities. Artificial neural networks (ANNs) algorithms were used to identify specific relationships between protein sets. Finally, we modelled the mechanisms of LDX for the most relevant comorbidities by using sampling methods and comorbidity-specific virtual patients in each case.This study predicts a strong relationship between LDX’s targets and proteins involved in BED and depression . Our results could be explained not only by LDX role in neurotransmitter regulation, but also by modulation of neuroplasticity , neuroinflammation , oxidative stress , and the hypothalamic-pituitary-adrenal (HPA) axis .These findings could be used in pre-clinical and clinical future investigations to assess optimal treatment for ADHD patients with psychiatric comorbidities.JRGC: speaker for Takeda and Shire, research funding from Shire and Lumbeck, collaborations with Laboratoires Servier JQ: speaker or scientific advisor for Takeda, Janssen, Rubio. Investigation funding: Instituto de Salud Carlos III. PR, CM, TPR: full-ti


The worldwide prevalence of ADHD is estimated at 5.3%; however, estimates vary as a function of a number of factors, including diagnostic methods, age, sex and geographical location. A review of studies is needed to clarify the epidemiology of ADHD in Canada. (2) Methods: A search strategy was created in PubMed and adapted for MEDLINE and PsycINFO. Papers were included if they examined diagnosed ADHD prevalence and/or incidence rates in any region of Canada, age group and gender. A snowball technique was used to identify additional papers from reference lists, and experts in the field were consulted. (3) Results: Ten papers included in this review reported on prevalence, and one reported on incidence. One study provided an overall prevalence estimate across provinces for adults of 2.9%, and one study provided an overall estimate across five provinces for children and youth of 8.6%. Across age groups (1 to 24 years), incidence estimates ranged from 0.4% to 1.2%, depending on province. Estimates varied by age, gender, province, region and time. (4) Conclusions: The overall Canadian ADHD prevalence estimate is similar to worldwide estimates for adults. Most studies reported on prevalence rather than incidence. Differences in estimates across provinces may reflect the varying number of practitioners available to diagnose and prescribe medication for ADHD across provinces. To achieve a more comprehensive understanding of the epidemiology of ADHD in Canada, a study is needed that includes all provinces and territories, and that considers estimates in relation to age, gender, ethnicity, geographical region, socioeconomic status and access to mental healthcare coverage. Incidence rates need further examination to be determined. Attention deficit hyperactivity disorder (ADHD) is recognized as the most common neurodevelopmental disorder of childhood. A frequently cited study by Polanszky of 2007 reported a worldwide ADHD prevalence estimate of 5.3% . StudiesIn addition to potential differences between countries, prevalence estimates may also vary due to the methods used and sample characteristics. Additionally, while prevalence estimates indicate the number of existing cases of a disorder in the population , incidence estimates indicate the number of new cases being added  population). When the duration of a disorder is short, and new instances are constant or increasing, incidence can trend higher than prevalence. However, when the duration of a disorder tends to be lifelong (as is the case for ADHD), prevalence can trend higher than incidence because new cases are added and existing cases remain. Thus, prevalence and incidence provide unique information which combined, help to clarify the epidemiology of ADHD.A few studies have examined the prevalence and/or incidence of ADHD specifically in the Canadian population, but these findings have not yet been summarized. To clarify the epidemiology of ADHD in Canada, a review of existing studies on the prevalence and incidence of diagnosed ADHD is needed. The aim of this review is to summarize Canadian ADHD prevalence and incidence estimates published in the past ten years and to consider these in relation to demographic , geographic and methodological factors.A search strategy to identify relevant literature using Boolean operators was developed using PubMed and adapted for Medline, and PsycInfo with the following terms: (ADHD or ADD or AD/HD or Attention *) and (Canada or Canadian or province * or territory or territory *) and . All studies were screened, and data were abstracted by two reviewers. A snowball technique  and experts were consulted to identify additional relevant papers. Papers published within the past 10 years (2012 to 2022) were included if they provided estimates of diagnosed ADHD prevalence or incidence based on data from the Canadian population, regardless of age group, gender or geographical location examined. Papers that focused on symptoms of ADHD without a diagnosis  and that focused on a particular environmental condition  were excluded.A total of ten papers are included in the review ,18,19,20This group of studies based estimates on data collected from 1999 ,20 to 20The papers with prevalence estimates included children alone ,17, adulFour of the papers provided overall prevalence estimates across Canadian provinces using national datasets ,13,14 orRegarding gender, while all papers acknowledged gender differences in ADHD prevalence, six provided separate estimates for males and females ,15,17,18The diagnosis of ADHD was established based on different informants and methods. Some relied on physician reports ,16,17,18None of the included studies provided an overall national prevalence estimate collapsed across age groups . However, one study provided an overall estimate of 2.9% across a large age range , gender  and all provinces . The one study that provided an estimate for children alone (aged 3 to 9 years) indicated that ADHD prevalence across provinces is approximately 1.1% for preschoolers and 4.1% for school-aged children . Of the A few of the studies indicate that compared to adults and preschoolers, ADHD diagnosis is higher in school-aged children ,15,17,20The subset of papers including children indicates that the prevalence of ADHD is approximately twice as high amongst males compared to females ,16,17,18None of the studies looked at differences in prevalence by ethnic background. One study compared differences between first and second-generation immigrants in British Columbia with a non-immigrant sample . PrevaleOnly one study looked at Canadian ADHD prevalence rates in relation to socioeconomic status (SES) and region  . This stOne study looked at differences in estimates across provinces and indicated that ADHD prevalence may be higher in certain provinces compared to others . FindingA number of the studies reviewed here indicate that ADHD diagnosis and the number of patients prescribed ADHD medication are increasing over time ,12,15,17None of the papers included in this review provided an incidence rate for ADHD across all age groups or using a national sample.The one paper that examined ADHD incidence did so across a wide age range (1 to 24 years) . FindingAcross age groups, the highest incidence estimate was found for Quebec (1.2%), followed by Nova Scotia (1.0%), Manitoba (0.8%) and Ontario (0.4%) .Based on one study, there is some indication that ADHD incidence is rising across time (1999 to 2012) in Manitoba, Nova Scotia and Quebec but remaining stable in Ontario .See According to Vasiliadis et al. (2017) , who repOnly one study in this review  examinedPsychiatrists prescribe stimulants least frequently (17.2%). This is in contrast to prescriptions for antidepressants, of which most are provided by general practitioners (48.1%), followed by psychiatrists (27.2%) and then pediatricians (11%).Another study included in this review looked at medications prescribed to patients with ADHD aged 1 to 24 years, and found that the majority (70%) are prescribed stimulant medication . The stuThe prevalence of diagnosed ADHD varies across provinces (from 0.5% in Ontario to 3.8% in Nova Scotia).The prevalence of ADHD and prescription of ADHD medication have increased over time 1999–2015) for all age groups and provinces  ,12,15,17 for all Prevalence is higher amongst children and adolescents than adults, both within individual provinces and across Canada ,15,18.Prevalence is higher amongst males than females at all ages, although the disparity may decrease with age ,17,18,20The incidence of diagnosed ADHD in children and youth varies across provinces (from 0.4% in Ontario to 1.2% in Quebec)  and has The aim of this review was to examine the prevalence and incidence rates of diagnosed ADHD in Canada in the past decade. Ten papers were included in this review that covered all provinces and age groups from preschoolers to older adults. Based on one paper across five provinces, overall ADHD prevalence in children and youth (ages 4 to 17 years) was estimated to be 8.6% , and basADHD prevalence and incidence estimates require further examination, as only two studies in the past decade have examined prevalence across all provinces. No study covers all provinces and territories, nor all age groups. These are important gaps, as findings from the group of studies reviewed here highlight significant variability in estimates by province and age, e.g., . All stuThere are a number of future directions and questions that should arise from this review. While some of the studies looked at estimates in relation to gender, only the dichotomy of males versus females was used. Additionally, only one study included here reported on ethnicity as a variable. Importantly, one study in this review highlighted variability in prevalence rates related to immigrant and refugee status , and anoCanadian studies on prevalence in the past decade indicate an upward trend in ADHD diagnosis and medication treatment across time and provinces. One possible explanation is that variations in study methodology play a role, as found in a recent systematic review and meta-regression analysis of worldwide studies . It was Differences in taxonomy used to identify ADHD across studies and within studies, across time, may also influence estimates. Some research suggests that prevalence estimates based on the International Classification of Diseases (ICD) may underestimate ADHD prevalence compared to those that rely on Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria ,26,27,28Provincial differences in ADHD prevalence/incidence and treatments  raise several questions regarding the types of services and number of practitioners available to diagnose and treat ADHD. While provincial differences may be an important factor influencing prevalence, Canada also has an additional consideration given its geography, including large distances between communities and the resulting impact on access to services . HoweverUpward trends across time in ADHD diagnosis and treatment may reflect improvements in diagnosis and in ADHD medications , since the use of stimulants is considered first-line treatment for ADHD. This trend may also be associated with the increased availability of mental health training for primary care practitioners and practice guidelines supporting the successful management of ADHD in primary care ,31. ConsThe prevalence of ADHD in Canada based on studies published in the past 10 years varies depending on age group, gender, location and methodological approach.Overall estimates across provinces and territories.Estimates moderated by age, gender, ethnicity, geographical location , socioeconomic status and access to mental health care insurance.Standardized methods for defining ADHD cases, particularly with regard to diagnostic criteria  and data sources ADHD case identification using a validated algorithm based on pre-established criteria (currently considered best practice for case determination when using large primary care datasets) .Incidence estimates tracked with demographic data.Future Canadian ADHD prevalence and incidence research would benefit from:


Does the risk of attention-deficit/hyperactivity disorder (ADHD) increase after pediatric stroke, and is that risk associated with family history of ADHD, adverse motor outcomes, or comorbid epilepsy?This nationwide cohort study of 1320 patients who had perinatal or childhood stroke and 13 141 matched controls found a 2-fold increased risk of ADHD after stroke. Development of adverse motor outcomes and/or epilepsy were associated with a further elevated risk in children with perinatal stroke.These findings suggest that children may face an increased risk of ADHD after stroke and that surveillance for ADHD should be considered by pediatricians performing follow-up of children with pediatric stroke. This cohort study uses data from nationwide Swedish registers to evaluate the risk of attention-deficit/hyperactivity disorder after perinatal and childhood ischemic stroke in a large cohort of children. Early detection of attention-deficit/hyperactivity disorder (ADHD) plays a crucial role in reducing negative effects on everyday life, including academic failure and poor social functioning. Children who survive ischemic strokes risk major disabilities, but their risk of ADHD has not been studied in nationwide cohorts.To assess the risk of ADHD in children after pediatric ischemic stroke.Participants in this Swedish nationwide cohort study included 1320 children diagnosed with ischemic stroke recorded in linked Swedish national registers from January 1, 1969, to December 31, 2016, without prior ADHD diagnosis. Ten matched controls were identified for each index case, and first-degree relatives were identified for index individuals and controls. Analyses were stratified by perinatal and childhood strokes and presence of comorbid adverse motor outcomes and/or epilepsy. End of follow-up was the date of ADHD diagnosis, death, or December 31, 2016, whichever occurred first. Data analyses were performed August 1 to 28, 2021.Pediatric ischemic stroke.International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, and/or prescribed ADHD medication recorded in the Medical Birth Register, National Patient Register, or Prescribed Drug Register after stroke. Cox proportional hazards regression was used to assess adjusted hazard ratios (aHRs) for ADHD after pediatric stroke, adjusting for parental age and ADHD in first-degree relatives.Attention-deficit/hyperactivity disorder identified using codes from the Of 1320 children with stroke included in the analysis (701 boys [53.1%]), 75 (45 boys [60.0%]) were diagnosed with ADHD after stroke compared with 376 (252 boys [67.0%]) among the controls . The risk was increased after both perinatal  and childhood  strokes and were similar if children born preterm or small for gestational age were excluded. Compared with controls, risks of ADHD were higher among children with perinatal stroke and adverse motor outcomes and/or epilepsy  than among those without these comorbidities . However, findings were similar in childhood stroke for children with adverse motor outcomes and/or epilepsy  and among those without these comorbidities .This cohort study of 1320 children with pediatric ischemic stroke suggests that there is an increased risk of ADHD, particularly in children with adverse motor outcomes and/or epilepsy, compared with controls. The risk increases after childhood strokes regardless of comorbidities. The reported prevalence of ADHD after pediatric stroke has ranged from 13% to 50%.11 However, it is unclear whether ADHD risk is increased in children with ischemic stroke who do not have these comorbidities.Children who survive an ischemic stroke face higher risks of neurological disabilities, including epilepsy, and adverse motor outcomes such as hemiplegia and cerebral palsy.12 and social functioning.13 The prevalence of childhood ADHD in the general population is estimated to be approximately 3% to 5%.14 Although the exact etiology of ADHD is often unclear, there is a strong hereditable component,15 and associations have been found with low birth weight, prematurity,16 male sex,17 traumatic brain injuries, and brain tumors.19Symptoms of inattention and hyperactivity, as well as cognitive deficits in individuals with ADHD, often have a negative impact on academic achievements20 which is approximately 6 times higher than in the general population. Children with epilepsy also have a 2.5 to 5.5 times higher risk of ADHD.21 Numerous studies have reported that cerebral palsy and epilepsy are common comorbidities after pediatric stroke,22 so we would also expect to see an increased risk of ADHD. However, it is unclear whether the risk of ADHD is increased in children with ischemic stroke who do not have these comorbidities. Previous studies assessing ADHD after pediatric stroke11 have had limited sample sizes and used varying definitions of ADHD. They have also been hospital based and/or did not include general population controls, which restricted the generalizability of their results.It has been reported that 19% to 35% of children with cerebral palsy also have ADHD,25 we hypothesized that first-degree relatives of patients who had pediatric stroke would have an increased risk of ADHD. We explored this hypothesis by assessing the risk of ADHD in first-degree relatives of patients with pediatric stroke without ADHD.The main aim of our study was to address these limitations by using data from nationwide registers to evaluate the risk of ADHD after pediatric ischemic stroke in a large cohort of children. We included family history of ADHD, prematurity, small for gestational age (SGA), comorbid adverse motor outcomes, and epilepsy in our analysis. We hypothesized that children who had pediatric stroke face a higher risk of ADHD even if not born preterm or SGA or not having comorbid adverse motor outcomes and/or epilepsy. Our secondary aim was to explore whether ADHD and ischemic stroke have a shared heredity. Because diverse conditions affecting the brain have been reported to be genetically related,27 and the Medical Birth Register.28 Individuals with ADHD before their stroke were excluded. The Total Population Register26 was used to identify 10 controls for each patient with stroke who were matched for sex, year of birth, and county of residence at the time of diagnosis. Parents, siblings, and offspring of patients and controls were identified from the Multigeneration Register, which is part of the Total Population Register. This cohort is part of PedStroke, a Swedish national study on pediatric stroke. Previous publications report mortality,29 risk of epilepsy,22 and adverse motor outcomes30 in the cohort. The study was approved by the regional ethics committee in Linköping. The authors had access to pseudonymized and encrypted data from Statistics Sweden only, therefore the ethics committee did not require individual informed consent.31 This report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and the Reporting of Studies Conducted Using Observational Routinely Collected Health Data (RECORD) reporting guidelines.This Swedish nationwide cohort study included children who were younger than 18 years with ischemic stroke between January 1, 1969, and December 31, 2016, and were alive 1 week after their stroke. They were identified using the National Patient RegisterInternational Classification of Diseases, Eighth Revision (ICD-8), International Classification of Diseases, Ninth Revision (ICD-9), and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10)  and assess the risk of ADHD after stroke. Each index individual was compared with his or her matched controls using an internal stratifying model. Analyses were adjusted for parental age at the birth of the child and for any ADHD diagnosis of parents and siblings. Unadjusted results can be found in eTables 2 and 3 in the 17 We performed sensitivity analyses for individuals without adverse motor outcomes or epilepsy by censoring at the time of the first diagnosis of adverse motor outcomes or epilepsy after stroke. We also evaluated the risk of ADHD in parents, siblings, and offspring of children with stroke and controls.Sensitivity analyses were performed separately for children not born preterm or SGA, for sex, and for children with and without adverse motor outcomes and/or epilepsy because all these conditions have been reported to increase the risk of ADHD.The data analyses were performed from August 1 to 28, 2021, using SAS statistical software, version 9.4 (SAS Institute Inc), and Stata, version 16.0 (StataCorp LLC). A 95% CI that excluded 1.00 defined statistical significance.After excluding 7 children with ADHD before their stroke, 1320 individuals who were younger than 18 years and had pediatric stroke between 1969 and 2016   were incThe 1320 index individuals with pediatric stroke were twice as likely to have ADHD compared with controls when adjusting for parental age and a family history of ADHD . The risk was similar between boys  and girls  . This inCompared with controls, the risk of developing ADHD was similar for the 422 children with adverse motor outcomes after stroke  and among those without adverse motor outcomes . The 293 children who had epilepsy after stroke had a slightly higher risk of ADHD compared with controls  than among those who did not develop epilepsy  .The 343 children with perinatal stroke also had an increased risk of ADHD  , which rThe risk of ADHD after childhood stroke was increased  , and it The siblings of patients with stroke had a higher risk of ADHD than the siblings of controls , and the same result was seen for both perinatal and childhood stroke . When on15 parental age,39 prematurity, or SGA.16 The increased risk was seen after both perinatal and childhood stroke, which is in line with the study by Williams et al.10 Other studies11 did not distinguish between perinatal and childhood strokes. Epilepsy and adverse motor outcomes have been associated with ADHD in the general population40 and are common sequelae after pediatric stroke.42 Therefore, we also ran sensitivity analyses that censored individuals with these comorbidities.This nationwide cohort study of 1320 patients with pediatric stroke identified a 2-fold increased risk of ADHD after pediatric ischemic stroke. That risk remained increased after known risk factors for ADHD were considered, such as a family history of ADHD,43 However, most of these studies included small cohorts.43 The exception was the study by Williams et al,10 which included 275 patients with pediatric stroke. To our knowledge, this is also the only study except ours that accounted for family history of ADHD. To our knowledge, our study is the largest to date to report an increased risk of a clinical diagnosis of ADHD after pediatric stroke.Previous studies have also reported increased risks of ADHD diagnosis or ADHD symptom level after pediatric strokes.20 and a Swedish population-based study44 reported that half of the 200 children with cerebral palsy had positive results for ADHD.The risk of ADHD was increased after perinatal stroke and increased 6 times if the child also had adverse motor outcomes. The expected adverse motor outcome after perinatal stroke is cerebral palsy. Attention-deficit/hyperactivity disorder is more common in individuals with cerebral palsy than in the general population,10 and Auvin et al.21 Clinicians are already advised to screen for ADHD when children have epilepsy because this outcome is a well-known comorbid condition.21 Genetic and environmental factors can contribute to the comorbidity of ADHD in epilepsy, as well as an imbalance between excitation and inhibition in the brain.45 This imbalance could also contribute to the development of ADHD.46As expected, children diagnosed with comorbid epilepsy after perinatal stroke had a higher risk of ADHD compared with controls than those with perinatal stroke without epilepsy. This result echoed the findings of Williams et alThe risk of ADHD was also increased after childhood stroke, and the presence of adverse motor outcomes was not associated with the risk. Adverse motor outcomes after childhood stroke most commonly consist of hemiplegia and, for some of the younger children, cerebral palsy, in addition to less severe palsies and paresis that are often caused by a smaller insult to the brain.Epilepsy seems to be a risk factor for ADHD after both childhood and perinatal strokes. However, compared with controls, the risk of ADHD was also increased after childhood stroke for those without adverse motor outcomes or epilepsy.18 In these cases, a decrease in the organization of white matter seems to play a crucial role in the development of ADHD,47 and this decrease could also be important in other disorders. Whether this outcome is the case after pediatric stroke needs to be elucidated.It has been reported that the risk of ADHD is increased after other brain insults during childhood, such as severe traumatic brain injuries.23 has demonstrated a high degree of genetic correlation between different psychiatric disorders. Thus, our results support the hypothesis that there is a genetic disposition that increases the risk of both ADHD and stroke.We found an increased risk of ADHD in the siblings of patients with pediatric stroke with and without ADHD. The rationale behind evaluating ADHD in relatives of these patients is that previous research11 Pediatric stroke is a relatively rare event, and this factor resulted in low power in most of the previous studies. Another major strength of the present study is its nationwide design. As recommended for follow-up studies,48 we matched controls and compared risks of ADHD between patients with stroke and controls. All data were collected prospectively. We adjusted for important confounders, such as ADHD in first-degree relatives, parental age, prematurity, and SGA. A diagnosis of ADHD was identified based on clinical ICD-9 and ICD-10 codes in contrast to previous studies using diagnoses based on questionnaires or research tests,43 which may overestimate the prevalence of ADHD.49 Stratified analyses of the risks of perinatal or childhood strokes and neurological comorbidities were performed. Data were retrieved from registers with high validity. The stroke diagnosis in our cohort has been validated.To our knowledge, this is the largest study of risk of ADHD in patients with pediatric stroke to date, and our results confirm findings of smaller, hospital-based studies.50 possibly because the follow-up time was limited to the date of the stroke diagnosis in the matched index case and that a diagnosis code for ADHD is only available after ICD-9 was implemented in 1987. The number of individuals in the exposed group was relatively small for some analyses, with wide 95% CIs for some aHRs. If possible, our results should therefore be confirmed in other large cohorts of patients with pediatric stroke.This study has some limitations. There is a possibility of detection bias by misclassification or underreporting, such as underreporting of stroke before the advent of modern imaging, and for surveillance bias if patients with stroke were more carefully observed. Some individuals might have had ADHD before the stroke, although the ADHD diagnosis was registered after the stroke. Fewer controls had ADHD (2.9%) than previously reported in Swedish national registers (4.3%),37 showed that 90% were arterial ischemic strokes. The proportion of perinatal strokes in our cohort was lower than expected. Some neonatal units may have used unspecific ICD codes  for perinatal stroke cases. Our study population was probably heterogenous in terms of the localization and size of the strokes. Outpatient diagnoses of ADHD have only been available since 2001. However, we estimate risks compared with controls, and the risks are probably not as influenced by this factor as the prevalence rates. We did not evaluate other mental health outcomes, socioeconomic status, parental health, or other child health variables that could have influenced our findings. In addition, we cannot rule out unmeasured and residual confounding variables that may have influenced the result.Owing to the limited number of individuals in some subgroups, we were also only able to report results compared with controls instead of making direct comparisons between children with and without comorbidities. We could not distinguish between different types of ischemic stroke, but a previous validation studyThe findings of this nationwide cohort study suggest that pediatric ischemic stroke was associated with a risk of ADHD irrespective of whether there was a family history of ADHD. This risk was even higher if there were adverse motor outcomes and/or epilepsy after perinatal stroke. Furthermore, the risk was increased in patients with childhood stroke who did not have these comorbidities. Ongoing surveillance for signs of ADHD should form an important part of follow-up programs after pediatric strokes, especially if individuals have comorbid adverse motor outcomes or epilepsy.


There is currently limited research on the intersection of pregnancy and ADHD and the unique pregnancy risk factors for mothers with an ADHD diagnosis. With an increased population of patients with ADHD in the recent decades and an increase in ADHD medication use during pregnancy it is important to consider what unique risks mothers with ADHD face during the perinatal period.Investigate a variety of outcomes in maternal ADHD.We identified female patients with a diagnosis of pregnancy and ADHD diagnosis. We also further separated the ADHD cohort for separate sub-analyses based on medication type. Odds ratios and relative risk were calculated from outcome incidence within each cohort. Cohorts were balanced on age, sex, and race.P = 0.768). The odds ratios ranged from 1.08 for anemia complicating pregnancy to 2.63 for depressive episodes. Most outcomes were between 1.2 and 1.8 times more likely to occur in the cohort with ADHD.We identified 45,737 pregnant females with ADHD. We matched these patients to pregnant females without ADHD, for a total of 42,916 pairs. Compared to the group without ADHD, mothers with ADHD had higher rates of every outcome except for HPV infection, which was statistically insignificant (This study presents substantial advancements in our knowledge of pregnancy-related ADHD care. Armed with an increased awareness of these potential complications and their relationship with ADHD, obstetricians, psychiatrists, and providers of all specialties may be able to reduce the rate of complications within this specific patient population. Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting an average of 5% of children globally and 2.5% of adults worldwide , 2. ThisThroughout the lifespan, ADHD is associated with several comorbidities and research consistently supports that those with ADHD are at greater risk of adverse life outcomes , 5. ComoWhen considering ADHD with a lifespan perspective, one particularly important developmental period for clinicians to clearly understand associated health needs and risks is female adolescence. As physicians grow more comfortable assessing and diagnosing ADHD in children and adolescents, they can expect to see more women in their reproductive years with a history of ADHD. It is important to consider the risks associated with ADHD and the corresponding treatment or withheld treatment in the setting of pregnancy.It is estimated that approximately 8% of women will experience some sort of pregnancy related complication . ComplicAdditionally, some obstetric complications require close monitoring and follow up, as there is no cure for these conditions, only management. Prime examples of these types of complications are the hypertensive disorders, specifically preeclampsia. 2%–5% of pregnancies are complicated by preeclampsia . It is rThere is currently limited research on the intersection of pregnancy and ADHD and the unique pregnancy risk factors for mothers with an ADHD diagnosis. There are many studies that investigate risk factors for children developing ADHD , but even these studies rarely track the ADHD history of parents and do not consider the effect of ADHD on parental health . With anWhile there is little data regarding the early infancy and pregnancy periods for women with ADHD, mental health issues such as depression, bipolar disorder, and anxiety disorders are associated with increased pregnancy and birth complications . Many ofThe gold standard treatment of ADHD is a combination of behavioral therapy and psychostimulant use, most often methylphenidate or amphetamine derivatives. Many women continue to need their medication throughout reproductive years and rely on their medication for optimal functioning in school, home, and the workplace . PrescriThis is an especially important line of research as women with ADHD have an increased risk of unplanned pregnancies . ChildhoThe aim of this study is to address pregnancy outcomes amongst patients with ADHD and those who do not have ADHD. Additionally, the obstetric outcomes of patients with ADHD will be further analyzed based on medication regimen.This study consisted of a population-based retrospective analysis of patient health records from the TriNetX database, which contains electronic medical records from large healthcare organizations and has shown utility for a variety of medical fields , 7. TriNUsing International Classification of Diseases (ICD) codes, we identified all female patients with a diagnosis of pregnancy (Z33). We then separated patients by ADHD diagnosis (F90). We also further separated the ADHD cohort for separate sub-analyses based on medication type, including use of stimulant medications, non-stimulant medications, or either of these or no medication use. Stimulant medications were identified as belonging to either the amphetamine- or phenidate- classes. Non-stimulant medications included: guanfacine, clonidine, bupropion, atomoxetine, or viloxazine. Patients identified as on “any medications” were limited to the use of one identified medication at once. The 18 studied outcomes were identified from prior research on complication epidemiology. We studied pre-eclampsia, pre-existing hypertension, gestational hypertension, renal disease, post-partum depression, depressive episode, iron deficiency anemia, gestational diabetes, eclampsia, HPV, pre-term delivery, spontaneous abortion, cardiac disease complicating pregnancy, TORCH infections, anemia complicating pregnancy, malnutrition, early pregnancy hemorrhage, and hyperemesis gravidarum. Further information on specific codes and locations used can be found in t-test was used to compare event rates between cohorts. Relative risk and odds ratios with a 95% confidence interval were also calculated from event rates. The results from the overall analysis are compiled in P < 0.05. As this study contained only de-identified aggregate data, the Colorado Multiple Institutional Review Board (COMIRB) designated it as non-human research not in need of approval.Using the TriNetX software, we performed 2 sets of statistical analysis. One analysis was between the cohort with ADHD and the cohort without, and the other analysis separated the ADHD cohort by medication type. Prior to comparison, the cohorts were balanced based on age, ethnicity, and race using nearest-neighbor matching to a difference in propensity scores <0.1. After matching, cohorts had no significant differences age, ethnicity, or race. P = 0.768). The odds ratios ranged from 1.08 for anemia complicating pregnancy to 2.63 for depressive episodes. Most outcomes were between 1.2 and 1.8 times more likely to occur in the cohort with ADHD.We identified 45,737 pregnant females with ADHD. We matched these patients to pregnant females without ADHD, for a total of 42,916 pairs with no statistical differences in age, race, or ethnicity. Compared to the group without ADHD, mothers with ADHD had higher rates of every outcome except for HPV infection, which was statistically insignificant (P = 0.211); patients on non-stimulant medications had lower rates in 13 of 18 outcomes, and 5 insignificant results; finally, patients on any individual medication had statistically significant results for all outcomes, which were lower for every outcome except for HPV.Sub-analysis of medication regimen revealed differences for each studied regimen. Compared to the cohort of ADHD patients without any recorded medications: patients on stimulant medications had statistically lower rates of every outcome, with the exception of HPV which was statistically insignificant (Complete results are in Our study confirmed higher rates of all studied outcomes in mothers with ADHD compared to those without ADHD. With the exception of HPV infection, statistical significance was present for all outcomes after adjusting for the potential confounding variables of age, race, and ethnicity. Our data aligned with prior areas of research for many outcomes, such as gestational diabetes and different presentations of hypertension . It alsoThe two studied types of anemia, iron deficiency and nonspecific anemia complicating pregnancy, present an association that is a novel finding and a unique opportunity for beneficial intervention. Iron deficiency has recently become the focus of several studies relating to ADHD. Patients with ADHD have higher rates of iron deficiency, which can worsen on certain medications . RelatedOur study is the first to present findings relating to multiple medication regimens and obstetric complications in ADHD. The first FDA approval for a non-stimulant drug was in 2004, and non-stimulant treatment of ADHD is becoming more common. Viloxazine was approved in 2021, and while bupropion has not been officially approved for ADHD use, we included it due to substantial research and its frequency of off-label use , 43. IntWith the exception of HPV, every outcome studied in the ADHD medication sub-analysis was less common for patients on medications compared to patients without medication use. Our methodology excluded patients using multiple ADHD medications at once, as the vast majority of ADHD patients do not require simultaneous use, and those that do typically have increased and therapy-resistant symptoms. For approximately half of the outcomes, non-stimulant medications had the largest reduction in risk. Cardiac disease complicating pregnancy was the only event with the “any medication” cohort having the largest reduction, with the remaining events having stimulant medications as the largest difference. The lack of a distinct pattern across risk differences between medication types may indicate the association present in our data is related to a conscious awareness of the patient's ADHD, rather than a specific health advantage of one subtype. For example, stimulant prescriptions are limited to a 3 months' supply in most states before the patient needs to interact with their provider again, yet non-stimulants are subject to different rules. Based on the widespread decrease in complication risk when a patient's ADHD is being treated with medications, the value of an ADHD-knowledgeable health care professional involved in a pregnant patient's care is substantial.The safety of ADHD medication use during pregnancy has been well-studied. In a review of available data regarding perinatal exposure to psychostimulants and associated risks, researchers concluded that women with moderate-to-severe ADHD should not necessarily be counseled to suspend their ADHD treatment based on these findings . Untreatin utero may cause an increased risk of ADHD later in life. However, a recent study conducted by Lemelin showed that after adjusting for confounders there is no increased risk of in utero exposure to ADHD medications and increased risk of developing ADHD (After reviewing the current literature, many ADHD medications are not shown to have significant negative outcomes in infant health and obstetric outcomes. Studies show that methylphenidate may have a slight increased risk of cardiac malformations, possible increased risk of spontaneous abortion, preterm birth, preeclampsia, and perinatal complications. However, methylphenidate is the preferred drug in the breastfeeding period and the risk of the above complications was quite minimal . Other sing ADHD . While sing ADHD .Our study has unique value for psychiatrists, obstetricians, and all providers treating pregnant patients with ADHD. While our study only focuses on association and does not ascribe causation to any one factor, the strength of the measured differences in risk suggests certain interventions may be worthwhile considerations. The first and most important intervention supported by our data is increased awareness and monitoring throughout the pregnancy of a female with ADHD. Many outcomes in our study can be prevented or mitigated through early intervention, and if providers have a higher index of suspicion for complications in patients with ADHD it may ultimately lower the prevalence of these conditions. Medication management of ADHD is another intervention that is supported by our data, given the nearly universal decrease in outcomes for patients on any of the studied medications. Finally, patients with ADHD may benefit from increased counseling from their health care providers, both before and during pregnancy. This counseling should address iron intake, safe sex practices, and the importance of regular prenatal and perinatal care. Visual and narrative information has shown particular utility in patients with neurodevelopmental disorders like ADHD. It may be worthwhile for providers to describe a case in which a patient did not receive adequate care in comparison to a case in which a patient did receive care that addressed both their pregnancy and their ADHD. If the provider is able to communicate effectively with the patient, the impact of ADHD on the pregnancy may be minimized.While our study does address shortcomings in prior research of pregnancy and ADHD, such as controlling for age, race, and ethnicity, our study does have some limitations that may limit the generalizability of our findings. The database used for this study only contains deidentified, aggregate information, which prevents us from analyzing certain elements relevant to the field. For example, we are unable to know why patients were specifically prescribed non-stimulant medications that may have been used for a condition other than ADHD. Similarly, we are unable to confirm that patients were taking the recorded medications during their pregnancy. We also did not examine many other comorbid conditions, such as depression, anxiety, or substance use, which may have impacted the results. Finally, we limited our analysis to ICD codes, which likely underestimates the true rate of the complications, as ICD codes must be inputted manually. As such, it is unlikely providers would enter a code without the corresponding condition being present, but it is possible that a condition could be treated without the ICD code being recorded. However, the substantial size of our study mitigates each of these limitations and ensures our findings do have relevance for many patients and providers.This study presents substantial advancements in our knowledge of pregnancy-related ADHD care. It contains a substantially larger patient base than previous research, and controls for age, race, and ethnicity; three confounding variables that can affect findings greatly. It also confirms associations that are known to affect patients with ADHD in general but have yet to be linked to maternal ADHD specifically, such as anemia and iron deficiency, hyperemesis gravidarum, TORCH infections, and depression. Armed with an increased awareness of these potential complications and their relationship with ADHD, obstetricians, psychiatrists, and providers of all specialties may be able to reduce the rate of complications within this specific patient population.


A clear majority of the studies investigated non-pharmacological therapies (∼80%), including many behavioral options, such as social skills training, sleep and physical activity interventions, meditation and hypnotherapy. Devices, complementary and other alternative methods of ADHD treatment are also gaining attention. The pharmacological group accounts for ∼20% of all the studies. The most common drug classes include central nervous system stimulants , selective noradrenaline reuptake inhibitors , and alpha2 adrenergic receptor agonists . Several studies investigated antidepressants , and atypical antipsychotics  but these are yet not approved by the FDA for ADHD treatment. We discuss the quantitative trends in clinical trials and provide an overview of the new drug agents and non-pharmacological therapies, drug targets, and novel treatment options.Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders having a high influence on social interactions. The number of approved treatments and clinical trials for ADHD have increased markedly during the recent decade. This analytical review provides a quantitative overview of the existing pharmacological and non-pharmacological methods of ADHD treatments investigated in clinical trials during 1999–2021. A total of 695 interventional trials were manually assessed from  Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder, which can be reliably diagnosed in children, adolescents, and adults . The disADHD has been associated with genetic, neurological and environmental factors and combinations thereof , but theThere is a growing number of ADHD treatments that target and alleviate the core symptoms of ADHD and functional impairment . There aThere are several reviews about the field of ADHD treatment . A systeComprehensive information about the non-pharmacological methods was presented in a review analyzing 54 studies . This woIn this review, we provide a quantitative analysis of ADHD treatment methods that have reached clinical trials starting from 1999 to the end of 2020. We aimed to show the diversity of treatment options, their features and the trends looking closer into therapies that seem to be gaining attention.clinicaltrials.gov–one of the largest web-based resources providing access to summary information on clinical studies on a wide variety of diseases and conditions  were included in the analysis. There were no criteria for inclusion regarding the gender and age of participants. All studies up until 4 January 2021 were analyzed.All trials included in this review were taken from nditions . An advaclincialtrials.gov. Some trials had incorrectly/ambiguously assigned phases, thus requiring their correction. If a study had a double phase , we took an earlier one since it is not clear whether a trial has successfully transitioned to the next phase. If the phase was categorized as « Not applicable», «Early Phase 1» we classified it as Phase 1. For devices, according to the FDAs classification, the term « Phase» is not correct, thus we used the term « Stage»   were also eligible for inclusion provided that these conditions were associated with ADHD. Studies with no participants were excluded from the analysis. Thus, by manual selection, 398 studies were excluded and a total of 695 studies were included in this review. Information regarding NCT number, study title, study status, researched condition, intervention, phase of the study, completion date of the study, and date when its results were first posted was collected for each included trial through l stage) . ExploraWe have analyzed and classified treatment methods from the included studies, using classification from previously published articles on the topic .Pharmacological interventions:1) stimulant drugs:- etc.)• Norepinephrine and dopamine reuptake inhibitors • Selective noradrenaline reuptake inhibitor (atomoxetine)other approved or unapproved drugs used in ADHD:- etc.)• Antidepressants   2) Non-pharmacological interventions:psychological:- etc.)• Behavior management interventions • Cognitive training interventions • Supplementary interventions and dietary interventions   devices- • Transcranial direct current stimulation (tDCS)• Transcranial random noises stimulation (tRNS)• Repetitive transcranial magnetic stimulation (rTMS)• Direct transcranial magnetic stimulation (dTMS)• External trigeminal nerve stimulation (eTNS)• Virtual reality (VR)3) Combined interventionsThe following classification was applied:go.drugbank.com, genome. jp, uniprot.org, and fda.gov in a similar way as we have done previously . All devices encountered in clinical trials were divided into the corresponding groups presented in the classification. If a device could not be assigned to any of the aforementioned classes, we classified them as « Unspecified device class». If a study contained multiple therapies  or a combination of them, each therapy was considered separately in the analysis. It is also important to note, that trends in clinical trials were in our main focus, and the data obtained during the analysis do not correlate with the actual application of methods in clinical practice.etc.). It should be mentioned that the prevailing majority of psychological and complementary and alternative methods belongs to the phase categorized as « Not Applicable». For the sake of simplicity, we classified these studies as « Phase 1», however, this could lead to data misinterpretation. More specific analyses focusing on behavioral therapies should consider detailed classification of these studies. For example, NIH proposes to classify behavioral therapy trials based on the setting of a trial, starting from basic science in the research setting and finishing with trials in community settings  during or prior to the intervention. Thus, some of the interventions that were listed as single might have been combined with other forms of ADHD treatment. Additionally, some trials included several conditions, and therefore it is possible that ADHD was not necessarily the major focus of each trial, which could cause misleading data regarding certain trends. Some drugs were indicated in the trials without specifying their names, hence they could not be attributed to any particular class. In some trials on non-pharmacological methods, on the contrary, there was a name of the therapy class , but based on the description of the study, it was not always clear what particular device  or therapy  were used. In such cases, each therapy and device were considered as a unique entity  . The fivvia enhancing monoamines level in the brain, targeting monoamine transporters (We investigated the drug targets associated with ADHD. sporters .D (2) dopamine receptor, 5-hydroxytryptamine receptor 2A  are the key targets of antipsychotics . All memHistamine receptor H3 (gene name: HRH3) is another promising target. Several studies have shown histamine to exert a significant modulatory effect on different brain functions, such as arousal, control of pituitary hormone secretion, cognitive functions, motivation, goal-directed behavior, memory, sleep-wake cycle , and be In We see upward trends in the number of devices, psychological, as well as complementary and alternative methods, while the number of drug agents fell sharply from 11 agents in 2005 to one agent in 2018 . It can Our next step was to analyze phase distributions of the trials per year. We sought to explore what kinds of therapies demonstrate the increase in phase 1 clinical trials. Also, based on the data presented in Surprisingly, we can notice that the overwhelming majority of agents are discontinued, 31 out of 44 agents in total for all of the classes taken for analysis. The main reason for drug discontinuation was lack of efficacy or safety  . It is wsertraline, a selective serotonin reuptake inhibitor (SSRI) antidepressant .Our data shows an intriguing slight increase in the number of device studies , startinThe next most popular device class that appeared in clinical trials was repetitive transcranial magnetic stimulation (rTMS) that was cleared by the FDA for the treatment of major depression and obsessive compulsive disorder . It is aAs of 2021, there are at least two devices that received FDA approval for the treatment of ADHD: Monarch eTNS System and EndeavorRx. Monarch eTNS System is the first device-based ADHD treatment, that received clearance from the FDA . It is aNon-pharmacological methods, in addition to devices, include two big groups: psychological therapies and complementary and alternative therapies. Based on our data, it is clear that the number of complementary and alternative interventions has increased for the past decade, with the largest number of studies in the physical activity (PA) field . AerobicThe main growth in the field of psychological therapies could be explained by behavior interventions. There are two clinical trials in particular that worth noting: NCT03628781 and NCT04402528. Behavioral therapies happened to be rather effective in eliminating the symptoms of ADHD . HoweverThis review provides comprehensive quantitative data on pharmacological and non-pharmacological methods for the treatment of ADHD that have reached clinical trials in children, adolescents, and adults, covering 695 studies. Overall, we see that the number of unique non-pharmacological interventions  is threeThere are 12 drugs approved by the FDA for treatment of ADHD . In addition to approved agents, in the classes that have at least two unique representatives, there are five novel emerging drugs  being tested in the clinical trials with one, three, and one agent that have reached phases 1, 2, and 3, respectively. Also, there are three repurposed drugs  that have been earlier approved for the treatment of other indications and now are tested in clinical trials for ADHD. And two drugs  with a suspended clinical development. The largest class of ADHD pharmacological treatment are central nervous system stimulants  that act predominantly by regulating the brain levels of monoamines (mostly dopamine and norepinephrine), drugging the sodium-dependent noradrenaline transporter and sodium-dependent dopamine transporter. Antidepressants are the class with the highest number of unique agents in clinical trials . Antidepressants could be prescribed to treat ADHD in patients who did not respond or showed intolerance to stimulants since antidepressants have a similar mechanism of action and drug the same targets  as psychostimulants. However, the FDA has not specifically approved these medications for this.We see that there is a clear increase in the number of behavior management trials and cognitive training trials . The sucOverall, the increase in the number of non-pharmacological studies may be related to the fact that interventions are focused on the individuals with ADHD as they grow up and can be modified from childhood to adulthood, exerting influence on the most problematic behavioral symptoms at that stage in time. As children mature, non-pharmacological interventions may be changed according to the developmental needs and circumstances related to the particular individual. For each age category, there are the most preferred methods of non–pharmacological treatment, such as parent training for preschool children or parent training and classroom interventions for school-age individuals . BesidesDespite the fact, that the number of unique pharmacological interventions is not high , drugs rADHD treatment can also be provided by using combinations of different methods. As previous studies have shown, the combination of methylphenidate hydrochloride with behavioral therapies had some significant effects on ADHD symptomatology, which perfectly correlates with the data obtained during our analysis, where the predominant number of approved drugs are stimulants  and the We can conclude that the area of ADHD treatment is gaining increased complexity with high variety of different treatment options, such as drugs, behavior management interventions, cognitive training therapies, supplementary interventions, devices, mind and body interventions. There are several reasons that drive the increased variety of therapies to treat ADHD such as the misuse of stimulant medications, the ability of behavior therapies to target mainly behavior problems without normalizing the level of catecholamines in the brain, financial limitations, and family logistical challenges. Future research is warranted to gain a deeper understanding of the potential effects of non-pharmacological therapies (including devices) to provide a mechanistic explanation on how these interventions  impact the pathology of ADHD or comorbid symptoms. In addition, it is common that treatment of ADHD begins after the disease has already become detrimental to a person’s life when all characteristic disease symptoms are present. Hence, early diagnosis and prevention of the disorder is likely to become increasingly important area. Lastly, it is also important to investigate how available and future treatment options  impact the person’s social life and career longitudinally since these long-term outcome measures are effectively one of the main reasons to treat ADHD in the first place .


This research work specifically concerns the impact study of the engraving finishing geometry on the final properties of tissue paper. This work led us to conclude that, even though the sheets individually present a higher hand-feel (HF) value for the straight finishing geometry, the highest softness was obtained in the two-ply prototype for the round finishing geometry. Moreover, this study confirmed that the HF value reduces with the increase of the bulk, being more accentuated for the micropattern. Relevant differences could not be seen in the spreading kinetics of the liquid droplets over time. Thus, the finishing geometry of the 3D plates did not impact the absorption kinetics on these samples. The finite element model allows us to understand the effect of the plate pattern and its finishing geometry on the paper, and the simulation results were in accordance with the experimental results, showing the same trend where patterns with a round finishing geometry marked the tissue-paper sheet more than patterns with a straight finishing did.Embossing is a functional and strategic process for creating high-quality multi-sensory tissue-paper products. Embossing modifies the sheet surface by generating hill and/or valley designs, changing the third-dimension  Enhancing both originality and creativity is often a brand’s selling and advertising argument. Therefore, embossing is a key process for producing high-quality multi-sensory products. Embossing is a type of compressive action that is carried out during tissue-paper converting by creating a pattern/engraving on paper with different depths, thus altering the sheet topography . In addiIn theory, any kind of paper and/or cardboard can be embossed, considering the material properties, thickness, composition, fiber type, fiber length, and mechanical-strength properties . Thus, bulkier materials will respond like a sponge, as they are more compressible, requiring higher pressure to make the engraving permanent. On the other hand, if this pressure exceeds the limit of the material, the embossing process will cause permanent damage to its structure, and this will appear on the surface of the sheet of paper .A limitation of the embossing process is related to the dimensions and geometry of the embossing-pattern elements. Patterns with fine details, such as dots and fine lines, cannot be engraved to a high depth, as fine details are predisposed to tearing the sheet of paper. High-quality embossing is not only related to the engraving depth; the ability of the paper to stretch and adapt to the embosser is an equally important physical limitation . There a2), height of the dots, and the angle that the dot makes with the base, affect the deformation of the sheet and, consequently, the mechanical properties of the embossed product. Thus, Khan [From the work developed by Khan , it was us, Khan  concludeus, Khan , the novThe influence of embossing pressure, time, and rubber hardness on the final properties of tissue paper is known from previous works ,8. In thEucalyptus globulus (hardwood) and 70% Pinus pinaster (softwood) bleached kraft pulps. This paper, denominated by B, had a grammage of 16.7 g/m2 and was produced on a paper machine with a single layer headbox and with a ceramic creping blade. Moreover, for the execution of this work, four steel embossing plates were used, two of them with a deco pattern and the other two with a micropattern. Each steel plate presents dimensions of 210 × 297 mm and a different line or dot finishing geometry. In To carry out this work, industrial creped toilet-base tissue paper from one Portuguese factory was used. The composition of the used paper was a mixture of 30% sl to the paper denomination, and those with round lines are designated by drl. The samples embossed with the micropattern with straight dots are designated by adding the abbreviation msd to the paper denomination, and those with round dots by mrd.All the tissue samples are denominated according to each 3D steel-plate pattern and finishing geometry. Samples embossed with the deco pattern with straight lines are designated by adding the abbreviation dThis work started by performing the embossing operation itself, with the four different embossing patterns engraved on steel plates. The two deco-pattern plates differ in the finishing geometry of the lines (straight or round), while the two micropattern plates differ in the finishing geometry of the dots (straight or round). ® VantageNX Universal testing machine, in agreement with the tissue standard ISO 12625-4:2005, and thickness and bulk were determined by using a FRANK-TPI® Micrometer, fulfilling the tissue standard ISO 12625-3:2014. On all the embossed samples, the softness was tested with a Tissue Softness Analyzer (TSA) from EMTEC® equipment. For the computation of the handfeel (HF), the TP II and the QA I algorithms were used.All the tissue samples engraved with the four embossing patterns were tested in terms of thickness/bulk and their mechanical tensile strength in the machine direction (MD) and in the machine cross direction (CD). Tensile tests were performed in a Thwing-AlbertThe samples were also analyzed by using three different modules of the customized optical system for the visual inspection of their surfaces, for the topographic reconstruction of the samples in three-dimensions, and also for the study of their interaction with liquid droplets. Specifically, the first module of the optical system ,10,11 enThe effect of the plates’ pattern geometry can be analyzed in terms of stress field and how the finishing geometry affects the plasticity after the embossing process, using the finite element models. Thus, different models were proposed to investigate in more detail these effects on the permanent deformations after the embossing process.TM does not have a native constitutive law for orthotropic plasticity material, a user material subroutine for explicit simulations (VUMAT) linked to the commercial finite element software ABAQUSTM was implemented, using an orthotropic elastic–plastic material model, proposed by Mäkelä and Östlund [Since ABAQUS Östlund . This ma Östlund . The modA, B, C, and D were calibrated from tensile-test results by using the following Equations (4)–(11) [The VUMAT subroutine was implemented by using the concept of an isotropic plasticity equivalent , conside(4)–(11) :(4)A=1−1The parameters For the CD, the equation is as follows (Equation (13)):Note that, for Equation (13), the repeated indices do not mean the usual summation rule used in the indicial notation. Finally, the parameter K22 = K33, since the mechanical behavior in CD (direction 2) is similar to that on the thickness direction (direction 3). Thus, A = 1 for all models. For deco models, B = 2.40, C = 2.40, and D = 1.38, and for micro models, B = 2.44, C = 2.44, and D = 1.40. Since the tensile vs. strain curves had a similar shape, those parameters are almost the same in both MD (direction 1) and CD (direction 2).In the case of this study, it is possible to consider The Hooke’s law for plane stress, small strain, and linear elastic orthotropic material is given by using Equation (15):The implementation of this model is similar to the well-known The finite-element-model dimensions and boundary conditions are presented in The boundary conditions were imposed to represent the embossing process. Thus, all the displacements’ degrees of freedom were restricted in the bottom of the rubber base, and a prescribed displacement was applied on the top of the plate, corresponding to a manufacture pressure of 2.8 bar applied during the embossing process. To model the contact interactions between each part of the model, hard contact was considered for normal behavior, and the tangential behavior was modeled by using penalty interaction with 0.3 for friction coefficient.The model has 473,694 20-node hexahedral elements (C3D20) for the simulation of the micro die with round finishing dots, and 476,153 20-nodes hexahedral (C3D20) elements for the deco die with round finishing lines. To improve the simulation, the straight finishing dots of the micro die was modeled with 443,206 10-node tetrahedral mixed-mode elements (C3D10M), and 1,491,454 10-node tetrahedral mixed-mode elements (C3D10M) for the straight finishing lines of the deco die.For all models, paper was simulated by using a 4-node reduced integration membrane element (M3D4R). The structured mesh has a total of 250,000 elements. Finally, the rubber base was modeled by using a total of 216,000 8-node hexahedral elements (C3D8).10 = 0.810343 MPa and D1 = 0.56956 MPa−1), and for NR-BG (C10 = 0.409852 MPa and D1 = 1.126109 MPa−1). Paper was modeled as a user orthotropic material . As mentioned above, the parameters B, C, and D for the IPE model consider the different mechanical behavior for the deco pattern and micropattern.This model uses 3 different types of materials: steel for the die ; a hyper-elastic isotropic material model for the rubber basis, SBR-PR  consider a manufacture pressure of 2.8 bar applied during the embossing process.This work began with the mechanical characterization and determination of the bulk of the previously embossed samples and the industrial base tissue paper. The results obtained are shown in The images obtained by analysis with the first module of the optical system of the tissue samples embossed with the four different 3D steel plates are presented in Regarding the essays conducted with the third module of the optical system, the images and the results obtained for the study of the spreading dynamics of a liquid droplet on the surface of the tissue-paper samples engraved with the different embossing plates can be seen in By combining the deco and micro embossed sheets for each finishing geometry, straight or round, a prototype of a two-ply finished product was obtained. With the aim of optimizing the softness as a function of the 3D steel-plate finishing geometry in the embossing process, the handfeel (HF) of each one of these prototypes was measured, and the results are shown in In order to better understand the effect of embossing on softness, J2 invariant) model results for the round- and straight-line finishing of the deco pattern, respectively, as well as the deformed shape, and The finite element models can predict the effect of the die finishing geometry on the paper. Looking at From the images shown in By observing the images seen in the By analyzing The study of the impact of the finishing geometry of the line and dots (straight or round) of steel 3D plates in the embossing process led us to conclude that, although the sheets individually present a higher HF value for straight finishing geometry, in the two-ply prototype, the highest softness was obtained for the prototype with the round finishing geometry. Moreover, for the sheets embossed individually, it was verified that the HF value decreases with the increase of the bulk, and this was more accentuated for the micropattern.It was also concluded that there are no relevant differences in the spreading kinetics of the liquid droplets over time. Thus, the finishing geometry of the steel 3D plates does not affect the absorption kinetics of these products.The finite element model allowed to understand the effect of the plate patterns’ finishing geometry on the paper due to the embossing process changing the plastic stress field. The simulation results were in accordance with the experimental results. These were able to show a trend where patterns with round geometry marked the tissue-paper sheet more than patterns with straight finishing did. This increase of the marks corresponds to an increase of bulk. Furthermore, this tool enables the optimization of process parameters; —in this work, particularly in regard to the pattern’s finishing geometry—in a virtual environment, thus avoiding a costly trial–error approach.This study highlighted the importance of the patterns’ finishing geometry and its impact on the final properties of tissue-paper products. The authors consider that the obtained results contribute to creating a better understanding of the embossing process when analyzing the impact of each embossing operation condition separately—in this case, the finishing geometry of the lines and dots in the finish of steel 3D plates.


Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) typically experience poorer attentional control. According to the attention network theory, attentional control relies on three interacting networks of alerting, orienting, and executive control. In ADHD, it is mainly the alerting and executive control networks that are suggested and found to be compromised.In the current study, we investigated if a group-based metacognitive remediation program  in adults with ADHD would enhance attentional control using an experimental measure of the attention network theory. We expected that GMT would specifically enhance the executive control and alerting networks.Data from post- and follow up-assessments of 21 adults (age: 39.05 [11.93]) with ADHD who had completed GMT were included. Linear mixed-effects modeling revealed significant improvements in the functioning of the executive control network for the majority of the participants, although a small subset of participants showed a negative development following the intervention. Results also showed an improvement in the orienting network at follow up, but no change in the alerting network.The results may indicate that improvements in the functioning of the executive control network are central to the positive effects of GMT reported in disorders characterized by impaired attentional control.Trial registration: The study was retrospectively registered in the ISRCTN (Identifier: ISRCTN91988877) on the 18/01/2021.The online version contains supplementary material available at 10.1186/s40359-022-00902-9. Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) struggle with elevated symptoms of inattention and/or hyperactivity/impulsivity in their everyday life . TypicalGMT is a group-based metacognitive remediation program aimed at reducing deficiencies of goal management, based on Duncan’s  attentioGMT has been shown to have positive effects on measures of executive control and attention in several patient groups , 24. HowThe attention network theory –29 offerIn the present study, we investigated the effects of GMT , 18, 46 We expected (1) that adults with ADHD would show improvements in the executive control and alerting networks following GMT and not on the orienting network. (2) To find the most consistent change in the executive control network since goal achievement through efficient conflict detection is emphasized as a main mechanism in GMT . In addiM = 39.05, SD = 11.93, 57% males). A total of 13 of these 21 participants (61.9%) fulfilled the criteria for at least one other ongoing disorder according to the M.I.N.I. Plus ) and a total of four participants showed increases in the flanker conflict-effect from baseline to post-assessment (Range = [2.6 – 79.7 ms]). Similarly, five participants showed an increase in the flanker conflict-effect from baseline to follow up-assessment (Range = [3.3 – 116.1 ms]). Three of these participants showed an increase from baseline at both timepoints. An inspection showed that all three were men, that two out of the three were older than the average of the sample , and that the first two had an IQ below the average level of the sample . The first two of these participants used medication for ADHD, whereas the last participant did not use such medication. ASRS-scores at baseline were close to the average of the sample  and increased in parallel with increases in flanker conflict effects for the first two participants at post-assessment  but were greatly reduced for the last participant (45 to 28) despite an increase in the flanker conflict effect. At follow-up all three participants reported changes in ASRS-scores in the same direction as the direction of the flanker conflict-effect relative to post-assessment scores . The first participant reported ongoing anxiety disorders  and body dysmorphic disorder, whereas the other two screened positive for antisocial personality disorder.As can be seen in Fig. In the current open trial, we investigated the effects of GMT on executive control and attention allocation as defined by the attention network theory (29) in adults with ADHD. The results supported our expectation that improvements would be found in the executive control network following GMT. However, against our á priori expectation we found no significant changes following GMT on the alerting scores but rather a change in orienting attention scores. The positive change in executive control was detectable immediately after the intervention ended, whereas the change in orienting attention appeared on the follow-up assessment six months later.The current findings showing improvements in executive control following GMT are in line with previous studies showing that this network is malleable to improvement after non-pharmacological interventions in adults with  and withwhen stimuli appear on the screen may also affect an alertness to where the same stimuli appear (see 28). An improvement in the orienting attention and/or the executive control network may therefore reflect higher alertness following GMT despite this not being overtly observed through higher alerting scores following GMT.The adults with ADHD did not show the expected improvement in alertness after GMT. Rather, and in contrast to our expectations, they showed significant changes in results on the measure of the orienting network at follow up. Interestingly, these findings are in accordance with previous studies of mindfulness training showing effects on executive control and orienting after shorter periods of training , 45. It In addition to the traditional focus on treatment effects on a group level, it is of clinical relevance to look at individual change scores to investigate if some participants may have a negative effect of GMT. Our sample was too small to statistically test differences between the three men who, on visual inspection of the flanker conflict score , appeared to have a negative effect by being less efficient on both assessments after GMT compared to baseline. However, by looking at other variables/scores of clinical interest from the assessments of these three male participants, we observed that with the exception of sex and that two out of three had a comorbid antisocial personality disorder (according to the M.I.N.I. Plus), there did not appear to be any specific variable included in our study in which these participants systematically differed from the rest of the sample and that could explain the differential effect of GMT on ANT-R. However, of interest, their negative change on the flanker conflict score for the most part mirrored changes in ADHD symptom reports on ASRS after GMT. It is challenging to delineate if this negative development was due to lack of effect of GMT or if something else occurred in these participants’ lives that prevented them from engaging in the remediation practices of GMT. Few studies show such individual effect scores of GMT or of other types of treatment. This can be an important way to improve the understanding of which participants experience both positive and negative effects, and thereby improve individually targeted treatment in patient groups.We believe that the current results support the use of attention network theory and the ANT-R in future studies of interventions for ADHD and in investigations of GMT, and that such studies may provide important insights into potential mechanisms involved in reducing symptoms and impairments associated with the disorder being studied. Furthermore, the recruitment of a clinically-based sample of adults with ADHD probably increased the transferability of the results to patients with ADHD seeking treatment in the health care system. Also, the description of individual trajectories and the attempts to characterize individual differences in effects of the intervention can be an inspiration for adapting the same approach in future treatment studies.There are several limitations to the current study. First of all, due to the lack of a control group, practice effects cannot be ruled out. We do, however, believe that the differential effects on the separate networks and the differing timing of effects speak against such an interpretation. Investigations of practice effects in Flanker-tasks also seem to indicate that these are relatively small and quite equal between congruent and incongruent trials , 84. SecWe argue that the current results indicate that there is reason to believe that GMT may be an advantageous intervention for adults with ADHD and that this should be evaluated in a larger randomized trial. Furthermore, we believe that inclusion of brain imaging techniques in such a trial could clarify the current results and inform the validity of the possible explanations discussed above.The current open trial found an improvement in one aspect of attention, namely executive control, following GMT in a sample of adults with ADHD. Our finding thus suggests that GMT may be an efficient intervention for ADHD and further, that improvements in executive control may be a potential mechanism of change for adults with ADHD using this training procedure. A possible brain-correlated mechanism explaining this improvement may be enhanced functioning or connectivity in the ACC and/or insula following the intervention. Future randomized controlled studies of GMT are encouraged to include the ANT-R in combination with brain imaging techniques such as fMRI to increase the neurobiological understanding of effects of GMT in ADHD and other patient groups.Additional file 1: Table S1: Summary of linear mixed-effects model comparisons for the Flanker Conflict-Effect. Additional file 2: Fig. S1: A graphical illustration of observed vs predicted flanker conflict effects for each individual participant


Introduction: A link between having a neurodevelopmental disorder, such as attention deficit hyperactivity disorder (ADHD) and school absenteeism, has been found in previous studies. Why ADHD poses a risk for absenteeism remains unclear, and insight into the mechanisms of the association is needed. The aim of the present study was to investigate school attendance problems (SAP) and both the symptoms related and the perceived reasons for them, as reported by adolescents with ADHD (n = 95), compared with neurotypical adolescents .Method: The current study  was part of the School absence in Finland-project. SAPs were measured with the Inventory of School Attendance Problems (ISAP). The ISAP questionnaire contains a symptom scale (ISAP S) and a function scale (ISAP F), which shows if and how the symptoms impacts school attendance. A linear mixed effects model was used to analyze outcomes on the ISAP factors, controlling for background variables living status, gender, other diagnoses, highest level of education for the parent and age.Results: Results show that adolescents with ADHD had been more absent from school compared to neurotypical adolescents during the prior 12-weeks. Adolescents with ADHD showed significantly more symptoms of agoraphobia/panic, problems within the family and problems with parents than neurotypical peers. The symptoms separation anxiety, agoraphobia/panic, aggression, problems within the family and problems with parents more often were perceived as the reason for SAP (ISAP F).Discussion: The results are in line with our initial hypotheses and previous studies. Because of the low response rate on the ISAP F scale, the results regarding reasons for SAPs should be interpreted with caution. Future research could examine specific preventive actions of SAPs for adolescents with ADHD, and different subtypes of ADHD. School absenteeism is known to have negative consequences, as it can affect children both short term, for instance academically , 2014 anThere are many reasons for children to be absent from school. Health-related problems  and lackAttention deficit hyperactivity disorder, or ADHD, is a condition characterized by inattention and hyperactivity-impulsivity or either of them . To be dComorbidities are common among children with ADHD and it is, in fact, more common than uncommon to have another diagnosis or other symptoms in addition to ADHD . StudiesChildren with ADHD are more absent from school compared to other children . In addiAs mentioned, it is common for children with ADHD to have comorbid disorders/symptoms . It is iHaving problems with peers is also common among youth with attention problems , and havConcluding, prior research has highlighted several areas within education and school, which may be problematic for children and youth with ADHD. The same areas are, however, often the reason for SAP also for neurotypical children. The first aim of the present study was to compare self-reported non-attendance between adolescents with ADHD and neurotypical adolescents. The second aim related to the symptoms associated with SAP. Do neurotypical and adolescents with ADHD differ in symptom severity, and on which symptoms related to SAP that are most common?Furthermore, it is unclear, if and to what extent the symptoms and difficulties actually contribute to or are the reason for the SAPs. The idea to differentiate between symptom and function has existed for a long time in the literature on SAP. The hypotheses of the current study are:Adolescents with ADHD will show a higher level of school non-attendance compared to neurotypical adolescents.Adolescents with ADHD will have a higher level of the comorbid symptoms that are common among adolescents with ADHD compared to neurotypical youth: social anxiety, separation anxiety, depression, agoraphobia/panic, somatic complaints, and aggression. Adolescents with ADHD will have more problems with peers and/or teachers and/or parents.a priori hypotheses about which symptoms relate more to SAPs, or how the groups differ were made, due to the lack of previous research addressing the question.Adolescents with ADHD will report that increased symptoms in the areas described in hypothesis 2 will also have an impact on their SAPs. No School Absence in Finland project. The project started with translating the instruments School Refusal Assessment Scale-Revised  was 14.9 (SD = 0.85) and for the adolescents with ADHD (N = 95) 15.0 (SD = 1.01). The total collected sample had N = 2,137 responses of which 568 were incomplete and thus excluded (see n = 15), to enable comparisons between neurotypical and adolescents with ADHD.The final sample with complete responses was 1,569, consisting of 952 Swedish-speaking adolescents and 617 Finnish-speaking adolescents. The average age for the neurotypical adolescents , who the participant was living with  and the socioeconomical status of the family. The socioeconomical status factor was measured by the parents’ highest educational level. The educational level was categorized into five separate groups, the highest being a university degree and the lowest to not have any type of degree after elementary school. The questionnaire also included questions about the participants other diagnoses, for example depression, cancer, asthma, and diabetes. Living status, gender, other diagnoses, highest level of education for the parent and age were included in all models, to account for variance explained by these background variables.α ≤ 0.88, 3 testlets/scale; The measure for this study was The Inventory of School Attendance Problems (ISAP) questionnaire . ISAP watidyverse . The differences between adolescents with ADHD and neurotypical adolescents were significant on all the factors, except for the factor measuring performance anxiety.Independent samples t-tests were performed to compare means between the groups for both symptoms (ISAP S) and function (ISAP F) for SAPs see ,3. The hM = 0.58, SD = 0.77), but the highest mean for the neurotypical group was somatic complaints . The differences between groups were statistically significant on the factors measuring depression, agoraphobia/panic, school aversion/attractive alternatives, aggression, and problems within the family. The effect sizes for the group differences on ISAP S and ISAP F were small to moderate (Cohen’s d: 0.19–0.57).The second part of the ISAP questionnaire measured if the symptom was the reason for the participants’ SAPs (ISAP F). The highest mean for adolescents with ADHD was again school aversion/other attractive alternatives , either with or without permission form parents and/or school. The corresponding percentage of neurotypical adolescents was 8%, meaning that the percentage of absence was twice as high among adolescents with ADHD.b = 0.16; SE = 0.05; p < 0.001), aggression , problems within the family , and problems with parents . In the multivariate analyses, living status, age, gender, other diagnoses, and the socioeconomical status were controlled for.Results also show that adolescents with ADHD had, compared to the neurotypical adolescents, a higher level of all the symptoms (ISAP S), except on the factor measuring performance anxiety see . Althougb = 0.09, SE = 0.40, p = 0.032), agoraphobia/panic , school aversion/attractive alternatives , aggression , problems within the family , and problems with parents  as reasons for their SAPs.Adolescents with ADHD also had higher points on every ISAP factor that showed if the symptom was the reason for their SAPs  on the ISAP F scale, in both groups . Twenty-The present study aimed to investigate the differences between adolescents with ADHD and neurotypical adolescents regarding SAPs. It was hypothesized that adolescents with ADHD would have a higher level of school absenteeism compared to neurotypical adolescents. It was also hypothesized that adolescents with ADHD would have a higher level of those common ADHD and SAP-related symptoms, which were measured by the ISAP questionnaire. Furthermore, we expected that at least some of the symptoms would be perceived as the reason for the SAP. Data was gathered with the ISAP questionnaire from a total of 1,569 adolescents, aged 11–18 in different schools in Finland.In accordance with our initial hypothesis and previous studies , our resThe findings show that adolescents with ADHD had a higher level of almost all the symptoms on the ISAP questionnaire. Only the factor measuring performance anxiety was lower among adolescents with ADHD, although not to a statistically significant degree. The factors measuring agoraphobia/panic, aggression and problems with parents were statistically significantly higher, when controlling also for living status, age, gender, other diagnoses, and socioeconomical status. The results are, therefore, in line with the hypothesis and in accordance with previous research showing that it is common among adolescents with ADHD to also have agoraphobia/panic , 1997, aThe adolescents with ADHD also showed higher scores on every ISAP factor showing if the symptoms were the reason for their SAPs (ISAP F). The results were statistically significant on the factors measuring separation anxiety, agoraphobia/panic, school aversion/other attractive alternatives, aggression, problems within the family, and problems with parents. The results are in line with the hypothesis, that is, the symptoms that are common among adolescents with ADHD have an impact on their school attendance. The results also support previous research about how ADHD alone might not explain the SAP and that having comorbid symptoms can increase SAPs more than ADHD alone . This thAgoraphobia/panic as a reason for SAPs is not surprising considering the clinical picture of SAPs. Agoraphobia is described as having a desire to avoid situations or places that one cannot easily escape . There mAggressive behavior among adolescents with ADHD has been found in prior studies. Aggressive behavior could be related to being suspended from school, and hence, also to SAP. Also, aggression could be related to problems with peers and/or teachers, even if those factors were not significantly different between the groups. School aversion/other attractive alternatives could be interpreted as truancy, i.e., absence due to low motivation, and the desire to do something more rewarding outside of school, often without the knowledge of parents and/or school . In addiThe significant results regarding separation anxiety were unexpected considering that children with ADHD have more problematic conflicts with their parents compared to neurotypical children  and thatLastly, a note on self-report data. It is important to remember that adolescents might not fully understand their symptomatology and difficulties. Adolescents can have symptoms of depression or anxiety, but they might have a hard time recognizing, and putting their feelings into words. Therefore, the self-evaluation of symptoms should be made multiple times and/or together with a close adult for an increased understanding of the symptoms. It is also important to gather information from multiple informants, such as parents and school personnel.The current study comes with certain strengths and limitations. The study had 1,569 participants, and the relatively large sample size can be seen as a strength in the current study. However, the sample was not representative of the adolescent population in Finland. In addition, the ADHD group had only 95 participants, which might have led to the statistical power not being optimal, and some differences did not reach statistical significance. The ADHD group’s sample size also meant that the comparison between different subtypes of ADHD was not possible. However, the symptomatology between different subtypes may differ significantly, and future studies should analyze subgroups separately. Furthermore, the questionnaire was lengthy, possibly affecting willingness to complete it.Another limitation is that all the participants did not answer all the questions in the questionnaire. The second part of the ISAP questionnaire (ISAP F), that is, the part that measures if the symptoms are the reason for the participants SAPs, had a low response rate with answers only from 57% of the participants. Also, the item concerning being afraid of tests was not answered by 39% of participants, reflecting possible problems with this specific item. Because of the low response rate, the results regarding reasons for SAPs should be interpreted with caution. It can be speculated that the reason for the low response rate could be due to not understanding the instructions on how to fill in the questionnaire correctly, or that the participants found it difficult to evaluate if the symptoms were the reason for their SAPs. Also, a missing answer on the function scale could be interpreted as a zero, that is, no impact on school attendance, if the participant had replied not having the symptom in question.In conclusion, the current study shows differences between adolescents with ADHD and neurotypical adolescents regarding SAPs. This study considers both symptoms that are linked to SAP and to what extent the symptoms are the reason for school attendance problems. The result of this study showed that adolescents with ADHD reported both more symptoms related to SAP, and that the symptom more often was the reason for the SAP. However, the associations reached statistical significance only for part of the symptoms and reasons. The symptoms agoraphobia/panic, aggression, and problems with parents were also perceived as reasons for SAPs. In addition, school aversion and problems with family and separation anxiety were statistically higher among adolescents with ADHD as reasons for SAPs.Future research could examine differences between adolescents with different combinations of neuroatypicalities, such as ADHD in combination with autism spectrum disorder, and how additive diagnoses affect school attendance and possible SAPs. Future research should also examine which protective actions could be used to prevent school absenteeism in neuroatypical adolescents.katarina.alanko@abo.fi.The datasets presented in this article are not readily available because the dataset is available after the end of the project period, starting 2024. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Åbo Akademi Ethical Board. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.KA is the principal investigator, responsible for design, data collection and revision of intellectual content. SN is responsible for drafting of the manuscript, and parts of statistical analyses. ML conducted statistical analyses and revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.The study was funded by the C.G. Sundell foundation.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. 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